Hemolysis Related Complications in SCD. A Phase II Study With Voxelotor
Status:
Not yet recruiting
Trial end date:
2024-01-15
Target enrollment:
Participant gender:
Summary
Intro:
Sickle cell disease is a genetic disorder caused by a mutation of the β hemoglobin called
HbS, which causes red blood cell (RBC) abnormalities responsible for hemolysis, mainly
intravascular, leading to chronic anemia. Intravascular hemolysis is responsible for severe
inflammation and endothelial dysfunction.
Maintaining hemoglobin in its oxygenated R-conformation is one of the strategies for
inhibiting the polymerization of HbS. Previous experimental therapeutic approaches having
this effect have been discontinued due to poor pharmaceutical properties or toxicity.
Nevertheless, they proved the validity of the concept by demonstrating an increase in
oxyhemoglobin and a decrease in biomarkers of hemolysis.
Voxelotor binds to the α chain of globin and maintains Hb in its R conformation, thereby
inhibiting the polymerization of HbS while increasing the affinity of Hb for oxygen.
Because of its mechanism of action affecting anemia and hemolysis, Voxelotor is a promising
treatment for the prevention and treatment of renal and cerebral arterial disease.
Hypothesis/Objective :
Investigator hypothesis is that the treatment by Voxelotor (GBT440) will improve intra
vascular hemolysis and will increase the total mass of hemoglobin with beneficial effects on
organ function.
The primary objective of the study is to evaluate the biological activity of Voxelotor on the
reduction of intra vascular hemolysis measured by plasma hemoglobin.
The secondary objectives of the study will aim at characterizing the effects of GBT 440
Voxelotor on:
- Intra vascular hemolysis measured by plasma Heme
- Total hemoglobin mass (MHb)
- RBCs lifespan
- Blood volumes (plasma volume (PV), red blood cell mass (RBCM), total blood volume (BV))
- Blood viscosity
- Cerebral perfusion
- Cerebrovascular vaso-reactivity
- Cognitive function (MoCA)
- Six minute walk test
- Renal perfusion and iron deposits in renal cortex
- Measurement of Glomerular filtration rate Estimation of glomerular filtration rate
(CKD/EPI equation)
- Urine albumin/creatinine ratio
- Ability to decrease or stop erythropoietin in patients under EPO treatment
- Safety (VOC, ACS, Priapism) and tolerability of voxelotor
- RBC properties
Method:
This is an open-label, single-arm, single-stage phase II trial in patients treated with
Voxelotor 1500 mg daily for 48 weeks. Assessments will be done during the study at week 0,
week 6, week 12, week 24, week 36 and week 48.