Anemia, Sickle Cell, Hematologic Diseases
Conditions
Keywords
Blood Diseases, Sickle Cell Anemia
Brief summary
The purpose of this study is to determine if hydroxyurea therapy is effective in the prevention of chronic end organ damage in pediatric patients with sickle cell anemia.
Detailed description
BACKGROUND: In 1995, the Multicenter Study of Hydroxyurea (MSH) demonstrated that hydroxyurea is effective in decreasing the frequency of painful crises, hospitalizations for crises, acute chest syndrome, and blood transfusions by 50%. The recently completed phase II study of hydroxyurea in children (PED HUG) demonstrated that children have a response to hydroxyurea similar to that seen in adults in terms of increasing fetal hemoglobin levels and total hemoglobin, and decreasing complications associated with sickle cell anemia. In addition, this study demonstrated that the drug does not adversely affect growth and development between the ages of 5 and 15. A recently completed pilot study of hydroxyurea given to children between the ages of 6 months and 24 months demonstrated that the drug is tolerated well by small infant, and that the fetal hemoglobin switch can be forced to remain in the on position by hydroxyurea administration. A Special Emphasis Panel (SEP) met on April 12, 1996 to review the results of the MSH trial and the progress to date of the PED HUG study. The SEP recommended that NHLBI undertake the BABY HUG trial. DESIGN NARRATIVE: BABY HUG is a randomized, double-blind, placebo-controlled study to determine if hydroxyurea can prevent the onset of chronic end organ damage in young children with sickle cell anemia. Approximately 200 children with sickle cell disease will be recruited to receive either hydroxyurea or placebo. The children will be screened at study entry for signs of abnormal brain, kidney, pulmonary, and splenic function, and developmental milestones. They will then be randomly assigned to receive either hydroxyurea or placebo and followed yearly to assess chronic end organ damage of the major organ systems. The primary endpoint will be a 50% reduction in rates of damage to the major organs with surrogate markers of organ function during follow-up in Phase II of the trial.
Interventions
DRUGHydroxyurea
Participants will receive hydroxyurea.
DRUGPlacebo
Participants will receive placebo.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
9 Months to 18 Months
Healthy volunteers
No
Inclusion criteria
* Majority fetal and sickle (FS or SF) hemoglobin pattern confirmed centrally by electrophoresis (screening may begin at 7 months of age)
Exclusion criteria
* Chronic transfusion therapy * Cancer * Less than 5th percentile (10th percentile for the pilot study) height, weight, or head circumference for age * Severe developmental delay (e.g., cerebral palsy or other mental retardation, Grade III/IV intraventricular hemorrhage) * Stroke with neurological deficit * Surgical splenectomy * Participating in other clinical intervention trials * Probable or known diagnosis of Hemoglobin S-Hereditary Persistence of Fetal Hemoglobin * Known hemoglobin S-beta plus thalassemia (hemoglobin A present) * Any condition or chronic illness, which in the opinion of the principal investigator, makes participation unadvised or unsafe * Inability or unwillingness to complete baseline (pre-enrollment) studies, including blood or urine specimen collection, liver-spleen scan, abdominal sonogram, neurological examination, neuropsychological testing, or transcranial Doppler ultrasound (interpretable study not required, but confirmed velocity greater than 200 cm/sec results in ineligibility) * Previous or current treatment with hydroxyurea (HU) or another anti-sickling drug * The following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Differences of the Change in Qualitative Splenic Function From Baseline | Before initiation of treatment and at 2 years | Primary Endpoint: Spleen function was assessed by uptake of 99mTc sulfur colloid on liver-spleen scan before initiation of treatment (baseline) and 2 years later (exit). The results of each of the two scans were categorized as normal, functional but abnormal, or not functional by a panel of nuclear medicine specialists blinded to treatment assignment. The proportion of patients whose paired scans demonstrated a decline in splenic function was compared in the hydroxyurea versus placebo groups. The change in splenic function from baseline to 2 years was defined as worse if it changed from normal to decreased or absent, or decreased to absent; and not worse if it changed from decreased to decreased, normal to normal, or decreased to normal. