Study to Evaluate the Effect of GBT440 on TCD in Pediatrics With Sickle Cell Disease

This study is a Phase 3, randomized, double-blind, placebo-controlled study of voxelotor in pediatric participants, aged ≥ 2 to < 15 years old, with Sickle Cell Disease. The study will be conducted at approximately 50 international clinical sites, and will enroll approximately 224 participants. Participants will be randomized in a 1:1 ratio to receive voxelotor or placebo. All participants younger than 12 years of age and randomized to voxelotor will receive a dose based on their body weight, to provide exposure corresponding to the adult dose of 1500 mg/day.

• Voxelotor (Drug): Participants are randomized 1:1 to receive voxelotor or placebo.
• Placebo (Drug): Matching placebo.

Primary outcomes

• Change From Baseline in Time-Averaged Maximum of Mean Velocity (TAMMV) Arterial Cerebral Blood Flow at Week 24 [Baseline (value at screening), Week 24]: TAMMV is an ultrasound measurement used in transcranial Doppler (TCD) to assess blood flow in cerebral arteries. TCD flow velocities were categorized as follows: (i) Normal: < 170 centimeter per second (cm/sec); (ii) Conditional: 170 to < 200 cm/sec - the eligible participant population for this study; (iii) Abnormal: >= 200 cm/sec.

Secondary outcomes

• Change From Baseline in TAMMV Arterial Cerebral Blood Flow at Week 48 [Baseline (value at Screening), Weeks 48]: TAMMV is an ultrasound measurement used in TCD to assess blood flow in cerebral arteries. TCD flow velocities were categorized as follows: (i) Normal: < 170 cm/sec; (ii) Conditional: 170 to < 200 cm/sec - the eligible participant population for this study; (iii) Abnormal: >= 200 cm/sec.
• Time to Conversion to Abnormal TCD Flow [Up to 96 weeks]: Time to conversion was the number of weeks from the date of randomization to the date of first determined TCD assessment when an abnormal TCD flow velocity (>= 200 cm/sec) was determined. TCD flow velocities were categorized as follows: (i) Normal: < 170 cm/sec; (ii) Conditional: 170 to < 200 cm/sec - the eligible participant population for this study; (iii) Abnormal: >= 200 cm/sec. The stratified Log Rank Test was stratified by stratification factors: baseline HU use (yes; no), age group (2 to <= 8 years; >8 to <15 years), and baseline TAMMV value (170 cm/sec to < 185 cm/sec; 185 cm/sec to < 200 cm/sec).
• Time to Reversion to Normal TCD Flow [Up to 96 weeks]: TCD was used to assess cerebral artery blood flow velocity in children with sickle cell disease (SCD). Time to first normal TCD flow was the number of weeks from randomization to the date of first determined normal TCD flow. Normal is < 170 cm/sec.
• Percentage of Participants With TAMMV Reduced by >=15 cm/Sec From Baseline at Weeks 24, 48 and 96 [At Weeks 24, 48 and 96]: In this outcome measure, percentage of participants whose TAMMV reduced by >=15 cm/sec from Baseline at Weeks 24, 48 and 96 is reported. TAMMV is an ultrasound measurement used in TCD to assess blood flow in cerebral arteries. TCD flow velocities are categorized as follows: (i) Normal: < 170 cm/sec; (ii) Conditional: 170 to < 200 cm/sec - the eligible participant population for this study; (iii) Abnormal: >= 200 cm/sec.
• Change From Baseline in Hemoglobin (Hb) at Weeks 24, 48 and 96 [Baseline (value at Screening), Weeks 24, 48 and 96]: Change from baseline in hemoglobin at weeks 24, 48 and 96 were reported in this outcome measure.
• Percent Change From Baseline in Unconjugated Bilirubin at Weeks 24, 48 and 96 [Baseline (value at Screening), Weeks 24, 48 and 96]: Percent change from baseline in unconjugated bilirubin at weeks 24, 48 and 96 was reported in this outcome measure.
• Percent Change From Baseline in Reticulocyte at Weeks 24, 48 and 96 [Baseline (value at Screening), Weeks 24, 48 and 96]: Percent change from baseline in reticulocyte at weeks 24, 48 and 96 was reported in this outcome measure.
• Percent Change From Baseline in Absolute Reticulocyte at Weeks 24, 48 and 96 [Baseline (value at Screening), Weeks 24, 48 and 96]: Percent change from baseline in absolute reticulocyte at weeks 24, 48 and 96 was reported in this outcome measure.
• Percent Change From Baseline in Lactate Dehydrogenase (LDH) at Weeks 24, 48 and 96 [Baseline (value at Screening), Weeks 24, 48 and 96]: Percent change from baseline in LDH at weeks 24, 48 and 96 was reported in this outcome measure.
• Annualized Incidence Rate of Vaso-Occlusive Crises (VOCs) [From randomization to the last dose date, post-randomization HU initiation with no HU at baseline, end of study or study termination, whichever occurred earlier (maximum up to 110 weeks)]: VOC was defined as a composite of acute painful crisis and/or acute chest syndrome (ACS). Annualized incidence rate was defined as total number of events per total person-years on treatment. Total person-years was the sum of participants treatment period in years, which included the time from randomization date to the earliest of (last dose date, post-randomization HU initiation for participants with no HU at baseline, end of study, or study termination). The 95% CI of rate displayed the exact Poisson confidence limits.

