Optimizing Hydroxyurea Dosage With Pharmakokinetic in Patients Suffering of Moderate to Severe Sickle Cell Anemia

NCT06761560 | Not Yet Recruiting Phase 2 DMC

• 1 other identifier: 2023-4674
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this study is to evaluate if patients with sickle cell disease can achieve a maximum tolerate dose of hydroxuyrea (HU) over a period of 12 months faster with pharmacokinetic testing than the standard of care bloodwork follow-up. Pharmacokinetic test is used to evaluate the process by which drugs are absorbed, distributed in the body, localized in the tissues, and is excreted. Patient will be a randomized (coin toss method) into 2 groups. Group A will have an increase of their HU dosage with pharmacokinetic results and Group B will have an increase of their HU dosage following the standard of care bloodwork follow-up. Group C will include patient with sickle cell disease that has been taking HU for at least 12 months and will undergo a pharmacokinetic dosage to check the level of HU only one time.

Conditions

Sickle Cell Disease (SCD)

Keywords

hydroxyurea; pharmacokinetic; sickle cell disease

Outcome Measures

Primary Outcomes (1)

• Evaluation of HU-PK at 6 months between group A and group B

  Pharmakocinetic dosage of hydroxyurea will be determined at 6 months in group A and group B. We hypothesize that HU-PK in group B may be lower (suboptimal) compared to group A.

  At 6 months

Secondary Outcomes (4)

• Time to reach maximal tolerated dose (MTD)

  3, 6, 9 and 12 months

• Fetal hemoglobin

  at 3, 6 and 12 months

• Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) in group A and B

  From enrollment to 12 months

• Evaluation of % of patients reaching AUC of 115 +/- 15mg*h/L at 12 months compared to the percentage of patients in group C reaching the same AUC

  At 12 months

Study Arms (3)

Group A

EXPERIMENTAL

Patient starting hydroxyurea that will have PK sample procurements at different timpoints over a period of 12 months until HU-AUC shows MTD

Diagnostic Test: Pharmacokinetic based dosage change

Group B

NO INTERVENTION

Patient starting hydroxuyrea that will be followed as per standard of care over a period of 12 months until MTD has been reached

Group C

EXPERIMENTAL

Patient will undergo one PK sample procurement to evaluate level of HU-AUC after 12 months of taking hydroxyurea.

Diagnostic Test: Pharmacokinetic dosing

Interventions

Pharmacokinetic based dosage change DIAGNOSTIC_TEST

This study will compare 2 groups of sickle cell patients that are receiving hydroxyurea. Group A will have an increase in their dosage based on the pharmacokinetic result over a period of 12 months and Group B will have an increase in their dosage based on the standard of care follow-up over a period of 12 months. The aim is to evaluate if the group A can reach MTD faster than than the Group B

Group A

Pharmacokinetic dosing DIAGNOSTIC_TEST

Patient with sickle cell disease will undergo one pharmacokinetic test after taking 12 months of hydroxyurea to evaluate HU-AUC at that timepoint

Group C

Eligibility Criteria

• Age: 6 Months - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Have had confirmed diagnosis of SCD at CHU Sainte-Justine biochemistry lab with hemoglobin electrophoresis.
• Be patients with SS, SBThal0.
• Agree to take hydroxyurea for a period of 12 months
• Be between age of 6months old and 18 years old.
• Have consented for participation in the study.
• Have had confirmed diagnosis of SCD at CHU Sainte-Justine biochemistry lab with hemoglobin electrophoresis.
• Be patients with SS, SBThal0.
• Have taken hydroxyurea for a period of at least 12 months, and have received HU at a stable dose and at MTD for at least 6 months.
• Be between age of 6months old and 18 years old.
• Have consented for participation in the study.

You may not qualify if:

• Patients with sickle cell genotype other than SS or SBThal0 (SC, SBThal+, SE or SD)
• Patients on chronic transfusion program
• Patients have received a blood transfusion in the last 4 weeks of study enrollment.
• Have received a hematopoietic stem-cell transplantation
• Creatinine \>2x normal for age
• ALT\>2x normal for age
• Sexually active females unwilling to comply with reliable method of birth control
• Pregnancy
• Conditions which in the opinion of the investigator, would compromise participation in the study will be excluded.

Sponsors & Collaborators

• Yves Pastore: lead
• St. Justine's Hospital: collaborator

Study Sites (1)

CHU Sainte-Justine

Montreal, Quebec, H3T 1C5, Canada

Location

Related Publications (14)

• Verduzco LA, Nathan DG. Sickle cell disease and stroke. Blood. 2009 Dec 10;114(25):5117-25. doi: 10.1182/blood-2009-05-220921.

  PMID: 19797523 BACKGROUND

• Meier ER. Treatment Options for Sickle Cell Disease. Pediatr Clin North Am. 2018 Jun;65(3):427-443. doi: 10.1016/j.pcl.2018.01.005.

  PMID: 29803275 BACKGROUND

• McGann PT, Niss O, Dong M, Marahatta A, Howard TA, Mizuno T, Lane A, Kalfa TA, Malik P, Quinn CT, Ware RE, Vinks AA. Robust clinical and laboratory response to hydroxyurea using pharmacokinetically guided dosing for young children with sickle cell anemia. Am J Hematol. 2019 Aug;94(8):871-879. doi: 10.1002/ajh.25510. Epub 2019 Jun 12.