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Renal Function That Was Measured by Diethylenetriaminepentaacetic Acid (DTPA) Glomerular Filtration Rate (GFR) | Before initiation of treatment and at 2 years | DTPA GFR was originally a co-primary efficacy outcome for the study. Later in May 29, 2009, this measurement was discontinued because of statistical futility (an extremely small chance that the difference between treatment groups would be statistically significant for this outcome) and the small risk posed by the radiation exposure involved with performing the DTPA GFR test. Subjects who had missing data at baseline or 2 years measurement were excluded from the analysis (29 subjects from the hydroxurea, and 31 subjects from the placebo group excluded). |
| Change From Baseline in the Renal Function That Was Measured by Glomerular Filtration Rate (GFR) (Calculated Using Schwartz Formula) | Before initiation of treatment and at 2 years | Schwartz formula used to calculate GFR is: 0.55× height (cm)/serum creatinine (mg/dL). Where height is in cm and serum creatinine is in mg/dL. Children with missing baseline or 2 years GFR were excluded from the analysis. |
| Change From Baseline in the Renal Function That Was Measured by GFR (Calculated Using New Schwartz Formula) | Before initiation of treatment and at 2 years | GFR was calculated using new Schwartz formula: 39.1× \[height (cm)/serum creatinine (mg/dL)\]0.516 × \[1.8/cystatin C\]0.294 × \[30/blood urea nitrogen\]0.169 × \[1.099\]if male × \[height(m)/1.4\]0.188. Children with missing baseline or 2 years GFR were excluded from the analysis. |
Countries
United States
Participant flow
Recruitment details
200 patients planned; 233 patients screened; 197 patients eligible for study participation; 193 patients randomized to study treatment; 191 patients initiated study treatment
Participants by arm
| Arm | Count |
|---|---|
| Hydroxyurea Participants will receive hydroxyurea. | 96 |
| Placebo Participants will receive placebo. | 97 |
| Total | 193 |
Baseline characteristics
| Characteristic | Placebo | Total | Hydroxyurea |
|---|---|---|---|
| Age, Categorical <=18 years | 97 Participants | 193 Participants | 96 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 13.56 Months STANDARD_DEVIATION 2.74 | 13.56 Months STANDARD_DEVIATION 2.66 | 13.57 Months STANDARD_DEVIATION 2.6 |
| 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 | 87 Participants | 181 Participants | 94 Participants |
| Race (NIH/OMB) More than one race | 5 Participants | 5 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 6 Participants | 2 Participants |
| Race (NIH/OMB) White | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment United States | 97 participants | 193 participants | 96 participants |
| Sex: Female, Male Female | 57 Participants | 109 Participants | 52 Participants |
| Sex: Female, Male Male | 40 Participants | 84 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 96 | 0 / 97 |
| other Total, other adverse events | 95 / 96 | 95 / 97 |
| serious Total, serious adverse events | 19 / 96 | 35 / 97 |
Outcome results
Primary
Treatment Differences of the Change in Qualitative Splenic Function From Baseline
Primary Endpoint: Spleen function was assessed by uptake of 99mTc sulfur colloid on liver-spleen scan before initiation of treatment (baseline) and 2 years later (exit). The results of each of the two scans were categorized as normal, functional but abnormal, or not functional by a panel of nuclear medicine specialists blinded to treatment assignment. The proportion of patients whose paired scans demonstrated a decline in splenic function was compared in the hydroxyurea versus placebo groups. The change in splenic function from baseline to 2 years was defined as worse if it changed from normal to decreased or absent, or decreased to absent; and not worse if it changed from decreased to decreased, normal to normal, or decreased to normal.
