NCT02850406终止2 期
A Phase 2a, Open-label, Single and Multiple Dose Study to Evaluate the Pharmacokinetics, Safety, Tolerability and Treatment Effect of GBT440 in Pediatric Participants With Sickle Cell Disease
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- Pfizer
- 入组人数
- 147
- 试验地点
- 20
- 主要终点
- Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor in Whole Blood
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 6 Months 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female participants with homozygous hemoglobin SS (HbSS) or hemoglobin S beta0 thalassemia (HbS β0thal)
- •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
- •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.
- •Hemoglobin (HB):
- •Part A - No restriction
- •Parts B, C, & D - Hb ≤ 10.5 g/dL
- •For Part C only: Participants 12 to 17 years of age must have a TCD velocity of ≥ 140 cm/sec measured anytime during screening.
排除标准
- •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
- •Requires chronic transfusion therapy
- •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).
- •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.
研究组 & 干预措施
Voxelotor
Experimental
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)
干预措施: Voxelotor (Drug)
结局指标
主要结局
Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor in Whole Blood
时间窗: 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)
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: Baseline, Week 24
Part C: Change From Baseline to Week 48 in Cerebral Blood Flow
时间窗: 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.
次要结局
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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))
- 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)
- Part D: Time to Initial Hemoglobin Response(From first dose of study treatment (Day 1) up to Week 48)
- 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)
- 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)
- Part A: Percentage Hemoglobin (Hb) Occupancy(15 days)
- Part B: Percentage of Days With SCD Symptom Exacerbation During the First 24 Weeks of Treatment(From Day 1 up to 24 weeks)
- 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)
- 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)
- Part C: Time to Initial Hemoglobin Response(From first dose of study treatment (Day 1) up to Week 48)
- Part B: Change From Baseline to Week 12 and 24 in Cerebral Blood Flow(Baseline, Weeks 12 and 24)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- Part C: Percentage Hemoglobin Occupancy of Voxelotor(Day 28)
- Part C: Percentage of Participants With Normal Transcranial Doppler (TCD) Flow Velocity at Week 48(Week 48)
- Part C: Annualized Incidence Rate of Stroke Events(Up to Week 48)
- 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)
研究者
研究点 (20)
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