Protocol Title

A Phase 3, Double-blind, Randomized, Placebo-controlled, Multicenter Study of GBT440 Administered Orally to Patients with Sickle Cell Disease

Protocol Number

GBT440-031

Sponsor

Global Blood Therapeutics, Inc.
400 East Jamie Court Suite #101
South San Francisco, CA  94080

Study Drug

·    GBT440 capsules or tablets, 300 mg each, administered orally

·    Matching placebo, administered orally

Number of Clinical Sites

The study will be conducted at approximately 75 international clinical sites.

Number of Study Participants

Approximately 340 total participants with Sickle Cell Disease (SCD), adults and adolescents (up to approximately 400) will be enrolled, as follows:

Group 1: Approximately 60 participants

Group 2: Up to approximately 90 participants; enrollment begins with participant #61 and ends when the Group 3 dose has been selected from the Group 1 Analysis

Group 3: At least 190 participants and up to 250 participants; enrollment begins when the Group 3 dose has been selected from the Group 1 Analysis

Treatment

Group 1: Participants will be randomized in a 1:1:1 ratio to receive GBT440 900 mg/day, GBT440 1500 mg/day, or matching placebo

Group 2: Participants will be randomized in a 1:1:1 ratio to receive GBT440 900 mg/day, GBT440 1500 mg/day, or matching placebo

Group 3: Participants will be randomized in a 1:1 ratio to receive GBT440 (900 mg/day or 1500 mg/day), or matching placebo

Objectives

Primary

The primary objective is to assess the efficacy of GBT440 in adolescents and adults with SCD as measured by improvement in anemia.

Secondary

The secondary objectives are to evaluate the effects of GBT440 compared to placebo on SCD symptom exacerbation and Total Symptom Score (TSS) from Patient Reported Outcome measurement (PRO), measures of anemia and hemolysis, and other clinical measures (e.g., vaso-occlusive crisis [VOC], Acute Chest Syndrome [ACS], hospitalization, red blood cell [RBC] transfusions, opioid use).

Exploratory

The exploratory objectives are to evaluate the effects of GBT440 compared to placebo on the EuroQol EQ-5D-5L health questionnaire (EQ-5D-5L™), days missed from work/school, and measures related to SCD pathophysiology and to evaluate measures predictive of response to GBT440.

Safety

The safety objectives are to assess the safety of GBT440 compared to placebo based on adverse events (AEs), clinical laboratory tests, physical examinations, and other clinical measures (e.g., discontinuations due to AEs, dose reductions).

Pharmacokinetics

The pharmacokinetic (PK) objective is to assess the PK of GBT440 as evaluated by population PK analysis.

Study Design

STUDY DESIGN

This study is a randomized, placebo-controlled, double blind, parallel group, multicenter study of participants, age 12 to 65 years, with SCD (HbSS, HbSC,HbSβ0 thalassaemia or other Sickle Cell Syndrome variants) conducted in three groups of study participants, Groups 1, 2, and 3. The key purposes for each group are:

Group 1:

·      Dose selection: GBT440 dose (900 or 1500 mg) for further study.

·      Final definition of endpoints for patient reported outcomes measure for the Main Population Analysis

·      Electronic patient reported outcomes (ePRO) qualification for the Main Population Analysis

Group 2:

·      To allow for a seamless transition from Group 1 to Group 3 by continuing enrollment and data collection in the study during the Group 1 treatment period and data analysis (referred to as Group 1 Analysis).

Group 3:

·      Establish efficacy and safety of GBT440 at the selected dose. The final data analysis set ( referred to as the Main Population) will include

§  Group 2 participants

·      Assigned to placebo

·      Assigned to the selected dose and

§  All Group 3 participants.

Open Label Extension (under separate protocol)

Participants will be given the option to enroll in an open label extension study to receive GBT440 at the selected dose.

The open label extension study will be available to eligible participants who:

·      Were included in the Group 1 Analysis regardless of the treatment arm to which they were randomized.

·      Were randomized in Group 2 to the dose not selected for Group 3.

·      Were included in Group 3 and completed through end of treatment.

The Study Schematic is provided in Figure 1, at the end of the Synopsis.

