Study to Evaluate the Effect of GBT440 in Pediatrics With Sickle Cell Disease

Phase 2

Conditions: Sickle Cell Disease
Sickle Cell, Anemia, Hemolytic, Congenital, Hematologic Diseases

Registration Number: LBCTR2019090195

Lead Sponsor: Global Blood Therapeutics Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Complete

Sex: All

Target Recruitment: 38

Inclusion Criteria

1. Male or female participants with homozygous hemoglobin SS (HbSS) or hemoglobin S beta0 thalassemia (HbS ß0 thal).
2. Age:
• Part A – 6 to 17 years of age (Cohort 1 [12 to 17] and Cohort 2 [6 to 11] as defined in the Study Design)
• Part B – 12 to 17 years of age
• Part C – 4 to 17 years of age
• Part D – 6 months to < 4 years of age
3. Hydroxyurea (HU) therapy:
• Parts A, B, and C – A participant taking HU may be enrolled if the dose has been stable for at least 3 months with no anticipated need for
dose adjustments during the study and no sign of hematological toxicity.
• Part D – A participant taking HU may be enrolled if the dose has been stable for at least 1 month. Titration to the maximum tolerated dose
(MTD) is allowed during the study.
4. Hemoglobin (Hb):
• Part A – No restriction
• Part B – Hb = 10.5 g/dL
• Part C – Hb = 10.5 g/dL
• Part D – Hb = 10.5 g/dL
5. Written informed parental/guardian consent and participant assent has been obtained per institutional review board (IRB)/Ethics Committee
(EC) policy and requirements, consistent with ICH guidelines.
6. Participants in Part B (only) of the study must complete a minimum of 14 days with ePRO to be enrolled. Investigator discretion will be used
to determine if a participant who has previously been screen failed due to a lack of baseline ePRO data collection can be invited back for rescreening.
7. If sexually active and female, must agree to abstain from sexual intercourse or to use a highly effective method of contraception throughout
the study period and for 30 days after discontinuation of study drug. If sexually active and male, must agree to abstain from sexual intercourse
or willing to use barrier methods of contraception throughout the study period and for 30 days after discontinuation of study drug.
8. Females of child-bearing potential are required to have a negative pregnancy test before the administration of study drug.
9. Sufficient venous access to permit collection of PK samples and monitoring of laboratory safety variables, in the opinion of the Investigator.
10. For Part C only, participants 12 to 17 years of age must have a TCD velocity = 140 cm/sec by nonimaging TCD or = 125 cm/sec by TCDi
measured anytime during screening.

Exclusion Criteria

1. Any one of the following requiring medical attention within 14 days prior to signing the informed consent form (ICF):
• Vaso-occlusive crisis (VOC)
• Acute chest syndrome (ACS)
• Splenic sequestration crisis
• Dactylitis
2. Requires chronic transfusion therapy.
3. History of stroke or meeting criteria for primary stroke prophylaxis (history of two TCD measurements = 200 cm/sec by nonimaging TCD or =
185 cm/sec by TCDi).
• For the potential modification, addition of approximately 20 participants enrolled in Part C, TCD = 170 cm/sec by nonimaging TCD or = 155
cm/sec by TCDi.
4. Transfusion within 30 days prior to signing the ICF.
5. Renal dysfunction requiring chronic dialysis or creatinine = 1.5 mg/dL.
6. Hepatic dysfunction characterized by alanine aminotransferase (ALT) > 4× upper limit of normal (ULN) for age.
7. Clinically relevant cardiac abnormality, in the opinion of the Investigator, such as:
• Hemodynamically significant heart disease, eg, congenital heart defect, uncompensated heart failure, or any unstable cardiac condition
• An arrhythmic heart condition requiring medical therapy
8. QTcF > 450 msec, congenital long QT syndrome, second or third degree heart block at rest (with the exception of asymptomatic Mobitz type
I second degree heart block).
9. Received an investigational drug within 30 days or 5 half-lives, whichever is longer, of signing the ICF.
10. Heavy smoker (defined as smoking more than 10 cigarettes/day or its nicotine equivalent including e-cigarettes).
11. Unlikely to comply with the study procedures.
12. Other medical, psychological, or addictive condition that, in the opinion of the Investigator, would confound or interfere with evaluation of
safety and/or PK of the investigational drug, prevent compliance with the study protocol, or preclude informed consent.
13. Participants who do not have a TCD window (Part B and C only) (ie, participants who are unable to have a TCD due to skull ossification).
14. For Part C only, prior participation in Part B.
15. Active symptomatic COVID-19 infection.
In addition, for Part D only:
16. Body weight < 5 kg for 1 month prior to the screening visit and at the screening visit.
17. Any condition affecting drug absorption, such as major surgery involving the stomach or small intestine (prior cholecystectomy is
acceptable).
18. 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).
19. Clinically significant bacterial, fungal, parasitic, or viral infection currently receiving or that will require therapy.
• Participants with acute bacterial infection requiring antibiotic use should delay screening until the course of antibiotic therapy has been
completed and the infection has resolved, in the opinion of the investigator.
• Known active hepatitis A, B, or C infection or human immunodeficiency virus (HIV)-positive.
• Known active malaria.

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
ame: Part A: Pharmacokinetic profile of GBT440 including maximum concentration;Timepoints: Pre-dose to Day 15;Measure: Pharmacokinetic profile;Name: Part A: Pharmacokinetic profile of GBT440 including the time taken to reach the maximum concentration;Timepoints: Pre-dose to Day 15;Measure: Pharmacokinetic profile;Name: Part A: Pharmacokinetic profile of GBT440 including the total drug concentration over time;Timepoints: Pre-dose to Day 15;Measure: Pharmacokinetic profile;Name: Part B: Change in hemoglobin;Timepoints: Baseline to Week 24;Measure: Hemoglobin in Blood;Name: Part C: Change in cerebral blood flow;Timepoints: Baseline to Week 48;Measure: TAMM TCD velocity;Name: Part D;Timepoints: During Study Duration;Measure: Incidence of TEAEs and SAEs

Secondary Outcome Measures

Name	Time	Method

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