Select acute intervention trials for acute vaso-occlusive episodes in SCD
| Primary efficacy end point . | Drug . | Main study findings and lessons . |
|---|---|---|
| Effect on course of pain crisis | Cetiedil (Benjamin LJ et al, 1986)19 | Despite significant reduction in the number of painful sites and shortening of the duration of pain episodes, cetiedil was not developed further for SCD |
| Effect on duration and severity of pain crisis | Methylprednisolone (Griffin TC et al, 1994)20 | Treatment with methylprednisolone resulted in significantly shorter inpatient analgesic therapy vs placebo, but more patients on methylprednisolone had recurrent pain episodes shortly after treatment than those on placebo |
| Effect on duration of pain crisis | Purified poloxamer-188 (Orringer EP et al, 2001; Casella JF et al, 2021)21,22 | In earlier trial, treatment with poloxamer-188 significantly decreased the duration of pain episodes especially in children and those on hydroxyurea. In a subsequent trial, poloxamer-188 did not significantly shorten the time to last dose of parenteral opioids. |
| (1) Effect on time to resolution of vaso-occlusive crisis; and (2) in patients with acute chest syndrome death from any cause, need for endotracheal intubation, decrease of PaO2/FiO2 ≥15 mm Hg between days 1 and 3, and augmented therapy defined as new transfusion or phlebotomy | Inhaled nitric oxide (Gladwin MT et al, 2011; Maitre B et al, 2015)23,24 | Study of patients with vaso-occlusive episodes showed no significant difference in the time to resolution of painful episodes, length of hospitalization, pain scale scores, or opioid use. In study of patients with acute chest syndrome, no significant difference was seen between those who received inhaled nitric oxide vs placebo. |
| Effect on painful crisis | Tinzaparin (Qari MH et al, 2007)25 | Treatment with tinzaparin resulted in significant reductions in number of days with most severe pain scores, overall duration of pain episodes, and duration of hospitalization vs placebo. There were concerns regarding the dose of analgesia used in the standard arm of the trial and the risk of bleeding with use of therapeutic doses of tinzaparin. |
| (1) Efficacy in children requiring hospitalization for severe pain necessitating parenteral narcotics (2) Effect on analgesic usage, quantified by difference in the mean analgesic MQS | Arginine (Morris CR et al, 2013; Onalo R et al, 2021)26,27 | Treatment with IV arginine significantly reduced total parenteral opioid use and lowered pain scores at discharge vs placebo. Treatment with oral arginine in Nigerian children resulted in a significantly lower mean total analgesic MQS vs placebo, with faster mean rate of decline in the worst pain scores, shorter time to pain episode resolution, and reduced hospital stay. |
| Effect on duration of vaso-occlusive crisis in hospitalized patients | Sevuparin (Biedmond BJ et al, 2021)28 | No significant difference was seen in the median time to resolution of pain episodes between sevuparin and placebo groups |
| Effect on time to resolution of vaso-occlusive crisis | Rivipansel (Telen MJ et al, 2015; Dampier CD et al, 2023)29,30 | In the phase 2 trial, rivipansel significantly reduced the mean cumulative IV opioid analgesic use by 83% vs placebo, with clinically meaningful but not significant reductions in mean and median times to resolution of acute pain episode. The phase 3 trial showed no significant difference in the median time to readiness to discharge between rivipansel and placebo. Post hoc analysis revealed significant benefit with early treatment within 26.4 hours of onset of acute pain episode. |
| Efficacy and toxicity in children hospitalized with mild to moderately severe acute chest syndrome | Dexamethasone (Bernini JC et al, 1998)31 | Treatment with dexamethasone resulted in a significantly shorter hospital stay, prevented clinical deterioration, and reduced the need for blood transfusion, but more patients on dexamethasone were readmitted within 72 hours after discharge vs placebo |
| Effect on reduction in activated iNKT cells activation in patients admitted for acute pain crisis | Regadenoson (Field JJ et al, 2017)32 | No significant difference in proportion of patients with >30% reduction in activated iNKT cells in regadenoson vs placebo. Furthermore, there were no differences in the duration of hospital stay, mean total opioid use, or pain scores between the treatment groups. The dose of regadenoson in the trial may have been too low to reduce iNKT cell activation |
| Effect on duration of stay in patients hospitalized for vaso-occlusive crisis | Magnesium (Brousseau DC et al, 2015)33 | No difference in length of stay, HRQoL or opioid use between magnesium and placebo groups |
