Anemia, Sickle Cell, Cerebrovascular Accident, Hematologic Diseases, Hemochromatosis
Conditions
Keywords
Blood Diseases
Brief summary
The purpose of this study is to compare standard therapy (transfusions and chelation) with alternative therapy (hydroxyurea and phlebotomy) for the prevention of secondary stroke and management of iron overload in children with sickle cell anemia (SCA).
Detailed description
BACKGROUND: Stroke occurs in 10% of children with SCA and has a very high risk of recurrence without therapy. Affected children receive chronic erythrocyte transfusions to prevent a secondary stroke, which are effective but have limited long-term utility due to transmission of infectious agents, erythrocyte alloantibody and autoantibody formation, and iron overload. Transfusion acquired iron overload can cause chronic organ damage with hepatic fibrosis and cirrhosis, poor growth and development, cardiac arrhythmias, and early sudden death in young patients with SCA and stroke. An alternative to transfusions for secondary stroke prevention that also addresses the issue of transfusion acquired iron overload is clearly needed. Hydroxyurea can prevent acute vaso-occlusive events in SCA, but its utility for cerebrovascular disease and for the prevention of secondary stroke in SCA is not proven. Pilot data indicate hydroxyurea can prevent stroke recurrence in children with SCA; after transfusions are discontinued, serial phlebotomy reduces iron burden. DESIGN NARRATIVE: This is a Phase III randomized clinical trial for children with SCA. The hypothesis is that hydroxyurea and phlebotomy can maintain an acceptable stroke recurrence rate and significantly reduce the hepatic iron burden. The primary aim is to compare standard therapy (transfusions and chelation) with alternative therapy (hydroxyurea and phlebotomy) for the prevention of secondary stroke and management of iron overload. Additional aims include comparisons of growth and development, frequency of non-stroke neurological and other sickle-related events, and quality of life. The use of hydroxyurea for secondary stroke prevention, coupled with removal of excess iron by phlebotomy, would represent a significant improvement in the management of individuals with SCA and stroke. If hydroxyurea is effective for the prevention of secondary stroke, it may also be beneficial for other children with SCA and cerebrovascular disease, including those at risk for primary stroke. The trial includes approximately 130 children (5.0-18.9 years of age with 65 subjects per treatment arm) with SCA who have had symptomatic cerebral infarctions and have been treated with red cell transfusions for at least 18 months. After completing baseline screening studies, half the participants will be switched to a therapeutic program of hydroxyurea and phlebotomy. Half of the participants will remain on transfusion and chelation. The composite primary endpoint in this study is to compare two modalities of treatment for the prevention of secondary stroke and management of iron overload. The impetus for this trial is the fact that long-term transfusion and chelation therapy in children is difficult, is frequently unsuccessful, and is often complicated by severe symptomatic iron overload, particularly of the heart, lungs, and liver.
