GBT021601-021: A Study in Adult and Pediatric Participants With SCD

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of GBT021601.

Detailed Description
-----------------
This is a three-part, multicenter, Phase 2/3 study of orally administered GBT021601 in participants with sickle cell disease (SCD). Part A will evaluate the safety, tolerability, and efficacy of GBT021601 in adult participants with SCD to determine an optimal dose. Part B will evaluate the efficacy of GBT021601 versus placebo in adult and pediatric participants with SCD for 48 weeks. Part C will evaluate the pharmacokinetics (PK) and safety of single and multiple doses (MD) of open-label single arm GBT021601 administered to pediatric participants.

Official Title
-----------------
A Phase 2/3 Randomized, Multicenter Study of GBT021601 Administered Orally to Participants With Sickle Cell Disease and an Open-Label Pharmacokinetics Study in Pediatric Participants With Sickle Cell Disease

Conditions
-----------------
Sickle Cell Disease

Intervention / Treatment
-----------------
* Drug: GBT021601


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Part A, Part B, and Part C: Male or female with SCD Participants with stable Hb value as judged by the Investigator For participants taking hydroxyurea and/or L-glutamine, the dose must be stable for at least 90 days prior to signing the ICF or assent and with no anticipated need for dose adjustments during the study in the opinion of the Investigator. Part B: Participants with SCD ages 12 to 65 years, inclusive Participants with more than or equal to 2 and ≤ 10 VOCs within 12 months of Screening. Exclusion Criteria: Part A, Part B, and Part C: Participants who had more than 10 VOC within 12 months of screening Female participant who is breastfeeding or pregnant Participants who receive RBC transfusion therapy regularly or received an RBC transfusion ---for any reason within 90 days of Day 1 Participants hospitalized for sickle cell crisis or other vaso-occlusive event within 14 days of signing the ICF

Ages Eligible for Study
-----------------
Minimum Age: 6 Months
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Part A<br>Initially, participants will be randomized 1:1 to 100 mg and 150 mg daily. Upon review of the 150 mg safety data from at least 6 participants, there will be 1:1:1 randomization: 100 mg, 150 mg, and up to 200 mg. Participants will then receive maintenance once daily doses through Week 12. | Drug: GBT021601<br>* Tablets which contain GBT021601 drug substance<br>|
| Placebo Comparator: Part B<br>Following the selection of the optimal safe and effective dose from Part A of the study, Part B of the study will assess the efficacy and safety of 48 weeks of the optimal dose, compared to placebo | Drug: GBT021601<br>* Tablets which contain GBT021601 drug substance<br>|
| Experimental: Part C<br>100 mg dose in cohort C1, dose level for cohorts C2 to C4 to be determined based on emerging data | Drug: GBT021601<br>* Tablets which contain GBT021601 drug substance<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A | Number of adult participants with change from baseline in hemoglobin (Hb) through week 12 as measured by change in GBT021601 concentrations from baseline or percentage change from baseline of clinical measures of anemia Hb and hemolysis (including indirect bilirubin, reticulocytes and lactate dehydrogenase). | Through week 12 | 
| Part B | Proportion of participants with an increase from baseline of >1 g/dL in Hb at week 48 as measured by change in GBT021601 concentrations from baseline or percentage change from baseline of clinical measures of anemia (hemoglobin) and hemolysis (including indirect bilirubin, reticulocytes and lactate dehydrogenase). | Through week 48 | 
| Part C | Assess the pharmacokinetics (PK), while observing maximum concentration (Cmax) after a single dose as measured by a noncompartmental PK analysis or population PK analysis using nonlinear mixed-effect modeling. To characterize GBT021601 PK in plasma and whole blood following a single dose. | Through Week 6 | 
| Part C | Assess the PK, while observing minimum concentration (Cmin) and Cmax after multiple dose administration as measured by a 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 multiple doses. | Through Week 2 |