Sickle Cell Disease, Vaso-Occlusive Crises
Conditions
Brief summary
Sickle cell disease is a severe monogenic genetic disorder caused by an autosomal recessive mutation of the β-globin gene, leading to production of abnormal hemoglobin (HbS). It primarily affects individuals from Africa or the French overseas territories. In France, approximately 26,000 patients are affected. Improved care has significantly increased life expectancy. Vaso-occlusive crises (VOC) are the main clinical complication. They result from polymerization of HbS, deforming red blood cells and causing capillary occlusion, tissue hypoxia, intense bone pain, and frequent hospitalizations. In France in 2015, 25,150 hospitalizations were recorded, 61% of which were for VOC. Iloprost is a prostacyclin (PGI2) analogue with vasodilatory, anti-platelet, anti-inflammatory, and antioxidant properties. It is used to treat severe limb ischemia and Raynaud's phenomenon, administered by IV infusion for 5 to 28 days. It is well tolerated and has shown efficacy for bone pain related to bone marrow edema. Its rapid and sustained action makes it an interesting candidate for VOC, which are comparable to ischemic-origin pain. To date, only one reported case of iloprost use for a VOC exists, showing rapid and lasting improvement. This randomized, multicenter, double-blind, placebo-controlled clinical trial aims to evaluate the efficacy of iloprost in patients hospitalized for VOC, with the objective of reducing pain and opioid consumption. This comprehensive approach could significantly improve VOC management.
Interventions
DRUGIloprost
1 ampoule IV over 6 h daily for 5 days diluted in 250 mL G5%
DRUGPlacebo
250 mL G5% IV over 6 h daily for 5 days
Sponsors
University Hospital, Rouen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients with major sickle cell syndrome (all genotypes). 2. Age ≥18 years 3. Require hospitalization and IV opioids for VOC treatment. 4. Admitted less than 36 hours before inclusion; H0 = hospital admission time. 5. Have read and signed informed consent. 6. For women: * Of childbearing potential (defined by the CTCG as a fertile woman, after menarche and until menopause, except in cases of permanent sterility, including hysterectomy, bilateral salpingectomy, or bilateral oophorectomy); * Using a highly effective method of contraception according to CTCG recommendations (combined hormonal contraception \[containing estrogens and progestogens\] associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner, sexual abstinence) for at least 4 weeks prior to inclusion and throughout the entire duration of systemic exposure to the study treatment. AND * Having a negative urine pregnancy test at inclusion; * Postmenopausal: Menopause, according to CTCG recommendations, is defined as the absence of menstruation for 12 months without any other medical cause. Elevated follicle-stimulating hormone (FSH) levels in the postmenopausal interval can be used to confirm postmenopausal status in women who are not using hormonal contraception or hormone replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 7\. Affiliated with a social security system
Exclusion criteria
1. Patients with a contraindication to iloprost (ILOPROST ZENTIVA 100 micrograms/mL, solution for dilution for infusion): 1. pregnancy, breastfeeding 2. Hypersensitivity to the active substance or to any of the excipients. 3. Conditions where the risk of bleeding may be increased due to the effects of iloprost on platelets (e.g., active peptic ulcer, trauma, intracranial hemorrhage). 4. severe coronary disease 5. recent MI \<6 months 6. heart failure NYHA II-IV 7. severe arrhythmias 8. suspicion of pulmonary congestion 2. Active smoking 3. Patient presenting with hepatic impairment or renal impairment requiring dialysis 4. Patient presenting with a contraindication to 5% glucose (Glucose 5% FRESENIUS KABI France solution for infusion): 1. Hypersensitivity to corn 2. Uncontrolled hyperglycemia, 3. Decompensated diabetes, 4. Other known glucose intolerances (e.g. situations of metabolic stress, acute shock states, collapse), 5. Hyperosmolar coma, 6. Hyperlactatemia, 7. Metabolic acidosis, 8. Fluid overload. The administration of high volumes may in particular result, due to fluid overload, in the following contraindications: 9. Hyperhydration 10. Acute heart failure 11. Pulmonary edema 5. Hypersensitivity to 5% glucose 6. Severe malnutrition 7. Thiamine deficiency in chronic alcoholic patients 8. Patient presenting with arterial hypotension 9. Patient having experienced a cerebrovascular event within the last 3 months 10. History of documented opioid dependence 11. Individuals deprived of liberty or under legal protection. 12. Patient included in PROSTASICKLE within last 90 days. 13. Participation in another drug trial within previous month.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Opioid consumption | 28 days following randomization | Mean opioid consumption in morphine equivalent mg/day over the 28 days following randomization |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean pain | 28 days following randomization | Mean pain according to the VAS (Visual Analog Scale) over the first 28 days. The VAS used in this study will be a scale from 0 to 10, with ratings ranging from "no pain" (0) to "the worst pain" (10). If the patient has multiple painful areas, the worst pain should be reported. |
