Back to resultsEXTEND EXpanding Treatment for Existing Neurological Disease
Primary Purpose
Sickle Cell Anemia
Status
Recruiting
Phase
Phase 2
Locations
Jamaica
Study Type
Interventional
Intervention
Hydroxyurea
Sponsored by
About this trial
This is an interventional treatment trial for Sickle Cell Anemia
Eligibility Criteria
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)
Sites / Locations
- Sickle Cell UnitRecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Hydroxyurea Treatment
Arm Description
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.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
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.
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.
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.
Full Information
NCT ID
NCT02556099
First Posted
May 18, 2015
Last Updated
January 20, 2023
Sponsor
Children's Hospital Medical Center, Cincinnati
Collaborators
Caribbean Institute for Health Research (CAIHR)
1. Study Identification
Unique Protocol Identification Number
NCT02556099
Brief Title
EXTEND EXpanding Treatment for Existing Neurological Disease
Official Title
EXpanding Treatment for Existing Neurological Disease (EXTEND)
Study Type
Interventional
2. Study Status
Record Verification Date
April 2022
Overall Recruitment Status
Recruiting
Study Start Date
August 2014 (undefined)
Primary Completion Date
December 2024 (Anticipated)
Study Completion Date
December 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Children's Hospital Medical Center, Cincinnati
Collaborators
Caribbean Institute for Health Research (CAIHR)
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell Anemia
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
100 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Hydroxyurea Treatment
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Hydroxyurea
Intervention Description
drug to be administered
Primary Outcome Measure Information:
Title
Maximum Time-Averaged Mean velocity (TAMV) on TCD exam
Description
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.
Time Frame
18 months
Secondary Outcome Measure Information:
Title
Serial TCD velocities
Description
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.
Time Frame
Screening, Baseline, month 6, month 12, month 18
Title
The cumulative incidence of neurological events
Description
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.
Time Frame
Screening/Baseline and approximately 3 years after the first enrollment
Title
Cumulative Incidence of Non-Neurological Events
Description
The cumulative incidence of non-neurological sickle cell-related events, including vaso-occlusion and splenic sequestration, will be estimated over the treatment period.
Time Frame
Screening/Baseline and approximately 3 years after the first enrollment
Title
Quality of Life Assessment
Description
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.
Time Frame
Baseline, 18 months, and approximately 3 years after the first enrollment
Title
Neuropsychological Assessment
Description
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.
Time Frame
Baseline, after 18 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Russell Ware, MD, PhD
Phone
513-803-4597
Email
russell.ware@cchmc.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Russell Ware, MD, PhD
Organizational Affiliation
Cincinnati Children's
Official's Role
Principal Investigator
Facility Information:
Facility Name
Sickle Cell Unit
City
Kingston
Country
Jamaica
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marvin Reid, MB BS PhD
Phone
876-927-1884
Email
marvin.reid@uwimona.edu.jm
First Name & Middle Initial & Last Name & Degree
Margaret Wisdom-Phipps, RN
Email
Margaret.wisdomphipps@uwimona.edu.jm
12. IPD Sharing Statement
Citations:
PubMed Identifier
27619954
Citation
Rankine-Mullings AE, Little CR, Reid ME, Soares DP, Taylor-Bryan C, Knight-Madden JM, Stuber SE, Badaloo AV, Aldred K, Wisdom-Phipps ME, Latham T, Ware RE. EXpanding Treatment for Existing Neurological Disease (EXTEND): An Open-Label Phase II Clinical Trial of Hydroxyurea Treatment in Sickle Cell Anemia. JMIR Res Protoc. 2016 Sep 12;5(3):e185. doi: 10.2196/resprot.5872.
Results Reference
derived
Learn more about this trial
EXTEND EXpanding Treatment for Existing Neurological Disease
We'll reach out to this number within 24 hrs