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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Drug: Voxelotor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants with homozygous hemoglobin SS (HbSS) or hemoglobin S beta0 thalassemia (HbS β0thal) 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 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Voxelotor<br>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) | Drug: Voxelotor<br>* Part A: Voxelotor will be administered as oral capsules or tablets Part B: Voxelotor will be administered as oral capsules or tablets Part C: Voxelotor will be administered as oral dispersible tablets or powder for oral suspension Part D: Voxelotor will be administered as oral dispersible tablets or powder for oral suspension<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Pharmacokinetic profile of voxelotor including maximum concentration | Maximum observed concentration (Cmax), area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-last), and area under the concentration-time curve from time zero extrapolated to infinity (AUC0-inf) of voxelotor in whole blood | Pre-dose to Day 15 | 
| Part A: Pharmacokinetic profile of voxelotor including the time taken to reach the maximum concentration | Maximum observed concentration (Cmax), area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-last), and area under the concentration-time curve from time zero extrapolated to infinity (AUC0-inf) of voxelotor in whole blood | Pre-dose to Day 15 | 
| Part A: Pharmacokinetic profile of voxelotor including the total drug concentration over time | Maximum observed concentration (Cmax), area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-last), and area under the concentration-time curve from time zero extrapolated to infinity (AUC0-inf) of voxelotor in whole blood | Pre-dose to Day 15 | 
| Part B: Change in hemoglobin | Change from baseline to Week 24 in Hb | Baseline to Week 24 | 
| Part C: Change in cerebral blood flow as measured by the TAMM TCD velocity | Change from baseline to 12 and 24 weeks in cerebral blood flow as measured by the time-averaged mean of the maximum (TAMM) TCD velocity | Baseline to Week 48 | 
| Part D: Treatment-Emergent Adverse Events and Serious Adverse Events | Participants will be monitored throughout the study for AEs, from the time informed consent is obtained through the EOS visit. The Investigator will assess each AE for seriousness, intensity and relationship to investigational product. | Baseline to Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Number of participants with treatment-related adverse events as assessed by CTCAE v4.03 |  | Days 1 - 15 | 
| Part B: Multiple Dose effect on Clinical Measures of Hemolysis |  | Day 1 - Week 24 | 
| Part B: Pharmacokinetic profile of voxelotor including maximum concentration |  | Pre-dose to Week 24 | 
| Part B: Pharmacokinetic profile of voxelotor including the time taken to reach the maximum concentration |  | Pre-dose to Week 24 | 
| Part B: Pharmacokinetic profile of voxelotor including the total drug concentration over time |  | Pre-dose to Week 24 | 
| Part C: Multiple dose effect on clinical measures of hemolysis |  | Baseline to Week 24 and Week 48 | 
| Part C: Change in cerebral blood flow as measured by TAMM TCD velocity |  | Baseline to Week 24 | 
| Part C: Time to initial Hemoglobin response | Change from baseline in Hb > 1g/dL | Baseline to Week 48 | 
| Part C: Pharmacokinetic profile of voxelotor including percent Hemoglobin occupancy |  | Baseline to Week 48 | 
| Part C: Proportion of participants with normal TCD flow velocity |  | Baseline to Week 48 | 
| Part C: Incidence of stroke and VOC |  | Baseline to Week 48 | 
| Part D: Pharmacokinetic profile of voxelotor including percent Hemoglobin occupancy |  | Baseline to Week 48 | 
| Part D: Change in Hemoglobin |  | Baseline to Week 24 and Week 48 | 
| Part D: Change in Lactate Dehydrogenase |  | Baseline to Week 24 and Week 48 | 
| Part D: Change in Indirect Bilirubin |  | Baseline to Week 24 and Week 48 | 
| Part D: Change in Reticulocyte Count |  | Baseline to Week 24 and Week 48 | 
| Part D: Time to initial Hemoglobin response | Change from baseline in Hb > 1g/dL | Baseline to Week 48 | 
| Part D: Incidence of stroke and VOC |  | Baseline to Week 48 |