Sickle Cell Anemia (HbSS), Sickle-β0-thalassemia (HbSβ0)
Conditions
Keywords
sickle cell anemia, SCD, sickle cell, hydroxyurea
Brief summary
The main reason for this research study is to learn more about hydroxyurea and the treatment of sickle cell anemia (SCA). Hydroxyurea is a medication that has been studied for many years and has been shown to provide benefits for people with SCA. In this research study, the investigators hope to learn more about how to improve the dosing and monitoring of hydroxyurea and learn more about the long-term effects of hydroxyurea over time. Hydroxyurea is usually dosed based only on your weight. Our study will use a new way to select a starting dose that is based on how each patient absorbs hydroxyurea.
Detailed description
The EHANCE study will address key knowledge gaps about hydroxyurea for young children with SCA in nine innovative ways: * Novel functional assessments of brain, heart, kidneys, spleen, and eyes to assess organ protection in young children who receive hydroxyurea at MTD; * State-of-the-art assays to assess the benefits of hydroxyurea on growth, development, and reproductive health into puberty including serial measurements of pubertal development and sex hormones; * A simplified PK-guided strategy to optimize hydroxyurea initiation and dosing, with a long-term goal of validating pharmacogenomic approaches to expand treatment and achieve sustained HbF induction; * A novel single-cell quantitative HbF/F-cell assay, developed utilizing imaging flow cytometry, will determine the distribution of HbF/F-cell across all F-cells, rather than simply estimating the mean value of HbF/F-cell; * Collection of genomic DNA samples to allow serial quantitation of clonal hematopoiesis in treated children, to evaluate the possibility for potential emergence of clones with an increased risk of leukemic transformation; * Studies on primary erythroblasts freshly isolated from patients and control subjects with single cell multiome analysis to evaluate in vivo cis and trans-acting elements that regulate HbF and how they are affected by hydroxyurea; * Evaluation of cellular mechanisms by which hydroxyurea at MTD can regularly achieve \>30% HbF with near-pancellular distribution, similar to levels currently touted with 'curative' gene therapy regimens; * Exploration of the benefits of early hydroxyurea treatment initiation, in terms of γ-globin de-repression to optimize HbF induction, through unknown cellular mechanisms that may be developmentally regulated. 3\. SPECIFIC AIMS Aim 1: Document the long-term benefits and risks of long-term hydroxyurea treatment at MTD. Aim 2: Perform pharmacokinetic (PK) and pharmacodynamic (PD) assessment of hydroxyurea at MTD. Aim 3: Investigate the cellular mechanisms by which hydroxyurea leads to induction of protective HbF and how timing of treatment initiation and dose optimization affect the efficacy of this process.
Interventions
DRUGPK-optimized oral hydroxyurea at MTD until 15 years of age.
Because people are different, we will measure how each participant's body absorbs and eliminates the medicine, hydroxyurea, using blood tests. This information will be used to determine the best dose for each participant (rather than using the same weight-based dose for everyone).
Sponsors
Greater Cincinnati Foundation
Children's Hospital Medical Center, Cincinnati
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Prospective, open-label, single-arm therapeutic trial of pharmacokinetics (PK)-optimized oral hydroxyurea at maximum tolerated dose (MTD) for the treatment of sickle cell anemia (SCA) with long-term follow-up.
Eligibility
Sex/Gender
ALL
Age
6 Months to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of sickle cell anemia (HbSS) or sickle-β0-thalassemia (HbSβ0) * Age 6 months at the time of enrollment * Clinical decision by patient, family, and healthcare provider to initiate hydroxyurea therapy
Exclusion criteria
* Current treatment with regularly scheduled blood transfusions * Sickle-hemoglobin C disease (HbSC), sickle-β+-thalassemia (HbSβ+)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite Organ Injury | Through study completion, an average of 10 years | Evidence of injury in any of four critical organ systems: brain, kidney, heart, or spleen. Participants will be classified as having met the composite endpoint if they fulfill at least one of the organ-specific criteria listed: cerebral infarction (silent or overt) or steno-occlusive vasculopathy by MRI of brain; urine albumin-to-creatinine ratio (UACR) \> 300 mg/g; extracellular volume fraction (ECV) \> 0.35 on cardiac MRI; or erythrocyte pit count \< 5% |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Longitudinal change in hemoglobin concentration (g/dL) | Through study completion, an average of 10 years. | A beneficial laboratory response to hydroxyurea would include less severe anemia (measured by hemoglobin concentration). This is reported in a complete blood count (CBC). |
| Longitudinal change in reticulocyte count (10^9/L) | Through study completion, an average of 10 years. | A beneficial laboratory response to hydroxyurea would include a decreased reticulocyte count, indicating less severe anemia. This is reported with a complete blood count (CBC). |
| Longitudinal change in absolute neutrophil count (10^9/L) | Through study completion, an average of 10 years. | A surrogate marker of hydroxyurea effectiveness and adherence is the absolute neutrophil count (ANC). Hydroxyurea is titrated according to the ANC. This is reported in a complete blood count (CBC) with differential leukocyte count. |
| longitudinal change in fetal hemoglobin percentage (HbF%) | Through study completion, an average of 10 years | HbF is a well-established mechanistic surrogate marker in SCA that is strongly associated with reduced sickling and organ injury across multiple organ systems. This endpoint will quantify the sustained biological effectiveness of early PK-guided hydroxyurea dosing. |
| F-cell fraction (%) | Through study completion, an average of 10 years. | Flow cytometric determination of the fraction of HbF-containing red blood cells (F-cells). |
| Adverse events | Through study completion, an average of 10 years. | The occurrence of adverse events while on study will be continually monitored and recorded. |
| Longitudinal change in mean cell volume (fL) | Through study completion, an average of 10 years. | A surrogate marker of hydroxyurea effectiveness and adherence is the mean cell volume (MCV). This is reported in a complete blood count (CBC). |
Countries
United States
Contacts
Primary ContactWendi L. Long, Sr. Regulatory Specialist, BS, CCRC
Backup ContactTeresa Latham, Research Director, DrPH
Outcome results
None listed