Adolescent Participants

Initially only adult participants will be enrolled. Adolescent participants (12 to <18 years) will be included in enrollment/randomization when:

1) Single dose PK data and modeling from Study GBT440-007 are available to confirm the appropriate dose for adolescent participants, and

2) The Data Safety Monitoring Board (DSMB) has reviewed the safety data from at least 18 adults enrolled in this study of which at least 6 adults have received 1500 mg GBT440 for at least 4 weeks to confirm acceptable safety and tolerability before adolescents can be enrolled. Sites will be notified when adolescent participants can be enrolled in this study.

At the time that these criteria are met, adolescents will begin to enroll (as early as in Group 1); a minimum of 50 adolescents will be included in the Main Population.

Screening and Randomization

After signing the informed consent form (ICF), participant screening will include medical history, vital signs, electrocardiogram (ECG), complete physical exam (PE) including height and weight, blood chemistry including iron studies, hematology laboratory tests, serum pregnancy test for women, and urinalysis. The ePRO measure assessment must be completed for at least 75% of days of a 28-day Screening period. All screening procedures must be completed within 35 days before randomization. Laboratory tests will be performed by a central laboratory.

Study DRUG INFORMATION

Participants receiving 1500 mg GBT440 will receive five 300 mg capsules or tablets, administered orally, once daily; participants receiving 900 mg GBT440 will receive three 300 mg capsules or tablets, and 2 placebo capsules or tablets administered orally, once daily. Participants randomized to placebo will receive 5 placebo capsules or tablets administered orally, once daily. Study drug may be taken with or without food. Participants in Group 1 must take their study drug in the mornings and must avoid high fat meals for 4 hours before and 4 hours after taking study drug. Group 2 and Group 3 participants may take study drug in the morning or evening, preferably at same time each day throughout the study ( Group 2 and Group 3 participants have no food restrictions/requirements).

Dose Modifications

Guidelines for dose modification are provided in Table 1and Table 2at the end of the Synopsis. The Medical Monitor should be notified of all dose modifications within 72 hours. Details regarding study medication kit preparation and dispensation are provided in the Site Operations Manual.

ANALYSIS GROUPS AND specifications

Analysis will be conducted on populations:

·      Group 1 Population

·      Main Population: Group 2 (placebo and selected dose treatment arm only) and Group 3, combined

Group 1:  

·      When the 60^th participant reaches 12 weeks of treatment, data from the 60 participants will be unblinded, and a Group 1 Analysis will be conducted.

·      The Group 1 Analysis will include PK, efficacy (primarily Hb response, ePRO endpoints, proportions of days with symptom exacerbation and change from Baseline in TSS), and safety endpoints, to inform the following for Group 3:

o   Dose selection will be performed: GBT440 dose (900 or 1500 mg) for further study.

o   Final definition of endpoints for patient reported outcomes measure for the Main Population Analysis

o   Electronic patient reported outcomes (ePRO) qualification for the Main Population Analysis.

o   Other potential modifications to the study: Allowable modifications will be to continue both doses if risk/benefit is unclear, to discontinue one of the doses if the second dose risk/benefit is clear, selection of intermediate dose (1200 mg) if the analysis suggests a better risk/benefit

·      Data from Group 1 will not be combined with data from Groups 2 and 3 for the Main Population Analysis. 

·      The Sponsor may change or re-order the secondary endpoints for the Main Population Analysis based on the Group 1 Analysis and prior to unblinding of Main Population data.

Group 2:

·      Group 2 includes study participants who enroll while the Group 1 Analysis is conducted.

·      Randomization will continue 1:1:1 until a decision has been reached on the dose selected for use in Group 3.

·      Once the GBT440 dose is selected for Group 3, participants who have received the non-selected GBT440 dose in Group 2 will be offered open label treatment under a separate protocol.

·      Only participants in Group 2 assigned to placebo, and to the selected GBT440 dose for Group 3, will be included in the Main Population Analysis.

Group 3:

·      Group 3 participants will be randomized in a 1:1 ratio to receive the GBT440 selected dose or placebo. Group 3 will be included in the Main Population Analysis.

