A Study to Evaluate GBT021601-012 Single Dose and Multiple Dose in Participants With Sickle Cell Disease (SCD)

An Intrapatient Single Dose and Multiple Ascending Dose Study to Evaluate the Pharmacokinetics, Safety, Tolerability, and Pharmacodynamics of GBT021601, a Hemoglobin S Polymerization Inhibitor, in Participants With Sickle Cell Disease (SCD)

The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics (PK), and pharmacodynamics (i.e., how the body absorbs, distributes, breaks down, and excretes) of GBT021601, a hemoglobin S (HbS) polymerization inhibitor, in participants with SCD, following single and multiple ascending doses.

Study Overview

• Status: Completed
• Conditions: Sickle Cell Disease
• Intervention / Treatment: Drug: GBT021601

Detailed Description

This is an open-label intrapatient single dose followed by a multiple dose escalation study in at least six (6) participants with SCD.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33147
      • Advanced Pharma CR, LLC
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Children's Healthcare of Atlanta AFLAC Center
    • Atlanta, Georgia, United States, 30329
      • Visionaries Clinical Research LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or Female with SCD
• Participants with SCD ages 18 to 60 years, inclusive.
• Participant has provided documented informed consent.
• Patients with stable and close to baseline hemoglobin value
• Patients on HU should be on stable dose for at least 90 days prior to signing ICF

Exclusion Criteria:

• Patients had more than 10 VOC within 12 months of screening
• Patients who are pregnant or nursing
• Patients who receive RBC transfusion therapy regularly or received an RBC transfusion for any reason within 60 days of signing the ICF
• Hospitalized for sickle cell crisis or other vaso-occlusive event within 14 days of signing the ICF or within 24 days prior to Day 1 treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Single-dose Period (Part A); Refer to Study Description	Drug: GBT021601; Tablets and capsules which contain GBT021601 drug substance
Experimental: Multiple Ascending-dose Period (Part B and Part C); Refer to Study Description	Drug: GBT021601; Tablets and capsules which contain GBT021601 drug substance

