EXTEND EXpanding Treatment for Existing Neurological Disease

  • End date
    Dec 24, 2024
  • participants needed
  • sponsor
    Children's Hospital Medical Center, Cincinnati
Updated on 24 April 2022
transcranial doppler ultrasonography


The primary goal of the Phase II EXTEND trial is to investigate the effects of open-label hydroxyurea treatment, escalated to maximum tolerated dose, for children with Sickle Cell Anemia and either conditional (170 - 199 cm/sec) or abnormal (≥200 cm/sec) Transcranial Doppler velocities. The primary endpoint will be measured after 18 months of hydroxyurea but treatment will continue until a common study termination date.


Hydroxyurea treatment: Participants will be treated with open-label hydroxyurea, available as 500 mg capsules or liquid (100 mg/mL). Hydroxyurea will be administered once daily by mouth. Participants will be monitored monthly to maximum tolerated dose and quarterly thereafter with periodic clinical evaluations, laboratory tests, and transcranial doppler examinations every 6 months.

Hydroxyurea will be titrated to the maximum tolerated dose as defined by mild marrow suppression, even if the participant has clinical well-being at a lower hydroxyurea dose. The target absolute neutrophil count (ANC)on hydroxyurea therapy will be < 3.0 x 109/L, but the marrow suppression should also include reduction of the reticulocyte count. Hydroxyurea dosing will commence at 20 mg/kg/day. Dose escalation will occur in 5 mg/kg/day increments, adjusting every 8 weeks unless dose-limiting hematological toxicity occurs (defined as ANC < 1.0 x 109/L, hemoglobin concentration < 5 gm/dL or 20% below baseline, absolute reticulocyte count < 80 x 109/L unless hemoglobin concentration >9.0 gm/dL, or platelet count < 80 x 109/L) or the target neutropenia (ANC < 3.0 x 109/L) is achieved. Based on pilot data and experience in other clinical trials, most pediatric participants require hydroxyurea doses of 20-30 mg/kg/day to reach this target absolute neutrophil count .

After reaching maximum tolerated dose, minor hydroxyurea dose adjustments can be made periodically, as necessary based on weight changes and blood counts, to maintain the optimal laboratory response and to prevent dose-related toxicity. If the absolute neutrophil count (ANC) rises above the target range on 2 consecutive visits, compliance will be reinforced and the dose may be adjusted by 2.5 mg/kg/day at eight week intervals to a maximum of 35 mg/kg/day or 2000 mg/day. For hydroxyurea dosing, the current body weight will be used, with dose escalations guided by hematological toxicity. Hydroxyurea will be reduced or even temporarily discontinued for hematological toxicities, e.g., ANC < 1.0 x 109/L, hemoglobin < 5.0 gm/dL, or 20% below baseline, absolute reticulocyte count < 80 x 109/L unless hemoglobin concentration > 9.0 gm/dL, or platelets < 80 x 109/L.

Condition Sickle Cell Anemia
Treatment hydroxyurea
Clinical Study IdentifierNCT02556099
SponsorChildren's Hospital Medical Center, Cincinnati
Last Modified on24 April 2022


Yes No Not Sure

Inclusion Criteria

Pediatric participants with a severe form of sickle cell anemia (HbSS, HbSβ0 thalassemia, HbSD, HbSOArab)
Age: ≥ 2 and ≤ 17 years of age, at the time of enrollment
Time-averaged maximum velocity (TAMV) TCD Velocity in the conditional (170 - 199 cm/sec) or abnormal (≥200 cm/sec) range by Transcranial Doppler ultrasonography examination within 6 months of enrollment, abnormal or conditional TCD velocity and currently on commercial hydroxyurea for primary stroke prevention, or previously enrolled in SCATE, a previous stroke with abnormal or conditional TCD prior to stroke event
Parent or guardian willing and able to provide informed consent and child gives assent
Ability to comply with study related treatments, evaluations, and follow- up visits

Exclusion Criteria

Inability to take or tolerate daily oral hydroxyurea, including
Known allergy to hydroxyurea therapy
Known positive serology to HIV infection
Known malignancy
Current lactation
Abnormal historical laboratory values (most recent pre-enrollment values unless
Hemoglobin concentration < 6.0 gm/dL
previously enrolled in SCATE)
Absolute reticulocyte count < 100 x 109/L with a hemoglobin concentration < 8.0 gm/dL
White Blood Cell (WBC) count < 3.0 x 109/L
Absolute neutrophil count (ANC) < 1.0 x 109/L
Platelet count < 100 x 109/L
Use of therapeutic agents for sickle cell disease (e.g., hydroxyurea, arginine
Current participation in other therapeutic clinical trials, except SCATE
Known serum creatinine more than twice the upper limit for age AND
decitabine, magnesium, chronic transfusions) within 3 months of enrollment
0 mg/dL
unless they have an abnormal TCD velocity and receive commercial hydroxyurea
for primary stroke prevention or were previously enrolled in the SCATE study
Pregnancy (for post-menarchal females only)
or for secondary stroke prevention in a child with a previous stroke
Erythrocyte transfusion within the past 2 months
Previous stem cell transplant or other myelosuppressive therapy (unless they have an abnormal TCD velocity and receive commercial hydroxyurea for primary stroke prevention or for secondary stroke prevention in a child with a previous stroke or were previously enrolled in SCATE)
Any condition or chronic illness, which in the opinion of the clinical investigator
makes participation ill-advised
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