Study to Evaluate the Effect of GBT440 in Pediatrics With Sickle Cell Disease
- Registration Number
- NCT02850406
- Lead Sponsor
- Pfizer
- Brief Summary
This study consists of four parts, Parts A, B, C, and D.
* Part A is a single dose pharmacokinetic (PK) study in pediatric participants with Sickle Cell Disease ages 6 to 17 years.
* Part B is a multiple dose, safety, exploratory, efficacy, and PK study in adolescent participants with Sickle Cell Disease ages 12 to 17 years.
* Part C is a multiple dose, safety, tolerability, and PK study, which includes the assessment of hematological effects and the effect on TCD flow velocity of voxelotor in pediatric participants with Sickle Cell Disease ages 4 to 17 years.
* Part D is a multiple dose, safety, tolerability, and PK study, which examines the hematological effects of voxelotor in pediatric participants with Sickle Cell Disease ages 6 months to \< 4 years.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 147
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Male or female participants with homozygous hemoglobin SS (HbSS) or hemoglobin S beta0 thalassemia (HbS β0thal)
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Age:
- Part A - 6 to 17 years of age
- Part B - 12 to 17 years of age
- Part C - 4 to 17 years of age
- Part D - 6 months to <4 years of age
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Hydroxyurea (HU) therapy:
- Parts A, B, and C: A participant taking hydroxyurea (HU) may be enrolled if the dose has been stable for at least 3 months with no anticipated need for dose adjustment during the study and no sign of hematological toxicity.
- Part D: A participant taking HU may be enrolled if the dose has been stable for at least 1 month. Titration to the maximum tolerated dose (MTD) is allowed during the study.
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Hemoglobin (HB):
- Part A - No restriction
- Parts B, C, & D - Hb ≤ 10.5 g/dL
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For Part C only: Participants 12 to 17 years of age must have a TCD velocity of ≥ 140 cm/sec measured anytime during screening.
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Any one of the following requiring medical attention within 14 days of signing the Informed Consent Form (ICF):
- Vaso-occlusive crisis (VOC)
- Acute chest syndrome (ACS)
- Splenic sequestration crisis
- Dactylitis
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Requires chronic transfusion therapy
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History of stroke or meeting criteria for primary stroke prophylaxis (history of two TCD measurements ≥ 200 cm/sec by non-imaging TCD or ≥185 cm/sec by TCDi).
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Transfusion within 30 days prior to signing the ICF
Exclusion Criteria for Part D Only:
- Body weight <5 kg for 1 month prior to the screening visit and at the screening visit.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Voxelotor Voxelotor Subjects to receive daily oral dosing of voxelotor according to which Part (A, B, C, or D), the subject is participating in: * Part A: Subjects to receive daily oral dosing of voxelotor for 1 day (single dose) * Part B: Subjects to receive daily oral dosing of voxelotor for up to 24 weeks (multiple dose) * Part C: Subjects to receive daily oral dosing of voxelotor for up to 48 weeks (1500mg or 1500mg equivalent dose) * Part D: Subjects to receive daily oral dosing of voxelotor for up to 48 weeks (1500mg equivalent dose)
- Primary Outcome Measures
Name Time Method Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor in Whole Blood pre-dose, 2, 8, 24, 48, 96,168 and 336 hours post-dose AUC0-inf was calculated as AUCt + Ct/lambdaz, where AUCt=area under the concentration-time curve at designated time, Ct is the last quantifiable concentration for whole blood and lambdaz=elimination rate constant.
Part D: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) From start of study treatment up to 28 days after study treatment discontinuation (Up to 52 weeks) An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product during the course of a clinical investigation. TEAE was defined as an AE that emerged on or after initiation of study drug (having been absent pre-treatment), or an AE that existed pre-treatment and worsened on treatment (relative to the pre-treatment state) through 28 days after study drug discontinuation. An SAE was any AE that resulted in any of the following outcomes: death, life threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, congenital anomaly or birth defect, other important medical events. AEs were classified as SCD-related and non-SCD related.
Part A: Maximum Concentration (Cmax) of Voxelotor in Whole Blood pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Voxelotor in Whole Blood pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose AUC0-last was calculated using the linear/log trapezoid rule.
Part B: Change From Baseline to Week 24 in Hemoglobin Level Baseline, Week 24 Part C: Change From Baseline to Week 48 in Cerebral Blood Flow Baseline, Week 48 Cerebral blood flow was measured using transcranial Doppler (TCD) sonography. Change from baseline in cerebral blood flow as measured by the time-averaged mean of the maximum (TAMM) TCD velocity is reported.