Time frame: Before initiation of treatment and at 2 years
Population: Subjects who had baseline and 2 years splenic function measurements, and had baseline measurement different from absent splenic function. A total of 26 hydroxyurea and 23 placebo subjects had missing data or had absent splenic function at baseline.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Hydroxyurea | Treatment Differences of the Change in Qualitative Splenic Function From Baseline | Worse | 19 Participants |
| Hydroxyurea | Treatment Differences of the Change in Qualitative Splenic Function From Baseline | Not worse | 51 Participants |
| Placebo | Treatment Differences of the Change in Qualitative Splenic Function From Baseline | Worse | 28 Participants |
| Placebo | Treatment Differences of the Change in Qualitative Splenic Function From Baseline | Not worse | 46 Participants |
Comparison: The primary analysis compared the frequency of worsening spleen function (from normal to decreased or absent, or decreased to absent) and not worsening (from decreased to decreased, normal to normal, or decreased to normal) as measured by splenic uptake on a technetium-99m (99mTc) sulfur colloid liver-spleen scan. Children with missing data or absent spleen function at baseline were excluded from the analysis (26 subjects from hydroxyurea and 23 subjects from placebo group were excluded).p-value: 0.21Fisher Exact
Secondary
Change From Baseline in the Renal Function That Was Measured by Diethylenetriaminepentaacetic Acid (DTPA) Glomerular Filtration Rate (GFR)
DTPA GFR was originally a co-primary efficacy outcome for the study. Later in May 29, 2009, this measurement was discontinued because of statistical futility (an extremely small chance that the difference between treatment groups would be statistically significant for this outcome) and the small risk posed by the radiation exposure involved with performing the DTPA GFR test. Subjects who had missing data at baseline or 2 years measurement were excluded from the analysis (29 subjects from the hydroxurea, and 31 subjects from the placebo group excluded).
Time frame: Before initiation of treatment and at 2 years
Population: Subjects who had baseline and 2 years measurements
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxyurea | Change From Baseline in the Renal Function That Was Measured by Diethylenetriaminepentaacetic Acid (DTPA) Glomerular Filtration Rate (GFR) | 22.56 mL/min/1.73m^2 | Standard Deviation 54.67 |
| Placebo | Change From Baseline in the Renal Function That Was Measured by Diethylenetriaminepentaacetic Acid (DTPA) Glomerular Filtration Rate (GFR) | 20.74 mL/min/1.73m^2 | Standard Deviation 51.07 |
Comparison: The change from baseline to exit as measured by DTPA GFR were compared between treatment groups.p-value: 0.93ANOVA
Secondary
Change From Baseline in the Renal Function That Was Measured by GFR (Calculated Using New Schwartz Formula)
GFR was calculated using new Schwartz formula: 39.1× \[height (cm)/serum creatinine (mg/dL)\]0.516 × \[1.8/cystatin C\]0.294 × \[30/blood urea nitrogen\]0.169 × \[1.099\]if male × \[height(m)/1.4\]0.188. Children with missing baseline or 2 years GFR were excluded from the analysis.
Time frame: Before initiation of treatment and at 2 years
Population: All subjects who had baseline and 2 years GFR calculated using the new Schwartz formula (39.1× \[height (cm)/serum creatinine (mg/dL)\]0.516 × \[1.8/cystatin C\]0.294 × \[30/blood urea nitrogen\]0.169 × \[1.099\]if male × \[height(m)/1.4\]0.188).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxyurea | Change From Baseline in the Renal Function That Was Measured by GFR (Calculated Using New Schwartz Formula) | 10.57 mL/min/1.73m^2 | Standard Deviation 20.78 |
| Placebo | Change From Baseline in the Renal Function That Was Measured by GFR (Calculated Using New Schwartz Formula) | 14.33 mL/min/1.73m^2 | Standard Deviation 24.01 |
Comparison: The change in GFR from baseline to exit were compared between treatment groups. GFR was calculated using new Schwartz formula.p-value: 0.48ANOVA
Secondary
Change From Baseline in the Renal Function That Was Measured by Glomerular Filtration Rate (GFR) (Calculated Using Schwartz Formula)
Schwartz formula used to calculate GFR is: 0.55× height (cm)/serum creatinine (mg/dL). Where height is in cm and serum creatinine is in mg/dL. Children with missing baseline or 2 years GFR were excluded from the analysis.
Time frame: Before initiation of treatment and at 2 years
Population: All subjects who had baseline and 2 years GFR calculated using Schwartz formula (0.55× height (cm)/serum creatinine (mg/dL)).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxyurea | Change From Baseline in the Renal Function That Was Measured by Glomerular Filtration Rate (GFR) (Calculated Using Schwartz Formula) | 28.65 mL/min/1.73m^2 | Standard Deviation 76.46 |
| Placebo | Change From Baseline in the Renal Function That Was Measured by Glomerular Filtration Rate (GFR) (Calculated Using Schwartz Formula) | 33.36 mL/min/1.73m^2 | Standard Deviation 95.85 |
Comparison: The change from baseline to exit as measured by GFR (calculated using Shwartz formula) were compared between treatment groups.p-value: 0.43ANOVA