Interventions
PROCEDURERed Cell Transfusions
Red Blood Cell Transfusions
PROCEDUREIron Chelation
Iron Chelation Therapy
DRUGHydroxyurea
Hydroxyurea
PROCEDUREPhlebotomy
Phlebotomy
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
St. Jude Children's Research Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Pediatric subjects with severe forms of sickle cell anemia (HbSS, HbSβ0 thalassemia, HbSOArab) * Age range of 5.0-18.9 years, inclusive, at the time of study entry * Initial (primary) completed overt clinical stroke after the age of one year (12 months) with documented infarction on brain computed tomography (CT) or magnetic resonance imaging (MRI) * At least 18 months of chronic monthly erythrocyte transfusions since primary stroke * Transfusional iron overload, defined as a previously documented liver iron concentration (LIC) greater than or equal to 5.0 mg Fe per gram of dry weight liver or serum ferritin greater than or equal to 500 ng/mL on two independent measurements * Adequate monthly erythrocyte transfusions with average HbS less than or equal to 45% (the upper limit of the established academic community standard) in the 6 months prior to study entry * Parent or guardian willing and able to provide informed consent with verbal or written assent from the child (less than 18 years of age) or subject willing and able to provide informed consent (older than 18 years of age) * Ability to comply with study-related treatments, evaluations, and follow-up
Exclusion criteria
* Inability to receive or tolerate chronic red blood cell (RBC) transfusion therapy, due to any of the following: 1. Multiple RBC alloantibodies making cross-matching difficult or impossible 2. RBC autoantibodies making cross-matching difficult or impossible 3. Religious objection to transfusions that preclude their chronic use 4. Non-compliance with transfusions in the 6 months prior to study entry (temporary exclusion) * Inability to take or tolerate daily oral hydroxyurea, due to any of the following: 1. Known allergy to hydroxyurea therapy 2. HIV infection 3. Cancer 4. Pregnant or breastfeeding 5. Previous stem cell transplant or other myelosuppressive therapy * Clinical and laboratory evidence of hypersplenism, due to any of the following: 1. Palpable splenomegaly greater than 5 cm below the left costal margin and 2. Transfusion requirement greater than 250 mL/kg in the 12 months prior to study entry * Abnormal laboratory values at initial evaluation (temporary exclusion): 1. Pre-transfusion hemoglobin concentration less than 7.0 gm/dL 2. White blood cell (WBC) count less than 3.0 x 109/L 3. Absolute neutrophil count (ANC) less than 1.5 x 109/L 4. Platelet count less than 100 x 109/L 5. Serum creatinine more than twice the upper limit for age OR greater than or equal to 1.0 mg/dL * Current participation in other therapeutic clinical trials * Current use of other therapeutic agents for SCA (e.g., arginine, decitabine, magnesium) * Any condition or chronic illness, such as a positive tuberculin (PPD) test, which in the opinion of the study physician makes study participation ill-advised * Inability or unwillingness to complete required screening studies, including blood tests, brain MRI/magnetic resonance angiography (MRA), and liver biopsy * A sibling enrolled in SWiTCH
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of an Adjudicated Secondary Stroke During the 30-month Treatment Period | Because the study was terminated early, time frame is from beginning of treatment until end of treatment (up to 30 Months) | Secondary stroke is the first component of the composite primary endpoint and considers the number of participants with recurrent secondary stroke events during 30 months of treatment. Stroke was defined as any clinical event with brain injury due to vascular disease. All neurological events underwent formal stroke adjudication. |
| Liver Iron Content (LIC) Change-from-baseline | Because the study was terminated early, time frame is from beginning of treatment until end of treatment (up to 30 Months) | LIC change-from-baseline is the second component of the composite primary endpoint. LIC was measured by quantitative liver biopsy at baseline and at 30 months or exit from the study.LIC values were transformed into Log10 values prior to computing the change from baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) | Baseline, mid-point (week 64), and study exit after up to 30-month treatment period (due to study termination) | The PedsQL(TM) Measurement Model is a modular approach to measuring health-related quality of life (HRQOL) in healthy children and adolescents and those with acute and chronic health conditions. It has a Likert 5-points scale (never to almost always) which were transformed to a 0 to 100 scale based on the PedsQL scoring algorithms, higher scores indicating better quality of life characteristics. |
| Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) | Baseline, midpoint (week 64), and study exit (up to 30 months of treatment) | The PedsQLTM Measurement Model is a modular approach to measuring health-related quality of life (HRQOL) in healthy children and adolescents and those with acute and chronic health conditions. It has a Likert 5-points scale (never to almost always) which were transformed to a 0 to 100 scale based on the PedsQL scoring algorithms, higher scores indicating better quality of life characteristics. |
| Barthel Index (Change From Baseline) | Baseline and study exit after up to 30-month treatment period (due to study termination) | The Barthel Index is a measure of activities of daily living (ADL) and assesses the degree of disability in a particular participant. The index records indicators of independence in terms of the disability caused by impairments, such as those that may be sequelae of stroke. The index was used as a record of what the participant did, not as a record of what the participant could do. Barthel scores range from 0 to 100, with higher scores indicating greater independence in daily living activities (caring for oneself). |
| Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)-Excluding Verbal | Baseline and study exit after up to 30-month treatment period (due to study termination) | This test is designed to assess both broad and narrow cognitive abilities in children age 4 years and above as well as to measure major aspects of academic achievement in persons aged 2-90 years. Scaled scores range from 0-100. Higher scores mean better abilities/achievements. |
| Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)- Verbal Ability | Baseline and study exit after up to 30-month treatment period (due to study termination) | This test is designed to assess both broad and narrow cognitive abilities in children age 4 years and above as well as to measure major aspects of academic achievement in persons aged 2-90 years. Higher scores mean better abilities/achievements. Scaled scores range from 0-100. |
| Growth and Development - Height (Change From Baseline to Endpoint) | Baseline to end of study participation (up to 136 weeks) | — |
| Growth and Development - Weight (Change From Baseline to Endpoint) | baseline to end of study participation (up to 136 weeks) | — |
Countries
United States
Participant flow
Recruitment details
Phase III First Patient In: 31-October-2006; Last Patient Last Visit: 15-December-2010; 25 medical clinics in the United States of America.
