Optimizing the Management of Sickle Cell Patients on Hydroxyurea: The Value of Therapeutic Pharmacological Monitoring

NCT06464458 | Recruiting

• 1 other identifier: 8100
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Brief Summary: \* A short description of the clinical study, including a brief statement of the clinical study's hypothesis, written in language intended for the lay public. Limit: 5000 characters. 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.

Conditions

Sickle Cell Disease

Keywords

Sickle cell; Hydroxyurea; Therapeutic drug monitoring; Pharmacokinetics; SIKLOS®; HYDREA®

Outcome Measures

Primary Outcomes (1)

• 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

Study Arms (2)

Arm A (Control)

NO INTERVENTION

DDepending on haematological tolerance (MTD), dose adjustment is proposed if necessary to achieve neutrophils between 1.5 - 3.0 G/L and reticulocytes between 100 - 200 G/L, without exceeding the maximum dose of 35 mg/kg. The titration step is 5 mg/kg except in the case of CrCl ≤ 60 ml/min; 2.5 mg/kg step in this case.

Arm B

EXPERIMENTAL

HU dose adaptation according: * HU AUC with a target AUC and subject to haematological tolerance. * T2H (at V2, V3, V4), subject to haematological tolerance.

Other: management on hydroxyurea by therapeutic pharmacological monitoring

Interventions

management on hydroxyurea by therapeutic pharmacological monitoring OTHER

HU dose adaptation according: * HU AUC with a target AUC and subject to haematological tolerance. * T2H (at V2, V3, V4), subject to haematological tolerance.

Arm B

Eligibility Criteria

• Age: 2 Years - 35 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Subjects aged between 2 and 35 years.
• For very young children hydroxyurea is only initiated in cases of severe sickle cell disease.
• Sickle cell genotype: HbSS
• Subjects who have been hospitalised for CVO in the last 3 months and for whom HU treatment is to be initiated and/or whose treatment is not balanced or is less than 30 mg/kg, regardless of the length of treatment
• For a woman of childbearing potential:
• Patient accepting highly effective contraception for the duration of study participation and 182 days after discontinuation of the study or treatment.
• Initiation of HU treatment in a patient requiring intensification of therapy in the context of sickle cell disease
• Patient hospitalised (e.g. vaso-occlusive crisis) and/or whose HU treatment is not balanced (MTD not reached)
• Informed consent signed, as appropriate, by :
• The patient and/or
• The holder(s) of parental authority and the minor subject if capable of discernment
• Subject affiliated to a social health insurance scheme or beneficiary
• Subject who has been informed of the results of the prior medical examination, and/or of whom the holder(s) of parental authority has (have) been informed
• Subject able to understand the objectives and risks of the research and to give dated and signed informed consent

You may not qualify if:

• HU patient who has achieved MTD (based on haematological criteria) or is not therapeutically ineffective or hydroxyurea dosage \> 35 mg/kg/day.
• Refusal to accept the use of a highly effective contraceptive method as defined during HU treatment and for 182 days for females and 92 days for males following such treatment (fertile patients only)
• Patient with a parental plan within 18 months
• Hypersensitivity to the active substance or to any of the excipients of the medicinal product
• Severe hepatic impairment
• Severe renal insufficiency
• Toxic signs of myelosuppression
• Neutrophils \< 1500/mm3
• Platelets \< 80 000/mm3
• Haemoglobin \< 4.5 g/dL
• Reticulocytes \< 80,000/mm3 if haemoglobin concentration \< 9 g/dL
• Patient with HIV
• Unable to give subject informed information (subject in emergency situation)
• Inability of the subject to undergo the medical follow-up of the trial for geographical, social or psychological reasons
• Subject under guardianship or curatorship

Sponsors & Collaborators

• University Hospital, Strasbourg, France: lead

Study Sites (1)

Strasbourg University Hospital

Strasbourg, 67091, France

RECRUITING

MeSH Terms

Conditions

Anemia, Sickle Cell

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Paillard

  University Hospital, Strasbourg, France

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Mariem DRIDI

CONTACT

+33 3 88 11 60 08; mariem.dridi@chru-strasbourg.fr

Myriam DURAND

CONTACT

+33 3 88 115 124; myriam.durand@chru-strasbourg.fr

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Masking Details: Pharmacokinetics results of patients in Arm A
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 12, 2024
• First Posted: June 18, 2024
• Study Start: February 8, 2023
• Primary Completion: August 7, 2025
• Study Completion: August 7, 2025
• Last Updated: February 13, 2025

Record last verified: 2024-06

Locations

FR (1)