NOTCHES1: Novel Therapies in Children with Sickle Cell Disease

A Phase IIa, Open-label, Single and Multiple Dose Study to Evaluate the Pharmacokinetics, Safety, Tolerability and Exploratory Treatment Effect of GBT440 in Adolescents with Sickle Cell Disease


Sickle Cell Disease

Phase I/II

Diseases Treated:

Sickle cell disease

Eligibility Overview:

  • 12 to 17 years old
  • Diagnosis of sickle cell disease
  • Able to swallow capsules


  1. Brief Summary

    Currently, there are no approved drugs that specifically target the underlying mechanism of sickle cell disease. This study will evaluate the investigational drug GBT440, a small molecule allosteric modulator of hemoglobin oxygen affinity that is designed to block polymerization and the sickling of red blood cells.

    In laboratory studies, GBT440 increased hemoglobin’s affinity for oxygen and showed a high specificity of binding to hemoglobin. Results also indicated improved sickle blood viscosity, deformability and filterability. Preliminary studies in healthy adults and adults with sickle cell disease have shown the drug to be well tolerated.

    This two-part study will evaluate GBT440 in adolescents. Part A will evaluate single dose GBT440; Part B will test multiple doses of GBT440 for 28 days.

    Primary Objectives

    • Part A: To characterize the pharmacokinetics of GBT440 in plasma and whole blood following a single dose
    • Part B: To evaluate the safety and tolerability of GBT440 following multiple doses

    Eligibility Criteria

    Inclusion criteria include:

    • 12 to 17 years old
    • Diagnosis of homozygous hemoglobin SS (HbSS0) or hemoglobin S beta thalassemia (HbSβ0 thal)
    • Weight
      • Part A: ≥ 40 kg
      • Part B: ≥ 30 kg
    • If taking hydroxyurea, must have been stable for at least 3 months with no anticipated need for dose adjustments during the study and no sign of hematological toxicity
    • Hemoglobin (Hb):
      • Part A – No restriction
      • Part B - Hb ≤ 10.0 g/dL
    • Able to swallow capsules

    Exclusion Criteria include:

    • Any one of the following requiring medical attention within 14 days prior to consent:
      • Vaso-occlusive crisis (VOC)
      • Acute chest syndrome (ACS)
      • Stroke
      • Splenic sequestration crisis
      • Dactylitis
    • Requires chronic transfusion therapy
    • Smokes more than 10 cigarettes a day or nicotine equivalent, including e-cigarettes
    • Renal dysfunction requiring chronic dialysis or creatinine ≥ 1.5 mg/dL
    • History of hepatic compromise or severe liver disease

    Study Sites

    St. Jude Children’s Research Hospital
    Memphis, Tennessee

    Collaborating sites in and outside the U.S.

  2. About this study

    Sickle cell disease is the most common inherited blood disorder in the U.S. and affects about 100,000 Americans. It is most common among African-Americans and Hispanics. Treatments for sickle cell disease include blood transfusions, medications and stem cell transplants.

    Normal, healthy red blood cells are soft and round. They allow the blood to flow freely in the body. Sickle cell patients have red blood cells that are hard and shaped like a banana or sickle. These blood cells prevent the normal flow of blood in the body.

    This study will test a new medicine called GBT440 to treat sickle cell disease. GBT440 is a drug that might increase the number of red blood cells and reduce the number of sickled cells in the blood. GBT440 is an investigational drug and has not yet been approved by the U.S. Food and Drug Administration (FDA). Although GBT440 has been given to adults with sickle cell disease, it has not been given to teenagers.

    There are two parts to this study: Part A and Part B. Participants in Part A will take one dose of GBT440 and visit the St. Jude outpatient Hematology Clinic seven times. Participants in Part B will take GBT440 once a day for 28 days in a row and visit the St. Jude clinic eight times.

    Purpose of this clinical trial

    The main purpose of this study is to find out how the teenage body handles GBT440 and how safe the drug is for this age group.

    Eligibility overview

    • 12 to 17 years old
    • Diagnosis of sickle cell disease
    • Able to swallow capsules
  3. NOTCHES1  Quick View
    Sponsor  Global Blood Therapeutics identifier  NCT02850406
    Trial start date June 2016
    Estimated enrollment 30
    Study type Interventional
    Study phase Phase II

    Sickle cell disease

    Ages 12 to 17 years old
    Principal investigator Jeremie Estepp, MD
    Study site St. Jude Children's Research Hospital and collaborating sites in and outside the U.S.
    For a consultation or to discuss NOTCHES1 St. Jude Physician/Patient Referral Office


St. Jude Children’s Research Hospital
262 Danny Thomas Place
Memphis, TN 38105  USA
Voice: 1-888-226-4343 or 901-595-4055
24-Hour Emergency Access Pager: 1-800-349-4334

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