Efficacy, Safety, and population pharmacokinetics of low-dose vs. standard dose hydroxyurea in paediatric patients suffering from Sickle cell disease: A randomized double-blind active-control non-inferiority clinical trial.

Background 

Sicklecell anemia is a neglected genetic disease affecting various parts of the countryespecially the tribal population and presents with varied clinical scenariosaffecting the health of children significantly. Hydroxyurea is a cytotoxic drugused mainly in cancer chemotherapy, is being used for the treatment of sickle cellanemia. It is available only as 500 mg capsules in India . Therefore appropriate dose cannot be administered to the pediatric patients and steady state is not achieved with erratic dosing schedules adopted. Thus a low dose hydroxyurea formulation is the need of the hour. Also, it has several serious toxicities due to bone marrow suppression. Therefore, the dose optimizationwith respect to safety and efficacy of hydroxyurea is of paramount importance inthe management of this disease. This study will add significantly to themaximization of therapeutic efficacy of hydroxyurea while minimizing theadverse effects leading to improved quality of life of Sickle cell patients.

Objectives

Primary

a)      To compare the efficacy of low dosehydroxyurea against the normal dose in pediatric patients suffering from sicklecell disease in terms of pain response.

Secondary

a)      To compare the efficacy of low andnormal dose hydroxyurea in patients with sickle cell disease in terms of changein HbF levels.

b)      To determine the populationpharmacokinetic profile of hydroxyurea in Indian patients.

c)      To demonstrate the superiority oflow dose hydroxyurea against a normal dose preparation in terms of safety

Methodology

Study Design

A randomized active-controlled double-blind parallel group non- inferiority clinical trial.

Study Setting

In patient department of Hematology in All India Institute of Medical Sciences, Bhubaneswar.

Study Groups

a)      Pediatric patients of sickle cell disease receiving 10 mg/kg of hydroxyurea.

b)      Pediatric Patients of sickle cell disease receiving 20 mg/kg of hydroxyurea

Sample size

15 in each group (power of 85% and alpha error of 5%)

Inclusion criteria

a)       Sickle cell Anemia patients between 6-18 years of age having weight 15kg to 60 kg already on Hydroxyurea or started on hydroxyurea (20 mg/kg dose or 10mg/kg dose) characterized by episodes of painful crisis. Painful crisis is defined as a presence of pain for 4 or more hours requiring the intervention with any injectable analgesics.

b)      Patients willing to provide informed consent and assent.

Exclusion criteria

a)       Patients with other forms of sickle cell syndromes.

b)      Patients on any immunosuppression drugs or any immunological disorder.

c)       Patients with abnormal liver function tests.

d)      Patients allergic to any drug provided during the study period.

Details of Control(s)

Normal dose (20mg/kg/day) of oral hydroxyurea.

Details of intervention

Low dose (10mg/kg/day) of hydroxyurea.

Duration of study

1 year 6 months

Outcome measures

a)       To compare the reduction in the incidence of painful crises between the two dosage groups (primary).

b)      To compare the reduction in the frequency of blood transfusion requirements between the two groups.

c)       To compare the reduction in incidence of stroke, vaso-occlusive crises, and acute chest syndrome between the two groups.

d)       To compare the change in HbF levels between the two groups.

e)       To compare the safety parameters such as incidence of myelotoxicity, gastrointestinal, respiratory and hepatotoxicity between the two groups.

f)       To evaluate the population pharmacokinetic parameters, individual pharmacokinetic parameters, and the variation in the pharmacokinetic parameters for the two dosage forms.

Investigation specifically related to Protocols

Liver Function test, kidney function test, Hematological parameters such as Hb level, HbF level, reticulocyte count, RBC and WBC counts.

Statistics

To test the non-inferiority hypothesis, with thepower of 85 % and alpha error limited to 5%, the sample size required wasestimated to be 15 per group. No difference between the groups was assumed withrespect to the number of pain crises and standard deviation of 1. The non-inferioritymargin was set to -1 while considering the difference in the number of paincrises between the two groups.

Continuousdata will be expressed as mean (SD) and the categorical data will be representedas proportions. The normality of the data will be assessed by Shapiro-Wilktest. The difference between the groups for the various endpoints will beassessed using unpaired “t†test or Mann Whitney U-test for continuous databased on the data distribution. Similarly, chi-square test will be applied forcategorical data. Linear and logistic regression will be used to detect therole of baseline and clinical parameters with the response rate in each group. P<0.05will be considered significant. Statistical softwareIBM SPSS version 26 will be used for analysis. Hierarchy analysis will beperformed to ascertain the role of genetic polymorphisms in the responders andnon-responders in both the groups. The individual pharmacokinetic parametersestimated will be maximum concentration attained, time to maximum concentrationattained, absorption and elimination rate constants, elimination half-life ofthe drug and area under the curve for time-concentration profile. Populationpharmacokinetic analysis will be performed by non-linear mixed effect modeling(NLME) to determine the variability of pharmacokinetic parameters forhydroxyurea in pediatric sickle cell disease patients.  Fixed parameters like theta and eta, andrandom parameters like omega and epsilon will be determined using NLME modelingafter the determination of compartmentalization of hydroxyurea followingintravenous administration. NLME will also be used to determine therelationship between pharmacokinetic and pharmacodynamic parameters. Afterconstruction of a robust model, dose prediction will be done with the help oftheta, eta, epsilon and omega parameters.

Ethical considerations

Thestudy will commence following approvalof the Institutional Ethics Committee. The above study will be done as per theNational ethical guidelines for biomedical and health research involving humanparticipants (ICMR 2017) guidelines. Written informed consent and assent willbe taken from all eligible and willing patients. Confidentiality of studyparticipants and study related documents will be strictly maintained, whichwill be accessed only by authorized study personnel.