Pre-assignment details
Participant qualification was initially evaluated by medical chart review and interview. Subsequent to subject consent, subjects were further screened to confirm eligibility. Screening included, in part, expert verification of initial stroke and of liver biopsy results prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Hydroxyurea/Phlebotomy 1: The Hydroxyurea/Phlebotomy group includes participants randomized to Alternative Treatment. Participants commenced hydroxyurea treatment at 20 mg/kg/day with step-wise escalation to maximum tolerated dose (MTD) defined by mild myelosuppression (absolute neutrophil count 2-4 x 10\^9/L). Transfusions continued for 4-9 months during an overlap phase using a modified schedule to protect against recurrent stroke during hydroxyurea dose escalation. Once MTD was reached and transfusions were discontinued, phlebotomy commenced with a target of 10 mL/kg (maximum volume 500mL) blood removed monthly to reduce iron burden. Lower phlebotomy volumes (5 mL/kg) were recommended if participants were excessively anemic (hemoglobin concentration 7.0-7.9 gm/dL); phlebotomy was not performed if the hemoglobin level was \<7.0 gm/dL. The total duration of study treatment was 30 months after randomization, with a final study visit scheduled 6-months after discontinuation of study treatments. | 67 |
| Transfusion/Chelation 2: The Transfusion/Chelation group includes participants randomized to Standard Treatment. Participants continued to receive monthly blood transfusions designed to maintain ≤30% HbS, with local discretion regarding type of transfusion (e.g., simple or erythrocytapheresis). These participants also received daily iron chelation typically with deferasirox (Exjade®). Children already on chelation initially maintained their current dose, while those starting deferasirox received 20 mg/kg/day, with dose escalation in both groups as indicated and tolerated. | 66 |
| Total | 133 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adjudicated stroke (study endpoint) | 7 | 0 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Protocol Violation | 5 | 1 |
| Overall Study | Study termination | 27 | 35 |
| Overall Study | Withdrawal by Subject | 2 | 3 |
Baseline characteristics
| Characteristic | Total | Transfusion/Chelation | Hydroxyurea/Phlebotomy |
|---|---|---|---|
| Age at index stroke | 5.9 years STANDARD_DEVIATION 2.87 | 6.2 years STANDARD_DEVIATION 2.75 | 5.6 years STANDARD_DEVIATION 2.97 |
| Age, Categorical <=18 years | 120 Participants | 60 Participants | 60 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 6 Participants | 7 Participants |
| Age Continuous | 13.1 years STANDARD_DEVIATION 3.89 | 13.3 years STANDARD_DEVIATION 3.76 | 13.0 years STANDARD_DEVIATION 4.05 |
| Duration of Transfusion | 7.2 years STANDARD_DEVIATION 3.72 | 7.0 years STANDARD_DEVIATION 3.61 | 7.4 years STANDARD_DEVIATION 3.85 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 127 Participants | 64 Participants | 63 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| History of recurrent stroke No | 119 participants | 62 participants | 57 participants |
| History of recurrent stroke Yes | 14 participants | 4 participants | 10 participants |
| History of splenomegaly No | 95 Participants | 50 Participants | 45 Participants |
