| Protocol No: | ECCT/20/11/05 | Date of Protocol: | 05-12-2019 |
| Study Title: | A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Voxelotor (GBT440) in Pediatric Participants with Sickle Cell Disease (HOPE Kids 2) |
| Study Objectives: | Primary Objective
The primary objective is to evaluate the effect of voxelotor compared to placebo on the TCD time-averaged mean of the maximum velocity (TAMMV) arterial cerebral blood flow at 24 weeks in SCD participants ≥ 2 to < 15 years of age with conditional (170 to < 200 cm/sec) TCD flow velocity.
Secondary Objectives
The secondary objectives are to evaluate the effects of voxelotor compared to placebo on:
Exploratory Objectives
The exploratory objectives will assess the effect of voxelotor compared to placebo on:
Safety Objective The safety objective is to assess the safety and tolerability of voxelotor compared to placebo.
Pharmacokinetic Objective
The pharmacokinetic (PK) objective is to assess the PK of voxelotor as evaluated by PPK analysis.
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| Laymans Summary: | This application concerns a Phase 3 pediatric study (GBT440-032) in which it is proposed to show the effect of voxelotor compared to placebo on the transcranial doppler (TCD) time averaged maximum of the mean velocity (TAMMV) arterial cerebral blood flow at 24 weeks in sickle cell disease (SCD) participants ≥ 2 to < 15 years of age with conditional (170 cm/sec to < 200 cm/sec) TCD velocity. Voxelotor (formerly known as GBT440) is an orally administered small molecule that inhibits HbS polymerization by allosterically modifying hemoglobin-oxygen (Hb-O2) affinity and is being developed for the treatment of sickle cell disease (SCD). Voxelotor was designed to bind to HbS with preferential partitioning into RBCs. It binds covalently and reversibly via Schiff base to the N-terminal valine of the Hb α chain (ie, a single voxelotor molecule binding per HbS tetramer in a 1:1 stoichiometry) and allosterically (Eaton, 1999) increases HbS oxygen (O2) affinity (Oksenberg, 2016), stabilizing the oxyHb state and inhibiting polymerization (Oksenberg, 2016). The voxelotor binding site is distant from heme pockets and therefore it can increase O2 affinity without sterically blocking the release of O2. Details regarding GBT’s clinical development program for SCD are available in the most current version of the Investigator’s Brochure (Version 7.1). As of 05 November 2019, a total of 24 clinical development studies (5 studies in SCD, 2 studies in idiopathic pulmonary fibrosis (IPF), 15 clinical pharmacology studies, and 1 study of healthy participants under hypoxic conditions) and the expanded access program (which includes 1 clinical study) have enrolled approximately 823 unique participants. The 823 participants consist of 379 participants with SCD (257 adults and 122 pediatric participants), 378 healthy participants (including participants with severe renal impairment [not on dialysis] and participants with hepatic impairment), 43 adult participants with IPF, 23 participants from the expanded access program (6 adolescents and 17 adults), 15 participants from the GBT sponsored expanded access protocol, and 8 participants from single-patient investigational new drug (IND) access. Study GBT440-032 consists of 3 periods: • Screening: up to 35 days prior to randomization • Treatment: 96 weeks • Follow-Up: 28 days (4 weeks) after the last dose Approximately 224 participants aged ≥ 2 to < 15 years will be randomized 1:1 to voxelotor or placebo. Participants ≥ 12 years old will be administered a fixed dose of voxelotor 1500 mg per day. Participants younger than 12 years of age will receive voxelotor at a weight-based (1500 mg-equivalent) dose. At least 15 participants from 2 years to < 4 years of age will be enrolled. Administration of voxelotor will be initiated in participants < 4 years or age after the DSMB has reviewed safety and PK data from at least 12 participants < 30 kg treated with voxelotor for at least 28 days. These data for at least 12 participants may be generated from any voxelotor clinical studies. Following completion of study treatment, eligible participants will be given the option to enroll in an open label extension study (under a separate protocol) to receive voxelotor. |
| Abstract of Study: |
Investigational Product:
Voxelotor as 300 and 500 mg tablets or as 300, 400, 600, and 900 mg powder for oral suspension (packaged in stick pack pouches) Matching placebo
Number of Clinical Sites: The study will be conducted at approximately 50 international clinical sites.
