Select prevention trials for acute vaso-occlusive episodes in SCD
| Primary efficacy end point . | Drug . | Study findings and lessons . | Alternative end points . |
|---|---|---|---|
| Effect on hemolytic rate and frequency of crisis | Sodium cyanate (Gillette PN et al, 1974)34 | Treatment with sodium cyanate resulted in dose-related increase in hemoglobin. Retrospective analysis revealed a significant decrease in mean frequency of acute pain episodes between 2 groups of patients with low and high hemoglobin carbamylation. Further development of sodium cyanate was not pursued because of subsequent evidence of its toxicity. | — |
| Effect on pain crisis | Ticlopidine (Cabannes R et al, 1984)35 | Treatment with ticlopidine decreased the number of pain episodes, mean duration of pain episodes, and severity of pain episodes vs placebo | — |
| Effect on frequency of painful crises in adults and effect on splenic function and kidney function in very young children | Hydroxyurea (Charache S et al, 1995; Wang WC et al, 2011; de Montalembert M et al, 2021)36-38 | Treatment with hydroxyurea decreased the rate of pain episodes and increased the time periods to first and second crises and hospitalizations because of pain episodes, acute chest syndrome, and blood transfusion. A trial in infants showed similar decreases in pain episodes, acute chest syndrome, and blood transfusion but had no significant effect on the primary end points (splenic function or eGFR). | Hydroxyurea has also been evaluated for other clinical end points, including primary and secondary stroke prevention |
| Effect on frequency of acute sickle cell–related painful crises | Senicapoc (Ataga KI et al, 2011)39 | Treatment with senicapoc significantly increased hemoglobin and decreased hemolysis but did not decrease the rate of acute pain episodes compared with placebo | Hemoglobin and complications related to hemolysis (eg, stroke risk and chronic kidney disease) |
| Rate of vaso-occlusive crisis (composite of painful crisis or acute chest syndrome) | Prasugrel (Heeney MM et al, 2016)40 | No significant difference was seen in the rate of vaso-occlusive events per person-year when prasugrel was compared with placebo | — |
| Number of pain crises through week 48 | l-glutamine (Niihara Y et al, 2018)41 | Patients on l-glutamine had significantly fewer pain episodes, hospitalizations, and acute chest syndrome vs those on placebo | — |
| Annual rate of sickle cell–related pain crises | Crizanlizumab (Ataga KI et al, 2017)42 | Treatment with crizanlizumab at 5 mg/kg of body weight every 4 weeks resulted in significantly lower median rate of acute pain episodes and longer time periods to first and second pain episodes vs placebo. The recently completed phase 3 STAND trial reported no significant difference between crizanlizumab either at 5 mg/kg or 7.5 mg/kg every 4 weeks vs placebo in reducing the annualized rates of vaso-occlusive episodes leading to a health care visit over the first year after randomization. | — |
| Effect on frequency of SCD pain days per patient year | N-acetylcysteine (Sins JWR et al, 2018)43 | Treatment with N-acetylcysteine at a dose of 600 mg twice a day for 6 months did not significantly decrease the rate of SCD-related pain days per patient year, hospital admission days, number of admissions, or days with home analgesic use vs placebo | — |
| Effect on change in average daily pain scores | Canakinumab (Rees DC et al, 2022)44 | Canakinumab did not significantly decrease diary-reported daily pain scores vs placebo | — |
| Effect on the rate of vaso-occlusive crises (composite of painful crises and/or acute chest syndrome) | Ticagrelor (Heeney MM et al, 2022)45 | Treatment of children with ticagrelor did not significantly decrease the rate of vaso-occlusive episodes vs placebo | — |
| Primary efficacy end point . | Drug . | Study findings and lessons . | Alternative end points . |
|---|---|---|---|
| Effect on hemolytic rate and frequency of crisis | Sodium cyanate (Gillette PN et al, 1974)34 | Treatment with sodium cyanate resulted in dose-related increase in hemoglobin. Retrospective analysis revealed a significant decrease in mean frequency of acute pain episodes between 2 groups of patients with low and high hemoglobin carbamylation. Further development of sodium cyanate was not pursued because of subsequent evidence of its toxicity. | — |
| Effect on pain crisis | Ticlopidine (Cabannes R et al, 1984)35 | Treatment with ticlopidine decreased the number of pain episodes, mean duration of pain episodes, and severity of pain episodes vs placebo | — |
| Effect on frequency of painful crises in adults and effect on splenic function and kidney function in very young children | Hydroxyurea (Charache S et al, 1995; Wang WC et al, 2011; de Montalembert M et al, 2021)36-38 | Treatment with hydroxyurea decreased the rate of pain episodes and increased the time periods to first and second crises and hospitalizations because of pain episodes, acute chest syndrome, and blood transfusion. A trial in infants showed similar decreases in pain episodes, acute chest syndrome, and blood transfusion but had no significant effect on the primary end points (splenic function or eGFR). | Hydroxyurea has also been evaluated for other clinical end points, including primary and secondary stroke prevention |
| Effect on frequency of acute sickle cell–related painful crises | Senicapoc (Ataga KI et al, 2011)39 | Treatment with senicapoc significantly increased hemoglobin and decreased hemolysis but did not decrease the rate of acute pain episodes compared with placebo | Hemoglobin and complications related to hemolysis (eg, stroke risk and chronic kidney disease) |
| Rate of vaso-occlusive crisis (composite of painful crisis or acute chest syndrome) | Prasugrel (Heeney MM et al, 2016)40 | No significant difference was seen in the rate of vaso-occlusive events per person-year when prasugrel was compared with placebo | — |
| Number of pain crises through week 48 | l-glutamine (Niihara Y et al, 2018)41 | Patients on l-glutamine had significantly fewer pain episodes, hospitalizations, and acute chest syndrome vs those on placebo | — |
| Annual rate of sickle cell–related pain crises | Crizanlizumab (Ataga KI et al, 2017)42 | Treatment with crizanlizumab at 5 mg/kg of body weight every 4 weeks resulted in significantly lower median rate of acute pain episodes and longer time periods to first and second pain episodes vs placebo. The recently completed phase 3 STAND trial reported no significant difference between crizanlizumab either at 5 mg/kg or 7.5 mg/kg every 4 weeks vs placebo in reducing the annualized rates of vaso-occlusive episodes leading to a health care visit over the first year after randomization. | — |
| Effect on frequency of SCD pain days per patient year | N-acetylcysteine (Sins JWR et al, 2018)43 | Treatment with N-acetylcysteine at a dose of 600 mg twice a day for 6 months did not significantly decrease the rate of SCD-related pain days per patient year, hospital admission days, number of admissions, or days with home analgesic use vs placebo | — |
| Effect on change in average daily pain scores | Canakinumab (Rees DC et al, 2022)44 | Canakinumab did not significantly decrease diary-reported daily pain scores vs placebo | — |
| Effect on the rate of vaso-occlusive crises (composite of painful crises and/or acute chest syndrome) | Ticagrelor (Heeney MM et al, 2022)45 | Treatment of children with ticagrelor did not significantly decrease the rate of vaso-occlusive episodes vs placebo | — |
eGFR, estimated glomerular filtration rate.