Ignite Creation Date:
2024-07-17 @ 11:15 AM
Last Modification Date:
2024-10-26 @ 3:32 PM
Study NCT ID:
NCT06464458
Status:
RECRUITING
Last Update Posted:
2024-06-18
First Post:
2024-06-12
Brief Title:
Optimizing the Management of Sickle Cell Patients on Hydroxyurea The Value of Therapeutic Pharmacological Monitoring
Sponsor:
University Hospital Strasbourg France
Organization:
University Hospital Strasbourg France
Study Overview
Official Title:
Optimizing the Management of Sickle Cell Patients on Hydroxyurea The Value of Therapeutic Pharmacological Monitoring
Status:
RECRUITING
Status Verified Date:
2024-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
OPTIMDREP
Brief Summary:
Brief Summary A short description of the clinical study including a brief statement of the clinical studys 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 mgkgd 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 mgkg 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 mgkgday 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
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 mgkgd 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 mgkg 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 mgkgday 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
Detailed Description:
Information visit V0 - 7 days to V0 - 6 months Patients seen in a routine consultation will be informed about the project in an interview with the doctor and the information leaflet will be given to the patient andor hisher parents In case a patient is admitted to a conventional ward information about the study will be given in a meeting with the doctor They will have 7 days to think about it If they agree to participate in the study a second appointment will be made with sufficient time for reflection for the signing of the consent form
The information and consent of minor patients will be the subject of an adapted procedure In example a specific notice will be provided for children of a comprehensible age under 11 years In addition an information leaflet will be provided and adapted to the level of understanding of each age category for minor patients 11 to 16 years adults
Inclusion visit V0 - 7 days to V0 - 173 days Prior to any research-related examination the free informed and signed consent of the parents and the minor if applicable the legal representative or the patient if of age is obtained after a reflection period has been respected
The date on which the subject or the parents and the minor if applicable or the legal representative agreed to participate in the research is noted in the medical file as is the date of any objection to participation if applicable
In addition the consent of the minor subject will be sought if heshe reaches hisher majority during hisher participation in the research
During this visit the eligibility criteria will be checked and if the patient is eligible heshe andor hisher legal representatives will be able to sign the consent
- Randomisation visit V0 visit
The following examinationsactions will be performed to confirm the subjects eligibility for further participation in the study
Collection of medical surgical and lifestyle history
Physical examination weight height blood pressure heart rate medical examination
Randomisation is then carried out by the investigator or a delegated person via the Internet using the Cleanweb platform which is accessed by the investigator or the delegated person using their personal access codes It allows the allocation of the treatment group ie
Arm A Control Dose adjustment based on haematological assessment
Arm B Experimental Dosage adjustment based on AUC at D1 then control of the pharmacokinetic target by T2H and monitoring of haematological tolerance
HU is then taken orally
The drug should be taken under the usual conditions for children
Samples are then taken on EDTA tubes They will allow the calculation of the patients exposure to the drug AUC
The patient is given a prescription for a test to be carried out in the city at D15 after the introduction of the HU or after the dosage has been adjusted in order to assess tolerance MTD
Visit V1 M3 As at the first visit the usual clinical and biological examinations are performed
The results of the PK assay and tolerance MTD being available a dosage adjustment is proposed according to the patients randomisation arm and without exceeding the maximum dose of 35 mgkg
Arm A adjustment in 5 mgkg steps or 25 mgkg if CrCl60mlmin according to maximal toxic dose MTD
Arm B Adaptation according to V1 HU AUC A prescription for a CBC to be carried out in the city at D15 after the dosage adjustment is given to the patient in order to assess tolerance
V2 visits M6 - 1 month As at the first visit the usual clinical and biological examinations are performed
The results of the PK assay and tolerance MTD being available a dosage adjustment is proposed according to the patients randomisation arm and without exceeding the maximum dose of 35 mgkg
Arm A adjustment in 5 mgkg steps or 25 mgkg if CrCl60mlmin according to maximal toxic dose MTD
Arm B Adaptation according to V1 HU AUC A prescription for a CBC to be carried out in the city at D15 after the dosage adjustment is given to the patient in order to assess tolerance
Visit 3 M9 - 1 month and visit 4 M12 - 1 month
As at the first visit the usual clinical and biological examinations are performed
