Double-Blind, Placebo-Controlled Randomized Controlled Trial of Hydroxyurea for HbSC: Results of the Prospective Identification of Variables As Outcomes for Treatment (PIVOT) Trial

Introduction: Hydroxyurea is the current standard of care treatment for sickle cell anemia (HbSS or HbS/beta-zero thalassemia), with proven laboratory and clinical benefits across the lifespan. In contrast, there are no clear hydroxyurea treatment indications for HbSC disease, due to lack of consensus study endpoints and few prospective data. In addition to acute vaso-occlusive events, other laboratory and clinical variables might serve as suitable endpoints for HbSC in a definitive trial. We now report the primary study results of PIVOT, a Phase 2, double-blind, placebo-controlled trial of hydroxyurea for children and adults with HbSC disease, designed to identify useful outcomes of treatment (PACTR 202108893981080).

Methods: PIVOT was conducted in Accra Ghana at Korle Bu Teaching Hospital’s Department of Child Health (children) and Ghana Institute of Clinical Genetics (adults). Inclusion criteria included known HbSC disease, between 5.0 – 50.0 years of age. Exclusion criteria included recent transfusion (temporary), cytopenia (temporary), pregnancy, or current disease-modifying therapy. After enrollment, study participants received a battery of laboratory tests and clinical assessments, before 1:1 randomization to 12 months of treatment with either hydroxyurea (Siklos®) or placebo at 20 mg/kg/day, donated by Theravia. Participants were initially monitored monthly with two possible 2.5 mg/kg/day dose escalations based on blood counts, followed by bimonthly monitoring until Month 12 with repeat assessments. The primary study endpoint was the frequency of dose-limiting toxicities (DLT), while key secondary endpoints included (1) laboratory changes; (2) incidence rate ratio (IRR) of sickle-related adverse events, hospitalizations, transfusions, and malaria; (3) organ assessments of proteinuria, spleen volume by abdominal ultrasound, retinal exam, cerebral oximetry, and (4) quality of life. Exploratory study endpoints included specialized testing for whole blood viscosity, erythrocyte deformability, and point-of-sickling.

Results: A total of 243 patients (123 children, 120 adults) enrolled in PIVOT; 29 failed screening and 214 were randomized to study treatment but 2 were later found to be ineligible, so the final analysis included 212 participants. Baseline lab parameters included hemoglobin (Hb) = 11.0 ± 1.2 g/dL, mean corpuscular volume (MCV) = 74 ± 7 fL, fetal hemoglobin (HbF) = 2.3 ± 1.8%, absolute neutrophil count (ANC) = 3.7 ± 1.8 x 10⁹/L, and absolute reticulocyte count (ARC) = 101 ± 33 x 10⁹/L. Participants were randomized to hydroxyurea (N=107) or placebo (N=105) at an average starting dose of 20.0 ± 0.4 mg/kg/day, and the average Month 12 dose was 20.3 ± 2.8 mg/kg/day. Compared to placebo, more participants assigned to the hydroxyurea treatment arm had DLT (32.7% vs 10.5%, p<0.001), but almost all cytopenias were transient Grade 2 neutropenia or thrombocytopenia. An additional DLT endpoint of elevated hemoglobin occurred in 12 participants (20 events) on hydroxyurea versus 10 participants (11 events) on placebo. Compared to placebo, laboratory benefits with hydroxyurea included increased MCV (+17 fL) and HbF (+7.6%), plus modest decreases in ANC (-1.1 x 10⁹/L) and ARC (-30 x 10⁹/L), but no significant change in Hb (-0.1 g/dL). Clinical benefits with hydroxyurea included significantly fewer vaso-occlusive painful events (IRR = 0.38, 95% CI = 0.28-0.52, p<0.0001) and fewer hospitalizations (IRR = 0.42, 95% CI = 0.22-0.83, p=0.012). Malaria was also less frequent but not significant (IRR = 0.77, 95% CI= 0.47-1.26, p=0.30). Both children and adults had decreased vaso-occlusive event rates. A protocol-specified composite endpoint of any acute sickle-related complication occurred in 37 participants on hydroxyurea and 69 on placebo (χ² = 20.4, p<0.0001).

Conclusions: In the placebo-controlled PIVOT trial, hydroxyurea treatment at 20 mg/kg/day was well-tolerated in both children and adults with HbSC, and was associated with significantly fewer painful vaso-occlusive events and fewer hospitalizations, suggesting that hydroxyurea provides effective disease-modifying treatment for HbSC. Hydroxyurea treatment led to measurable benefits in multiple hematological parameters and only mild reversible cytopenias. Standard clinical vaso-occlusive events can serve as the primary study endpoint for a future multi-center definitive Phase 3 trial.