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

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Voxelotor (GBT440) in Pediatric Participants With Sickle Cell Disease (HOPE Kids 2)

Status

Terminated

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04218084

Acronym

HOPE Kids 2

Enrollment

236

Registered

2020-01-06

Start date

2020-11-11

Completion date

2024-11-06

Last updated

2026-03-10

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Sickle Cell Disease

Keywords

Sickle Cell Disease, Transcranial Doppler Ultrasound (TCD)

Brief summary

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 primary objective is to evaluate the effect of voxelotor on the TCD (Transcranial Doppler Ultrasound) measurements in SCD participants in this age range.

Detailed description

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.

Interventions

DRUGVoxelotor

Participants are randomized 1:1 to receive voxelotor or placebo.

DRUGPlacebo

Matching placebo.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Masking description

Double-Blind, Placebo-Controlled

Eligibility

Sex/Gender

ALL

Age

2 Years to 14 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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.

Countries

Egypt, Ghana, Italy, Kenya, Nigeria, Oman, Saudi Arabia, United Kingdom, United States

Contacts

STUDY_DIRECTORPfizer CT.gov Call Center

Pfizer

Participant flow

Pre-assignment details

A total of 236 participants were assigned to the study treatment. Study was terminated based on sponsor decision.

Participants by arm

Arm	Count
Voxelotor Participants aged greater than or equal to 12 years of age received 1500 mg voxelotor tablet orally once daily for 96 weeks. Participants less than 12 years of age received voxelotor at a weight based (1500 mg-equivalent) dose. Participants were followed up to 4 weeks after last dose of study drug.	120
Placebo Participants received voxelotor matched placebo orally once daily for 96 weeks. Participants were followed up to 4 weeks after last dose of study drug.	116
Total	236

Baseline characteristics

Characteristic	Total	Placebo	Voxelotor
Age, Customized Age 12 to < 15 Years	29 Participants	14 Participants	15 Participants
Age, Customized Age 2 to less than (<) 4 Years	24 Participants	10 Participants	14 Participants
Age, Customized Age 4 to < 12 Years	183 Participants	92 Participants	91 Participants
Ethnicity (NIH/OMB) Ethnicity Hispanic or Latino	1 Participants	0 Participants	1 Participants
Ethnicity (NIH/OMB) Ethnicity Not Hispanic or Latino	227 Participants	113 Participants	114 Participants
Ethnicity (NIH/OMB) Ethnicity Unknown or Not Reported	8 Participants	3 Participants	5 Participants
Race/Ethnicity, Customized Race African	149 Participants	80 Participants	69 Participants
Race/Ethnicity, Customized Race Arab	23 Participants	11 Participants	12 Participants
Race/Ethnicity, Customized Race Black or African American	10 Participants	2 Participants	8 Participants
Race/Ethnicity, Customized Race Multi-Racial	52 Participants	23 Participants	29 Participants
Race/Ethnicity, Customized Race White	2 Participants	0 Participants	2 Participants
Sex: Female, Male Sex Female	122 Participants	59 Participants	63 Participants
Sex: Female, Male Sex Male	114 Participants	57 Participants	57 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	8 / 120	2 / 116
other Total, other adverse events	81 / 120	83 / 116
serious Total, serious adverse events	63 / 120	43 / 116

Outcome results

Primary

Change From Baseline in Time-Averaged Maximum of Mean Velocity (TAMMV) Arterial Cerebral Blood Flow at Week 24

TAMMV was defined as the time averaged maximum of the mean velocity arterial cerebral blood flow and was measured using transcranial Doppler (TCD). Analysis was performed using mixed model for repeated measures (MMRM) including treatment, study visit, treatment by visit interaction, baseline hydroxyurea (HU) use (yes; no), age group (2 to \<= 8 years; \>8 to \<15 years), and baseline TAMMV value (170 centimeter per second \[cm/sec\] to \< 185 cm/sec; 185 cm/sec to \< 200 cm/sec) as fixed effect terms and used a compound symmetry covariance matrix for within-participant variability.

Time frame: Baseline (value at screening), Week 24

Population: ITT analysis population included all randomized participants. Here, Overall Number of Participants Analyzed'' signifies number of participants evaluable for this outcome measure.

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Voxelotor	Change From Baseline in Time-Averaged Maximum of Mean Velocity (TAMMV) Arterial Cerebral Blood Flow at Week 24	-12.15 Centimeter per second (cm/sec)
Placebo	Change From Baseline in Time-Averaged Maximum of Mean Velocity (TAMMV) Arterial Cerebral Blood Flow at Week 24	-4.42 Centimeter per second (cm/sec)

Comparison: Week 24p-value: 0.004395% CI: [-13.03, -2.42]Mixed Models for Repeated Measures

Secondary

Annualized Incidence Rate of Vaso-Occlusive Crises (VOCs)

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. 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 initiation for participants with no hydroxyurea at baseline, end of study, and data cutoff date). The 95% CI of rate displayed the exact Poisson confidence limits.