EXTEND EXpanding Treatment for Existing Neurological Disease

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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EXpanding Treatment for Existing Neurological Disease (EXTEND)

Conditions
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Sickle Cell Anemia

Intervention / Treatment
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* Drug: Hydroxyurea


Participation Criteria
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Eligibility Criteria
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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 previously enrolled in SCATE): Hemoglobin concentration < 6.0 gm/dL 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, decitabine, magnesium, chronic transfusions) within 3 months of enrollment unless they have an abnormal TCD velocity and receive commercial hydroxyurea for primary stroke prevention or were previously enrolled in the SCATE study or for secondary stroke prevention in a child with a previous stroke. Current participation in other therapeutic clinical trials, except SCATE Known serum creatinine more than twice the upper limit for age AND 1.0 mg/dL Any condition or chronic illness, which in the opinion of the clinical investigator makes participation ill-advised Pregnancy (for post-menarchal females only) 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)

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hydroxyurea Treatment<br>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. | Drug: Hydroxyurea<br>* drug to be administered<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Time-Averaged Mean velocity (TAMV) on TCD exam | The primary endpoint of the EXTEND trial is the maximum Time-Averaged Mean velocity (TAMV) on TCD exam performed after 18 months of hydroxyurea treatment, compared to pre-treatment velocity. | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serial TCD velocities | Serial TCD velocities will be measured every 6 months during the trial. The outcome measure will be the highest TAMV obtained in the main intracranial arteries: middle cerebral artery (MCA), internal carotid artery (ICA), or internal carotid bifurcation (Bif). The TCD velocities at 6-month intervals of hydroxyurea treatment, compared to the baseline pre-treatment TCD values, will describe the potential efficacy of hydroxyurea to reduce elevated TCD velocities. | Screening, Baseline, month 6, month 12, month 18 | 
| The cumulative incidence of neurological events | The cumulative incidence of neurological events, which include both stroke and non-stroke neurological events, will be determined over the treatment period. All potential stroke events will be centrally reviewed by an independent MCC-appointed medical monitor. | Screening/Baseline and approximately 3 years after the first enrollment | 
| Cumulative Incidence of Non-Neurological Events | The cumulative incidence of non-neurological sickle cell-related events, including vaso-occlusion and splenic sequestration, will be estimated over the treatment period. | Screening/Baseline and approximately 3 years after the first enrollment | 
| Quality of Life Assessment | Quality of Life will be measured at baseline, after 18 months of hydroxyurea treatment, and at study exit using the PedsQL 4.0. The outcome measure will be the overall score obtained by this Quality of Life instrument, as scored by the parent or caregiver. This Quality of Life instrument has been previously standardized and validated in children with chronic illness. A sickle cell disease-specific PedsQL instrument may also be used if available. | Baseline, 18 months, and approximately 3 years after the first enrollment | 
| Neuropsychological Assessment | Neurodevelopment will be measured at baseline and after 18 months of hydroxyurea treatment, using a standardized neuropsychological assessment tool such as the Wechsler assessments of intelligence. The neuropsychological assessment will be administered as developmentally appropriate, and thus may not be administered to all participants. The outcome measure will be the overall score obtained by this tool. | Baseline, after 18 months |