BLINDING

This study is a double-blind study. The GBT440 and placebo capsules or tablets will be matched for shape, size, and color.

For Group 1, with the exception of those noted below in Unblinding for Analysis, all individuals involved in the conduct of the study (i.e., site staff and study participants, contract research organization [CRO] personnel, Sponsor personnel) will be blinded to randomized treatment assignment.  

For Groups 2 and 3, all individuals involved in the conduct of the study (i.e., site staff and study participants, Clinical CRO personnel, all Sponsor personnel) will be blinded to randomized treatment assignment. Drug Supply will remain unblinded throughout the study.

Unblinding for Analysis

Group 1: To facilitate the Group 1 Analysis, certain Sponsor representatives and Sponsor designees will be unblinded to treatment assignments prior to and during the analysis (including the biostatistics CRO and external groups for bioanalytical PK/PD, and ePRO analyses). The blinded Sponsor study team members will be unblinded to the Group 1 Analysis results only after the Group 1 Analysis is complete.

Group 2: Participants randomized to the non-selected dose will be unblinded and offered the option to enroll in an open label extension study. For the remaining Group 2 participants, unblinding to treatment assignment will occur after database lock for the Main Population Analysis.

Group 3: Unblinding to treatment assignment will occur after database lock for the Main Population Analysis.

Unblinding for Laboratory Test Assessment

Local laboratory tests including hematology laboratory tests may be used as needed per standard of care to manage AEs (such as hospitalization for VOC), and in these circumstances, the laboratory data may need to be unblinded.

Because knowledge of certain laboratory assessments (Hb, hematocrit [Hct], RBC count, total and unconjugated bilirubin, and absolute and % reticulocyte count) may suggest the treatment assignment, these measurements will be redacted to the Investigator and monitored on a regular basis by the DSMB. Results of redacted laboratory tests will be communicated to the Investigator if a participant’s absolute reticulocyte count declines to <80 × 10⁸/L or Hb declines to <5.0 g/dL (but this does not require breaking of the treatment assignment blind). This is to ensure participant safety by allowing the Investigator to monitor for potential bone marrow suppression, as described in hydroxyurea (HU) monitoring guidelines (NHLBI 2014) (National Heart, Lung, and Blood Institute; NHLBI; 2014). All other laboratory assessments (not redacted) will be available to the Investigator. Anonymized laboratory results will be available to the Sponsor.

Unblinding for Medical Need

If a medical condition should arise for which appropriate treatment cannot be decided without knowledge of the GBT440-031 study treatment assignment, the Investigator will contact the Sponsor to request permission to unblind. Pregnancy is considered a medical condition that requires unblinding. Upon written approval of the Sponsor, unblinding procedures will be followed as outlined in the Site Operations Manual and documented in the Investigator site file and the case report form (CRF).

Data AND Safety Monitoring Board

An independent DSMB will monitor the safety and conduct of the trial. The DSMB will be comprised of medical and statistical representatives. The DSMB can provide recommendations to the Sponsor regarding stopping the study or discontinuing a treatment arm or otherwise modifying the study design or conduct.

The DSMB will review:

·       The Group 1 Analysis and provide an assessment of the benefit to risk ratio of the 900 mg and 1500 mg doses.

·       Safety data from at least 18 adults enrolled in this study of which at least 6 adults have received 1500 mg GBT440 for at least 4 weeks to confirm acceptable safety and tolerability before adolescents can be enrolled. The sites will be notified when adolescent participants can be enrolled in this study.

·       Safety data on a periodic basis as defined in the DSMB Charter.

Sites will be informed of the DSMB recommendations only if the recommendations lead to changes in the study conduct.

The composition, responsibilities, and other details of the DSMB will be described in the DSMB Charter.

Safety Assessments

Participant safety and tolerability will be monitored during the study using standard measures, including physical examinations, vital signs (including blood pressure [BP] and pulse rate), 12 lead ECGs, safety laboratory tests, urinalysis, concomitant medication usage and AE monitoring. All laboratory tests (including during the screening period) will be performed through a central laboratory.

