Crizanlizumab for the prevention of pain crises in sickle cell disease

Kenneth Ataga, Abdullah Kutlar, Julie Kanter, Darla Liles, Rodolfo Cancado, João Friedrisch, Troy H. Guthrie, Jennifer Knight-Madden, Ofelia A. Alvarez, Victor R. Gordeuk, Sandra Gualandro, Marina P. Colella, Wally R. Smith, Scott A. Rollins, Jonathan W. Stocker, Russell P. Rother

Research output: Contribution to journalArticle

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Abstract

BACKGROUND The up-regulation of P-selectin in endothelial cells and platelets contributes to the cell-cell interactions that are involved in the pathogenesis of vaso-occlusion and sickle cell-related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P-selectin, were evaluated in patients with sickle cell disease. METHODS In this double-blind, randomized, placebo-controlled, phase 2 trial, we assigned patients to receive low-dose crizanlizumab (2.5 mg per kilogram of body weight), high-dose crizanlizumab (5.0 mg per kilogram), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary end point was the annual rate of sickle cell-related pain crises with high-dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to first and second crises, annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism) and the acute chest syndrome, and patientreported outcomes were also assessed. RESULTS A total of 198 patients underwent randomization at 60 sites. The median rate of crises per year was 1.63 with high-dose crizanlizumab versus 2.98 with placebo (indicating a 45.3% lower rate with high-dose crizanlizumab, P = 0.01). The median time to the first crisis was significantly longer with high-dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P = 0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P = 0.02). The median rate of uncomplicated crises per year was 1.08 with high-dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9% lower rate with high-dose crizanlizumab, P = 0.02). Adverse events that occurred in 10% or more of the patients in either activetreatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain. CONCLUSIONS In patients with sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell-related pain crises than placebo and was associated with a low incidence of adverse events.

Original languageEnglish (US)
Pages (from-to)429-439
Number of pages11
JournalNew England Journal of Medicine
Volume376
Issue number5
DOIs
StatePublished - Feb 2 2017

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Sickle Cell Anemia
Placebos
Pain
Acute Chest Syndrome
P-Selectin
Hydroxyurea
Priapism
Arthralgia
Pruritus
Random Allocation
Chest Pain
Cell Communication
Vomiting
Diarrhea
Up-Regulation
Blood Platelets
Endothelial Cells
Body Weight
Safety
Antibodies

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Ataga, K., Kutlar, A., Kanter, J., Liles, D., Cancado, R., Friedrisch, J., ... Rother, R. P. (2017). Crizanlizumab for the prevention of pain crises in sickle cell disease. New England Journal of Medicine, 376(5), 429-439. https://doi.org/10.1056/NEJMoa1611770

Crizanlizumab for the prevention of pain crises in sickle cell disease. / Ataga, Kenneth; Kutlar, Abdullah; Kanter, Julie; Liles, Darla; Cancado, Rodolfo; Friedrisch, João; Guthrie, Troy H.; Knight-Madden, Jennifer; Alvarez, Ofelia A.; Gordeuk, Victor R.; Gualandro, Sandra; Colella, Marina P.; Smith, Wally R.; Rollins, Scott A.; Stocker, Jonathan W.; Rother, Russell P.

In: New England Journal of Medicine, Vol. 376, No. 5, 02.02.2017, p. 429-439.