- Secondary Outcome Measures
Name Time Method Part A: Maximum Concentration (Cmax) of Voxelotor in Red Blood Cells (RBC) pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose Part C: Percent Change From Baseline to Weeks 24 and 48 in Indirect Bilirubin Baseline, Weeks 24 and 48 Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor in Plasma pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose AUC0-inf was calculated as AUCt + Ct/lambdaz, where AUCt=area under the concentration-time curve at designated time, Ct is the last quantifiable concentration for plasma and lambdaz is the elimination rate constant.
Part A: Time at Which Cmax Was Observed (Tmax) for Voxelotor in Plasma pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose Part A: Terminal Elimination Half-Life (T1/2) for Voxelotor in Whole Blood pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose T1/2 was the time measured for the drug concentration to decrease by one half.
Part A: Terminal Elimination Half-Life (T1/2) for Voxelotor in Plasma pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose T1/2 was the time measured for the drug concentration to decrease by one half.
Part A: Maximum Concentration (Cmax) of Voxelotor in Plasma pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Voxelotor in Plasma pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose AUC0-last was calculated using the linear/log trapezoid rule.
Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Voxelotor in RBC pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose AUC0-last was calculated using the linear/log trapezoid rule.
Part B: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor for Whole Blood and Plasma Day 1 (pre-dose, 2, 8, 24 hours post-dose), pre-dose on Weeks 2, 4, 8, 12, 16, 20 and 24 AUC0-inf was calculated as AUCt + Ct/lambdaz, where AUCt=area under the concentration-time curve at designated time, Ct is the last quantifiable concentration and lambdaz is the elimination rate constant.
Part B: Terminal Elimination Half-life of Voxelotor for Plasma and Whole Blood Day 1 (pre-dose, 2, 8, 24 hours post-dose), pre-dose on Weeks 2, 4, 8, 12, 16, 20 and 24 T1/2 was the time measured for the drug concentration to decrease by one half.
Part B: Accumulation Ratio (Rac) of Voxelotor for Plasma and Whole Blood Day 1 (0 to 24 hours post-dose) and Day 28 (0 to 24 hours post-dose) Accumulation ratio was calculated as ratio of area under the concentration-time curve from time 0 to 24 hours (AUC0-24) at steady-state (Day 28) to AUC0-24 on Day 1.
Part D: T1/2 of Voxelotor for Plasma and Whole Blood Day 1 (anytime between 15 minutes to 2 hours post-dose), pre-dose on Weeks 2, 8, 12, 16, 24, 36 and 48 T1/2 was the time measured for the drug concentration to decrease by one half.
Part D: Time to Initial Hemoglobin Response From first dose of study treatment (Day 1) up to Week 48 Time to initial Hb response, defined as the time from first dose of study treatment to the first occurrence of a change from baseline in Hb \> 1 g/dL.
Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor in RBC pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose AUC0-inf was calculated as AUCt + Ct/lambdaz, where AUCt=area under the concentration-time curve at designated time, Ct is the last quantifiable concentration and lambdaz is the elimination rate constant.
Part A: Time at Which Cmax Was Observed (Tmax) for Voxelotor in Whole Blood pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose Part A: Time at Which Cmax Was Observed (Tmax) for Voxelotor in RBC pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose Part A: Terminal Elimination Half-Life (T1/2) for Voxelotor in RBC pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose T1/2 was the time measured for the drug concentration to decrease by one half.
Part A: Percentage Hemoglobin (Hb) Occupancy 15 days Percentage hemoglobin occupancy (% Hb Occupancy) refers to the percentage of hemoglobin molecules within red blood cells that were bound to study drug. Concentration of voxelotor in whole blood and plasma was used to calculate %Hb occupancy. Percentage Hb occupancy within RBCs was estimated using the formula:
(\[Concentration of voxelotor in whole blood- {1-hematocrit}\]\*\[Concentration of voxelotor in plasma/hematocrit\])/5000\*100.Part B: Percentage of Days With SCD Symptom Exacerbation During the First 24 Weeks of Treatment From Day 1 up to 24 weeks SCD symptoms were measured using the Patient Reported Outcome (PRO), Sickle Cell Disease Severity Measure (SCDSM) which was a self-administered 9-item questionnaire of SCD core symptoms including pain severity, frequency, and type, as well as fatigue and mental acuity, on a 4-point response scale that was completed daily using a handheld electronic device by the participants.