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	An adverse event (AE) was any untoward medical occurrence in a study participant administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. A treatment-emergent AE (TEAE) was an AE that occurs or worsens during the on-treatment period defined as the time from the first dose of study drug through minimum of 56 days after last dose of study treatment. A Serious Adverse Event (SAE) was any untoward medical occurrence at any dose that: resulted in death; was life-threatening experience (immediate risk of death); required inpatient hospitalization or prolongation if existing hospitalization; resulted in persistent or significant disability/ incapacity; resulted in congenital anomaly/birth defect; was considered an important medical event. TEAEs and SAEs were reported for both Sickle Cell Disease (SCD) and non-SCD related events, in this outcome measure.	From first dose of study drug (Day 1) to at least 56 days after last dose of study drug (up to a maximum of 316 days)
Number of Participants With Clinically Significant Physical Examination Findings	Physical examination included were general appearance, head, ears, eyes, nose, throat, neck, skin, cardiovascular system, respiratory system, gastrointestinal system, musculoskeletal system, lymph nodes, and nervous system. Clinically significant physical examination abnormalities were considered as adverse events based on investigator's discretion.	Baseline (Day 1) up to at least 56 days after last dose of study drug (up to a maximum of 316 days)
Number of Participants With Clinically Significant Change From Baseline in Laboratory Parameters	Laboratory parameters included hematology(hemoglobin,hematocrit,red blood cell count,platelet count,white blood cell count,total neutrophils,eosinophils,monocytes,basophils,lymphocytes);blood chemistry(blood urea,nitrogen, creatinine,glucose,calcium,sodium,potassium,chloride,total bicarbonate,aspartate aminotransferase,alanine aminotransferase,total bilirubin,alkaline phosphatase,uric acid albumin,total protein);urinalysis(decimal logarithm of reciprocal of hydrogen ion activity [pH], glucose, protein, blood,ketones, microscopy[urine tested positive for blood or protein]),urine drug screening:cannabinoids,amphetamines,methamphetamines,opiates,methadone,cocaine,benzodiazepines,phencyclidine,barbiturates,alcohol breath test. Hemoximetry RBC deformability,dense cells test; erythropoietin,follicle stimulating hormone,pregnancy test,Serology panel for HIV 1/2 antibody,Hepatitis A, B and C,SARS CoV-2.Clinical significance of any parameter was determined at the investigator's discretion.	Baseline (Day 1) up to at least 56 days after last dose of study drug (up to a maximum of 316 days)
Number of Participants With Clinically Significant Change From Baseline in Vital Signs	Vital signs assessments included were systolic and diastolic blood pressure, heart rate, respiratory rate and body temperature. These measurements were taken after the participants had rested for at least 5 minutes in the supine position. Any clinically significant abnormal vital sign assessment required at least one repeat measurement. Clinical significance of any parameter was determined based on investigator's discretion.	Baseline (Day 1) up to at least 56 days after last dose of study drug (up to a maximum of 316 days)
Number of Participants With Clinically Significant Change From Baseline in Electrocardiogram (ECG)	ECG values included here were Heart rate (HR), PR, QRS, QT, and QTcF intervals, interpretation of the tracings (eg, rhythm, presence of arrhythmia or conduction defects, any evidence of myocardial ischemia/infarction, or ST segment, T-wave, and U-wave abnormalities). Abnormal and clinically significant 12-lead ECG included QT interval corrected for heart rate according to Fridericia's formula (QTcF) > 450 millisecond (ms), QRS interval >= 120 ms, PR interval > 220 ms, based on the average of triplicated ECG, assessed at Screening and Day-1. If any of these test results were out of range, then the test could be repeated once (in triplicate).	Baseline (Day 1) up to at least 56 days after last dose of study drug (up to a maximum of 316 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum GBT021601 Concentration (Cmax) in Plasma, Whole Blood and Red Blood Cells (RBCs): Part A	Cmax was defined as the peak concentration observed directly from the experimental data without any interpolation.	Pre-dose, 0.25 hour (hr), 0.5 hr, 1 hr, 2 hrs, 4 hrs, 6 hrs, 8 hrs,12 hrs, 24 hrs, 36 hrs, 48 hrs, 72 hrs, 168 hrs, 336 hrs, 504 hrs, 672 hrs, 1008 hrs post-dose on Day 1
