Optimizing the Management of Sickle Cell Patients on Hydroxyurea: The Value of Therapeutic Pharmacological Monitoring
NCT Number: NCT06464458
Acronym: OPTIMDREP
Status: RECRUITING
Study Type: INTERVENTIONAL
Phases: NA
Conditions: Sickle Cell Disease
Interventions: OTHER: management on hydroxyurea by therapeutic pharmacological monitoring
Sponsor: University Hospital, Strasbourg, France
Sex: ALL
Age: CHILD, ADULT
Enrollment: 30
Study Design: Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: SINGLE (PARTICIPANT)|Primary Purpose: TREATMENT
Start Date: 2023-02-08
Completion Date: 2025-08-07
Locations: Strasbourg University Hospital, Strasbourg, 67091, France

Summary:
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Severe forms of sickle cell syndrome are characterized by the occurrence of repeated vaso-occlusive crises (CVO), early complications and a high morbidity and mortality in these patients. Intensified management is then required, with the introduction of hydroxyurea treatment and then, if it proves ineffective, a transfusion program or even a haematopoietic stem cell allograft. These latter treatments present significant risks of adverse effects for the patient (haemochromatosis, erythrocyte alloimmunisation for the transfusion program, risk of GVH, chemotherapy-related toxicity, MVO for the allograft).

Hydroxyurea (HU) is the first treatment based on the specific pathophysiology of sickle cell disease. It is the first line of therapeutic intensification for adult patients and children (age ≥ 2 years) with major sickle cell disease. By mainly increasing the percentage of fetal haemoglobin (HbF), HU decreases the frequency of CVO, complications, hospitalizations and prolongs the life expectancy of patients.

The initial dose of HU, recommended by the ANSM, is 15 mg/kg/d once daily. However, the optimal dose cannot be predicted at the start of treatment, which is why a dosage adjustment is essential. The usual dose is between 15 and 35 mg/kg per day.

Typically, the dose is increased every 3 months until a mild myelosuppression tolerated by the patient is reached, indicating that the maximum tolerated dose (MTD) has been reached. When the dose of HU has reached the MTD, the ratio of clinical (reduced frequency of vaso-occlusive attacks) and biological (better % of HbF) benefits to risk (toxicity) is optimal for the patient.

The disadvantages of this practice are that:

* dose escalation can be long (9-12 months)
* clinicians may be reluctant to escalate HU to MTD
* patients are treated sub-optimally during the therapeutic adaptation period.

Recent work has shown that it is beneficial for the patient to adjust the initial dose using a pharmacological therapeutic approach in addition to monitoring haematological tolerance.

Thus, by customizing the dose of HU using an area under the curve (AUC) measurement at the initial intake of HU at a standardized dose (20 mg/kg/day), the MTD would be achieved in a faster time frame of 6-9 months.

The primary objective of our trial is to identify the methodology that will most effectively decrease the time to reach the MTD (therapeutic target). The immediate benefit will be a reduction in CVO which is the major clinical problem and leads to a risk of complications in sickle cell disease.

Primary Outcome Measures: Comparison of the time to obtained MTD in 2 groups of sickle cell patients on hydroxyurea with different treatment follow-up methodology: MTD follow up or therapeutic pharmacological monitoring, - Arm A (Control): The dosage adjustment is quarterly from M3 onwards and will be made on hematological (WBC) tolerance. The increase of the dosage in HU will be 5 mg/kg every 3 months (or 2.5 mg/kg in case of renal insufficiency with ClCr ≤ 60 ml /min) until MTD is achieved and within a limit of 35 mg/kg/day (max 2500mg).

- Arm B (Experimental): Dose adjustment will be done at the M3 visit based on the results of the Pharmacokinetic analysis (AUC) performed on the day of the first HU intake after inclusion. At the quarterly visits V1 (3 months) to V4 (12 months), a HU assay at time T = 2H associated with monitoring of hematological monitoring of hematological tolerance will be performed to verify the pharmacokinetic stability in the child after the dosage adjustment., Theoretical start date: January 2023 Duration of inclusion period: 30 months Duration of participation of each subject: 16 months Total study duration: 46 months