Part B: Percent Change From Baseline to Weeks 12 and 24 in Lactate Dehydrogenase (LDH) Baseline, Weeks 12 and 24 Part B: Percent Change From Baseline to Weeks 12 and 24 in Percentage Reticulocytes Baseline, Weeks 12 and 24 Part B: Cmax of Voxelotor in Whole Blood and Plasma Day 1 (pre-dose, 2, 8, 24 hours post-dose), pre-dose on Weeks 2, 4, 8, 12, 16, 20 and 24 Part B: Change From Baseline to Week 21 to 24 in the Sickle Cell Disease Severity Measure (SCDSM) Total Symptom Score (TSS) Baseline, Weeks 21 to 24 The SCDSM was a self-administered 9-item questionnaire of SCD core symptoms including pain severity, frequency, and type, as well as fatigue and mental acuity, on a 4-point response scale with a range of 0 (strongly disagree) to 4 (strongly agree) that was completed daily using a handheld electronic device by the participants. TSS was calculated as the sum of the 9-item questionnaire scores scaled to a 100-point scale with a range of 0 (no symptoms) to 100 (most severe symptoms). Baseline TSS was the average of the non-missing score during the Screening period. The average of change from baseline in SCDSM TSS score for the 4-week period (Week 21 to 24) is reported.
Part B: Percent Change From Baseline to Weeks 12 and 24 in Indirect Bilirubin Baseline, Weeks 12 and 24 Part B: Percentage Hemoglobin Occupancy Day 28 Percentage hemoglobin occupancy (% Hb Occupancy) refers to the percentage of hemoglobin molecules within red blood cells that were bound to study drug. Concentration of voxelotor in whole blood and plasma was used to calculate %Hb occupancy. Percentage Hb occupancy within RBCs was estimated using the formula:
(\[Concentration of voxelotor in whole blood- {1-hematocrit}\]\*\[Concentration of voxelotor in plasma/hematocrit\])/5000\*100.Part C: Time to Initial Hemoglobin Response From first dose of study treatment (Day 1) up to Week 48 Time to initial Hb response was defined as the time from first dose of study treatment to the first occurrence of a change from baseline in Hb \> 1 gram per deciliter (g/dL).
Part B: Change From Baseline to Week 12 and 24 in Cerebral Blood Flow Baseline, Weeks 12 and 24 Cerebral blood flow was measured using TCD sonography. Change from baseline in cerebral blood flow as measured by TAMM TCD velocity is reported.
Part C: Percent Change From Baseline to Weeks 24 and 48 in LDH Baseline, Weeks 24 and 48 Part C: Annualized Incidence Rate of Vaso-occlusive Crisis (VOC) Events Up to Week 48 VOC events included preferred terms of sickle cell anaemia with crisis, acute chest syndrome, pneumonia necrotising and pneumonia. Annualized incidence rate was calculated as total number of events divided by total person years. Total person years=sum of participants treatment period in years, which covered the time from first dose to last dose.
Part D: Cmax of Voxelotor for Plasma and Whole Blood Day 1 (anytime between 15 minutes to 2 hours post-dose), pre-dose on Weeks 2, 8, 12, 16, 24, 36 and 48 Part D: Percentage Hemoglobin Occupancy Day 28 Percentage hemoglobin occupancy (% Hb Occupancy) refers to the percentage of hemoglobin molecules within red blood cells that were bound to study drug. Concentration of voxelotor in whole blood and plasma was used to calculate %Hb occupancy. Percentage Hb occupancy within RBCs was estimated using the formula:
(\[Concentration of voxelotor in whole blood- {1-hematocrit}\]\*\[Concentration of voxelotor in plasma/hematocrit\])/5000\*100.Part D: Percent Change From Baseline to Weeks 24 and 48 in LDH Baseline, Weeks 24 and 48 Part D: Percent Change From Baseline to Weeks 24 and 48 in Indirect Bilirubin Baseline, Weeks 24 and 48 Part D: Annualized Incidence Rate of Stroke Events Up to Week 48 Annualized incidence rate was calculated as total number of events divided by total person years. Total person years=sum of participants treatment period in years, which covered the time from first dose to last dose.
Part C: Change From Baseline to Weeks 24 and 48 in Hemoglobin Level Baseline, Weeks 24 and 48 Part C: Change From Baseline to Week 24 in Cerebral Blood Flow Baseline, Week 24 Cerebral blood flow was measured using TCD sonography. Change from baseline in cerebral blood flow as measured by TAMM TCD velocity is reported.
