Prevention of conversion to abnormal transcranial Doppler with hydroxyurea in sickle cell anemia: A Phase III international randomized clinical trial

Abstract

Children with sickle cell anemia (SCA) and conditional transcranial Doppler (TCD) ultrasound velocities (170-199 cm/sec) may develop stroke. However, with limited available clinical data, the current standard of care for conditional TCD velocities is observation. The efficacy of hydroxyurea in preventing conversion from conditional to abnormal TCD (≥200 cm/sec), which confers a higher stroke risk, has not been studied prospectively in a randomized trial. Sparing Conversion to Abnormal TCD Elevation (SCATE #NCT01531387) was a National Heart, Lung, and Blood Institute-funded Phase III multicenter international clinical trial comparing alternative therapy (hydroxyurea) to standard care (observation) to prevent conversion from conditional to abnormal TCD velocity in children with SCA. SCATE enrolled 38 children from the United States, Jamaica, and Brazil [HbSS (36), HbSβ(0) -thalassemia (1), and HbSD (1), median age = 5.4 years (range, 2.7-9.8)]. Because of the slow patient accrual and administrative delays, SCATE was terminated early. In an intention-to-treat analysis, the cumulative incidence of abnormal conversion was 9% (95% CI = 0-35%) in the hydroxyurea arm and 47% (95% CI = 6-81%) in observation arm at 15 months (P = 0.16). In post hoc analysis according to treatment received, significantly fewer children on hydroxyurea converted to abnormal TCD velocities when compared with observation (0% vs. 50%, P = 0.02). After a mean of 10.1 months, a significant change in mean TCD velocity was observed with hydroxyurea treatment (-15.5 vs. +10.2 cm/sec, P = 0.02). No stroke events occurred in either arm. Hydroxyurea reduces TCD velocities in children with SCA and conditional velocities.

Figure 1. Consort diagram of the SCATE study

* These 12 subjects were either not yet confirmed or already centrally confirmed as conditional TCD, but not randomized due to early study suspension and later study closure. **Two subjects did not receive hydroxyurea due to drug unavailability at one of the sites.

Figure 2. Cumulative incidence of conversion to abnormal TCD

B> A. In the intention-to-treat analysis, conversion to abnormal TCD velocity was higher in the observation arm, but not statistically significant (p=0.17). B. In the post-hoc as-treated analysis, conversion to abnormal TCD velocity was significantly higher in the observation arm (p=0.02).

Figure 3. Change in TCD velocity according to treatment

B> Children randomized to hydroxyurea had a mean reduction of 15.5 cm/sec, whereas those on the observation arm had a mean increase of 10.2 cm/sec (p=0.02).