Table 1.
Major historical acute intervention and prevention trials for VOCs in SCD
| Acute intervention trials for VOCs | Prevention trials for VOCs | ||||||
|---|---|---|---|---|---|---|---|
| Drug | Primary efficacy end point | Results | Reference | Drug | Primary efficacy end point | Results | Reference |
| Cetiedil | Effect on course of pain crisis | Cetiedil (0.4 mg/kg) significantly reduced the number of painful sites on all treatment days and shortened the total time in crisis. | Benjamin et al57 | Sodium cyanate | Effect on hemolytic rate and frequency of crisis | Decrease in the hemolytic rate (evidenced by increased Hb) and mean frequency crisis was seen in patients receiving cyanate. Increase in Hb was directly proportional to the amount of carbamylation achieved. Frequency of crisis was decreased in patients with higher carbamylation. |
Gillette et al58 |
| Methylprednisolone | Effect on duration and severity of pain crisis | Reduced duration of inpatient analgesic therapy, but majority of patients were readmitted for recurrent pain. | Griffin et al59 | Ticlopidine | Effect on pain crisis | Treatment with ticlopidine decreased the number of VOCs, mean duration of VOCs, and severity of VOCs. | Cabannes et al50 |
| Purified poloxamer-188 | Effect on duration of pain crisis | In an earlier study, poloxamer-188 significantly reduced the duration of VOC, especially in children (≤15 years) and patients receiving concurrent hydroxyurea. Subsequent study showed no significant difference in the mean time to the last dose of parenteral opioids between poloxamer-188 and placebo. |
Orringer et al34; Casella et al35 | Hydroxyureaa | Effect on frequency of painful crises in adults and children | Treatment with hydroxyurea significantly reduced VOCs, hospitalizations due to VOCs, ACS, and blood transfusion compared to placebo. | Charache eta al13; Wang et al14 |
| Inhaled NO | Effect on time to resolution of VOC | An earlier study showed significantly less morphine use over 6 hours but no difference between inhaled NO and placebo on duration of hospitalization. A subsequent larger study showed no significant difference in median time to resolution of VOC, length of hospitalization, or median opioid usage between inhaled NO and placebo. |
Gladwin et al41; Weiner et al60 | Senicapoc | Effect on frequency of painful acute sickle cell–related crises | Phase 2 study showed a dose-dependent increase in Hb with senicapoc vs placebo. Phase 3 study showed increase in Hb but no significant reduction in VOC compared to placebo. |
Ataga et al25 |
| Tinzaparin | Effect on painful crisis | Tinzaparin significantly reduced the severity and duration of VOC and duration of hospitalization. | Qari et al53 | Prasugrel | Rate of VOC (composite of painful crisis or ACS) | No significant difference in the rate of VOC between prasugrel and placebo. | Heeney et al51 |
| Arginine | Efficacy in children requiring hospitalization for severe pain necessitating parenteral narcotics | Arginine significantly reduced total analgesic usage, pain scores, time to crisis resolution, and total length of hospital stay. | Morris61 | L-glutaminea | Number of pain crises | Treatment with L-glutamine resulted in reduced VOC, hospitalizations, and ACS compared to placebo. | Niihara et al27 |
| Sevuparin | Effect on duration of VOC in hospitalized patients | No difference in time to VOC resolution or discontinuation of IV opioids between sevuparin and placebo. | Biemond33 | Crizanlizumaba | Annual rate of sickle cell–related pain crises | In the phase 2 SUSTAIN trial, crizanlizumab significantly decreased median rate of VOC and increased median times to first and second VOC. In the phase 3 STAND trial, no significant difference in the annualized rates of VOC was seen with crizanlizumab compared to placebo. |
Ataga et al29; Novartis AG30 |
| Rivipansel | Effect on time to resolution of VOC | In phase 2 trial, treatment with rivipansel significantly reduced cumulative IV opioid dose and resulted in clinically meaningful reduction in time to crisis resolution. In the phase 3 trial, no significant benefit was seen in shortening the time to readiness for discharge, time to discharge, or discontinuation of IV opioids. |
Telen et al31; Dampier et al32 | NAC | Effect on frequency of SCD pain days | No reduction in the rate of SCD-related pain days per patient-year, hospital admission days, number of admissions, or days with home analgesic use with NAC+ compared to placebo. | Sins et al28 |
| Regadenoson | Effect on reduction in invariant natural killer T-cell activation in patients admitted for acute pain crisis | Regadenoson infusion did not decrease the hospitalization duration, total opioid use, or pain scores compared with placebo. | Field et al37 | Canakinumab | Effect on change in average daily pain scores | No decrease in daily SCA-related pain, but canakinumab significantly reduced markers of inflammation compared with placebo. | Rees et al39 |
| Magnesium | Effect on length of stay in patients hospitalized for VOC | IV magnesium use did not shorten the length of hospitalization, reduce opioid use, or improve quality of life compared to placebo. | Brousseau et al26 | Ticagrelor | Effect on the rate of VOCs (composite of painful crises and/or ACS) | No reduction in VOC with ticagrelor compared to placebo. | Heeney et al52 |
ACS, acute chest syndrome; Hb, hemoglobin; IV, intravenous; NAC, N-acetyl cysteine; SCA, sickle cell anemia; VOC, vaso-occlusive crisis.
a
Clinical trials resulted in approval of these drugs by the FDA.