Part C: Cmax of Voxelotor for Plasma and Whole Blood Day 1 (15 minutes to 2 hours post-dose), pre-dose on Weeks 4, 8, 12, 16, 20, 24, 36 and 48 Part D: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor for Plasma and Whole Blood Day 1 (anytime between 15 minutes to 2 hours post-dose), pre-dose on Weeks 2, 8, 12, 16, 24, 36 and 48 AUC0-inf was calculated as AUCt + Ct/lambdaz, where AUCt=area under the concentration-time curve at designated time, Ct is the last quantifiable concentration and lambdaz is the elimination rate constant.
Part D: Change From Baseline to Weeks 24 and 48 in Hemoglobin Level Baseline, Weeks 24 and 48 Part C: Percent Change From Baseline to Weeks 24 and 48 in Percentage Reticulocytes Baseline, Weeks 24 and 48 Part C: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor for Whole Blood and Plasma Day 1 (15 minutes to 2 hours post-dose), pre-dose on Weeks 4, 8, 12, 16, 20, 24, 36 and 48 AUC0-inf was calculated as AUCt + Ct/lambdaz, where AUCt=area under the concentration-time curve at designated time, Ct is the last quantifiable concentration and lambdaz is the elimination rate constant.
Part C: Terminal Elimination Half-life (T1/2) of Voxelotor for Whole Blood and Plasma Day 1 (15 minutes to 2 hours post-dose), pre-dose on Weeks 4, 8, 12, 16, 20, 24, 36 and 48 T1/2 was the time measured for the drug concentration to decrease by one half.
Part C: Percentage Hemoglobin Occupancy of Voxelotor Day 28 Percentage hemoglobin occupancy (% Hb Occupancy) refers to the percentage of hemoglobin molecules within red blood cells that were bound to study drug. Concentration of voxelotor in whole blood and plasma was used to calculate %Hb occupancy. Percentage Hb occupancy within RBCs was estimated using the formula:
(\[Concentration of voxelotor in whole blood- {1-hematocrit}\]\*\[Concentration of voxelotor in plasma/hematocrit\])/5000\*100.Part C: Percentage of Participants With Normal Transcranial Doppler (TCD) Flow Velocity at Week 48 Week 48 Normal TCD flow velocity was considered as \< 170 centimeter per second (cm/sec) by non-imagining TCD or \< 155 cm/sec by imaging transcranial Doppler (TCDi). Percentage of participants with normal TCD flow velocity at Week 48 by Baseline TCD group (i.e. Baseline normal TCD \[\<170 cm/sec\] and Baseline conditional TCD \[\>=170 cm/sec\] is reported.
Part C: Annualized Incidence Rate of Stroke Events Up to Week 48 Annualized incidence rate was calculated as total number of events divided by total person years. Total person years=sum of participants treatment period in years, which covered the time from first dose to last dose.
Part D: Percent Change From Baseline to Weeks 24 and 48 in Reticulocytes Count Baseline, Weeks 24 and 48 Part D: Annualized Incidence Rate of VOC Events Up to Week 48 VOC events included preferred terms of 'Sickle cell anemia with crisis', 'Acute chest syndrome', 'Pneumonia necrotising,' and 'Pneumonia. Annualized incidence rate was calculated as total number of events divided by total person years. Total person years=sum of participants treatment period in years, which covered the time from first dose to last dose.
Trial Locations
- Locations (20)
Brentwood Clinic UCSF Benioff Children's Hospital Oakland
🇺🇸Brentwood, California, United States
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
Children's Healthcare of Atlanta Scottish Rite
🇺🇸Atlanta, Georgia, United States
Ann & Robert H. Lurie Children's Hospital of Chicago
🇺🇸Chicago, Illinois, United States
University of Illinois at Chicago Clinical Research Center
🇺🇸Chicago, Illinois, United States
Our Lady of the Lake Children's Hospital (IP Address)
🇺🇸Baton Rouge, Louisiana, United States
Children's Mercy Hospital
🇺🇸Kansas City, Missouri, United States
Rutgers-Robert Wood Johnson Medical School
🇺🇸New Brunswick, New Jersey, United States
Brody School of Medicine at East Carolina University
🇺🇸Greenville, North Carolina, United States
University Hospitals Cleveland Medical Center, Rainbow Babies & Children's Hospital
🇺🇸Cleveland, Ohio, United States
Scroll for more (10 remaining)Brentwood Clinic UCSF Benioff Children's Hospital Oakland🇺🇸Brentwood, California, United States