Research output: Contribution to journalArticle

Ataga, K, Kutlar, A, Kanter, J, Liles, D, Cancado, R, Friedrisch, J, Guthrie, TH, Knight-Madden, J, Alvarez, OA, Gordeuk, VR, Gualandro, S, Colella, MP, Smith, WR, Rollins, SA, Stocker, JW & Rother, RP 2017, 'Crizanlizumab for the prevention of pain crises in sickle cell disease', New England Journal of Medicine, vol. 376, no. 5, pp. 429-439. https://doi.org/10.1056/NEJMoa1611770
Ataga, Kenneth ; Kutlar, Abdullah ; Kanter, Julie ; Liles, Darla ; Cancado, Rodolfo ; Friedrisch, João ; Guthrie, Troy H. ; Knight-Madden, Jennifer ; Alvarez, Ofelia A. ; Gordeuk, Victor R. ; Gualandro, Sandra ; Colella, Marina P. ; Smith, Wally R. ; Rollins, Scott A. ; Stocker, Jonathan W. ; Rother, Russell P. / Crizanlizumab for the prevention of pain crises in sickle cell disease. In: New England Journal of Medicine. 2017 ; Vol. 376, No. 5. pp. 429-439.
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abstract = "BACKGROUND The up-regulation of P-selectin in endothelial cells and platelets contributes to the cell-cell interactions that are involved in the pathogenesis of vaso-occlusion and sickle cell-related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P-selectin, were evaluated in patients with sickle cell disease. METHODS In this double-blind, randomized, placebo-controlled, phase 2 trial, we assigned patients to receive low-dose crizanlizumab (2.5 mg per kilogram of body weight), high-dose crizanlizumab (5.0 mg per kilogram), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary end point was the annual rate of sickle cell-related pain crises with high-dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to first and second crises, annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism) and the acute chest syndrome, and patientreported outcomes were also assessed. RESULTS A total of 198 patients underwent randomization at 60 sites. The median rate of crises per year was 1.63 with high-dose crizanlizumab versus 2.98 with placebo (indicating a 45.3{\%} lower rate with high-dose crizanlizumab, P = 0.01). The median time to the first crisis was significantly longer with high-dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P = 0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P = 0.02). The median rate of uncomplicated crises per year was 1.08 with high-dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9{\%} lower rate with high-dose crizanlizumab, P = 0.02). Adverse events that occurred in 10{\%} or more of the patients in either activetreatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain. CONCLUSIONS In patients with sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell-related pain crises than placebo and was associated with a low incidence of adverse events.",
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T1 - Crizanlizumab for the prevention of pain crises in sickle cell disease

AU - Ataga, Kenneth

AU - Kutlar, Abdullah

AU - Kanter, Julie

AU - Liles, Darla

AU - Cancado, Rodolfo

AU - Friedrisch, João

AU - Guthrie, Troy H.

AU - Knight-Madden, Jennifer

AU - Alvarez, Ofelia A.

AU - Gordeuk, Victor R.

AU - Gualandro, Sandra

AU - Colella, Marina P.

AU - Smith, Wally R.

AU - Rollins, Scott A.

AU - Stocker, Jonathan W.

AU - Rother, Russell P.

PY - 2017/2/2

Y1 - 2017/2/2

N2 - BACKGROUND The up-regulation of P-selectin in endothelial cells and platelets contributes to the cell-cell interactions that are involved in the pathogenesis of vaso-occlusion and sickle cell-related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P-selectin, were evaluated in patients with sickle cell disease. METHODS In this double-blind, randomized, placebo-controlled, phase 2 trial, we assigned patients to receive low-dose crizanlizumab (2.5 mg per kilogram of body weight), high-dose crizanlizumab (5.0 mg per kilogram), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary end point was the annual rate of sickle cell-related pain crises with high-dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to first and second crises, annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism) and the acute chest syndrome, and patientreported outcomes were also assessed. RESULTS A total of 198 patients underwent randomization at 60 sites. The median rate of crises per year was 1.63 with high-dose crizanlizumab versus 2.98 with placebo (indicating a 45.3% lower rate with high-dose crizanlizumab, P = 0.01). The median time to the first crisis was significantly longer with high-dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P = 0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P = 0.02). The median rate of uncomplicated crises per year was 1.08 with high-dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9% lower rate with high-dose crizanlizumab, P = 0.02). Adverse events that occurred in 10% or more of the patients in either activetreatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain. CONCLUSIONS In patients with sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell-related pain crises than placebo and was associated with a low incidence of adverse events.

AB - BACKGROUND The up-regulation of P-selectin in endothelial cells and platelets contributes to the cell-cell interactions that are involved in the pathogenesis of vaso-occlusion and sickle cell-related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P-selectin, were evaluated in patients with sickle cell disease. METHODS In this double-blind, randomized, placebo-controlled, phase 2 trial, we assigned patients to receive low-dose crizanlizumab (2.5 mg per kilogram of body weight), high-dose crizanlizumab (5.0 mg per kilogram), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary end point was the annual rate of sickle cell-related pain crises with high-dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to first and second crises, annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism) and the acute chest syndrome, and patientreported outcomes were also assessed. RESULTS A total of 198 patients underwent randomization at 60 sites. The median rate of crises per year was 1.63 with high-dose crizanlizumab versus 2.98 with placebo (indicating a 45.3% lower rate with high-dose crizanlizumab, P = 0.01). The median time to the first crisis was significantly longer with high-dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P = 0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P = 0.02). The median rate of uncomplicated crises per year was 1.08 with high-dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9% lower rate with high-dose crizanlizumab, P = 0.02). Adverse events that occurred in 10% or more of the patients in either activetreatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain. CONCLUSIONS In patients with sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell-related pain crises than placebo and was associated with a low incidence of adverse events.

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