| History of splenomegaly Yes | 38 Participants | 16 Participants | 22 Participants |
| Liver iron concentration | 14.5 mg ferritin/gram dry weight liver | 13.9 mg ferritin/gram dry weight liver | 14.5 mg ferritin/gram dry weight liver |
| Prior use of Desferal (deferoxamine mesylate) Missing | 4 participants | 3 participants | 1 participants |
| Prior use of Desferal (deferoxamine mesylate) No | 38 participants | 19 participants | 19 participants |
| Prior use of Desferal (deferoxamine mesylate) Yes | 91 participants | 44 participants | 47 participants |
| Prior use of Exjade (deferasirox) Missing | 4 participants | 3 participants | 1 participants |
| Prior use of Exjade (deferasirox) No | 17 participants | 8 participants | 9 participants |
| Prior use of Exjade (deferasirox) Yes | 112 participants | 55 participants | 57 participants |
| Prior use of hydroxyruea No | 125 participants | 63 participants | 62 participants |
| Prior use of hydroxyruea Yes | 8 participants | 3 participants | 5 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 126 Participants | 64 Participants | 62 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 133 participants | 66 participants | 67 participants |
| Sex: Female, Male Female | 61 Participants | 35 Participants | 26 Participants |
| Sex: Female, Male Male | 72 Participants | 31 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 65 / 67 | 65 / 66 |
| serious Total, serious adverse events | 29 / 67 | 14 / 66 |
Outcome results
Primary
Liver Iron Content (LIC) Change-from-baseline
LIC change-from-baseline is the second component of the composite primary endpoint. LIC was measured by quantitative liver biopsy at baseline and at 30 months or exit from the study.LIC values were transformed into Log10 values prior to computing the change from baseline.
Time frame: Because the study was terminated early, time frame is from beginning of treatment until end of treatment (up to 30 Months)
Population: Intent-to-treat AND both baseline and 30-month post-treatment LICs.
| Arm | Measure | Value (LOG_MEAN) | Dispersion |
|---|---|---|---|
| Hydroxyurea/Phlebotomy | Liver Iron Content (LIC) Change-from-baseline | -0.006 mg ferritin/gram dry weight liver | Standard Deviation 0.187 |
| Transfusion/Chelation | Liver Iron Content (LIC) Change-from-baseline | -0.120 mg ferritin/gram dry weight liver | Standard Deviation 0.387 |
Comparison: Concluding that Hydroxyurea/Phlebotomy group is better than the Transfusion/Chelation group required rejecting the STROKE null hypothesis (see previous primary endpoint analysis) in favor of the alternative: Hydroxyurea/Phlebotomy recurrent stroke rate is less than Transfusion/Chelation rate plus 0.20 AND rejecting the IRON null hypothesis in favor of the alternative: Hydroxyurea/Phlebotomy baseline-adjusted mean log10 transformed LIC is less than for Transfusion/Chelation.p-value: 0.144Mixed Models Analysis
Primary
Occurrence of an Adjudicated Secondary Stroke During the 30-month Treatment Period
Secondary stroke is the first component of the composite primary endpoint and considers the number of participants with recurrent secondary stroke events during 30 months of treatment. Stroke was defined as any clinical event with brain injury due to vascular disease. All neurological events underwent formal stroke adjudication.
