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

Обзор

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.

Вмешательства

• Диагностический тест Pharmacokinetic based dosage change
  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
• Диагностический тест Pharmacokinetic dosing
  Patient with sickle cell disease will undergo one pharmacokinetic test after taking 12 months of hydroxyurea to evaluate HU-AUC at that timepoint

Первичные конечные точки

• Evaluation of HU-PK at 6 months between group A and group B [Срок оценки: At 6 months]

Вторичные конечные точки (4)

• Time to reach maximal tolerated dose (MTD) [Срок оценки: 3, 6, 9 and 12 months]
• Fetal hemoglobin [Срок оценки: at 3, 6 and 12 months]
• Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) in group A and B [Срок оценки: 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 [Срок оценки: At 12 months]

Критерии участия

Inclusion Criteria (Group A and B) :

• 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.

Inclusion Criteria (Group C) :

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Другое

Центры проведения

Канада · 1 центр

• CHU Sainte-Justine — Montreal

Публикации

• 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
• 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
• 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
• 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
• 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
• 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
• 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. PMID 21571150
• 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

Идентификаторы

NCT: NCT06761560 · 2023-4674

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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