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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Iron Overload, Oxidative Stress, Thalassemia Major

Intervention / Treatment
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* Drug: Omega 3
* Drug: Nigella Sativa Oil
* Drug: Hydroxyurea
* Drug: Honey
* Drug: Deferoxamine
* Procedure: blood transfusion session


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Any case with full manifestation of β-THALASSEMIA major disease #Aged from 7-15 years old # accompanied with ineffective erythropoiesis # with low hemoglobin level # with iron overload Exclusion Criteria: The presence of any other chronic illness. Patient age>15 years old or < 7 years old. The presence of concomitant myocardial infarction, stroke, acute chest syndrome. The patient suffers from any other type of anemia.

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Four experimental groups, one control group. Each experimental group receives different experimental treatments plus traditional treatment in the hospital and the control group receives only traditional treatment.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Omega-3 experimental group<br>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<br>* Omega-3 supplementation (300-400mg EPA & 200-300mg DHA) per day for 8 consecutive months up to 10 months<br>Drug: Deferoxamine<br>* 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.<br>Procedure: blood transfusion session<br>* Regular blood transfusion session based on patient hematological profile starts from one session every 2 weeks.<br>|
| Experimental: Nigella sativa experimental group<br>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: Nigella Sativa Oil<br>* Nigella sativa supplementation (1g black seed oil contain 1% thymoquinone) per day for 8 consecutive months up to 10 months<br>Drug: Deferoxamine<br>* 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.<br>Procedure: blood transfusion session<br>* Regular blood transfusion session based on patient hematological profile starts from one session every 2 weeks.<br>|
| Experimental: Hydroxyurea experimental group<br>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: Hydroxyurea<br>* hydroxyurea medication (5 to 15mg/kg) per day for 8 consecutive months up to 10 months.<br>Drug: Deferoxamine<br>* 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.<br>Procedure: blood transfusion session<br>* Regular blood transfusion session based on patient hematological profile starts from one session every 2 weeks.<br>|
| Experimental: Natural honey experimental group<br>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: Honey<br>* Natural honey(2.5 mg/kg dissolved in 250 ml water) per day for 8 consecutive months up to 10 months.<br>* Other names: Natural honey formulation;Drug: Deferoxamine<br>* 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.<br>Procedure: blood transfusion session<br>* Regular blood transfusion session based on patient hematological profile starts from one session every 2 weeks.<br>|
| Active Comparator: Ordinary hospital treatment group<br>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<br>* 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.<br>Procedure: blood transfusion session<br>* Regular blood transfusion session based on patient hematological profile starts from one session every 2 weeks.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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omega3, thymoquinone, hydroxyurea, pediatric Thalassemia Major, oxidative stress, iron chelation, iron overload, chelation activity of thymoquinone, antioxidant effect of omega3, anti-hemolysis effect of hydroxyurea