Sickle Cell AnemiaPhase 2NCT02556099
EXTEND EXpanding Treatment for Existing Neurological Disease
A Phase 2 study testing Hydroxyurea in people with Sickle Cell Anemia, run by Children's Hospital Medical Center, Cincinnati at 1 site in Jamaica.
Trial 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. Read more about this study
- Who is it for?
- Ages 2 to 17 years
- Conditions the study is for
- Sickle Cell Anemia
- What is being tested?
- Hydroxyurea
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 43 participants
- Where
- 1 siteJamaica
- Study dates
- Aug 2014to 16 Jan 2023
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 to 17 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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
Who cannot join
- 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):
Show all 19Show fewer
- 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)
Trial locations and contacts
1 site in 1 country.
About this study
Official title: EXpanding Treatment for Existing Neurological Disease (EXTEND)
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.
Read the 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.
- Conditions
- Sickle Cell Anemia
- Being tested
- Hydroxyurea
- Medical subject headings
- Anemia, Sickle Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
HydroxyureaDrug
drug to be administered
| Study group | Role | What they receive |
|---|---|---|
| Hydroxyurea Treatment | Experimental | 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. Receives: Drug: Hydroxyurea |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 18 months
Secondary outcomes (5)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline, after 18 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Sep 2015 (estimated)
- Study startAug 2014
- Primary completion16 Jan 2023
- Study completion16 Jan 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Sickle Cell AnemiaStudies of the same condition, open and under way.
- More trials run by Children's Hospital Medical Center, CincinnatiThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 43 participants (actual)
Sponsor and investigators
- Lead sponsor
- Children's Hospital Medical Center, Cincinnati
- Sponsor type
- University, hospital or other
- Collaborators
- Caribbean Institute for Health Research (CAIHR)
- Responsible party
- Sponsor
- Investigators
- Russell Ware, MD, PhD, Principal investigator, Cincinnati Children's
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02556099
- Sponsor's protocol ID
- 2014-2875 EXTEND
- Status last verified
- Jul 2025
- First submitted
- 18 May 2015
- Last updated
- 22 Aug 2025
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Power-Hays A, McElhinney KE, Williams TN, Mochamah G, Olupot-Olupot P, Paasi G, Reid ME, Rankine-Mullings AE, Opoka RO, John CC, McGann PT, Quinn CT, Punt NC, Smart LR, Stuber SE, Latham TS, Vinks AA, Ware RE. Hydroxyurea pharmacokinetics in children with sickle cell anemia across different global populations. Blood Adv. 2026 Jan 27;10(2):418-427. doi: 10.1182/bloodadvances.2025017254.
PubMed 41026975Rankine-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.
PubMed 27619954
Study at a glance
From the registry record, last updated by the sponsor on 22 Aug 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- EXpanding Treatment for Existing Neurological Disease (EXTEND)
- ClinicalTrials.gov ID
- NCT02556099
- Acronym / sponsor ID
- 2014-2875 EXTEND
- Conditions
- Sickle Cell Anemia
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 43 participants (actual)
- Lead sponsor
- Children's Hospital Medical Center, CincinnatiUniversity, hospital or other
- Collaborators
- Caribbean Institute for Health Research (CAIHR)
- Study start
- Aug 2014
- Primary completion
- 16 Jan 2023 (actual)
- Study completion
- 16 Jan 2023 (actual)
- First posted
- 22 Sep 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Hydroxyurea Treatment | Experimental | Drug: HydroxyureaHydroxyurea 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. |
Who may qualify
- Ages
- 2 to 17 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (19 listed)
- Inability to take or tolerate daily oral hydroxyurea, including
- Abnormal historical laboratory values (most recent pre-enrollment values unless previously enrolled in SCATE):
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Hydroxyureadrug to be administered | Drug | Hydroxyurea Treatment |
Primary outcome
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.
5 secondary outcomes
Serial TCD velocities
Time frame: Screening, Baseline, month 6, month 12, month 18
The cumulative incidence of neurological events
Time frame: Screening/Baseline and approximately 3 years after the first enrollment
Cumulative Incidence of Non-Neurological Events
Time frame: Screening/Baseline and approximately 3 years after the first enrollment
Quality of Life Assessment
Time frame: Baseline, 18 months, and approximately 3 years after the first enrollment
Neuropsychological Assessment
Time frame: Baseline, after 18 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Aug 2025.
- Derived from this study: PubMed 41026975Power-Hays A, McElhinney KE, Williams TN, Mochamah G, Olupot-Olupot P, Paasi G, Reid ME, Rankine-Mullings AE, Opoka RO, John CC, McGann PT, Quinn CT, Punt NC, Smart LR, Stuber SE, Latham TS, Vinks AA, Ware RE. Hydroxyurea pharmacokinetics in children with sickle cell anemia across different global populations. Blood Adv. 2026 Jan 27;10(2):418-427. doi: 10.1182/bloodadvances.2025017254.
- Derived from this study: PubMed 27619954Rankine-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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Russell Ware, MD, PhD principal investigator
Cincinnati Children's
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Hydroxyurea in people with Sickle Cell Anemia, run by Children's Hospital Medical Center, Cincinnati at 1 site in Jamaica.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Aug 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Jamaica. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum Time-Averaged Mean velocity (TAMV) on TCD exam (time frame: 18 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02556099, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Aug 2025.