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

Phase 3TerminatedNCT04218084

Pfizer236 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

236

Conditions

Sickle Cell Disease

Interventions

VoxelotorDRUG

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

PlaceboDRUG

Matching placebo.

Eligibility

Sex: ALLMin age: 2 YearsMax age: 14 Years

Medical Language ↔ Plain English

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

Locations (29)

Outcomes

Primary Outcomes

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

Secondary Outcomes

Change From Baseline in Transcranial Doppler (TCD) Flow Velocity at Week 48.

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 frame: From treatment initiation till study completion

Time to Conversion to Abnormal TCD Flow

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 frame: From treatment initiation till study completion

Time to Reversion to Normal TCD Flow

Time to first normal TCD flow was the number of weeks from randomization to the date of first normal (\<170 cm/sec) TCD flow.

Time frame: From treatment initiation till study completion

Percentage of Participants With TCD Flow Velocity Reduction Greater Than or Equal to (>=)15 cm/Sec at Weeks 24 and 48

Data from ClinicalTrials.gov

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Children's National Medical Center

Washington D.C., 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

University of Mississippi Medical Center

Jackson, Mississippi, United States

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Medical University of South Carolina

Charleston, South Carolina, United States

Texas Children's Hospital- Wallace Tower

Houston, Texas, United States

Alexandria Clinical Research Center, Faculty of Medicine, Alexandria University

Alexandria, Egypt

Zagazig University Hospital

Alexandria, Egypt

...and 19 more locations

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).

Time frame: From treatment initiation till study completion

Change From Baseline in Hemoglobin (Hb) at Weeks 24 and 48

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.

Time frame: From treatment initiation till study completion

Percent Change From Baseline in Unconjugated Bilirubin at Weeks 24 and 48

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.

Time frame: From treatment initiation till study completion

Percent Change From Baseline in Reticulocyte at Weeks 24 and 48

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.

Time frame: From treatment initiation till study completion

Percent Change From Baseline in Absolute Reticulocyte at Weeks 24 and 48

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.

Time frame: From treatment initiation till study completion

Percent Change From Baseline in Lactate Dehydrogenase (LDH) at Weeks 24 and 48

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.

Time frame: From treatment initiation till study completion

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.

Time frame: From treatment initiation till study completion