BACKGROUND: Repeated subcutaneous injections of a monoclonal antibody against the p40 subunit of interleukins 12 and 23, ustekinumab, were used to treat patients with relapsing-remitting multiple sclerosis (RRMS) to assess the drug's safety, efficacy, and pharmacokinetics. METHODS: In this phase II, multicentre, randomised, double-blind, placebo-controlled study, 249 patients with RRMS, aged 18-65 years, were eligible to be assigned equally (by a central randomisation procedure based on study site and presence or absence of gadolinium-enhancing T1-weighted lesions at baseline) to one of five groups that receivedplacebo or four different ustekinumab dosages at weeks 0, 1, 2, 3, 7, 11, 15, and 19. Ustekinumab doses were 27 mg, 90 mg q8w, 90 mg, or 180 mg; the 90 mg q8w dosage group received placebo substitute at weeks 7 and 15. The primary endpoint was the cumulative number of new gadolinium-enhancing T1-weighted lesions on serial cranial MRI through week 23. Patients were followed up through week 37. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00207727. FINDINGS: From August, 2004, to December, 2006, 249 patients underwent randomisation (49 forplacebo; 50 for each ustekinumab group). Ustekinumab treatment did not show a significant reduction in the primary endpoint for any dosage groups versus placebo. At week 37, adverse events occurred in 38 (78%) placebo-treated patients and 170 (85%) ustekinumab-treated patients, with infections most commonly reported. Serious adverse events occurred in one (2%) placebo-treated patient and six (3%) ustekinumab-treated patients. Malignant diseases were reported in two patients shortly after the initiation of ustekinumab treatment; both patients were withdrawn from the trial and given appropriate treatment, which resulted in complete remission. No serious infections, cardiovascular events, or exacerbation of demyelinating events occurred. A dose-dependent increase in serum concentrations of ustekinumab was recorded. INTERPRETATION: Ustekinumab is generally well tolerated but does not show efficacy in reducing the cumulative number of gadolinium-enhancing T1-weighted lesions in multiple sclerosis.
RCT Entities:
BACKGROUND: Repeated subcutaneous injections of a monoclonal antibody against the p40 subunit of interleukins 12 and 23, ustekinumab, were used to treat patients with relapsing-remitting multiple sclerosis (RRMS) to assess the drug's safety, efficacy, and pharmacokinetics. METHODS: In this phase II, multicentre, randomised, double-blind, placebo-controlled study, 249 patients with RRMS, aged 18-65 years, were eligible to be assigned equally (by a central randomisation procedure based on study site and presence or absence of gadolinium-enhancing T1-weighted lesions at baseline) to one of five groups that received placebo or four different ustekinumab dosages at weeks 0, 1, 2, 3, 7, 11, 15, and 19. Ustekinumab doses were 27 mg, 90 mg q8w, 90 mg, or 180 mg; the 90 mg q8w dosage group received placebo substitute at weeks 7 and 15. The primary endpoint was the cumulative number of new gadolinium-enhancing T1-weighted lesions on serial cranial MRI through week 23. Patients were followed up through week 37. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00207727. FINDINGS: From August, 2004, to December, 2006, 249 patients underwent randomisation (49 for placebo; 50 for each ustekinumab group). Ustekinumab treatment did not show a significant reduction in the primary endpoint for any dosage groups versus placebo. At week 37, adverse events occurred in 38 (78%) placebo-treated patients and 170 (85%) ustekinumab-treated patients, with infections most commonly reported. Serious adverse events occurred in one (2%) placebo-treated patient and six (3%) ustekinumab-treated patients. Malignant diseases were reported in two patients shortly after the initiation of ustekinumab treatment; both patients were withdrawn from the trial and given appropriate treatment, which resulted in complete remission. No serious infections, cardiovascular events, or exacerbation of demyelinating events occurred. A dose-dependent increase in serum concentrations of ustekinumab was recorded. INTERPRETATION:Ustekinumab is generally well tolerated but does not show efficacy in reducing the cumulative number of gadolinium-enhancing T1-weighted lesions in multiple sclerosis.
Authors: Frederik Barkhof; Jack H Simon; Franz Fazekas; Marco Rovaris; Ludwig Kappos; Nicola de Stefano; Chris H Polman; John Petkau; Ernst W Radue; Maria P Sormani; David K Li; Paul O'Connor; Xavier Montalban; David H Miller; Massimo Filippi Journal: Nat Rev Neurol Date: 2011-12-06 Impact factor: 42.937
Authors: Adam W Clarke; Lynn Poulton; Hoi Yi Wai; Stuart A Walker; Shanti David Victor; Teresa Domagala; Dragana Mraovic; Danyal Butt; Nina Shewmaker; Philip Jennings; Anthony G Doyle Journal: MAbs Date: 2010-09-01 Impact factor: 5.857
Authors: Stefan Haak; Andrew L Croxford; Katharina Kreymborg; Frank L Heppner; Sandrine Pouly; Burkhard Becher; Ari Waisman Journal: J Clin Invest Date: 2008-12-15 Impact factor: 14.808