Assessments will be performed at Screening, and prior to dosing (Baseline), and at defined times during the study. Assessments will include blood chemistry and hematology, GBT440 whole blood and plasma concentrations (for population PK analysis), erythropoietin levels, hemoglobin fetal (HbF) levels (Baseline, and End of Treatment [EOT]), physical examinations, ECGs, blood samples for biomarker testing, ePRO SCD Severity Measure (SCDSM), and eDiary. Once the participant initiates study drug treatment, assessments will be conducted every 2 weeks for the first 8 weeks, then every 4 weeks until end of study drug treatment. Safety assessments will be conducted at approximately 30 days after the last dose of study drug.

Assessment of AEs will begin at the time of signing the ICF and will continue through the last study visit. AEs and laboratory values will be graded with National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 (v4.03: June 14, 2010).

Participants enrolled will complete the EQ-5D-5L™ at defined times during the study. EQ-5D-5L™ is a standardized instrument for use as a measure of health outcome; it provides a simple descriptive profile and a single index value for health status.

Restrictions Regarding Concomitant Medications

GBT440 should be used with caution with CYP3A4 substrates with a narrow therapeutic index.

The use of strong inducers of CYP2B6, CYP2C9, CYP2C19, and CYP3A4/CYP3A5 is prohibited. The use of herbal medications (e.g., St. John’s Wort) is not allowed.

Duration of Study Participation

Duration of Treatment

Group 1: Minimum duration is 12 weeks, maximum duration is 72 weeks or up to the completion of the Group 1 Analysis, whichever comes first.

Group 2: Minimum duration is 2 weeks, maximum duration is 72 weeks.

Group 3: Minimum duration is 24 weeks, maximum duration is 72 weeks.

Duration of Study

Duration of study for an individual participant includes Screening (at least 28 days, but up to 35 days to account for Screening window flexibility), treatment for a minimum of 12 weeks and a maximum of 72 weeks, and an End of Study (EOS) visit at 4 weeks (± 7 days) after the last dose of study drug. From Screening through follow-up, total participation in this study for an individual participant may last from approximately 22 weeks to up to 81weeks. The minimum study duration is approximately 10 weeks (for participants in Group 2 enrolled at a dose not selected for Group 3). Participants will continue to be followed for efficacy and safety through at least the endpoint visit (Week 12 for Group 1 and Week 24 for the Main Population) regardless of treatment discontinuation.

Study Population

Inclusion Criteria

1.     Male or female study participants with sickle cell disease

·      Documentation of SCD genotype (HbSS, HbSC, HbSβthalassemia or other sickle cell syndrome variants) may be based on history of laboratory testing or must be confirmed by laboratory testing during screening

2.     Participants have had at least 1 episode of VOC in the past 12 months. For study eligibility, VOC is defined as a previously documented episode of ACS or acute painful crisis (for which there was no explanation other than VOC) which required prescription or healthcare professional‑instructed use of analgesics for moderate to severe pain (documentation must exist in the patient medical record prior to Screening)

3.     Age 12 to 65 years

4.     Hemoglobin (Hb) ≥6.0 and ≤10.5 g/dL during Screening

5.     Absolute reticulocyte count and % reticulocyte count must be >1.5 × upper limit of normal (ULN) during Screening

6.     For participants taking HU, the dose of HU (mg/kg) must be stable for at least 3 months prior to signing the ICF and with no anticipated need for dose adjustments during the study, in the opinion of the Investigator

7.     Participants must demonstrate 75% compliance with ePRO measure completion to be enrolled (participants will be given an ePRO device for at least 28 days during Screening; participants who are 60 to 74% compliant can re-screen once with Investigator approval; re‑screening is not allowed for participants who are <60% compliant)

8.     Participants, who if female and of child bearing potential, are using highly effective methods of contraception from study start to 3 months after the last dose of study drug, and who if male are willing to use barrier methods of contraception, from study start to 3 months after the last dose of study drug

9.     Participant has provided documented informed consent or assent (the ICF must be reviewed and signed by each participant; in the case of pediatric participants, both the consent of the participant’s legal representative or legal guardian, and the participant’s assent must be obtained)