  PMID: 31106898 BACKGROUND

• Dong M, McGann PT. Changing the Clinical Paradigm of Hydroxyurea Treatment for Sickle Cell Anemia Through Precision Medicine. Clin Pharmacol Ther. 2021 Jan;109(1):73-81. doi: 10.1002/cpt.2028. Epub 2020 Oct 8.

  PMID: 32869281 BACKGROUND

• Marahatta A, Ware RE. Hydroxyurea: Analytical techniques and quantitative analysis. Blood Cells Mol Dis. 2017 Sep;67:135-142. doi: 10.1016/j.bcmd.2017.08.009. Epub 2017 Aug 8.

  PMID: 28847416 BACKGROUND

• Hai X, Guo M, Gao C, Zhou J. Quantification of hydroxyurea in human plasma by HPLC-MS/MS and its application to pharmacokinetics in patients with chronic myeloid leukaemia. J Pharm Biomed Anal. 2017 Apr 15;137:213-219. doi: 10.1016/j.jpba.2017.01.008. Epub 2017 Jan 10.

  PMID: 28131939 BACKGROUND

• Wang WC, Ware RE, Miller ST, Iyer RV, Casella JF, Minniti CP, Rana S, Thornburg CD, Rogers ZR, Kalpatthi RV, Barredo JC, Brown RC, Sarnaik SA, Howard TH, Wynn LW, Kutlar A, Armstrong FD, Files BA, Goldsmith JC, Waclawiw MA, Huang X, Thompson BW; BABY HUG investigators. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet. 2011 May 14;377(9778):1663-72. doi: 10.1016/S0140-6736(11)60355-3.

  PMID: 21571150 BACKGROUND

• Thornburg CD, Files BA, Luo Z, Miller ST, Kalpatthi R, Iyer R, Seaman P, Lebensburger J, Alvarez O, Thompson B, Ware RE, Wang WC; BABY HUG Investigators. Impact of hydroxyurea on clinical events in the BABY HUG trial. Blood. 2012 Nov 22;120(22):4304-10; quiz 4448. doi: 10.1182/blood-2012-03-419879. Epub 2012 Aug 22.

  PMID: 22915643 BACKGROUND

• Yahouedehou SCMA, Adorno EV, da Guarda CC, Ndidi US, Carvalho SP, Santiago RP, Aleluia MM, de Oliveira RM, Goncalves MS. Hydroxyurea in the management of sickle cell disease: pharmacogenomics and enzymatic metabolism. Pharmacogenomics J. 2018 Dec;18(6):730-739. doi: 10.1038/s41397-018-0045-1. Epub 2018 Sep 12.

  PMID: 30206297 BACKGROUND

• Switzer JA, Hess DC, Nichols FT, Adams RJ. Pathophysiology and treatment of stroke in sickle-cell disease: present and future. Lancet Neurol. 2006 Jun;5(6):501-12. doi: 10.1016/S1474-4422(06)70469-0.

  PMID: 16713922 BACKGROUND

• Quinn CT. Sickle cell disease in childhood: from newborn screening through transition to adult medical care. Pediatr Clin North Am. 2013 Dec;60(6):1363-81. doi: 10.1016/j.pcl.2013.09.006.

  PMID: 24237976 BACKGROUND

• Hebbel RP. Ischemia-reperfusion injury in sickle cell anemia: relationship to acute chest syndrome, endothelial dysfunction, arterial vasculopathy, and inflammatory pain. Hematol Oncol Clin North Am. 2014 Apr;28(2):181-98. doi: 10.1016/j.hoc.2013.11.005.

  PMID: 24589261 BACKGROUND

• Kuypers FA. Hemoglobin s polymerization and red cell membrane changes. Hematol Oncol Clin North Am. 2014 Apr;28(2):155-79. doi: 10.1016/j.hoc.2013.12.002. Epub 2014 Jan 22.

  PMID: 24589260 BACKGROUND

• Pleasants S. Epidemiology: a moving target. Nature. 2014 Nov 13;515(7526):S2-3. doi: 10.1038/515S2a. No abstract available.

  PMID: 25390139 BACKGROUND

Related Links

• Related Info

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

Central Study Contacts

Yves Pastore, MD

CONTACT

514-345-4931; yves.pastore.med@ssss.gouv.qc.ca

Bianka Courcelle, Research nurse, RN

CONTACT

514-345-4931; bianka.courcelle.hsj@ssss.gouv.qc.ca

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Co-director Sickle Cell Programm, Principal Investigator

Model Details: Group A will receive dosing of hydroxyurea depending on the HU-AUC result at different timepoint until MTD Group B will receive dosing of hydroxyurea following the standard of care bloodwork follow-up until MTD Group C will undergo one pharmacokinetic testing after taking hydroxyurea for at least 12 months

Study Record Dates

• First Submitted: December 12, 2024
• First Posted: January 7, 2025
• Study Start: January 15, 2025
• Primary Completion (Estimated): November 25, 2027
• Study Completion (Estimated): November 25, 2027
• Last Updated: January 7, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)