Voxelotor Neurocognitive Function Study

A Phase 3b, Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Treatment Effect of Voxelotor on Neurocognitive Function in Pediatric Participants 8 to < 18 Years of Age With Sickle Cell Disease

This is a Phase 3b, randomized, double-blind, placebo-controlled, multicenter study to assess the treatment effect of voxelotor on neurocognitive function as assessed by the National Institute of Health (NIH) Toolbox Cognition Module of executive abilities in pediatric participants (8 to < 18 years) with SCD.

Study Overview

• Status: Terminated
• Conditions: Sickle Cell Disease
• Intervention / Treatment: Drug: Voxelotor Only Product in Oral Dose Form; Drug: Placebo

Detailed Description

Eligible participants will receive daily treatment with 1500 mg voxelotor or matching placebo for 12 weeks. During screening and at the end of 12 weeks participants will undergo a series of tests to measure the change in neurocognitive functions.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 17 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female participants with confirmed diagnosis of SCD (all genotypes). Documentation of SCD genotype is required and may be based on documented history of laboratory testing or confirmed by laboratory testing during Screening.
2. Aged 8 to < 18 years.
3. Screening Hb level 5.5 to 10.5 g/dL.
4. Able to answer NIH Toolbox Module questions validated and normed based on age and maternal education on tablet.
5. If participant is receiving HU they must have been on a stable dose for at least 90 days prior to signing the ICF/AF, with no dose modifications or initiation of HU planned or anticipated by the Investigator.
6. If participant is receiving erythropoiesis-stimulating agents (ESAs) they must have been on a stable dose for at least 12 weeks before enrollment with no dose modifications planned or anticipated by the Investigator.
7. Participants, who if female and of child-bearing potential, agree to use highly effective methods of contraception from study start to 30 days after the last dose of study drug and who if male, agree to use barrier methods of contraception and refrain from donating sperm from study start to 30 days after the last dose of study drug.
8. Females of child-bearing potential must have a negative pregnancy test before the administration of study drug.
9. Parental/guardian consent and participant assent (between ≥ 12 and < 18 years) per Institutional Review Board (IRB)/Independent ethics committee (IEC) policy and requirements, consistent with International Council for Harmonisation (ICH) guidelines.
10. Capable of complying with the requirements and restrictions in the protocol, and willing to participate in the study.

Exclusion Criteria:

1. Receiving chronic transfusion therapy.
2. Red blood cell (RBC) transfusion within 3 months before initiation of study drug or receives scheduled RBC transfusion therapy (also termed chronic, prophylactic, or preventive transfusion).
3. History of overt stroke including hemorrhagic stroke or transient ischemic attack (TIA) or spinal cord injury, magnetic resonance angiography (MRA)-defined vasculopathy, or magnetic resonance imaging (MRI)/transcranial doppler (TCD)-documented silent cerebral infarcts.
4. Congenital brain malformation, previously diagnosed severe developmental disability (eg, autism and/or intelligence quotient [IQ] < 60, and/or severe attention deficit hyperactivity disorder [ADHD]), or impairment that would prevent the use of a computer tablet.
5. Participant is taking or has received voxelotor (Oxbryta®) within 90 days prior to the Screening Visit.
6. Surgery within 8 weeks before Day 1 or planned elective surgery during the study.
7. Anemia due to bone marrow failure (eg, myelodysplasia).
8. Absolute reticulocyte count (ARC) < 100 × 10^9/L.
9. Screening alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 4× upper limit of normal (ULN).
10. Severe renal dysfunction (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m^2) or is on chronic dialysis.