Number of Study Participants: Approximately 224 participants with sickle cell disease (SCD), aged ≥ 2 to < 15 years.
Treatment: 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. Participants 12 years or older will take 1500 mg/day.
Participants will receive study drug as a tablet formulation or powder for oral suspension formulation (packaged in stick pack pouches). The tablet formulation is to be administered orally, once daily. Once swallowed, the tablet should be followed by drinking a liquid such as water. The powder for oral suspension formulation is to be dispersed in liquid and administered orally, once daily. Both dosage forms may be taken with or without food. The participant’s weight at screening will be used to determine their initial treatment dose. Dosing should be adjusted if the participant’s weight increases or decreases over 2 consecutive clinic visits. Participant’s weight will be measured and dose adjustments made as needed, as outlined in the protocol.
Objectives:
Primary Objective:
The primary objective is to evaluate the effect of voxelotor compared to placebo on the transcranial Doppler (TCD) time-averaged mean of the maximum velocity (TAMMV) arterial cerebral blood flow at 24 weeks in SCD participants ≥ 2 to < 15 years of age with conditional (170 to < 200 cm/sec) TCD flow velocity. Secondary Objectives: The secondary objectives are to evaluate the effects of voxelotor compared to placebo on:
Exploratory Objectives:
The exploratory objectives will assess the effect of voxelotor compared to placebo on:
Safety Objectives:
The safety objective is to assess the safety and tolerability of voxelotor compared to placebo. Pharmacokinetic Objectives: The pharmacokinetic (PK) objective is to assess the PK of voxelotor as evaluated by population pharmacokinetics (PPK) analysis. Study Design: The study will be conducted globally at approximately 50 clinical sites.
The study consists of 3 periods:
Screening: up to 35 days prior to randomization Treatment: 96 weeks Follow-Up: 28 days (4 weeks) after the last dose Approximately 224 participants aged 2 to < 15 years will be randomized 1:1 to voxelotor or placebo. Participants ≥ 12 years old will be administered a fixed dose of voxelotor 1500 mg/day. Participants younger than 12 years of age will receive voxelotor at a weight-based (1500 mg-equivalent) dose. Following completion of study treatment, eligible participants will be given the option to enroll in an open-label extension study (under a separate protocol) to receive voxelotor for a minimum of 3 years (3 years or until commercial product becomes available, whichever is longer). At the time of randomization, participants will be stratified by hydroxyurea (HU) use (yes/no), age (2 to ≤ 8 years; > 8 to < 15 years), Screening TCD flow velocity value (170 to < 185 cm/sec; 185 to < 200 cm/sec) and geographic region (Africa including Middle East and North Africa [MENA]; rest of world). Stratification of participants by age was chosen to evenly balance by age distribution using the expected median age of 8 years.
Dosing of participants between 2 and < 4 years of age:
At least 15 participants from 2 to < 4 years of age will be enrolled. Enrollment of participants <4 years of age will be initiated after the Data and Safety Monitoring Board (DSMB) has reviewed safety and PK data from at least 12 participants < 30 kg treated with voxelotor for at least 28 days. These data for at least 12 participants may be generated from any voxelotor clinical studies.
Duration of Study Participation: The duration of study involvement for an individual participant is expected to be approximately 105 weeks.
The study will end when the last participant’s last visit occurs.