Time frame: Because the study was terminated early, time frame is from beginning of treatment until end of treatment (up to 30 Months)
Population: The Intent-to-Treat population included all subjects who were randomized and who received any on-study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Hydroxyurea/Phlebotomy | Occurrence of an Adjudicated Secondary Stroke During the 30-month Treatment Period | Stroke | 7 participants |
| Hydroxyurea/Phlebotomy | Occurrence of an Adjudicated Secondary Stroke During the 30-month Treatment Period | No Stroke | 60 participants |
| Transfusion/Chelation | Occurrence of an Adjudicated Secondary Stroke During the 30-month Treatment Period | Stroke | 0 participants |
| Transfusion/Chelation | Occurrence of an Adjudicated Secondary Stroke During the 30-month Treatment Period | No Stroke | 66 participants |
Comparison: Concluding that Hydroxyurea/Phlebotomy group is better than the Transfusion/Chelation group required rejecting the STROKE null hypothesis in favor of the alternative: Hydroxyurea/Phlebotomy recurrent stroke rate is less than Transfusion/Chelation rate plus 0.20, the non-inferiority margin, AND rejecting the IRON null hypothesis in favor of the alternative: Hydroxyurea/Phlebotomy baseline-adjusted mean LIC is less than for Transfusion/Chelation (see next primary endpoint analysis).p-value: 0.214Log Rank
Secondary
Barthel Index (Change From Baseline)
The Barthel Index is a measure of activities of daily living (ADL) and assesses the degree of disability in a particular participant. The index records indicators of independence in terms of the disability caused by impairments, such as those that may be sequelae of stroke. The index was used as a record of what the participant did, not as a record of what the participant could do. Barthel scores range from 0 to 100, with higher scores indicating greater independence in daily living activities (caring for oneself).
Time frame: Baseline and study exit after up to 30-month treatment period (due to study termination)
Population: Intent-to-Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxyurea/Phlebotomy | Barthel Index (Change From Baseline) | -0.33 units on a scale | Standard Deviation 4.269 |
| Transfusion/Chelation | Barthel Index (Change From Baseline) | -0.53 units on a scale | Standard Deviation 6.316 |
Comparison: The change-from-baseline to endpoint scores were analyzed with an analysis of variance model (ANOVA) with treatment as stratum.p-value: 0.841ANOVA
Secondary
Growth and Development - Height (Change From Baseline to Endpoint)
Time frame: Baseline to end of study participation (up to 136 weeks)
Population: Intent-to-Treat with endpoint data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxyurea/Phlebotomy | Growth and Development - Height (Change From Baseline to Endpoint) | 4.40 cm | Standard Deviation 4.32 |
| Transfusion/Chelation | Growth and Development - Height (Change From Baseline to Endpoint) | 6.61 cm | Standard Deviation 5.87 |
p-value: 0.033ANCOVA
Secondary
Growth and Development - Weight (Change From Baseline to Endpoint)
Time frame: baseline to end of study participation (up to 136 weeks)
Population: Intent-to-Treat with endpoint data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxyurea/Phlebotomy | Growth and Development - Weight (Change From Baseline to Endpoint) | 3.83 kg | Standard Deviation 5.07 |
| Transfusion/Chelation | Growth and Development - Weight (Change From Baseline to Endpoint) | 6.36 kg | Standard Deviation 5.43 |
p-value: <0.01ANCOVA
Secondary
Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline)
The PedsQLTM Measurement Model is a modular approach to measuring health-related quality of life (HRQOL) in healthy children and adolescents and those with acute and chronic health conditions. It has a Likert 5-points scale (never to almost always) which were transformed to a 0 to 100 scale based on the PedsQL scoring algorithms, higher scores indicating better quality of life characteristics.