11. Clinically significant bacterial, fungal, parasitic, or viral infection which requires therapy.

    1. Patients with acute bacterial infection requiring antibiotic use should delay screening /enrollment until the course of antibiotic therapy has been completed.
    2. Patients with known active hepatitis A, B, or C or who are known to be human immunodeficiency virus (HIV) positive.
12. Symptomatic coronavirus disease of 2019 (COVID-19) infection.
13. Females who are breast-feeding or pregnant.
14. History of hematopoietic stem cell transplant or gene therapy.
15. Participants taking concomitant medications such as sensitive cytochrome P450 (CYP)3A4 substrates with a narrow therapeutic range, or strong CYP3A4 inducers
16. Participated in another clinical trial of an investigational product (or medical device) within 30 days or 5 half-lives of date of informed consent, whichever is longer, or is currently participating in another trial of an investigational product (or medical device).
17. Medical, psychological, or behavioral condition that, in the opinion of the Investigator, would confound or interfere with evaluation of safety and/or efficacy of the study drug, prevent compliance with the study protocol; preclude informed consent; or, render the participant unable/unlikely to comply with the study procedures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Matching Placebo	Drug: Placebo; During the Randomized Treatment Period, participants will be randomized in a 1:1 ratio to receive 1500 mg of voxelotor (or the weight-adjusted equivalent dose for participants < 12 years old), once daily (administered orally as tablets/PFOS) or matching placebo for 12 weeks in addition to ongoing standard of care (SOC) treatment.
Experimental: Active Drug; Voxelotor 1500mg or equivalent daily as a tablet or powder for oral suspension	Drug: Voxelotor Only Product in Oral Dose Form; During the Randomized Treatment Period, participants will be randomized in a 1:1 ratio to receive 1500 mg of voxelotor (or the weight-adjusted equivalent dose for participants < 12 years old), once daily (administered orally as tablets/PFOS) or matching placebo for 12 weeks in addition to ongoing standard of care (SOC) treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Executive Abilities Composite Score Assessed Using NIH Toolbox Cognition Module At Week 12	The NIH toolbox cognition module is a standardized cognitive battery comprising of executive function, episodic memory, language, processing speed, working memory, and attention as subdomains. The toolbox is comprised of 7 test instruments that measure 8 abilities within 6 major cognitive domains and have been categorized as executive abilities (Dimensional Change Card Sort Test, Flanker Inhibitory Control and Attention Test, and List Sorting Test) and nonexecutive abilities (Picture Vocabulary Test, Oral Reading Recognition Test, and Picture Sequence Memory Test). The NIH toolbox standard score has a mean of 100 and standard deviation (SD) of 15. The higher the score, the better the performance.	Baseline (last assessment prior to first dose of study treatment), Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Pattern Comparison Processing Speed Test Scores Assessed Using NIH Toolbox Cognition Module at Week 12	The NIH Toolbox Cognition Battery Test is a comprehensive set of neuro behavioral measurements used to assess cognitive, sensory and motor functions where a higher composite score equals better cognitive performance. The NIH Toolbox Cognitive Scores used the Fully Adjusted Scale score (also referred to as the fully corrected T-score) with a mean of 50 and standard deviation of 10.	Baseline (last assessment prior to first dose of study treatment), Week 12
Change From Baseline in Nonexecutive Cognitive Abilities Composite Score Assessed Using NIH Toolbox Cognition Module Up to Week 12	The NIH toolbox cognition module is a standardized cognitive battery comprising of executive function, episodic memory, language, processing speed, working memory, and attention as subdomains. The toolbox is currently comprised of 7 test instruments that measure 8 abilities within 6 major cognitive domains and have been categorized as executive abilities (Dimensional Change Card Sort Test, Flanker Inhibitory Control and Attention Test, and List Sorting Test) and nonexecutive abilities (Picture Vocabulary Test, Oral Reading Recognition Test, and Picture Sequence Memory Test). Baseline was defined as the last assessment performed prior to receiving the first dose of study treatment. The NIH toolbox standard score has a mean of 100 and SD of 15. The higher the score, the better the performance.	Baseline (last assessment prior to first dose of study treatment) up to Week 12
Change From Baseline in Hemoglobin Level Up to Week 12		Baseline (last assessment prior to first dose of study treatment) up to Week 12
Change From Baseline in Absolute Reticulocyte Count Up to Week 12		Baseline (last assessment prior to first dose of study treatment) up to Week 12
Change From Baseline in Percentage Reticulocyte Up to Week 12		Baseline (last assessment prior to first dose of study treatment) up to Week 12
Change From Baseline in Lactate Dehydrogenase (LDH) Up to Week 12		Baseline (last assessment prior to first dose of study treatment) up to Week 12
Change From Baseline in Unconjugated Bilirubin Up to Week 12		Baseline (last assessment prior to first dose of study treatment) up to Week 12
Percent Change From Baseline in Unconjugated Bilirubin, Absolute Reticulocyte, Percentage Reticulocytes, Lactate Dehydrogenase (LDH) Up to Week 12		Baseline (last assessment prior to first dose of study treatment) up to Week 12

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment Emergent Adverse Events (TEAEs)	An adverse event was defined as any untoward medical occurrence associated with the use of a drug in participants whether or not considered drug related. TEAEs were those events with onset dates that occurred during the treatment period.	From start of study treatment (Day 1) up to Week 12

Collaborators and Investigators

• Sponsor: Pfizer
• Investigators: Study Director: Pfizer CT.gov Call Center, Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): June 24, 2022
• Primary Completion (Actual): September 30, 2022
• Study Completion (Actual): September 30, 2022

Study Registration Dates

• First Submitted: January 10, 2022
• First Submitted That Met QC Criteria: January 27, 2022
• First Posted (Actual): February 8, 2022

Study Record Updates

• Last Update Posted (Estimated): May 2, 2024
• Last Update Submitted That Met QC Criteria: April 8, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell
• Other Study ID Numbers: GBT440-044; C5341028 (Other Identifier: Alias Study Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No