EXTEND EXpanding Treatment for Existing Neurological Disease
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|ClinicalTrials.gov Identifier: NCT02556099|
Recruitment Status : Recruiting
First Posted : September 22, 2015
Last Update Posted : August 7, 2018
|Condition or disease||Intervention/treatment||Phase|
|Sickle Cell Anemia||Drug: Hydroxyurea||Phase 2|
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 :||Interventional (Clinical Trial)|
|Estimated Enrollment :||100 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||EXpanding Treatment for Existing Neurological Disease (EXTEND)|
|Study Start Date :||August 2014|
|Estimated Primary Completion Date :||December 2022|
|Estimated Study Completion Date :||December 2024|
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
- 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.
- Serial TCD velocities [ Time Frame: Screening, Baseline, month 6, month 12, month 18 ]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.
- The cumulative incidence of neurological events [ Time Frame: Screening/Baseline and approximately 3 years after the first enrollment ]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.
- Cumulative Incidence of Non-Neurological Events [ Time Frame: Screening/Baseline and approximately 3 years after the first enrollment ]The cumulative incidence of non-neurological sickle cell-related events, including vaso-occlusion and splenic sequestration, will be estimated over the treatment period.
- Quality of Life [ Time Frame: Baseline, 18 months, and approximately 3 years after the first enrollment ]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.
- Neuropsychological Assessment [ Time Frame: Baseline, after 18 months ]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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02556099
|Contact: Russell Ware, MD, PhDfirstname.lastname@example.org|
|Contact: Courtney Little, BSN, RNemail@example.com|
|Principal Investigator:||Russell Ware, MD, PhD||Cincinnati Children's|