Study to Evaluate the Effect of GBT440 on TCD in Pediatrics With Sickle Cell Disease
- Registration Number
- NCT04218084
- Lead Sponsor
- Pfizer
- 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 236
- Male or female participants with Sickle Cell Anemia (SCA) HbSS, HbSβ0 thalassemia genotype
- TCD time averaged maximum of the mean velocity (TAMMV) arterial cerebral blood flow ≥ 170 to < 200cm/sec during the Screening Period
- Hb ≥ 5.5 and ≤ 10.5 g/dL during screening
- 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
- Written informed parental/guardian consent and participant assent (where applicable) has been obtained per IRB/EC policy and requirements, consistent with ICH guidelines.
- Body weight < 10kg at the screening visit
- Hospitalization for VOC or acute chest syndrome (ACS) within the 14 days prior to execution of informed consent/assent
- More than 10 VOCs within the past 12 months that required hospitalization, emergency room, or clinic visit
- Stroke resulting in focal neurological deficit; previous silent infarcts are permitted.
- Known history or findings suggestive of significant cerebral vasculopathy
- History of seizure disorder
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Matching placebo. Voxelotor Voxelotor Voxelotor 1500mg or equivalent daily as a tablet, dispersible tablet, or as powder for oral suspension.
- Primary Outcome Measures
Name Time Method 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 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.
- Secondary Outcome Measures
Name Time Method Change From Baseline in Transcranial Doppler (TCD) Flow Velocity at Week 48. From treatment initiation till study completion Change in TCD flow velocity from baseline to week 48 was analyzed using the MMRM model including treatment, study visit, treatment by visit interaction, baseline hydroxyurea 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) as fixed effect terms and used a compound symmetry covariance matrix for within-subject variability.
Time to Conversion to Abnormal TCD Flow From treatment initiation till study completion Time to conversion was the number of weeks from the date of randomization to the date of TCD assessment when an abnormal TCD flow velocity (\>= 200 cm/sec) is determined.
Time to Reversion to Normal TCD Flow From treatment initiation till study completion Time to first normal TCD flow was the number of weeks from randomization to the date of first normal (\<170 cm/sec) TCD flow.
Percentage of Participants With TCD Flow Velocity Reduction Greater Than or Equal to (>=)15 cm/Sec at Weeks 24 and 48 From treatment initiation till study completion TCD flow velocity reduction from Baseline ≥ 15 cm/sec at week 24, week 48 was analyzed using an exact Cochran-Mantel-Haenszel (CMH) general association test stratified for 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).
Change From Baseline in Hemoglobin (Hb) at Weeks 24 and 48 From treatment initiation till study completion Change from baseline in hemoglobin at weeks 24 and 48 was analyzed using the MMRM model including treatment, study visit, treatment by visit interaction, baseline hydroxyurea 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.
Percent Change From Baseline in Unconjugated Bilirubin at Weeks 24 and 48 From treatment initiation till study completion Percent change from baseline in unconjugated bilirubin at weeks 24 and 48 was reported in this outcome measure. Analysis was performed using MMRM including treatment, study visit, treatment by visit interaction, baseline hydroxyurea 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-subject variability.
Percent Change From Baseline in Reticulocyte at Weeks 24 and 48 From treatment initiation till study completion Percent change from baseline in reticulocyte at weeks 24 and 48 was reported in this outcome measure. Analysis was performed using MMRM including treatment, study visit, treatment by visit interaction, baseline hydroxyurea 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.
Percent Change From Baseline in Absolute Reticulocyte at Weeks 24 and 48 From treatment initiation till study completion Percent change from baseline in absolute reticulocyte at weeks 24 and 48 was reported in this outcome measure. Analysis was performed using MMRM including treatment, study visit, treatment by visit interaction, baseline hydroxyurea 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-subject variability.
Percent Change From Baseline in Lactate Dehydrogenase (LDH) at Weeks 24 and 48 From treatment initiation till study completion Percent change from baseline in LDH at weeks 24 and 48 was reported in this outcome measure. Analysis was performed using MMRM including treatment, study visit, treatment by visit interaction, baseline hydroxyurea 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-subject variability.
Annualized Incidence Rate of Vaso-Occlusive Crises (VOCs) From treatment initiation till study completion 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.
Trial Locations
- Locations (29)
Ain Shams University Hospital-Clinical Research Center (MASRI)
🇪🇬Cairo, Egypt
Department of Child Health, University of Ghana Medical School, College of Health Sciences
🇬🇭Accra, Ghana
Azienda Ospedaliera Universitaria (AOU) Meyer
🇮🇹Firenze, Italy
Azienda Ospedaliera Universita (AOU) Padova
🇮🇹Padova, Italy
Barau Dikko Teaching/ Kaduna State University
🇳🇬Kaduna, Nigeria
King Abdullah International Medical Research Center (KAIMR) Ministry of National Guard - Health
🇸🇦Riyadh, Saudi Arabia
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
University of Miami
🇺🇸Miami, Florida, United States
Children's Healthcare of Atlanta: Hughes Spalding
🇺🇸Atlanta, Georgia, United States
Boston Children's Hospital
🇺🇸Boston, Massachusetts, United States
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