The results of the PK assay and tolerance MTD being available a dosage adjustment is proposed according to the patients randomisation arm and without exceeding the maximum dose of 35 mgkg
Arm A adjustment in 5 mgkg steps or 25 mgkg if CrCl60mlmin according to maximal toxic dose MTD
Arm B Adaptation according to V1 HU AUC A prescription for a CBC to be carried out in the city at D15 after the dosage adjustment is given to the patient in order to assess tolerance
Visit V5 M15 On the day of visit 5 the patient is welcomed in the department
HU is taken at the usual dosage
Then the pharmacokinetic samples are taken
Subsequent follow-up
The study does not require specific follow-up However patients will continue to be followed by their referring physician in a day hospital or in a consultation every 3 months according to the usual management modalities
The information and consent of minor patients will be the subject of an adapted procedure In example a specific notice will be provided for children of a comprehensible age under 11 years In addition an information leaflet will be provided and adapted to the level of understanding of each age category for minor patients 11 to 16 years adults
Inclusion visit V0 - 7 days to V0 - 173 days Prior to any research-related examination the free informed and signed consent of the parents and the minor if applicable the legal representative or the patient if of age is obtained after a reflection period has been respected
The date on which the subject or the parents and the minor if applicable or the legal representative agreed to participate in the research is noted in the medical file as is the date of any objection to participation if applicable
In addition the consent of the minor subject will be sought if heshe reaches hisher majority during hisher participation in the research
During this visit the eligibility criteria will be checked and if the patient is eligible heshe andor hisher legal representatives will be able to sign the consent
- Randomisation visit V0 visit
The following examinationsactions will be performed to confirm the subjects eligibility for further participation in the study
Collection of medical surgical and lifestyle history
Physical examination weight height blood pressure heart rate medical examination
Randomisation is then carried out by the investigator or a delegated person via the Internet using the Cleanweb platform which is accessed by the investigator or the delegated person using their personal access codes It allows the allocation of the treatment group ie
Arm A Control Dose adjustment based on haematological assessment
Arm B Experimental Dosage adjustment based on AUC at D1 then control of the pharmacokinetic target by T2H and monitoring of haematological tolerance
HU is then taken orally
The drug should be taken under the usual conditions for children
Samples are then taken on EDTA tubes They will allow the calculation of the patients exposure to the drug AUC
The patient is given a prescription for a test to be carried out in the city at D15 after the introduction of the HU or after the dosage has been adjusted in order to assess tolerance MTD
Visit V1 M3 As at the first visit the usual clinical and biological examinations are performed
The results of the PK assay and tolerance MTD being available a dosage adjustment is proposed according to the patients randomisation arm and without exceeding the maximum dose of 35 mgkg
Arm A adjustment in 5 mgkg steps or 25 mgkg if CrCl60mlmin according to maximal toxic dose MTD
Arm B Adaptation according to V1 HU AUC A prescription for a CBC to be carried out in the city at D15 after the dosage adjustment is given to the patient in order to assess tolerance
V2 visits M6 - 1 month As at the first visit the usual clinical and biological examinations are performed
The results of the PK assay and tolerance MTD being available a dosage adjustment is proposed according to the patients randomisation arm and without exceeding the maximum dose of 35 mgkg
Arm A adjustment in 5 mgkg steps or 25 mgkg if CrCl60mlmin according to maximal toxic dose MTD
Arm B Adaptation according to V1 HU AUC A prescription for a CBC to be carried out in the city at D15 after the dosage adjustment is given to the patient in order to assess tolerance
Visit 3 M9 - 1 month and visit 4 M12 - 1 month
As at the first visit the usual clinical and biological examinations are performed
The results of the PK assay and tolerance MTD being available a dosage adjustment is proposed according to the patients randomisation arm and without exceeding the maximum dose of 35 mgkg
Arm A adjustment in 5 mgkg steps or 25 mgkg if CrCl60mlmin according to maximal toxic dose MTD
Arm B Adaptation according to V1 HU AUC A prescription for a CBC to be carried out in the city at D15 after the dosage adjustment is given to the patient in order to assess tolerance
Visit V5 M15 On the day of visit 5 the patient is welcomed in the department
HU is taken at the usual dosage
Then the pharmacokinetic samples are taken
Subsequent follow-up
The study does not require specific follow-up However patients will continue to be followed by their referring physician in a day hospital or in a consultation every 3 months according to the usual management modalities
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None