Evaluation of the Impact of Renal Function on the Pharmacokinetics of SIKLOS ® (DARH)

Evaluation of the Impact of Renal Function on the Pharmacokinetics of Hydroxyurea (SIKLOS ®) in Normal-renal Function, Hyperfiltrating and Renal Failure Sickle Cell Disease Patients (DARH)

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02522104

Enrollment

Registered

2015-08-13

Start date

2015-09-03

Completion date

2016-11-28

Last updated

2021-10-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Renal Function Disorder, Sickle Cell Disease

Keywords

Pharmacokinetics of Hydroxyurea

Brief summary

The use of hydroxyurea in sickle cell disease patients with glomerular hyperfiltration and renal failure requires a specific monitoring and dose adjustment in order to remain within the therapeutic interval while limiting the risk of toxicity or therapeutic failure. For this reason the investigators propose to compare the pharmacokinetic parameters of hydroxyurea in normal-renal function sickle cell patients to those of patients with glomerular hyperfiltration or moderate renal failure.

Interventions

DRUGSiklos

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

OTHER

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Age ≥ 18 years. * Male or female. * Sickle cell disease (SS or S-β0thal) confirmed by haemoglobin electrophoresis and genotyping by deoxyribonucleic acid (DNA) analysis. * Affiliation to a social security system. * Having freely consented in writing after being informed of the objective, programme and potential risks incurred. These criteria will apply to the 3 groups of sickle cell disease patients according to the renal function stage defined by the glomerular filtration rate (GFR) estimated by the formula of the Chronic Kidney Disease EPIdemiology (CKD EPI) collaboration without ethnic criterion during the last 6 months before inclusion: * Normal-renal function: 90 ≤ GFR ≤ 130 mL/min/1.73m2 in women or 140 mL/min/1.73m2 in men. * Moderate renal failure: 30 ≤ GFR ≤ 60 mL/min/1.73m2. * Glomerular renal hyperfiltration: GFR \> 130 mL/min/1.73m2 in women and GFR \> 140 mL/min/1.73m2 in men. * Treated with hydroxyurea (Siklos®) with a stable dosage for at least one week ± 2 days before inclusion in the study and dose administered in the morning at 9:00 ± 15 minutes.

Exclusion criteria

* Refusal to consent. * Patients that do not comply. * Occurrence of vaso-occlusive crisis in the month prior to the inclusion in the study. * Patients having had an exchange transfusion in the 15 days before inclusion in the study. * Patients participating in another clinical trial or in the exclusion period of a previous clinical trial. * Patients treated with a diuretic. * Dialysis patient. * Patients with an intercurrent disorder, especially inflammatory, that has not recovered for at least one month. * Pregnant or breast-feeding women. * Patients deprived of liberty or under legal protection. * Patients who cannot understand the objective and the course of the study, incapable of giving their consent. * In the event of severe hepatic failure. * In the event of severe renal failure (creatinine clearance \< 30 ml/min). * Patients who show toxic signs of bone marrow suppression.

Design outcomes

Primary

Measure	Time frame	Description
Measure of Plasmatic Data: Maximum Concentration (Cmax)	0 hour, 0.75 hour, 1.5 hours, 3 hours, 4 hours, 6 hours, 7.5 hours , 24 hours	Compare the pharmacokinetic parameters of hydroxyurea in normal-renal function sickle cell patients to those of patients with glomerular hyperfiltration or moderate renal failure
Measure of Plasmatic Data: Minimum Concentration (Cmin)	0 hour, 0.75 hour, 1.5 hours, 3 hours, 4 hours, 6 hours, 7.5 hours , 24 hours	Compare the pharmacokinetic parameters of hydroxyurea in normal-renal function sickle cell patients to those of patients with glomerular hyperfiltration or moderate renal failure
Measure of Plasmatic Data: Time to Obtain the Maximum Concentration (Tmax)	0 hour, 0.75 hour, 1.5 hours, 3 hours, 4 hours, 6 hours, 7.5 hours , 24 hours	Compare the pharmacokinetic parameters of hydroxyurea in normal-renal function sickle cell patients to those of patients with glomerular hyperfiltration or moderate renal failure
Measure of Plasmatic Data: Area Under the Curve (AUC0-24)	0 hour, 0.75 hour, 1.5 hours, 3 hours, 4 hours, 6 hours, 7.5 hours , 24 hours	Compare the pharmacokinetic parameters of hydroxyurea in normal-renal function sickle cell patients to those of patients with glomerular hyperfiltration or moderate renal failure
Measure of Plasmatic Data: Elimination Half-life (T½)	0 hour, 0.75 hour, 1.5 hours, 3 hours, 4 hours, 6 hours, 7.5 hours , 24 hours	Compare the pharmacokinetic parameters of hydroxyurea in normal-renal function sickle cell patients to those of patients with glomerular hyperfiltration or moderate renal failure
Measure of Plasmatic Data: Total Clearance (Cl Tot)	0 hour, 0.75 hour, 1.5 hours, 3 hours, 4 hours, 6 hours, 7.5 hours , 24 hours	Compare the pharmacokinetic parameters of hydroxyurea in normal-renal function sickle cell patients to those of patients with glomerular hyperfiltration or moderate renal failure
Measure of Plasmatic Data: Distribution Volume	0 hour, 0.75 hour, 1.5 hours, 3 hours, 4 hours, 6 hours, 7.5 hours , 24 hours	Compare the pharmacokinetic parameters of hydroxyurea in normal-renal function sickle cell patients to those of patients with glomerular hyperfiltration or moderate renal failure
Measure of Urinary Data: Hydroxyurea Urinary Fractions	From 0 to 4 hours, 4 to 7.5 hours and 7.5 to 24 hours	Compare the pharmacokinetic parameters of hydroxyurea in normal-renal function sickle cell patients to those of patients with glomerular hyperfiltration or moderate renal failure
Measure of Urinary Data: Renal Clearance (Cl Renal).	From 0 to 4 hours, 4 to 7.5 hours and 7.5 to 24 hours	Compare the pharmacokinetic parameters of hydroxyurea in normal-renal function sickle cell patients to those of patients with glomerular hyperfiltration or moderate renal failure

Countries

France

Participant flow

Participants by arm

Arm	Count
Normal-renal Function Patients with normal-renal function defined by 90 ≤ GFR ≤ 130 mL/min/1.73m2 in women or 140 mL/min/1.73m2 in men	10
Glomerular Hyperfiltration Patients with glomerular renal hyperfiltration defined by GFR \> 130 mL/min/1.73m2 in women and GFR \> 140 mL/min/1.73m2 in men.	12
Moderate Renal Failure Patients with moderate renal failure defined by 30 ≤ GFR ≤ 60 mL/min/1.73m2	5
Total	27

Baseline characteristics

Characteristic	Normal-renal Function	Glomerular Hyperfiltration	Moderate Renal Failure	Total
Age, Continuous	31.2 years STANDARD_DEVIATION 4.8	27.8 years STANDARD_DEVIATION 7.6	50.0 years STANDARD_DEVIATION 7.5	33.1 years STANDARD_DEVIATION 10.5
Sex: Female, Male Female	5 Participants	11 Participants	2 Participants	18 Participants
Sex: Female, Male Male	5 Participants	1 Participants	3 Participants	9 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 10	0 / 12	0 / 5
other Total, other adverse events	2 / 10	0 / 12	0 / 5
serious Total, serious adverse events	1 / 10	0 / 12	1 / 5