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CTRI Number  CTRI/2022/01/039317 [Registered on: 11/01/2022] Trial Registered Prospectively
Last Modified On: 17/10/2023
Post Graduate Thesis  Yes 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Randomized, Parallel Group, Active Controlled Trial 
Public Title of Study   Low dose hydroxyurea in sickle cell anemia 
Scientific Title of Study   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. 
Trial Acronym   
Secondary IDs if Any  
Secondary ID  Identifier 
NIL  NIL 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Dr Debasish Hota 
Designation  Professor and Head 
Affiliation  AIIMS Bhubaneswar 
Address  Department of Pharmacology, AIIMS bhubaneswar, Khordha, orissa

Khordha
ORISSA
751019
India 
Phone  9438884190  
Fax    
Email  pharm_debasish@aiimsbhubaneswar.edu.in  
 
Details of Contact Person
Scientific Query  
Name  Govind Mishra 
Designation  Senior Resident  
Affiliation  AIIMS Bhubaneswar 
Address  PG 2 HOSTEL ROOM 407, AIIMS HOUSING COMPLEX, SIJUA, PATRAPODA
PG 2 HOSTEL ROOM 407, AIIMS HOUSING COMPLEX, SIJUA, PATRAPODA
Khordha
ORISSA
751019
India 
Phone  8174005282  
Fax    
Email  mishragovind10@gmail.com  
 
Details of Contact Person
Public Query  
Name  Debasish Hota 
Designation  Professor and Head 
Affiliation  AIIMS Bhubaneswar 
Address  Department of Pharmacology, Academic Block first floor, All India Institute of Medical Sciences 751019

Khordha
ORISSA
751019
India 
Phone  9438884190  
Fax    
Email  pharm_debasish@aiimsbhubaneswar.edu.in  
 
Source of Monetary or Material Support  
Dr. Debasish Hota (PI) 
 
Primary Sponsor  
Name  All India Institute of Medical Sciences 
Address  AIIMS, Sijua, Patrapada, Bhubaneswar -751019 
Type of Sponsor  Government medical college 
 
Details of Secondary Sponsor  
Name  Address 
nil  nil 
 
Countries of Recruitment     India  
Sites of Study  
No of Sites = 1  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Debasish Hota  AIIMS Bhubaneswar  Department of Haematology, All India Institute of Medical Sciences 751019
Khordha
ORISSA 		 9438884190

pharm_debasish@aiimsbhubaneswar.edu.in 
 
Details of Ethics Committee  
No of Ethics Committees= 1  
Name of Committee  Approval Status 
Institutional ethics committee, AIIMS Bhubaneswar  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Not Applicable 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  (1) ICD-10 Condition: D649||Anemia, unspecified,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  Low dose hydroxyurea (10 mg/kg)  Sickle cell disease patients to receive oral low dose hydroxyurea (10 mg/kg). 
Comparator Agent  standard dose Hydroxyurea (20 mg/kg)  clinically diagnosed patients of Sickle cell disease will receive either low dose (10mg/kg) of hydroxyurea or the standard dose (20mg/kg). 
 
Inclusion Criteria  
Age From  6.00 Year(s)
Age To  18.00 Year(s)
Gender  Both 
Details  a) Sickle cell Anemia patients between 6-18 years of age having weight between 15-60 years either on Hydroxyurea or are started on hydroxyurea and characterized by pain episodes in the past. 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.
 
 
ExclusionCriteria 
Details  a) Patients with other forms of sickle cell syndromes.
b) Patients on any immunosuppression drugs.
c) Patients with abnormal liver function tests.
d) Patients allergic to any drug provided during the study period.
 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   Pre-numbered or coded identical Containers 
Blinding/Masking   Participant and Investigator Blinded 
Primary Outcome  
Outcome  TimePoints 
a) To compare the efficacy of low dose hydroxyurea against the normal dose in pediatric patients suffering from sickle cell disease in terms of pain response.  2, 4 and 6 months after baseline monitoring. 
 
Secondary Outcome  
Outcome  TimePoints 
a) To compare the efficacy of low and normal dose hydroxyurea in patients with sickle cell disease in terms of change in HbF levels.
b) To determine the population pharmacokinetic profile of hydroxyurea in Indian patients.
c) To demonstrate the superiority of low dose hydroxyurea against a normal dose preparation in terms of safety
 		 2, 4 and 6 months after baseline monitoring. 
 
Target Sample Size   Total Sample Size="30"
Sample Size from India="30" 
Final Enrollment numbers achieved (Total)= "90"
Final Enrollment numbers achieved (India)="90" 
Phase of Trial   Phase 4 
Date of First Enrollment (India)   01/02/2022 
Date of Study Completion (India) 05/06/2023 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Date Missing 
Estimated Duration of Trial   Years="1"
Months="6"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  		 Not Applicable 
Recruitment Status of Trial (India)  Completed 
Publication Details   After trial completion. 
Individual Participant Data (IPD) Sharing Statement

Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Response - NO
Brief Summary   Background 
Sickle cell anemia is a neglected genetic disease affecting various parts of the country especially the tribal population and presents with varied clinical scenarios affecting the health of children significantly. Hydroxyurea is a cytotoxic drug used mainly in cancer chemotherapy, is being used for the treatment of sickle cell anemia. 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 optimization with respect to safety and efficacy of hydroxyurea is of paramount importance in the management of this disease. This study will add significantly to the maximization of therapeutic efficacy of hydroxyurea while minimizing the adverse effects leading to improved quality of life of Sickle cell patients.
Objectives

Primary

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

Secondary

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

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

c)      To demonstrate the superiority of low 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 the power of 85 % and alpha error limited to 5%, the sample size required was estimated to be 15 per group. No difference between the groups was assumed with respect to the number of pain crises and standard deviation of 1. The non-inferiority margin was set to -1 while considering the difference in the number of pain crises between the two groups.

Continuous data will be expressed as mean (SD) and the categorical data will be represented as proportions. The normality of the data will be assessed by Shapiro-Wilk test. The difference between the groups for the various endpoints will be assessed using unpaired “t” test or Mann Whitney U-test for continuous data based on the data distribution. Similarly, chi-square test will be applied for categorical data. Linear and logistic regression will be used to detect the role of baseline and clinical parameters with the response rate in each group. P<0.05 will be considered significant. Statistical software IBM SPSS version 26 will be used for analysis. Hierarchy analysis will be performed to ascertain the role of genetic polymorphisms in the responders and non-responders in both the groups. The individual pharmacokinetic parameters estimated will be maximum concentration attained, time to maximum concentration attained, absorption and elimination rate constants, elimination half-life of the drug and area under the curve for time-concentration profile. Population pharmacokinetic analysis will be performed by non-linear mixed effect modeling (NLME) to determine the variability of pharmacokinetic parameters for hydroxyurea in pediatric sickle cell disease patients.  Fixed parameters like theta and eta, and random parameters like omega and epsilon will be determined using NLME modeling after the determination of compartmentalization of hydroxyurea following intravenous administration. NLME will also be used to determine the relationship between pharmacokinetic and pharmacodynamic parameters. After construction of a robust model, dose prediction will be done with the help of theta, eta, epsilon and omega parameters.

Ethical considerations 

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


 
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