Statistical Methods:
Primary Endpoint
The primary efficacy endpoint is the change from Baseline at 24 weeks in TAMMV arterial cerebral blood flow, as measured by TCD. Secondary Endpoints The secondary efficacy endpoints are as follows:
Exploratory Endpoints:
The exploratory endpoints are as follows:
Safety Endpoints
The safety endpoints include adverse events (AEs), clinical laboratory assessments, and vital signs. Pharmacokinetic Endpoint The endpoint is whole blood and plasma voxelotor PK as evaluated by PPK analysis using nonlinear mixed effects modeling.
Sample Size
The sample size is planned to provide sufficient statistical power for the primary efficacy analysis and for a robust safety database. In addition, the number of events required to assess secondary efficacy endpoints, eg, percentage conversion to abnormal TCD category, is also considered. For the primary endpoint (change from Baseline in TCD flow velocity [cm/sec]), assuming equal allocation across treatment groups and a common variance, an estimate of the number of participants in each of 2 treatment groups used the following assumptions in the power calculation:
Assuming a 20% drop out rate, a sample size of 112 participants per group provides > 95% power to detect the targeted treatment effect for the following hypothesis test using a Student’s t-test:
H0:µ1=µ2 vs. HA:µ1≠µ2
where µ1 and µ2 stand for mean change from Baseline in TCD flow velocity at Week 24 in voxelotor and placebo groups, respectively. For the secondary efficacy endpoint of percentage conversion to abnormal TCD category, assuming 35% of participant in the placebo group have experienced a TCD flow velocity > 200 cm/sec by Week 96, a hazard ratio of 0.5 between voxelotor group and placebo, a fixed follow up time of up to 96 weeks for each participant, and an overall 20% drop out rate, a total of 49 events is expected. This provides approximately 65% power for a log-rank test at a two-sided significance level of 5% and approximately 75% power at a two-sided significance level of 10% (PASS version 11).
Efficacy Analyses
The primary analysis of change in TCD flow velocity from Baseline to Week 24 will be performed using a mixed model for repeated measures (MMRM). Independent variables will include treatment, study visit, treatment by study visit interaction, and randomization stratification factors (ie, HU use, age, Screening TCD flow velocity, and geographic region). Within-subject variability will be modeled using an unstructured covariance matrix. The secondary endpoints will be analyzed as described below.
Safety and Tolerability Analyses
Safety analysis will be performed on all participants receiving at least one dose of study drug. Adverse events will be classified according to the Medical Dictionary for Regulatory Activities (MedDRA). The incidence of treatment-emergent adverse events (TEAEs), defined as an event that occurs on or after Day 1 of study treatment or the worsening of a preexisting condition on or after Day 1 of study treatment, will be tabulated by System Organ Class (SOC), preferred term, severity, and relationship to study drug. Changes in laboratory parameters (hematology, serum chemistry, and liver function tests) and vital signs (eg, blood pressure [BP], pulse, and body temperature) over time will be summarized descriptively. SCD-related AEs will be collected and summarized separately (including vaso-occlusive crisis [VOC], acute chest syndrome, osteonecrosis, priapism, etc.) Pharmacokinetic Analyses PPK analysis will consist of all participants who receive active study drug and have at least one measured concentration at a scheduled PK time point after the start of dosing. If any participants are found to be noncompliant with respect to dosing or have incomplete data, protocol deviations, or clinical events that affect PK, a decision will be made on a case-by-case basis as to their inclusion in the analysis. Participants in this population will be used for all PK summaries. PPK analyses using nonlinear mixed effects modeling will be performed to characterize voxelotor PK in plasma and whole blood. The influence of demographic covariates (such as body weight, height, age, gender) on voxelotor PK parameters (ie, clearance [CL] and volume of distribution) will be investigated. If appropriate, the voxelotor PK data may be pooled with PK data from other studies. Continuous variables will be descriptively summarized using mean, standard deviation (SD), coefficient of variation (CV%, as appropriate), median, minimum, maximum, and, as appropriate, geometric mean. Categorical variables will be descriptively summarized by presenting the number (frequency) and percentage in each category. |