Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder

Sean J Pittock, A. Berthele, K. Fujihara, H. J. Kim, M. Levy, J. Palace, I. Nakashima, M. Terzi, N. Totolyan, S. Viswanathan, K. C. Wang, A. Pace, K. P. Fujita, R. Armstrong, D. M. Wingerchuk

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Abstract

BACKGROUND Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing, autoimmune, inflammatory disorder that typically affects the optic nerves and spinal cord. At least two thirds of cases are associated with aquaporin-4 antibodies (AQP4-IgG) and complement-mediated damage to the central nervous system. In a previous small, open-label study involving patients with AQP4-IgG-positive disease, eculizumab, a terminal complement inhibitor, was shown to reduce the frequency of relapse. METHODS In this randomized, double-blind, time-to-event trial, 143 adults were randomly assigned in a 2:1 ratio to receive either intravenous eculizumab (at a dose of 900 mg weekly for the first four doses starting on day 1, followed by 1200 mg every 2 weeks starting at week 4) or matched placebo. The continued use of stable-dose immunosuppressive therapy was permitted. The primary end point was the first adjudicated relapse. Secondary outcomes included the adjudicated annualized relapse rate, quality-of-life measures, and the score on the Expanded Disability Status Scale (EDSS), which ranges from 0 (no disability) to 10 (death). RESULTS The trial was stopped after 23 of the 24 prespecified adjudicated relapses, given the uncertainty in estimating when the final event would occur. The mean (±SD) annualized relapse rate in the 24 months before enrollment was 1.99±0.94; 76% of the patients continued to receive their previous immunosuppressive therapy during the trial. Adjudicated relapses occurred in 3 of 96 patients (3%) in the eculizumab group and 20 of 47 (43%) in the placebo group (hazard ratio, 0.06; 95% confidence interval [CI], 0.02 to 0.20; P<0.001). The adjudicated annualized relapse rate was 0.02 in the eculizumab group and 0.35 in the placebo group (rate ratio, 0.04; 95% CI, 0.01 to 0.15; P<0.001). The mean change in the EDSS score was-0.18 in the eculizumab group and 0.12 in the placebo group (least-squares mean difference,-0.29; 95% CI,-0.59 to 0.01). Upper respiratory tract infections and headaches were more common in the eculizumab group. There was one death from pulmonary empyema in the eculizumab group. CONCLUSIONS Among patients with AQP4-IgG-positive NMOSD, those who received eculizumab had a significantly lower risk of relapse than those who received placebo. There was no significant between-group difference in measures of disability progression. (Funded by Alexion Pharmaceuticals; PREVENT ClinicalTrials.gov number, NCT01892345; EudraCT number, 2013-001150-10.).

Original languageEnglish (US)
Pages (from-to)614-625
Number of pages12
JournalNew England Journal of Medicine
Volume381
Issue number7
DOIs
StatePublished - Aug 15 2019

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Aquaporin 4
Neuromyelitis Optica
Recurrence
Placebos
Immunoglobulin G
Complement Inactivating Agents
Confidence Intervals
Immunosuppressive Agents
Empyema
eculizumab
Optic Nerve
Least-Squares Analysis
Respiratory Tract Infections
Uncertainty
Headache
Spinal Cord
Central Nervous System
Quality of Life
Lung
Antibodies

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Pittock, S. J., Berthele, A., Fujihara, K., Kim, H. J., Levy, M., Palace, J., ... Wingerchuk, D. M. (2019). Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder. New England Journal of Medicine, 381(7), 614-625. https://doi.org/10.1056/NEJMoa1900866

Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder. / Pittock, Sean J; Berthele, A.; Fujihara, K.; Kim, H. J.; Levy, M.; Palace, J.; Nakashima, I.; Terzi, M.; Totolyan, N.; Viswanathan, S.; Wang, K. C.; Pace, A.; Fujita, K. P.; Armstrong, R.; Wingerchuk, D. M.

In: New England Journal of Medicine, Vol. 381, No. 7, 15.08.2019, p. 614-625.