Exclusion Criteria

1.     More than 10 VOCs within the past 12 months that required a hospital, emergency room or clinic visit

2.     Female who is breast feeding or pregnant

3.     Patients who are receiving regularly scheduled blood (RBC) transfusion therapy (also termed chronic, prophylactic, or preventive transfusion) or have received a RBC transfusion for any reason within 28 days of signing the ICF

4.     Hospitalized for sickle cell crisis or other vaso-occlusive event within 14 days of signing the ICF (i.e., a vaso-occlusive event cannot be within 14 days prior to ICF )

5.     Hepatic dysfunction characterized by alanine aminotransferase (ALT) >4 × ULN

6.     Participants with clinically significant bacterial, fungal, parasitic or viral infection which require therapy:

·    Participants with acute bacterial infection requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed. 


·    Participants with known active hepatitis A, B, or C or who are known to be human immunodeficiency virus (HIV) positive

6.     Severe renal dysfunction (estimated glomerular filtration rate at the Screening visit; calculated by the central laboratory) <30mL/min/1.73 m² or on chronic dialysis

7.     History of malignancy within the past 2 years prior to treatment Day 1 requiring chemotherapy and/or radiation (with the exception of local therapy for non‑melanoma skin malignancy).

8.     History of unstable or deteriorating cardiac or pulmonary disease within 6 months prior to consent including but not limited to the following:

·    Unstable angina pectoris or myocardial infarction or elective coronary intervention

·    Congestive heart failure requiring hospitalization

·    Uncontrolled clinically significant arrhythmias

10.  Any condition affecting drug absorption, such as major surgery involving the stomach or small intestine (prior cholecystectomy is acceptable).

11.  Participated in another clinical trial of an investigational agent (or medical device) within 30 days or 5 half-lives of date of informed consent, whichever is longer, or is currently participating in another trial of an investigational agent (or medical device).

12.  Inadequate venous access as determined by the Investigator/site staff.

13.  Medical, psychological, or behavioral conditions, which, in the opinion of the Investigator, may confound study interpretation, interfere with compliance, or preclude informed consent.

Statistical Methods

Study Endpoints

The endpoints listed below are for the Main Population Analysis (Groups 2 and 3). The same endpoints will be evaluated for Group 1 participants at the Week 12 visit. In addition, for the Group 1 population, the primary efficacy measure is evaluated as two endpoints (details are provided in Section 10.2).

Primary Endpoint

Increase in Hb >1 g/dL from Baseline to Week 24. Participant is responder if Week 24 Hb is >1 g/dL compared to Baseline.

Secondary Endpoints

The first four endpoints are alpha-controlled.

·    Proportion of days with SCD symptom exacerbation during the first 24 weeks of treatment. This is the first-rank secondary endpoint.

•    Change from Baseline to Weeks 21–24 in the SCDSM TSS; for each participant, the TSS will be computed as follows: The Baseline TSS is the average of the score during the 28-day Screening period; during the treatment period, the TSS is the average score each 4-week period on treatment. The 4-week periods are Weeks 1–4, 5–8, 9–12, 13–16, 17–20, and 21–24 (and follows similarly for participants whose participation exceeds 24 weeks). This is the second-rank secondary endpoint.

•    Normalization of reticulocyte count at Week 24 (% reticulocytes <1.5 × ULN weeks)

·    VOC during the treatment period is defined as:

A composite of acute painful crisis or ACS and includes the following:

o   Moderate to severe pain lasting at least 2 hours

o   No explanation other than VOC

o   Requires oral or parenteral opioids, ketorolac, or other analgesics prescribed or directed by a healthcare professional

o   Must be documented in patient medical record that the patient was seen, or contacted the physician, within 1 day of the event. The event may take place in a medical setting (hospital, clinic, emergency room)

o   May include episodes of ACS (ACS is defined as an acute illness characterized by fever and/or respiratory symptoms, accompanied by a new pulmonary infiltrate on a chest X-ray

·     Rate of hospitalization for VOC during the treatment period

·     Change from Baseline to 24 weeks in hemolysis and related measures: % reticulocytes, unconjugated bilirubin, Hb, dense RBCs

·     Time to first ACS during the treatment period

·     Time to first RBC transfusions during the treatment period

·     Rate of opioid use, calculated as the proportion days that opioids were used each 4‑week period as recorded in an eDiary

