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

Phase 2TerminatedNCT02850406

Pfizer147 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

147

Conditions

Sickle Cell Disease

Interventions

* 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

Eligibility

Sex: ALLMin age: 6 MonthsMax age: 17 Years

Medical Language ↔ Plain English

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.

Locations (20)

Brentwood Clinic UCSF Benioff Children's Hospital Oakland

Brentwood, California, United States

Children's National Medical Center

Washington D.C., 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

...and 10 more locations

Outcomes

Primary Outcomes

Part A: Maximum Concentration (Cmax) of Voxelotor in Whole Blood

Time frame: 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

AUC0-last was calculated using the linear/log trapezoid rule.

Time frame: 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 Extrapolated to Infinity (AUC0-inf) of Voxelotor in Whole Blood

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.

Time frame: pre-dose, 2, 8, 24, 48, 96,168 and 336 hours post-dose

Part B: Change From Baseline to Week 24 in Hemoglobin Level

Time frame: Baseline, Week 24

Part C: Change From Baseline to Week 48 in Cerebral Blood Flow

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.

Time frame: Baseline, Week 48

Part D: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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.

Time frame: From start of study treatment up to 28 days after study treatment discontinuation (Up to 52 weeks)

Secondary Outcomes

Part A: Maximum Concentration (Cmax) of Voxelotor in Plasma

Time frame: pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose

Part A: Maximum Concentration (Cmax) of Voxelotor in Red Blood Cells (RBC)

Time frame: 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

AUC0-last was calculated using the linear/log trapezoid rule.

Time frame: 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

AUC0-last was calculated using the linear/log trapezoid rule.

Time frame: 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 Extrapolated to Infinity (AUC0-inf) of Voxelotor in Plasma

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.

Time frame: 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 Extrapolated to Infinity (AUC0-inf) of Voxelotor in RBC

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.

Time frame: 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

Time frame: 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

T1/2 was the time measured for the drug concentration to decrease by one half.

Time frame: 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

T1/2 was the time measured for the drug concentration to decrease by one half.

Time frame: 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

T1/2 was the time measured for the drug concentration to decrease by one half.

Time frame: pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose

Part A: Percentage Hemoglobin (Hb) Occupancy

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.

Time frame: 15 days

Part B: Percentage of Days With SCD Symptom Exacerbation During the First 24 Weeks of Treatment

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.

Time frame: From Day 1 up to 24 weeks

Part B: Change From Baseline to Week 21 to 24 in the Sickle Cell Disease Severity Measure (SCDSM) Total Symptom Score (TSS)

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.

Time frame: Baseline, Weeks 21 to 24

Part B: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor for Whole Blood and Plasma

Time frame: 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

T1/2 was the time measured for the drug concentration to decrease by one half.

Time frame: 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

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.

Time frame: Day 1 (0 to 24 hours post-dose) and Day 28 (0 to 24 hours post-dose)

Part B: Percentage Hemoglobin Occupancy

Time frame: Day 28

Part B: Change From Baseline to Week 12 and 24 in Cerebral Blood Flow

Cerebral blood flow was measured using TCD sonography. Change from baseline in cerebral blood flow as measured by TAMM TCD velocity is reported.

Time frame: Baseline, Weeks 12 and 24

Part C: Change From Baseline to Week 24 in Cerebral Blood Flow

Cerebral blood flow was measured using TCD sonography. Change from baseline in cerebral blood flow as measured by TAMM TCD velocity is reported.

Time frame: Baseline, Week 24

Part C: Time to Initial Hemoglobin Response

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).

Time frame: From first dose of study treatment (Day 1) up to Week 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

Time frame: 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

T1/2 was the time measured for the drug concentration to decrease by one half.

Time frame: 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

Time frame: Day 28

Part C: Percentage of Participants With Normal Transcranial Doppler (TCD) Flow Velocity at 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.

Time frame: Week 48

Part C: Annualized Incidence Rate of Vaso-occlusive Crisis (VOC) Events

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.

Time frame: Up to Week 48

Part C: Annualized Incidence Rate of Stroke Events

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.

Time frame: Up to Week 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

Time frame: 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: T1/2 of Voxelotor for Plasma and Whole Blood

T1/2 was the time measured for the drug concentration to decrease by one half.

Time frame: 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

Time frame: Day 28

Part D: Time to Initial Hemoglobin Response

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.

Time frame: From first dose of study treatment (Day 1) up to Week 48

Part D: Annualized Incidence Rate of VOC Events

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.

Time frame: Up to Week 48

Part D: Annualized Incidence Rate of Stroke Events

Time frame: Up to Week 48