5613260 A PHASE -- IIA-IIB, OPEN LABEL, SINGLE CENTER TRIAL TO STUDY SAFETY, TOLERABILITY AND EFFICACY OF MEMANTINE AS SUPPORTIVE LONG-TERM TREATMENT OF SICKLE CELL PATIENTS: TRIAL DESIGN AND ENROLLMENT

Abstract

Background: Sickle cell disease (SCD) is a life-threatening hematological disorder with a high rate of long-term comorbidities and a significant socioeconomic burden. Anemia, vaso-occlusive and pain crises, infections, and a high rate of long-term comorbidities are hallmarks of SCD. The pathophysiology of SCD is due to a single point mutation (Glu6Val) that causes polymerization of the mutant hemoglobin (HbS), resulting in red blood cells (RBC) sickling. Inflammation, hemolysis, microvascular obstruction, and organ damage characterize the clinical expression of SCD. The standard of care includes Hydroxycarbamide, symptomatic treatment, blood transfusions, new drugs, and bone marrow transplant as curative therapy. Our recent findings showed that N-methyl D-aspartate receptors (NMDARs) are up-regulated SCD-RBCs and Ca2+ uptake via NMDARs affects SCD-RBC hydration, and hypoxia-induced sickling (Hanggi P. et al., 2014). Inhibition of NMDARs with Memantine, a drug used in Alzheimer’s disease, emerges as a novel treatment in SCD. Memantine administration in 6 SCD adults demonstrated safety (Hegemann I. et al., 2020); and suggested a reduction of RBCs irreversible sickling (Makhro A, et al., 2020). Aims: This phase IIa-IIb open-label, single-center trial aims to study the safety, tolerability, and efficacy of Memantine in adults and teenagers with SCD (NCT03247218). Methods: This trial enrolled 23 SCD (SS and Sβ Thalassemia) 17 patients received Memantine for at least one year period, Hydroxycarbamide was continued administered. Starting dose of Memantine was 5 mg/day with escalation every 3 months, up to 15 mg/day in teenagers and up to 20 mg/day for adults. Patients were followed up monthly, a total of 6762 patients/days of follow-up were summarized. Results: The only safety events reported were transient headache and constipation in two patients; no adverse side effects were noticed. Overall, the number of admission days and emergency room visits decreased compared to the pre-screen period. The hemoglobin and fetal hemoglobin levels remain stable despite less use of blood transfusions; based on preliminary laboratory analysis a trend of reduction in hemolytic and inflammatory parameters can be noticed. Conclusions: The results of this phase IIa-IIb trial suggested safety and probable clinical benefit in long-term treatment with Memantine in SCD adolescents and adults. Full results of this trial are anticipated at the end of 2022 and a phase III trial will be required for the final assessment of the clinical benefit of Memantine treatment in SCD.