| Primary efficacy end point . | Drug . | Main study findings and lessons . |
|---|---|---|
| Effect on course of pain crisis | Cetiedil (Benjamin LJ et al, 1986)19 | Despite significant reduction in the number of painful sites and shortening of the duration of pain episodes, cetiedil was not developed further for SCD |
| Effect on duration and severity of pain crisis | Methylprednisolone (Griffin TC et al, 1994)20 | Treatment with methylprednisolone resulted in significantly shorter inpatient analgesic therapy vs placebo, but more patients on methylprednisolone had recurrent pain episodes shortly after treatment than those on placebo |
| Effect on duration of pain crisis | Purified poloxamer-188 (Orringer EP et al, 2001; Casella JF et al, 2021)21,22 | In earlier trial, treatment with poloxamer-188 significantly decreased the duration of pain episodes especially in children and those on hydroxyurea. In a subsequent trial, poloxamer-188 did not significantly shorten the time to last dose of parenteral opioids. |
| (1) Effect on time to resolution of vaso-occlusive crisis; and (2) in patients with acute chest syndrome death from any cause, need for endotracheal intubation, decrease of PaO2/FiO2 ≥15 mm Hg between days 1 and 3, and augmented therapy defined as new transfusion or phlebotomy | Inhaled nitric oxide (Gladwin MT et al, 2011; Maitre B et al, 2015)23,24 | Study of patients with vaso-occlusive episodes showed no significant difference in the time to resolution of painful episodes, length of hospitalization, pain scale scores, or opioid use. In study of patients with acute chest syndrome, no significant difference was seen between those who received inhaled nitric oxide vs placebo. |
| Effect on painful crisis | Tinzaparin (Qari MH et al, 2007)25 | Treatment with tinzaparin resulted in significant reductions in number of days with most severe pain scores, overall duration of pain episodes, and duration of hospitalization vs placebo. There were concerns regarding the dose of analgesia used in the standard arm of the trial and the risk of bleeding with use of therapeutic doses of tinzaparin. |
| (1) Efficacy in children requiring hospitalization for severe pain necessitating parenteral narcotics (2) Effect on analgesic usage, quantified by difference in the mean analgesic MQS | Arginine (Morris CR et al, 2013; Onalo R et al, 2021)26,27 | Treatment with IV arginine significantly reduced total parenteral opioid use and lowered pain scores at discharge vs placebo. Treatment with oral arginine in Nigerian children resulted in a significantly lower mean total analgesic MQS vs placebo, with faster mean rate of decline in the worst pain scores, shorter time to pain episode resolution, and reduced hospital stay. |
| Effect on duration of vaso-occlusive crisis in hospitalized patients | Sevuparin (Biedmond BJ et al, 2021)28 | No significant difference was seen in the median time to resolution of pain episodes between sevuparin and placebo groups |
| Effect on time to resolution of vaso-occlusive crisis | Rivipansel (Telen MJ et al, 2015; Dampier CD et al, 2023)29,30 | In the phase 2 trial, rivipansel significantly reduced the mean cumulative IV opioid analgesic use by 83% vs placebo, with clinically meaningful but not significant reductions in mean and median times to resolution of acute pain episode. The phase 3 trial showed no significant difference in the median time to readiness to discharge between rivipansel and placebo. Post hoc analysis revealed significant benefit with early treatment within 26.4 hours of onset of acute pain episode. |
| Efficacy and toxicity in children hospitalized with mild to moderately severe acute chest syndrome | Dexamethasone (Bernini JC et al, 1998)31 | Treatment with dexamethasone resulted in a significantly shorter hospital stay, prevented clinical deterioration, and reduced the need for blood transfusion, but more patients on dexamethasone were readmitted within 72 hours after discharge vs placebo |
| Effect on reduction in activated iNKT cells activation in patients admitted for acute pain crisis | Regadenoson (Field JJ et al, 2017)32 | No significant difference in proportion of patients with >30% reduction in activated iNKT cells in regadenoson vs placebo. Furthermore, there were no differences in the duration of hospital stay, mean total opioid use, or pain scores between the treatment groups. The dose of regadenoson in the trial may have been too low to reduce iNKT cell activation |
| Effect on duration of stay in patients hospitalized for vaso-occlusive crisis | Magnesium (Brousseau DC et al, 2015)33 | No difference in length of stay, HRQoL or opioid use between magnesium and placebo groups |
FiO2, fraction of inspired oxygen; iNKT cells, invariant natural killer T cells; MQS, Medication Quantification Scale.