Sex: All, ages: 2 Years to 14 Years

Inclusion Criteria:

1. Male or female participants with Sickle Cell Anemia (SCA) HbSS, HbSβ0 thalassemia genotype
2. TCD time averaged maximum of the mean velocity (TAMMV) arterial cerebral blood flow ≥ 170 to < 200cm/sec during the Screening Period
3. Hb ≥ 5.5 and ≤ 10.5 g/dL during screening
4. For participants taking HU, the dose of HU (mg/kg) must be stable for at least 90 days prior to signing the informed consent form (ICF) and/or assent form, and with no anticipated need for dose adjustments (other than weight based) or for initiation of HU for non-chronic use during the study, in the opinion of the Investigator
5. Written informed parental/guardian consent and participant assent (where applicable) has been obtained per IRB/EC policy and requirements, consistent with ICH guidelines.

Exclusion Criteria:

1. Body weight < 10kg at the screening visit
2. Hospitalization for VOC or acute chest syndrome (ACS) within the 14 days prior to execution of informed consent/assent
3. More than 10 VOCs within the past 12 months that required hospitalization, emergency room, or clinic visit
4. Stroke resulting in focal neurological deficit; previous silent infarcts are permitted.
5. Known history or findings suggestive of significant cerebral vasculopathy
6. History of seizure disorder
7. Has been treated with erythropoietin or other hematopoietic growth factors within 28 days of signing informed consent/assent or if, in the opinion of the Investigator, there is an anticipated need for such agents during the study
8. RBC transfusion therapy (also termed chronic, prophylactic, or preventative transfusion) or has received an RBC transfusion or exchange transfusion for any reason within 90 days of signing the informed consent/assent

Participant flow

Outcome results

• Change From Baseline in Time-Averaged Maximum of Mean Velocity (TAMMV) Arterial Cerebral Blood Flow at Week 24 (Primary), Least squares mean, cm/sec: Voxelotor -12.06 (-15.82 to -8.31); Placebo -4.29 (-8.17 to -0.40) (p 0.0048)
• Change From Baseline in TAMMV Arterial Cerebral Blood Flow at Week 48 (Secondary), Least squares mean, cm/sec: Voxelotor -10.33 (-14.14 to -6.52); Placebo -3.86 (-7.77 to 0.05) (p =0.0202)
• Time to Conversion to Abnormal TCD Flow (Secondary), Median, Weeks: Voxelotor NA (NA to NA); Placebo NA (NA to NA) (p =0.0981)
• Time to Reversion to Normal TCD Flow (Secondary), Median, Weeks: Voxelotor 9.3 (7 to 73); Placebo 17.0 (8 to 96)
• Percentage of Participants With TAMMV Reduced by >=15 cm/Sec From Baseline at Weeks 24, 48 and 96 (Secondary), Number, Percentage of participants: Voxelotor 38.3; Placebo 25.9 (p =0.0494)
• Change From Baseline in Hemoglobin (Hb) at Weeks 24, 48 and 96 (Secondary), Least squares mean, Grams per deciliter (g/dL): Voxelotor 0.89 (0.65 to 1.14); Placebo 0.18 (-0.08 to 0.44) (p =0.0001)
• Percent Change From Baseline in Unconjugated Bilirubin at Weeks 24, 48 and 96 (Secondary), Least squares mean, Percentage change: Voxelotor -21.83 (-30.65 to -13.01); Placebo 11.78 (2.59 to 20.98) (p <0.0001)
• Percent Change From Baseline in Reticulocyte at Weeks 24, 48 and 96 (Secondary), Least squares mean, Percent change: Voxelotor 54.36 (-1.27 to 109.99); Placebo 74.73 (18.24 to 131.22) (p =0.614)
• Percent Change From Baseline in Absolute Reticulocyte at Weeks 24, 48 and 96 (Secondary), Least squares mean, Percent change: Voxelotor 60.89 (7.22 to 114.56); Placebo 67.93 (13.10 to 122.75) (p =0.8571)
• Percent Change From Baseline in Lactate Dehydrogenase (LDH) at Weeks 24, 48 and 96 (Secondary), Least squares mean, Percent change: Voxelotor 2.62 (-3.25 to 8.49); Placebo 2.18 (-3.99 to 8.34) (p =0.9181)
• Annualized Incidence Rate of Vaso-Occlusive Crises (VOCs) (Secondary), Number, Events/ person-years: Voxelotor 1.098 (0.869 to 1.387); Placebo 0.580 (0.439 to 0.765)

Adverse events

Time frame: From randomization to the last dose date, post-randomization HU initiation with no HU at baseline, end of study or study termination, whichever occurred earlier (maximum up to 110 weeks)

Serious adverse events by term

Other adverse events by term

65 more terms not shown.

• Results publication: Bello-Manga H, Abdullahi SU, Hassab H, Brown B, Nduba V, Githanga J, Akinsete AM, El-Beshlawy A, Hanna D, Segbefia C, Okpala I, Tantawy A, Ogutu B, Tubman VN, Paintsil V, Wali Y, Essa M, Telfer P, Dixon S, Hickman A, Doss JF, Davis MW, Rupon J, Kirkham FJ, Brown RC; HOPE Kids 2 Investigators. HOPE Kids 2: Phase 3, Randomized Trial of Voxelotor in Children With SCD and Conditional Cerebral Blood Flow Velocities. Am J Hematol. 2026 Aug 28. doi: 10.1002/ajh.70457. Online ahead of print. PMID 42665434

• Study Protocol (PDF, 2023-07-19)
• Statistical Analysis Plan (PDF, 2025-01-31)

• Pfizer CT.gov Call Center, Study director, Pfizer

NIH grants: 2017