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)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 6
- 试验地点
- 3
- 主要终点
- Number of Participants With Clinically Significant Change From Baseline in Laboratory Parameters
研究概览
简要总结
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.
详细描述
This is an open-label intrapatient single dose followed by a multiple dose escalation study in at least six (6) participants with SCD.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Single-dose Period (Part A)
Refer to Study Description
干预措施: GBT021601 (Drug)
Multiple Ascending-dose Period (Part B and Part C)
Refer to Study Description
干预措施: GBT021601 (Drug)
结局指标
主要结局
Number of Participants With Clinically Significant Change From Baseline in Laboratory Parameters
时间窗: Baseline (Day 1) up to at least 56 days after last dose of study drug (up to a maximum of 316 days)
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.
Number of Participants With Clinically Significant Change From Baseline in Vital Signs
时间窗: Baseline (Day 1) up to at least 56 days after last dose of study drug (up to a maximum of 316 days)
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.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
时间窗: 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)
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.
Number of Participants With Clinically Significant Change From Baseline in Electrocardiogram (ECG)
时间窗: Baseline (Day 1) up to at least 56 days after last dose of study drug (up to a maximum of 316 days)
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).
Number of Participants With Clinically Significant Physical Examination Findings
时间窗: Baseline (Day 1) up to at least 56 days after last dose of study drug (up to a maximum of 316 days)
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.
次要结局
- Maximum GBT021601 Concentration (Cmax) in Plasma, Whole Blood and Red Blood Cells (RBCs): Part C(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 C(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(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(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 Oral Clearance (CL/F) in Plasma, Whole Blood and Red Blood Cells (RBCs): Part A(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(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(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)
- Minimum GBT021601 Concentration (Cmin) in Plasma, Whole Blood and Red Blood Cells (RBCs): Part B(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)
- 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(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(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)
- Maximum GBT021601 Concentration (Cmax) in Plasma, Whole Blood and Red Blood Cells (RBCs): Part A(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(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)
- Percentage Hemoglobin Occupancy(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(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(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(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(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 C(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 B(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(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(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(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)