Research output: Contribution to journalArticle

Pittock, SJ, Berthele, A, Fujihara, K, Kim, HJ, Levy, M, Palace, J, Nakashima, I, Terzi, M, Totolyan, N, Viswanathan, S, Wang, KC, Pace, A, Fujita, KP, Armstrong, R & Wingerchuk, DM 2019, 'Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder', New England Journal of Medicine, vol. 381, no. 7, pp. 614-625. https://doi.org/10.1056/NEJMoa1900866
Pittock, Sean J ; Berthele, A. ; Fujihara, K. ; Kim, H. J. ; Levy, M. ; Palace, J. ; Nakashima, I. ; Terzi, M. ; Totolyan, N. ; Viswanathan, S. ; Wang, K. C. ; Pace, A. ; Fujita, K. P. ; Armstrong, R. ; Wingerchuk, D. M. / Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder. In: New England Journal of Medicine. 2019 ; Vol. 381, No. 7. pp. 614-625.
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abstract = "BACKGROUND Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing, autoimmune, inflammatory disorder that typically affects the optic nerves and spinal cord. At least two thirds of cases are associated with aquaporin-4 antibodies (AQP4-IgG) and complement-mediated damage to the central nervous system. In a previous small, open-label study involving patients with AQP4-IgG-positive disease, eculizumab, a terminal complement inhibitor, was shown to reduce the frequency of relapse. METHODS In this randomized, double-blind, time-to-event trial, 143 adults were randomly assigned in a 2:1 ratio to receive either intravenous eculizumab (at a dose of 900 mg weekly for the first four doses starting on day 1, followed by 1200 mg every 2 weeks starting at week 4) or matched placebo. The continued use of stable-dose immunosuppressive therapy was permitted. The primary end point was the first adjudicated relapse. Secondary outcomes included the adjudicated annualized relapse rate, quality-of-life measures, and the score on the Expanded Disability Status Scale (EDSS), which ranges from 0 (no disability) to 10 (death). RESULTS The trial was stopped after 23 of the 24 prespecified adjudicated relapses, given the uncertainty in estimating when the final event would occur. The mean (±SD) annualized relapse rate in the 24 months before enrollment was 1.99±0.94; 76{\%} of the patients continued to receive their previous immunosuppressive therapy during the trial. Adjudicated relapses occurred in 3 of 96 patients (3{\%}) in the eculizumab group and 20 of 47 (43{\%}) in the placebo group (hazard ratio, 0.06; 95{\%} confidence interval [CI], 0.02 to 0.20; P<0.001). The adjudicated annualized relapse rate was 0.02 in the eculizumab group and 0.35 in the placebo group (rate ratio, 0.04; 95{\%} CI, 0.01 to 0.15; P<0.001). The mean change in the EDSS score was-0.18 in the eculizumab group and 0.12 in the placebo group (least-squares mean difference,-0.29; 95{\%} CI,-0.59 to 0.01). Upper respiratory tract infections and headaches were more common in the eculizumab group. There was one death from pulmonary empyema in the eculizumab group. CONCLUSIONS Among patients with AQP4-IgG-positive NMOSD, those who received eculizumab had a significantly lower risk of relapse than those who received placebo. There was no significant between-group difference in measures of disability progression. (Funded by Alexion Pharmaceuticals; PREVENT ClinicalTrials.gov number, NCT01892345; EudraCT number, 2013-001150-10.).",
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T1 - Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder

AU - Pittock, Sean J

AU - Berthele, A.

AU - Fujihara, K.

AU - Kim, H. J.

AU - Levy, M.

AU - Palace, J.

AU - Nakashima, I.

AU - Terzi, M.

AU - Totolyan, N.

AU - Viswanathan, S.

AU - Wang, K. C.

AU - Pace, A.

AU - Fujita, K. P.

AU - Armstrong, R.

AU - Wingerchuk, D. M.

