Hydroxy Urea, Omega 3, Nigella Sativa,Honey on Oxidative Stress and Iron Chelation in Pediatric Major Thalassemia

Impact of Combination Therapy Between Hydroxy Urea, Omega 3, Nigella Sativa and Honey on Antioxidant-oxidant Status and Reduction of Iron Overload in Pediatric Major Thalassemia

The aim of the present study is evaluating the strength of combination therapy of hydroxy urea, omega 3, nigella sativa and honey on antioxidant-oxidant status (OXIDATIVE STRESS) in response to reactive oxygen species production (LIPID PEROXIDATION) and their effect on iron intoxication (IRON CHELATION) in pediatric major thalassemia.

Study Overview

• Status: Completed
• Conditions: Iron Overload; Oxidative Stress; Thalassemia Major
• Intervention / Treatment: Drug: Omega 3; Drug: Deferoxamine; Procedure: blood transfusion session; Drug: Nigella Sativa Oil; Drug: Hydroxyurea; Drug: Honey

Detailed Description

Beta thalassemia is a blood disorder that reduces the production of hemoglobin. Hemoglobin is the iron-containing protein in red blood cells that carries oxygen to cells throughout the body. In people with beta thalassemia, low levels of hemoglobin lead to a lack of oxygen in many parts of the body. Affected individuals also have a shortage of red blood cells (anemia), which can cause pale skin, weakness, fatigue, and more serious complications. People with beta thalassemia are at an increased risk of developing abnormal blood clots. Beta thalassemia is classified into two types depending on the severity of symptoms: thalassemia major (also known as Cooley's anemia) and thalassemia intermedia. Of the two types, thalassemia major is more severe.

Beta-thalassemia syndromes are a group of hereditary blood disorders. It is characterized by reduced beta globin chain synthesis, resulting in reduced Hb in red blood cells (RBC), decreased RBC production and anemia.

Homozygotes for beta-thalassemia may develop either thalassemia major or thalassemia intermedia. Individuals with thalassemia major usually come to medical attention within the first 2 years and require regular blood transfusion to survive.

Affected infants with thalassemia major fail to thrive and become progressively pale. Feeding problems, diarrhea, irritability, recurrent bouts of fever, and enlargement of the abdomen, caused by splenomegaly, may occur. If a regular transfusion program that maintains a minimum Hb concentration of 95-105 g/L is initiated, then growth and development are normal until the age of 10-11 years. After the age of 10-11 years, affected individuals are at risk of developing severe complications related to posttransfusional iron overload, depending on their compliance with chelation therapy.

Complications of iron overload include growth retardation and failure of sexual maturation and also those complications observed in adults with hemachromatosis -associated hereditary hemochromatosis (HH): involvement of the heart (dilated myocardiopathy and pericarditis), liver (chronic hepatitis, fibrosis, and cirrhosis), and endocrine glands (resulting in diabetes mellitus and insufficiency of the parathyroid, thyroid, pituitary, and, less commonly, adrenal glands).

The underlying basis of b-thalassemia pathology is the diminished b-globin synthesis leading to a-globin accumulation and premature apoptotic destruction of erythroblasts, causing oxidative stress-induced ineffective erythropoiesis.

• Study Type: Interventional
• Enrollment (Actual): 350
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Egypt
  • Banī Suwayf, Egypt
    • Faculty of medicine, Beni-suef univeristy - Beni-Suef university hospital
  • Banī Suwayf, Egypt
    • Faculty of pharmacy, Beni-Suef University
  • Banī Suwayf, Egypt
    • Health insurance hospital
• Saudi Arabia
  • Mecca, Saudi Arabia
    • Maternity and Children hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 15 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Any case with full manifestation of β-THALASSEMIA major disease
2. #Aged from 7-15 years old
3. # accompanied with ineffective erythropoiesis
4. # with low hemoglobin level
5. # with iron overload

Exclusion Criteria:

1. The presence of any other chronic illness.
2. Patient age>15 years old or < 7 years old.
3. The presence of concomitant myocardial infarction, stroke, acute chest syndrome.
4. The patient suffers from any other type of anemia.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Omega-3 experimental group; 50 patients from each participating hospital that will receive Omega-3 supplementation (300-400mg EPA & 200-300mg DHA) per day for 8 consecutive months up to 10 months. in addition to experimental treatment this group will receive the traditional treatment of deferoxamine/deferasirox plus regular blood transfusion with dose de-escalation methods till efficacy of experimental treatment proved.	Drug: Omega 3; Omega-3 supplementation (300-400mg EPA & 200-300mg DHA) per day for 8 consecutive months up to 10 months; Drug: Deferoxamine; deferoxamine (SubQ infusion: 20 to 40 mg/kg/day over 8 to 12 hours, 6 to 7 nights per week, maximum daily dose: 40 mg/kg/day)for 8 consecutive months up to 10 months.; Procedure: blood transfusion session; Regular blood transfusion session based on patient hematological profile starts from one session every 2 weeks.
Experimental: Nigella sativa experimental group; 50 patients from each participating hospital that will receive Nigella sativa supplementation (1g black seed oil contain 1% thymoquinone) per day for 8 consecutive months up to 10 months. in addition to experimental treatment this group will receive the traditional treatment of deferoxamine/deferasirox plus regular blood transfusion with dose de-escalation methods till efficacy of experimental treatment proved.	Drug: Deferoxamine; deferoxamine (SubQ infusion: 20 to 40 mg/kg/day over 8 to 12 hours, 6 to 7 nights per week, maximum daily dose: 40 mg/kg/day)for 8 consecutive months up to 10 months.; Procedure: blood transfusion session; Regular blood transfusion session based on patient hematological profile starts from one session every 2 weeks.; Drug: Nigella Sativa Oil; Nigella sativa supplementation (1g black seed oil contain 1% thymoquinone) per day for 8 consecutive months up to 10 months
Experimental: Hydroxyurea experimental group; 50 patients from each participating hospital that will receive hydroxyurea medication (5 to 15mg/kg) per day for 8 consecutive months up to 10 months. in addition to the experimental treatment, this group will receive the traditional treatment of deferoxamine/deferasirox plus regular blood transfusion with dose de-escalation methods until the efficacy of experimental treatment proved.	Drug: Deferoxamine; deferoxamine (SubQ infusion: 20 to 40 mg/kg/day over 8 to 12 hours, 6 to 7 nights per week, maximum daily dose: 40 mg/kg/day)for 8 consecutive months up to 10 months.; Procedure: blood transfusion session; Regular blood transfusion session based on patient hematological profile starts from one session every 2 weeks.; Drug: Hydroxyurea; hydroxyurea medication (5 to 15mg/kg) per day for 8 consecutive months up to 10 months.
Experimental: Natural honey experimental group; 50 patients from each participating hospital that will receive natural honey(2.5 mg/kg dissolved in 250 ml water) per day for 8 consecutive months up to 10 months. in addition to the experimental treatment, this group will receive the traditional treatment of deferoxamine/deferasirox plus regular blood transfusion with dose de-escalation methods until the efficacy of experimental treatment proved.	Drug: Deferoxamine; deferoxamine (SubQ infusion: 20 to 40 mg/kg/day over 8 to 12 hours, 6 to 7 nights per week, maximum daily dose: 40 mg/kg/day)for 8 consecutive months up to 10 months.; Procedure: blood transfusion session; Regular blood transfusion session based on patient hematological profile starts from one session every 2 weeks.; Drug: Honey; Natural honey(2.5 mg/kg dissolved in 250 ml water) per day for 8 consecutive months up to 10 months.; Other Names: Natural honey formulation
Active Comparator: Ordinary hospital treatment group; 50 patients from each participating hospital that will receive the ordinary treatment of iron chelator agent of deferoxamine or deferasirox (SubQ infusion: 20 to 40 mg/kg/day over 8 to 12 hours, 6 to 7 nights per week, maximum daily dose: 40 mg/kg/day)for 8 consecutive months up to 10 months. in addition to iron chelator agent, this group receive regular blood transfusion session.	Drug: Deferoxamine; deferoxamine (SubQ infusion: 20 to 40 mg/kg/day over 8 to 12 hours, 6 to 7 nights per week, maximum daily dose: 40 mg/kg/day)for 8 consecutive months up to 10 months.; Procedure: blood transfusion session; Regular blood transfusion session based on patient hematological profile starts from one session every 2 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
F 2 -isoprostanes pg/mL	plasma F 2 -isoprostanes Picograms Per Millilitre measured by high pressure liquid chromatography assay	3 months
Total cholesterol Mg/dl	Total cholesterol milligrams per deciliter	10 months
HDL cholesterol Mg/dl	HDL cholesterol milligrams per deciliter	10 months
LDL cholesterol Mg/dl	LDL cholesterol milligrams per deciliter	10 months
Triglycerides Mg/dl	Triglycerides milligrams per deciliter	10 months
Serum total iron mcg/dL	Serum total iron micrograms per decilitre	10 months
% transferrin saturation	transferrin saturation percentage	10 months
C-reactive protein mg/L	C-reactive protein milligrams per deciliter	10 months
Serum Ferritin ng/ml	Serum Ferritin Nanograms per milliliter	10 months
Total Iron Binding Capacity (TIBC) mcg/dL	Total Iron Binding Capacity micrograms per decilitre	10 months
hemoglobin (Hbg) g/dL	hemoglobin (Hbg) gram/deciliter	10 months
mean corpuscular hemoglobin (MCH) pg/ml	mean corpuscular hemoglobin (MCH) Picograms Per Millilitre	10 months
leukocytes count μl	leukocytes in microliter	10 months
% Chelation activity Fe+++ - thymoquinone complex	Chelation activity of Ferric - thymoquinone complex in percentage measured by high pressure liquid chromatography coupled with gaschromatography - mass spectroscopy analysis	3 months
% Chelation activity Fe++ - thymoquinone complex	Chelation activity of Ferrous - thymoquinone complex in percentage measured by high pressure liquid chromatography coupled with gaschromatography- mass spectroscopy analysis	3 months
Lactic acid dehydrogenase U/L	Lactic acid dehydrogenase unit per litter	10 months
Reticulocyte count %	Reticulocyte count percentage	10 months
Hb-F level g/dL	hemoglobin- F level in gram per deciliter	10 months
Reticulocyte absolute count	Reticulocyte absolute count in a cubic milliliter of blood	10 months
White blood cells count	White blood cells count in a cubic milliliter of blood	10 months

