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

• ClinicalTrials.gov Identifier: NCT02522104
• Recruitment Status: Completed
• First Posted: August 13, 2015
• Results First Posted: August 27, 2021
• Last Update Posted: October 12, 2021
• Sponsor: ADDMEDICA SASA
• Information provided by (Responsible Party): ADDMEDICA SASA

Tracking Information

• First Submitted Date: August 4, 2015
• First Posted Date: August 13, 2015
• Results First Submitted Date: August 3, 2021
• Results First Posted Date: August 27, 2021
• Last Update Posted Date: October 12, 2021
• Actual Study Start Date: September 3, 2015
• Actual Primary Completion Date: November 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 3, 2021)

• Measure of Plasmatic Data: Maximum Concentration (Cmax) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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). [ Time Frame: 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

Original Primary Outcome Measures (submitted: August 11, 2015)

• Measure of plasmatic data: maximum concentration (Cmax) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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). [ Time Frame: 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

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Evaluation of the Impact of Renal Function on the Pharmacokinetics of SIKLOS ® (DARH)
• Official Title: 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)
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Other

Condition

• Sickle Cell Disease
• Renal Function Disorder

Intervention

Drug: Siklos

Other Name: hydroxyurea

Study Arms

• Experimental: Normal-renal function
  Normal-renal function: 90 ≤ GFR ≤ 130 mL/min/1.73m2 in women or 140 mL/min/1.73m2 in men
  Intervention: Drug: Siklos
• Experimental: Glomerular hyperfiltration
  Glomerular renal hyperfiltration: GFR > 130 mL/min/1.73m2 in women and GFR > 140 mL/min/1.73m2 in men.
  Intervention: Drug: Siklos
• Experimental: Moderate renal failure
  Moderate renal failure: 30 ≤ GFR ≤ 60 mL/min/1.73m2
  Intervention: Drug: Siklos

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 23, 2017): 40
• Original Estimated Enrollment (submitted: August 11, 2015): 42
• Actual Study Completion Date: November 28, 2016
• Actual Primary Completion Date: November 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France

Administrative Information

• NCT Number: NCT02522104
• Other Study ID Numbers: SIK-FR 14-1
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: ADDMEDICA SASA
• Original Responsible Party: Same as current
• Current Study Sponsor: ADDMEDICA SASA
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: BARTOLUCCI Pablo, MD; Centre de Référence des Syndromes Drépanocytaires Majeurs, Hôpital Henri-Mondor

• PRS Account: ADDMEDICA SASA
• Verification Date: August 2021