Maximum GBT021601 Concentration (Cmax) in Plasma, Whole Blood and Red Blood Cells (RBCs): Part B	Cmax was defined as the peak concentration observed directly from the experimental data without any interpolation.	Pre-dose, 0.25 hr to 1 hr, 2 to 4 hrs post-dose on Day 56, 63, 70, 77, 84, 91, 98, 105, 112
Maximum GBT021601 Concentration (Cmax) in Plasma, Whole Blood and Red Blood Cells (RBCs): Part C	Cmax was defined as the peak concentration observed directly from the experimental data without any interpolation.	Pre-dose on Day 1, 14, 28, 42 and 0.25 hr to 1 hr, 2 to 4 hrs post-dose on Day 28 and 42
Minimum GBT021601 Concentration (Cmin) in Plasma, Whole Blood and Red Blood Cells (RBCs): Part B	Cmin was defined as the lowest concentration observed directly from the experimental data without any interpolation.	Pre-dose, 0.25 hr to 1 hr, 2 to 4 hrs post-dose on Day 56, 63, 70, 77, 84, 91, 98, 105, 112
Minimum GBT021601 Concentration (Cmin) in Plasma, Whole Blood and Red Blood Cells (RBCs): Part C	Cmin was defined as the lowest concentration observed directly from the experimental data without any interpolation.	Pre-dose on Day 1, 14, 28, 42 and 0.25 hr to 1 hr, 2 to 4 hrs post-dose on Day 28 and 42
Time to Attain Maximum Serum Concentration (Tmax) in Plasma, Whole Blood and Red Blood Cells (RBCs): Part A	Maximum observed concentration was defined as the peak concentration observed directly from the experimental data without any interpolation. The time to the maximum observed concentration was defined as the time corresponding to Cmax.	Pre-dose, 0.25 hour (hr), 0.5 hr, 1 hr, 2 hrs, 4 hrs, 6 hrs, 8 hrs,12 hrs, 24 hrs, 36 hrs, 48 hrs, 72 hrs, 168 hrs, 336 hrs, 504 hrs, 672 hrs, 1008 hrs post-dose on Day 1
Area Under the Concentration Time Curve From Time Zero to the Next Dose (AUC0-tau) in Plasma, Whole Blood and Red Blood Cells (RBCs): Part A	AUC0-tau was defined from time 0 to time of the last quantifiable concentration and was calculated using the linear or logarithmic trapezoid rule. AUCtau was calculated by using hours*microgram per milliliter (hr*mcg)/mL.	Pre-dose, 0.25 hour (hr), 0.5 hr, 1 hr, 2 hrs, 4 hrs, 6 hrs, 8 hrs,12 hrs, 24 hrs, 36 hrs, 48 hrs, 72 hrs, 168 hrs, 336 hrs, 504 hrs, 672 hrs, 1008 hrs post-dose on Day 1
Area Under the Serum Concentration Time Curve From Time Zero Extrapolated to Infinite Time (AUCinf) in Plasma, Whole Blood and Red Blood Cells (RBCs): Part A	AUCinf was defined as the area calculated by linear/log trapezoid rule from time 0 to infinity with the area extrapolated from the last quantifiable concentration to infinity.	Pre-dose, 0.25 hour (hr), 0.5 hr, 1 hr, 2 hrs, 4 hrs, 6 hrs, 8 hrs,12 hrs, 24 hrs, 36 hrs, 48 hrs, 72 hrs, 168 hrs, 336 hrs, 504 hrs, 672 hrs, 1008 hrs post-dose on Day 1
Area Under the Concentration Time Curve From Time Zero up to Time 24 Hours (AUC 0-24) in Plasma, Whole Blood and Red Blood Cells (RBCs): Part A	AUC0-24 was defined as the area under the free plasma concentration time curve from time 0 to 24 hours post-dose.	Pre-dose, 0.25 hour (hr), 0.5 hr, 1 hr, 2 hrs, 4 hrs, 6 hrs, 8 hrs,12 hrs, 24 hrs post-dose on Day 1
Apparent Oral Clearance (CL/F) in Plasma, Whole Blood and Red Blood Cells (RBCs): Part A	CL/F was a quantitative measure of the rate at which a drug substance was removed from the blood. It was calculated as dose of GBT021601 by AUC from time 0 to infinity.	Pre-dose, 0.25 hour (hr), 0.5 hr, 1 hr, 2 hrs, 4 hrs, 6 hrs, 8 hrs,12 hrs, 24 hrs, 36 hrs, 48 hrs, 72 hrs, 168 hrs, 336 hrs, 504 hrs, 672 hrs, 1008 hrs post-dose on Day 1
Terminal Elimination Half-Life (t1/2) in Plasma, Whole Blood and Red Blood Cells (RBCs): Part A	t1/2 was the time measured for the plasma concentration to decrease by one half.	Pre-dose, 0.25 hour (hr), 0.5 hr, 1 hr, 2 hrs, 4 hrs, 6 hrs, 8 hrs,12 hrs, 24 hrs, 36 hrs, 48 hrs, 72 hrs, 168 hrs, 336 hrs, 504 hrs, 672 hrs, 1008 hrs post-dose on Day 1
Apparent Volume of Distribution (Vz/F) in Plasma, Whole Blood and Red Blood Cells (RBCs): Part A	Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/F was determined based on the fraction absorbed.	Pre-dose, 0.25 hour (hr), 0.5 hr, 1 hr, 2 hrs, 4 hrs, 6 hrs, 8 hrs,12 hrs, 24 hrs, 36 hrs, 48 hrs, 72 hrs, 168 hrs, 336 hrs, 504 hrs, 672 hrs, 1008 hrs post-dose on Day 1
Percentage Hemoglobin Occupancy	Percentage hemoglobin occupancy (%Hb Occupancy) refers to the proportion of hemoglobin molecules within red blood cells that were bound to study drug (GBT021601). Cmin and Cmax values was used to calculate %Hb occupancy: %Hb Occupancy = GBT021601*RBC per Mean Corpuscular Hemoglobin Concentration (MCHC).	Part A: Pre-dose,0.25,0.5,1,2,4, 6,8,12,24,36,48,72,168,336,504,672,1008 hrs on Day 1; Part B: Pre-dose,0.25 to 1,2 to 4 hrs post-dose on Day 56,63,70,77,84,91,98,105,112; Part C:Pre-dose on Day 1,14,28,42 and 0.25 to 1, 2 to 4 hrs post-dose on Day 28,42