Collaborators and Investigators

• Sponsor: Beni-Suef University
• Collaborators: University of Arizona; Maternity and Children Hospital, Makkah; Beni-Suef Health insurance hospital
• Investigators: Study Director: IVO IBRAHAM [Prof of Pharmacy, Clinical Translational Sciences], Ph.D., University of Arizona, College of Pharmacy; Study Director: AHMED A ALBERRY [Assistant prof of clinical pharmacology], Ph.D., Beni-Suef University, Faculty of medicine; Study Director: RAGHDA R SAYED [Lecturer of Clinical Pharmacy], Ph.D., Beni-Suef University, Faculty of Pharmacy; Principal Investigator: MOHAMED M ABDELWAHAB GAMALELDIN, Ph.D Student, Beni-Suef University, Faculty of Pharmacy; Study Director: Mohamed H Meabad [Prof of Pediatrics], M.D, Beni-Suef University, Faculty of medicine; Study Director: Ahmed F Mahmoud Hussein, MS.c, Beni-Suef Health insurance hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2019
• Primary Completion (Actual): December 20, 2020
• Study Completion (Actual): January 20, 2021

Study Registration Dates

• First Submitted: February 28, 2020
• First Submitted That Met QC Criteria: February 28, 2020
• First Posted (Actual): March 3, 2020

Study Record Updates

• Last Update Posted (Actual): January 27, 2021
• Last Update Submitted That Met QC Criteria: January 25, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: hydroxyurea; iron overload; oxidative stress; omega3; thymoquinone; pediatric Thalassemia Major; iron chelation; chelation activity of thymoquinone; antioxidant effect of omega3; anti-hemolysis effect of hydroxyurea
• Additional Relevant MeSH Terms: Metabolic Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Iron Metabolism Disorders; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Iron Overload; Thalassemia; beta-Thalassemia; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Chelating Agents; Sequestering Agents; Antisickling Agents; Iron Chelating Agents; Siderophores; Hydroxyurea; Deferoxamine
• Other Study ID Numbers: TQ/Omega-3 on Thalassemia

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No