| Length of hospital | 28 days following randomization | Length of hospital stay capped at 28 days |
| Acute chest syndrome during hospitalization | 28 days following randomization | — |
| Number of priapism episodes during hospitalization | 28 days following randomization | — |
| hemoglobin level | 5 days following randomization | Change in hemoglobin level (in g/dL) between baseline (day of randomization) and the 5-day assessment, or at hospital discharge if this occurs before 5 days |
| reticulocyte count | 5 days following randomization | Change in reticulocyte count (in giga/L) between baseline (day of randomization) and the 5-day assessment, or at hospital discharge if this occurs before 5 days |
| lactate dehydrogenase activity | 5 days following randomization | Change in lactate dehydrogenase activity (in IU/L) between baseline (day of randomization) and the 5-day assessment, or at hospital discharge if this occurs before 5 days |
| leukocyte count | 5 days following randomization | Change in leukocyte count (in giga/L) between baseline (day of randomization) and the 5-day assessment, or at hospital discharge if this occurs before 5 days |
| C-reactive protein | 5 days following randomization | Change in serum C-reactive protein concentration (in mg/L) between baseline (day of randomization) and the 5-day assessment, or at hospital discharge if this occurs before 5 days |
| thrombin generation test | 5 days following randomization | Change in thrombin generation test result via thrombin peak height between baseline (day of randomization) and the 5-day assessment, or at hospital discharge if this occurs before 5 days |
| D-dimers | 5 days following randomization | Change in D-dimers (μg/L) between baseline (day of randomization) and the 5-day assessment, or at hospital discharge if this occurs before 5 days |
| prothrombin fragments 1+2 | 5 days following randomization | Change in serum concentration of prothrombin fragments 1+2 (nmol/L) between baseline (day of randomization) and the 5-day assessment, or at hospital discharge if this occurs before 5 days |
| thrombomodulin concentration | 5 days following randomization | Change in serum thrombomodulin concentration (ng/mL) between baseline (day of randomization) and the 5-day assessment, or at hospital discharge if this occurs before 5 days |
| erythrocyte microvesicles | 5 days following randomization | Change in blood concentration of erythrocyte microvesicles (vesicles/μL) between baseline (day of randomization) and the 5-day assessment, or at hospital discharge if this occurs before 5 days |
| S-endothelin concentration | 5 days following randomization | Change in serum S-endothelin concentration (pg/mL) between baseline (day of randomization) and the 5-day assessment, or at hospital discharge if this occurs before 5 days |
| E-selectin concentration | 5 days following randomization | Change in serum E-selectin concentration (ng/mL) between baseline (day of randomization) and the 5-day assessment, or at hospital discharge if this occurs before 5 days |
| P-selectin concentration | 5 days following randomization | Change in serum P-selectin concentration (ng/mL) between baseline (day of randomization) and the 5-day assessment, or at hospital discharge if this occurs before 5 days |
| VCAM-1 concentration | 5 days following randomization | Change in serum VCAM-1 concentration (ng/mL) between baseline (day of randomization) and the 5-day assessment, or at hospital discharge if this occurs before 5 days |
| Number of vaso-occlusive crises | 90 days following randomization | occurring within 90 days after randomization, excluding the initial vaso-occlusive crisis |
| Total cost of management | 90 days following randomization | Total cost of management including prescription costs (notably iloprost) and costs associated with hospitalizations (from the health insurance perspective) |
| Time interval between randomization and last opioid use | 28 days following randomization | Time interval between randomization and last opioid use at 28 days |
| Duration of priapism episodes during hospitalization | 28 days following randomization | — |
Countries
France
Contacts
CONTACTMaximilien GRALL
CONTACTMylene HERVET
Outcome results
None listed