·     Length of hospitalization for VOC

Exploratory Endpoints

·    Change in health status compared to Baseline utilizing the EQ-5D-5L™

·    School and work attendance as measured in an eDiary. The rate of missed school and work days for each participant will be calculated as the proportion of days that school or work was missed every 4 weeks

·    Change from Baseline to 24 weeks in measures related to SCD pathophysiology, including lactate dehydrogenase (LDH), carboxyhemoglobin, glycated Hb Soluble P‑selectin, VCAM, ICAM, E-Selectin (and other exploratory measures that may be related to disease activity), urine albumin to creatinine ratio, serum cystatin C, Hb distribution width, RBC deformability (to be assessed at select centers), RBC phosphatidylserine expression (to be assessed at select centers), and TR jet velocity as assessed by echocardiography (to be assessed at select centers)

·    Resolution of jaundice at Week 24 (total bilirubin >2 × ULN at Baseline and ≤2 × ULN at 24 weeks)

Safety Endpoint

·    AEs, clinical laboratory tests, physical examinations, and vital signs

Pharmacokinetic Endpoint

·    PK of GBT440 as evaluated by population PK analysis using nonlinear mixed effects modeling

Sample Size

The sample size for the study is estimated to be approximately 340 participants (up to approximately 400 participants).

Group 1: Approximately 60 participants will be randomized 1:1:1 to GBT440 900 mg, 1500 mg, or placebo.

Group 2: Up to approximately 90 participants will be randomized 1:1:1 to GBT440 900 mg, 1500 mg, or placebo.

Group 3: At least 190 participants and up to 250 participants will be randomized 1:1 to GBT440 at the selected dose or placebo.

Sample Size for Group 1:

The primary efficacy measure , Hb, will be evaluated as 2 endpoints:

·       as change from Week 12 to Baseline (primary)

·       as a responder endpoint (change from Week 12 to Baseline >1 g/dL)

For the endpoint of change from Baseline in Hb, power calculations assume a mean treatment effect of 0.8 g/dL (GBT440 at either dose, minus placebo), the placebo change from Baseline is equal to 0, a per-group standard deviation (SD) of 0.6 g/dL. With N = 20 participants per arm, the power exceeds 95% of detecting a difference between either GBT440 arm (900 mg or 1500 mg) versus placebo. Power is calculated for the t-test and assumes that the data are normally distributed. The estimates of 0.8 g/dL and 0.6 g/dL for the treatment effect and SD, respectively, are based on data at Day 90 from Cohorts 16 and 17 from the GBT440-001 study.

For the responder endpoint at Week 12, the GBT440 dose arms will be pooled. Assuming responder proportions of 35% and 5% for GBT 440 (N = 40 after pooling data from the 900 and 1500 mg groups) and placebo (N = 20), respectively, the power with Fisher’s exact test at a two-sided alpha = 0.05 is 80%.

Sample Size for the Main Population Analysis:

The Main Population Analysis consists of Group 2 participants (estimated to be approximately 60, which includes approximately 30 selected GBT440 dose and 30 placebo patients) and Group 3 participants (minimum 190 patients and maximum 250 patients) for a total of 250 (minimum) to 310 (maximum).

For the Hb responder endpoint at Week 24, power exceeds 95% based on Fisher’s exact test and a two-sided alpha of 0.05, assuming a 35% and 5% response rate for GBT440 and placebo. A sample size larger than required for an adequately powered primary endpoint was selected for the safety database. The sample size for the primary and ePRO secondary endpoints for the Main Population Analysis will be re‑estimated from the Group 1 Analysis, and if necessary, will be increased up to a maximum of 310 participants to ensure adequate power for the first key secondary endpoint (proportion of days with SCD symptom exacerbation). The estimation will not require an alpha adjustment because data from the Group 1 Analysis will not be included in the Main Population Analysis .

Stratification

At the time of randomization, participants will be stratified for HU use (yes/no), geographic region (US, Europe, Other), and age (adolescent, 12 to <18 years, and adults, 18 to 65 years).