Time frame: Baseline, midpoint (week 64), and study exit (up to 30 months of treatment)
Population: Intent-to-Treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Hydroxyurea/Phlebotomy | Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) | Exit: School Functioning Score (n=55, 53) | 1.76 units on a scale | Standard Deviation 20.701 |
| Hydroxyurea/Phlebotomy | Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) | Midpoint: Social Functioning Score (n=46, 57) | 2.39 units on a scale | Standard Deviation 19.909 |
| Hydroxyurea/Phlebotomy | Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) | Exit: Social Functioning Score (n=54, 54) | 3.13 units on a scale | Standard Deviation 21.313 |
| Hydroxyurea/Phlebotomy | Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) | Exit: Emotional Functioning Score (n=55, 54) | 3.82 units on a scale | Standard Deviation 21.623 |
| Hydroxyurea/Phlebotomy | Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) | Midpoint: Total Functioning Score (n=47, 57) | 0.35 units on a scale | Standard Deviation 16.557 |
| Hydroxyurea/Phlebotomy | Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) | Exit: Physical Functioning Score (n=55, 54) | 3.41 units on a scale | Standard Deviation 17.639 |
| Hydroxyurea/Phlebotomy | Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) | Exit: Total Functioning Score (n=55, 54) | 2.90 units on a scale | Standard Deviation 16.154 |
| Hydroxyurea/Phlebotomy | Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) | Midpoint: Emotional Functioning Score (n=47, 57) | 1.06 units on a scale | Standard Deviation 18.236 |
| Hydroxyurea/Phlebotomy | Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) | Midpoint: Psychosocial Health Summary (n=47, 57) | 0.28 units on a scale | Standard Deviation 17.18 |
| Hydroxyurea/Phlebotomy | Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) | Midpoint: School Functioning Score (n=47, 57) | -1.03 units on a scale | Standard Deviation 24.437 |
| Hydroxyurea/Phlebotomy | Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) | Exit: Psychosocial Health Summary Score (n=57, 54) | 2.65 units on a scale | Standard Deviation 17.278 |
| Hydroxyurea/Phlebotomy | Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) | Midpoint: Physical Functioning Score (n=47, 57) | 0.46 units on a scale | Standard Deviation 22.642 |
| Transfusion/Chelation | Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) | Exit: Psychosocial Health Summary Score (n=57, 54) | 2.93 units on a scale | Standard Deviation 16.91 |
| Transfusion/Chelation | Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) | Midpoint: Social Functioning Score (n=46, 57) | 1.84 units on a scale | Standard Deviation 25.011 |
| Transfusion/Chelation | Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) | Midpoint: Emotional Functioning Score (n=47, 57) | 3.51 units on a scale | Standard Deviation 22.24 |
| Transfusion/Chelation | Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) | Exit: Emotional Functioning Score (n=55, 54) | 3.80 units on a scale | Standard Deviation 20.022 |
| Transfusion/Chelation | Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) | Midpoint: Physical Functioning Score (n=47, 57) | 3.18 units on a scale | Standard Deviation 16.308 |
| Transfusion/Chelation | Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) | Exit: Physical Functioning Score (n=55, 54) | 2.03 units on a scale | Standard Deviation 20.426 |
| Transfusion/Chelation | Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) | Midpoint: School Functioning Score (n=47, 57) | 4.56 units on a scale | Standard Deviation 21.615 |
| Transfusion/Chelation | Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) | Exit: Social Functioning Score (n=54, 54) | 2.87 units on a scale | Standard Deviation 21.732 |
| Transfusion/Chelation | Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) | Midpoint: Total Functioning Score (n=47, 57) | 3.26 units on a scale | Standard Deviation 16.23 |
| Transfusion/Chelation | Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) | Exit: Total Functioning Score (n=55, 54) | 2.62 units on a scale | Standard Deviation 16.593 |
| Transfusion/Chelation | Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) | Midpoint: Psychosocial Health Summary (n=47, 57) | 3.30 units on a scale | Standard Deviation 18.515 |
| Transfusion/Chelation | Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) | Exit: School Functioning Score (n=55, 53) | 2.74 units on a scale | Standard Deviation 20.418 |
Comparison: The change-from-baseline scores were analyzed with an analysis of variance model (ANOVA) with treatment as stratum.p-value: >0.05ANOVA
Secondary
Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline)
The PedsQL(TM) Measurement Model is a modular approach to measuring health-related quality of life (HRQOL) in healthy children and adolescents and those with acute and chronic health conditions. It has a Likert 5-points scale (never to almost always) which were transformed to a 0 to 100 scale based on the PedsQL scoring algorithms, higher scores indicating better quality of life characteristics.
