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

Study Overview
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Brief Summary
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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.

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

Official Title
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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)

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Drug: GBT021601


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety, as assessed by frequency and severity of adverse events (AEs) | AEs will be coded to system organ class and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA) and summarized. | 31 weeks | 
| Safety, as assessed by changes in Heart Rate | Number of participants with changes in heart rate (bpm) as compared to baseline | 31 weeks | 
| Safety, as assessed by changes in QTcF | Number of participants with changes in the QTcF interval from baseline | 31 weeks | 
| Safety, as assessed by changes in eGFR | Number of participants with changes in eGFR from baseline | 31 weeks | 
| Safety, as assessed by changes in alanine aminotransferase (ALT) | Number of participants with changes in alanine aminotransferase (ALT) | 31 weeks | 
| Safety, as assessed by changes in Blood pressure | Number of participants with changes in systolic (mmHg) and diastolic (mmHg) blood pressure from baseline | 31 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine plasma and whole blood concentrations of GBT021601 and calculate RBC concentrations. | Noncompartmental PK analysis or population PK analysis using nonlinear mixed-effect modeling will be performed to characterize GBT021601 PK in plasma, and whole blood following single and multiple doses. | 31 weeks | 
| Determine the pharmacodynamic effect of GBT021601 treatment. | Hemoximetry will be used to assess oxygen saturation in whole blood by generating oxygen equilibrium curves (OECs) which relate the extent of Hb-O2 saturation to the partial pressure of O2 (pO2) and measure the binding affinity of O2 to Hb. Red Blood Cell Deformability will be measured by an Osmoscan. Individual and mean PD marker data will be presented graphically. | 14 weeks | 
| To confirm the the relationship between time-matched GBT021601 concentrations and the change from baseline or percentage change from baseline of clinical measures of anemia and hemolysis. | To confirm the correlation between time-matched GBT021601 concentrations and the change from baseline or percentage change from baseline of clinical measures of anemia (hemoglobin) and hemolysis (including indirect bilirubin, reticulocytes and lactate dehydrogenase). | 14 weeks |