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

Sickle Cell Disease Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04983264
• Other study ID #: GBT021601-012
• Secondary ID: C5351002
• Status: Completed
• Phase: Phase 1
• Start date: May 21, 2021
• Est. completion date: December 6, 2022

Study information

• Verified date: December 2023
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 6
• Est. completion date: December 6, 2022
• Est. primary completion date: December 6, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Sickle Cell Disease

Intervention

Drug:
• GBT021601
Tablets and capsules which contain GBT021601 drug substance

Locations

Country	Name	City	State
United States	Children's Healthcare of Atlanta AFLAC Center	Atlanta	Georgia
United States	Visionaries Clinical Research LLC	Atlanta	Georgia
United States	Advanced Pharma CR, LLC	Miami	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

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