Time frame: Baseline, mid-point (week 64), and study exit after up to 30-month treatment period (due to study termination)
Population: Intent-to-Treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Hydroxyurea/Phlebotomy | Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) | Mid-point: School Functioning (n=43, 54) | 3.14 units on a scale | Standard Deviation 23.017 |
| Hydroxyurea/Phlebotomy | Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) | Mid-point: Emotional Functioning Score (n=43,54) | -0.99 units on a scale | Standard Deviation 19.709 |
| Hydroxyurea/Phlebotomy | Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) | Exit: Emotional Functioning Score (n=52, 54) | -1.25 units on a scale | Standard Deviation 28.265 |
| Hydroxyurea/Phlebotomy | Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) | Mid-point: Physical Functioning Score (n=43,64) | -1.71 units on a scale | Standard Deviation 33.011 |
| Hydroxyurea/Phlebotomy | Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) | Exit: Physical Functioning Score (n=53, 54) | 2.27 units on a scale | Standard Deviation 34.456 |
| Hydroxyurea/Phlebotomy | Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) | Exit: School Functioning (n=51,53) | -0.29 units on a scale | Standard Deviation 23.074 |
| Hydroxyurea/Phlebotomy | Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) | Mid-point : Social Functioning Score (n=42, 54) | 3.69 units on a scale | Standard Deviation 23.506 |
| Hydroxyurea/Phlebotomy | Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) | Exit : Social Functioning Score (n=53, 54) | 2.67 units on a scale | Standard Deviation 27.679 |
| Hydroxyurea/Phlebotomy | Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) | Mid-point: Total Functioning Score (n=43, 54) | 0.39 units on a scale | Standard Deviation 20.411 |
| Hydroxyurea/Phlebotomy | Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) | Exit: Total Functioning Score (n=53, 54) | 1.13 units on a scale | Standard Deviation 24.391 |
| Hydroxyurea/Phlebotomy | Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) | Mid-point: Psychosocial Health Summary (n=43,54) | 1.61 units on a scale | Standard Deviation 16.574 |
| Hydroxyurea/Phlebotomy | Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) | Exit: Psychosocial Health Summary (n=53, 54) | 0.33 units on a scale | Standard Deviation 21.535 |
| Transfusion/Chelation | Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) | Mid-point: Psychosocial Health Summary (n=43,54) | 0.59 units on a scale | Standard Deviation 17.072 |
| Transfusion/Chelation | Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) | Mid-point : Social Functioning Score (n=42, 54) | -0.35 units on a scale | Standard Deviation 20.858 |
| Transfusion/Chelation | Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) | Mid-point: Emotional Functioning Score (n=43,54) | 5.56 units on a scale | Standard Deviation 20.366 |
| Transfusion/Chelation | Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) | Exit: Total Functioning Score (n=53, 54) | 1.09 units on a scale | Standard Deviation 20.773 |
| Transfusion/Chelation | Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) | Exit: Emotional Functioning Score (n=52, 54) | 5.65 units on a scale | Standard Deviation 27.676 |
| Transfusion/Chelation | Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) | Exit : Social Functioning Score (n=53, 54) | -1.11 units on a scale | Standard Deviation 27.208 |
| Transfusion/Chelation | Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) | Mid-point: Physical Functioning Score (n=43,64) | -0.57 units on a scale | Standard Deviation 23.195 |
| Transfusion/Chelation | Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) | Exit: Psychosocial Health Summary (n=53, 54) | 2.11 units on a scale | Standard Deviation 20.278 |
| Transfusion/Chelation | Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) | Exit: Physical Functioning Score (n=53, 54) | -0.98 units on a scale | Standard Deviation 27.884 |
| Transfusion/Chelation | Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) | Mid-point: School Functioning (n=43, 54) | -3.34 units on a scale | Standard Deviation 22.546 |
| Transfusion/Chelation | Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) | Mid-point: Total Functioning Score (n=43, 54) | 0.20 units on a scale | Standard Deviation 16.974 |
| Transfusion/Chelation | Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) | Exit: School Functioning (n=51,53) | 2.83 units on a scale | Standard Deviation 24.564 |
Comparison: The change-from-baseline scores were analyzed with an analysis of variance model (ANOVA) with treatment as stratum, testing the hypothesis that the average change from baseline scores do not differ between the treatment groups.p-value: >0.05ANOVA
Secondary
Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)-Excluding Verbal
This test is designed to assess both broad and narrow cognitive abilities in children age 4 years and above as well as to measure major aspects of academic achievement in persons aged 2-90 years. Scaled scores range from 0-100. Higher scores mean better abilities/achievements.