Efficacy Population and Analysis

For each population, efficacy analysis will be performed on the Intent to Treat (ITT) population which includes all randomized participants.

The Group 1 Analysis will determine the GBT440 dose selected, and determine any further modifications to the study. There will no adjustment for multiplicity for the Group 1 population. If both GBT440 dose groups are selected in the Main Population Analysis, the comparisons will be of each GBT440 dose versus placebo, and will be adjusted for multiplicity via gatekeeping procedures outlined in the SAP.

Group 1 and Main Population Analysis

Primary Endpoint:

Hb Week 12 change from Baseline will be analyzed with a mixed effect repeated measures model (MMRM). The model will include terms for treatment, time, and treatment by time interaction. An unstructured covariance matrix will be used.

This analysis will be performed for the Group 1 Analysis: The comparison of treatments at Week 12 for each GBT440 dose versus placebo; the data beyond Week 12 will be presented descriptively.

This analysis will be performed for the Group 1 Analysis and Main Population Analysis: The Hb responder endpoint will be analyzed by the Cochran‑Mantel‑Haenszel (CMH) test for each GBT440 dose versus placebo.

Secondary Endpoints:

Where applicable, the Group 1 and Main Population will be analyzed with respect to their endpoint visit which is Week 12 for Group 1 and Week 24 for the Main Population. Analyses for Group 1 and the Main Population will be summarized beyond the endpoint visit. For example, for Group 1, proportion of days with SCD symptom exacerbation and change from Baseline in TSS will be summarized for visits after the endpoint visit, including Week 24.

The proportion of days with SCD exacerbation during the first 12 weeks of treatment will be analyzed by a fixed effects linear model.

Change from Baseline in the TSS will be analyzed with an MMRM.

Normalization of reticulocyte count will be analyzed by the CMH test.

The rate of VOC and rate of hospitalization due to VOC will be analyzed by the CMH row means scores test.

The plan for the Main Population Analysis will be described in further detail in the Statistical Analysis Plan (SAP) after results from the Group 1 Analysis become available and before unblinding the Main Population Analysis.

Missing Data: Proportion of participants with missing data for the primary and key secondary efficacy endpoints will be summarized by treatment group for study scheduled visits. Handling of missing data for analysis is described in the body of the protocol. The general rule is assigning a worst score for missing data due to hospitalization for VOC, and a worst score for RBC transfusions regardless of whether or not data are missing.

Safety Population and Analysis (Group 1 and Main Population)

The Safety Population is defined as all randomized participants who have received at least one dose of study medication. Participants will be analyzed based on medication received.

Data for participants who provide eDiary data but discontinue treatment will be included in the analysis. Descriptive statistics for healthcare utilization will be summarized in a separate report.

The incidence of treatment-emergent adverse events (TEAEs) will be tabulated by System Organ Class (SOC), preferred term, severity, and relationship to study drug. AEs that are considered to be related to study drug by the Investigator will be summarized. Changes in laboratory parameters and vital signs over time will be summarized.

Demographics (age, sex, ethnicity, and race) and Baseline characteristics (height and weight) will be summarized by treatment and overall medical history will be provided in a data listing.

Descriptive summaries will be provided for AEs, laboratory tests (hematology, serum chemistry, and coagulation), and vital signs (BP and pulse rate).

Pharmacokinetics Population and Analysis (Group 1 and Main Population)

The PK Population will consist of all participants who receive active study drug and have at least one measured concentration at a scheduled PK time point after the start of dosing. If any participants are found to be noncompliant with respect to dosing or have incomplete data, protocol violations, or clinical events that affect PK, a decision will be made on a case-by-case basis as to their inclusion in the analysis. Participants in this population will be used for all PK summaries.

Population PK analyses using nonlinear mixed effects modeling will be performed to characterize GBT440 PK in plasma, if applicable, or whole blood. The influence of demographic covariates (such as body weight, age, gender) on GBT440 PK parameters (i.e., clearance [CL] and volume of distribution) will be investigated. If appropriate, the GBT440 PK data may be pooled with PK data from other studies.

Summary statistics of PK parameters for whole blood, plasma, and RBCs will be presented including means, geometric means, SD, and coefficient of variation (CV), medians, and ranges.