Plasma Concentrations Versus Time Summary of GBT021601: Part A	The plasma concentration versus time summary was measured by the amount of specific substance in the bloodstream over the specified timepoint.	Pre-dose, 0.25 hour (hr), 0.5 hr, 1 hr, 2 hrs, 4 hrs, 6 hrs, 8 hrs,12 hrs, 24 hrs, 36 hrs, 48 hrs, 72 hrs, 168 hrs, 336 hrs, 504 hrs, 672 hrs, 1008 hrs post-dose on Day 1
Plasma Concentrations Versus Time Summary of GBT021601: Part B	The plasma concentration versus time summary was measured by the amount of specific substance in the bloodstream over the specified timepoint.	Pre-dose, 0.25 hr to 1 hr, 2 to 4 hrs post-dose on Day 56, 63, 70, 77, 84, 91, 98, 105, 112, 140,168, 196, 218
Plasma Concentrations Versus Time Summary of GBT021601: Part C	The plasma concentration versus time summary was measured by the amount of specific substance in the bloodstream over the specified timepoint.	Pre-dose on Day 1, 14, 28, 42 and 0.25 hr to 1 hr, 2 to 4 hrs post-dose on Day 28, 42, 70, 98
Whole Blood Concentrations Versus Time Summary of GBT021601: Part A	The whole blood concentration versus time summary was measured to find concentration of various components in whole blood that changed over a specified period. This helped to monitor the dynamics of blood components such as hemoglobin levels, hematocrit, or glucose concentration over time.	Pre-dose, 0.25 hour (hr), 0.5 hr, 1 hr, 2 hrs, 4 hrs, 6 hrs, 8 hrs,12 hrs, 24 hrs, 36 hrs, 48 hrs, 72 hrs, 168 hrs, 336 hrs, 504 hrs, 672 hrs, 1008 hrs post-dose on Day 1
Whole Blood Concentrations Versus Time Summary of GBT021601: Part B	The whole blood concentration versus time summary was measured to find concentration of various components in whole blood that changed over a specified period. This helped to monitor the dynamics of blood components such as hemoglobin levels, hematocrit, or glucose concentration over time.	Pre-dose, 0.25 hr to 1 hr, 2 to 4 hrs, post-dose on Day 56, 63, 70, 77, 84, 91, 98, 105, 112, 140,168, 196, 218
Whole Blood Concentrations Versus Time Summary of GBT021601: Part C	The whole blood concentration versus time summary was measured to find concentration of various components in whole blood that changed over a specified period. This helped to monitor the dynamics of blood components such as hemoglobin levels, hematocrit, or glucose concentration over time.	Pre-dose on Day 1, 14, 28, 42 and 0.25 hr to 1 hr, 2 to 4 hrs post-dose on Day 28, 42, 70, 98
Red Blood Cell Concentrations Versus Time Summary of GBT021601: Part A	The RBC concentration versus time summary was measured to identify quantity of RBC in a sample of blood over a specified duration. This analysis helped monitor RBC level over time.	Pre-dose, 0.25 hour (hr), 0.5 hr, 1 hr, 2 hrs, 4 hrs, 6 hrs, 8 hrs,12 hrs, 24 hrs, 36 hrs, 48 hrs, 72 hrs, 168 hrs, 336 hrs, 504 hrs, 672 hrs, 1008 hrs post-dose on Day 1
Red Blood Cell Concentrations Versus Time Summary of GBT021601: Part B	The RBC concentration versus time summary was measured to identify quantity of RBC in a sample of blood over a specified duration. This analysis helped monitor RBC level over time.	Pre-dose, 0.25 hr to 1 hr, 2 to 4 hrs post-dose on Day 56, 63, 70, 77, 84, 91, 98, 105, 112, 140,168, 196, 218
Red Blood Cell Concentrations Versus Time Summary of GBT021601: Part C	The RBC concentration versus time summary involved tracking a quantity of RBC in a sample of blood over a specified duration. This analysis helped to monitor RBC level over time.	Pre-dose on Day 1, 14, 28, 42 and 0.25 hr to 1 hr, 2 to 4 hrs post-dose on Day 28, 42, 70, 98

Collaborators and Investigators

• Sponsor: Pfizer
• Collaborators: Pfizer
• Investigators: Study Director: Pfizer 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): May 21, 2021
• Primary Completion (Actual): December 6, 2022
• Study Completion (Actual): December 6, 2022

Study Registration Dates

• First Submitted: May 27, 2021
• First Submitted That Met QC Criteria: July 27, 2021
• First Posted (Actual): July 30, 2021

Study Record Updates

• Last Update Posted (Actual): June 10, 2024
• Last Update Submitted That Met QC Criteria: December 6, 2023
• Last Verified: December 1, 2023

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: GBT021601-012; C5351002 (Other Identifier: Alias Study Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• 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