Time frame: Baseline and study exit after up to 30-month treatment period (due to study termination)
Population: Intent-to-Treat. Because the study was terminated, it was not possible to schedule the full battery of neurological assessments on all subjects. Only subjects with both baseline and end of study assessments were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Hydroxyurea/Phlebotomy | Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)-Excluding Verbal | Working memory (n=33, 34) | -7.67 units on a scale | Standard Deviation 22.545 |
| Hydroxyurea/Phlebotomy | Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)-Excluding Verbal | Executive processes (n=32, 33) | -0.72 units on a scale | Standard Deviation 9.323 |
| Hydroxyurea/Phlebotomy | Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)-Excluding Verbal | Processing speed (n=35, 33) | -0.80 units on a scale | Standard Deviation 14.046 |
| Hydroxyurea/Phlebotomy | Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)-Excluding Verbal | Broad reading (n=34, 33) | -0.29 units on a scale | Standard Deviation 8.615 |
| Hydroxyurea/Phlebotomy | Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)-Excluding Verbal | Broad attention (n=31, 33) | -4.36 units on a scale | Standard Deviation 12.693 |
| Hydroxyurea/Phlebotomy | Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)-Excluding Verbal | Broad math (n=34, 33) | -3.53 units on a scale | Standard Deviation 9.542 |
| Hydroxyurea/Phlebotomy | Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)-Excluding Verbal | General intellectual ability (n=33, 35) | -1.64 units on a scale | Standard Deviation 9.594 |
| Transfusion/Chelation | Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)-Excluding Verbal | Broad math (n=34, 33) | -5.76 units on a scale | Standard Deviation 14.292 |
| Transfusion/Chelation | Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)-Excluding Verbal | General intellectual ability (n=33, 35) | -3.00 units on a scale | Standard Deviation 6.535 |
| Transfusion/Chelation | Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)-Excluding Verbal | Processing speed (n=35, 33) | 2.06 units on a scale | Standard Deviation 13.245 |
| Transfusion/Chelation | Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)-Excluding Verbal | Working memory (n=33, 34) | -2.65 units on a scale | Standard Deviation 9.435 |
| Transfusion/Chelation | Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)-Excluding Verbal | Broad attention (n=31, 33) | -0.49 units on a scale | Standard Deviation 8.22 |
| Transfusion/Chelation | Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)-Excluding Verbal | Executive processes (n=32, 33) | -1.15 units on a scale | Standard Deviation 7.173 |
| Transfusion/Chelation | Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)-Excluding Verbal | Broad reading (n=34, 33) | -0.94 units on a scale | Standard Deviation 5.172 |
Comparison: The change-from-baseline scores were analyzed with an analysis of variance model (ANOVA) with treatment as stratum, testing the hypothesis that the average change from baseline scores do not differ between the treatment groups.p-value: >0.05ANOVA
Secondary
Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)- Verbal Ability
This test is designed to assess both broad and narrow cognitive abilities in children age 4 years and above as well as to measure major aspects of academic achievement in persons aged 2-90 years. Higher scores mean better abilities/achievements. Scaled scores range from 0-100.
Time frame: Baseline and study exit after up to 30-month treatment period (due to study termination)
Population: Intent-to-Treat. Because the study was terminated, it was not possible to schedule the full battery of neurological assessments on all subjects. Only subjects with both baseline and end of study assessments were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxyurea/Phlebotomy | Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)- Verbal Ability | 1.829 units on a scale | Standard Deviation 8.305 |
| Transfusion/Chelation | Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)- Verbal Ability | -2.487 units on a scale | Standard Deviation 8.806 |
Comparison: The change-from-baseline scores were analyzed with an analysis of variance model (ANOVA) with treatment as stratum, testing the hypothesis that the average change from baseline scores do not differ between the treatment groups.p-value: 0.039ANOVA