- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02556099
EXTEND EXpanding Treatment for Existing Neurological Disease
EXpanding Treatment for Existing Neurological Disease (EXTEND)
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
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.
Study Type
Enrollment (Estimated)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: Russell Ware, MD, PhD
- Phone Number: 513-803-4597
- Email: russell.ware@cchmc.org
Study Locations
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-
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Kingston, Jamaica
- Sickle Cell Unit
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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)
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Hydroxyurea Treatment
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 to be administered
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Maximum Time-Averaged Mean velocity (TAMV) on TCD exam
Time Frame: 18 months
|
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.
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18 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Serial TCD velocities
Time Frame: Screening, Baseline, month 6, month 12, month 18
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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.
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Screening, Baseline, month 6, month 12, month 18
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The cumulative incidence of neurological events
Time Frame: Screening/Baseline and approximately 3 years after the first enrollment
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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.
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Screening/Baseline and approximately 3 years after the first enrollment
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Cumulative Incidence of Non-Neurological Events
Time Frame: Screening/Baseline and approximately 3 years after the first enrollment
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The cumulative incidence of non-neurological sickle cell-related events, including vaso-occlusion and splenic sequestration, will be estimated over the treatment period.
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Screening/Baseline and approximately 3 years after the first enrollment
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Quality of Life Assessment
Time Frame: Baseline, 18 months, and approximately 3 years after the first enrollment
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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.
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Baseline, 18 months, and approximately 3 years after the first enrollment
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Neuropsychological Assessment
Time Frame: Baseline, after 18 months
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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.
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Baseline, after 18 months
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Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Russell Ware, MD, PhD, Cincinnati Children's
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Hematologic Diseases
- Genetic Diseases, Inborn
- Anemia
- Anemia, Hemolytic, Congenital
- Anemia, Hemolytic
- Hemoglobinopathies
- Nervous System Diseases
- Anemia, Sickle Cell
- Molecular Mechanisms of Pharmacological Action
- Nucleic Acid Synthesis Inhibitors
- Enzyme Inhibitors
- Antineoplastic Agents
- Antisickling Agents
- Hydroxyurea
Other Study ID Numbers
- 2014-2875 EXTEND
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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