PY - 2019/8/15

Y1 - 2019/8/15

N2 - BACKGROUND Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing, autoimmune, inflammatory disorder that typically affects the optic nerves and spinal cord. At least two thirds of cases are associated with aquaporin-4 antibodies (AQP4-IgG) and complement-mediated damage to the central nervous system. In a previous small, open-label study involving patients with AQP4-IgG-positive disease, eculizumab, a terminal complement inhibitor, was shown to reduce the frequency of relapse. METHODS In this randomized, double-blind, time-to-event trial, 143 adults were randomly assigned in a 2:1 ratio to receive either intravenous eculizumab (at a dose of 900 mg weekly for the first four doses starting on day 1, followed by 1200 mg every 2 weeks starting at week 4) or matched placebo. The continued use of stable-dose immunosuppressive therapy was permitted. The primary end point was the first adjudicated relapse. Secondary outcomes included the adjudicated annualized relapse rate, quality-of-life measures, and the score on the Expanded Disability Status Scale (EDSS), which ranges from 0 (no disability) to 10 (death). RESULTS The trial was stopped after 23 of the 24 prespecified adjudicated relapses, given the uncertainty in estimating when the final event would occur. The mean (±SD) annualized relapse rate in the 24 months before enrollment was 1.99±0.94; 76% of the patients continued to receive their previous immunosuppressive therapy during the trial. Adjudicated relapses occurred in 3 of 96 patients (3%) in the eculizumab group and 20 of 47 (43%) in the placebo group (hazard ratio, 0.06; 95% confidence interval [CI], 0.02 to 0.20; P<0.001). The adjudicated annualized relapse rate was 0.02 in the eculizumab group and 0.35 in the placebo group (rate ratio, 0.04; 95% CI, 0.01 to 0.15; P<0.001). The mean change in the EDSS score was-0.18 in the eculizumab group and 0.12 in the placebo group (least-squares mean difference,-0.29; 95% CI,-0.59 to 0.01). Upper respiratory tract infections and headaches were more common in the eculizumab group. There was one death from pulmonary empyema in the eculizumab group. CONCLUSIONS Among patients with AQP4-IgG-positive NMOSD, those who received eculizumab had a significantly lower risk of relapse than those who received placebo. There was no significant between-group difference in measures of disability progression. (Funded by Alexion Pharmaceuticals; PREVENT ClinicalTrials.gov number, NCT01892345; EudraCT number, 2013-001150-10.).

AB - BACKGROUND Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing, autoimmune, inflammatory disorder that typically affects the optic nerves and spinal cord. At least two thirds of cases are associated with aquaporin-4 antibodies (AQP4-IgG) and complement-mediated damage to the central nervous system. In a previous small, open-label study involving patients with AQP4-IgG-positive disease, eculizumab, a terminal complement inhibitor, was shown to reduce the frequency of relapse. METHODS In this randomized, double-blind, time-to-event trial, 143 adults were randomly assigned in a 2:1 ratio to receive either intravenous eculizumab (at a dose of 900 mg weekly for the first four doses starting on day 1, followed by 1200 mg every 2 weeks starting at week 4) or matched placebo. The continued use of stable-dose immunosuppressive therapy was permitted. The primary end point was the first adjudicated relapse. Secondary outcomes included the adjudicated annualized relapse rate, quality-of-life measures, and the score on the Expanded Disability Status Scale (EDSS), which ranges from 0 (no disability) to 10 (death). RESULTS The trial was stopped after 23 of the 24 prespecified adjudicated relapses, given the uncertainty in estimating when the final event would occur. The mean (±SD) annualized relapse rate in the 24 months before enrollment was 1.99±0.94; 76% of the patients continued to receive their previous immunosuppressive therapy during the trial. Adjudicated relapses occurred in 3 of 96 patients (3%) in the eculizumab group and 20 of 47 (43%) in the placebo group (hazard ratio, 0.06; 95% confidence interval [CI], 0.02 to 0.20; P<0.001). The adjudicated annualized relapse rate was 0.02 in the eculizumab group and 0.35 in the placebo group (rate ratio, 0.04; 95% CI, 0.01 to 0.15; P<0.001). The mean change in the EDSS score was-0.18 in the eculizumab group and 0.12 in the placebo group (least-squares mean difference,-0.29; 95% CI,-0.59 to 0.01). Upper respiratory tract infections and headaches were more common in the eculizumab group. There was one death from pulmonary empyema in the eculizumab group. CONCLUSIONS Among patients with AQP4-IgG-positive NMOSD, those who received eculizumab had a significantly lower risk of relapse than those who received placebo. There was no significant between-group difference in measures of disability progression. (Funded by Alexion Pharmaceuticals; PREVENT ClinicalTrials.gov number, NCT01892345; EudraCT number, 2013-001150-10.).

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