Different Treatment Modalities in the Management of the Painful Crisis in Pediatric Sickle- Cell Anemia

Study Overview
=================
Brief Summary
-----------------
The aim of the present study is comparing the effectiveness of different treatment regimens for investigating the therapeutic potential for each one in management of Vaso-occlusive pain in pediatric sickle cell disease. In addition, investigators apply the Cost-effectiveness analysis (CEA) as a form of economic analysis that compares the relative costs and outcomes (effects) for different treatment regimens on vaso-occlusive painful crisis.

Detailed Description
-----------------
Sickle cell disease is an inherited blood disorder characterized by defective hemoglobin (a protein in red blood cells that carries oxygen to the tissues of the body). Sickle cell disease involves the red blood cells, or hemoglobin, and their ability to carry oxygen. Normal hemoglobin cells are smooth, round, and flexible, like the letter O, so they can move through the vessels in our bodies easily. Sickle cell hemoglobin cells are stiff and sticky and form into the shape of a sickle, or the letter C, when they lose their oxygen. These sickle cells tend to cluster together and cannot easily move through the blood vessels. The cluster causes a blockage in small arteries or capillaries and stops the movement of healthy, normal oxygen-carrying blood. This blockage is what causes the painful and damaging complications of sickle cell disease. Acute vaso-occlusive crisis (VOC) is a hallmark of sickle cell disease (SCD). Multiple complex pathophysiological processes can result in pain during a VOC. Despite significant improvements in the understanding and management of SCD, little progress has been made in the management of pain in SCD, although new treatments are being explored. The Painful Episodes: The day-to-day management of sickle cell disease often equates with the management of acute and chronic pain. Patients manage many painful events at home so that hospital visits underestimate the frequency of pain Acute painful episodes are the most commonly encountered vaso-occlusive events in patients of all ages. Presumed to be caused by sickle vaso-occlusion, pain often starts in young children as the hand-foot syndrome or dactylitis, a painful swelling of hands and feet due to inflammation of the metacarpal and metatarsal periosteum. Painful episodes, which last from hours to many days, usually occur with little warning and a clear precipitating event is not often found.

Official Title
-----------------
Comparative Effectiveness of the Different Treatment Modalities for Management of Vaso-occlusive Painful Crisis in Pediatric Sickle Cell Disease

Conditions
-----------------
Vaso-occlusive Crisis, Sickle Cell Disease, Sickle Cell Anemia in Children

Intervention / Treatment
-----------------
* Drug: Omega 3
* Drug: Vit D
* Drug: Zinc sulfate
* Drug: Statins (Cardiovascular Agents)
* Drug: Hydroxy Urea
* Drug: Folic Acid Supplementation
* Drug: Morphine Sulfate
* Procedure: blood transfusion session


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Any case with the full manifestation of sickle cell disease accompanied by acute painful crisis aged from 5-15 years old. Exclusion Criteria: The presence of any other chronic illness. Patient age>18 years old or < 3 years old. Patients with hepatic diseases including cholestasis hepatic encephalopathy and jaundice. Patients with renal impairment Diabetic patients

Ages Eligible for Study
-----------------
Minimum Age: 5 Years
Maximum Age: 15 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Four experimental groups, one control group
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 the experimental treatment, this group will receive the traditional treatment of hydroxyurea, Folic acid, pain killer plus regular blood transfusion with a 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>* Other names: omega-3 supplementation capsules;Drug: Hydroxy Urea<br>* 50 patients from each participating hospital that will receive the ordinary treatment of Hydroxyurea (20 mg/kg/day) with monitoring blood count every 2 weeks maximum daily dose: (40 mg/kg/day) for 8 consecutive months up to 10 months.<br>* Other names: Hydroxy Urea tablet medication 20mg/kg/day;Drug: Folic Acid Supplementation<br>* Folic Acid dose of 0.5 to 1 mg daily for 3 to 4 weeks until definite hematologic response<br>* Other names: Folic Acid tablet medication 1mg/day;Drug: Morphine Sulfate<br>* Morphine medication as a pain killer is administered, if Patient weight <50 kg: Opioid naïve: Initial: 0.05 mg/kg/dose; usual maximum initial dose: 1 to 2 mg/dose.<br>* Other names: Morphine Sulfate intra venous medication;Procedure: blood transfusion session<br>* Regular blood transfusion session based on patient hematological profile starts from one session every 2 weeks.<br>|
| Experimental: Vit-D experimental group<br>50 patients from each participating hospital that will receive Vit-D medication (1500 IU to 3500 IU ) per day for 8 consecutive months up to 10 months. in addition to the experimental treatment, this group will receive the traditional treatment of hydroxyurea, Folic acid, pain killer plus regular blood transfusion with a dose de-escalation methods till efficacy of experimental treatment proved. | Drug: Vit D<br>* 50 patients from each participating hospital that will receive Vit-D medication (1500 IU to 3500 IU ) per day for 8 consecutive months up to 10 months. in addition to the experimental treatment, this group will receive the traditional treatment of hydroxyurea, Folic acid, pain killer plus regular blood transfusion with a dose de-escalation methods till efficacy of experimental treatment proved.<br>* Other names: Vit-D medication oral drops;Drug: Hydroxy Urea<br>* 50 patients from each participating hospital that will receive the ordinary treatment of Hydroxyurea (20 mg/kg/day) with monitoring blood count every 2 weeks maximum daily dose: (40 mg/kg/day) for 8 consecutive months up to 10 months.<br>* Other names: Hydroxy Urea tablet medication 20mg/kg/day;Drug: Folic Acid Supplementation<br>* Folic Acid dose of 0.5 to 1 mg daily for 3 to 4 weeks until definite hematologic response<br>* Other names: Folic Acid tablet medication 1mg/day;Drug: Morphine Sulfate<br>* Morphine medication as a pain killer is administered, if Patient weight <50 kg: Opioid naïve: Initial: 0.05 mg/kg/dose; usual maximum initial dose: 1 to 2 mg/dose.<br>* Other names: Morphine Sulfate intra venous medication;Procedure: blood transfusion session<br>* Regular blood transfusion session based on patient hematological profile starts from one session every 2 weeks.<br>|
| Experimental: Zinc supplements experimental group<br>50 patients from each participating hospital that will receive Zinc supplements (15 mg to 50 mg ) per day for 8 consecutive months up to 10 months. in addition to the experimental treatment, this group will receive the traditional treatment of hydroxyurea, Folic acid, pain killer plus regular blood transfusion with a dose de-escalation methods till efficacy of experimental treatment proved. | Drug: Zinc sulfate<br>* 50 patients from each participating hospital that will receive Zinc supplements (15 mg to 50 mg ) per day for 8 consecutive months up to 10 months. in addition to the experimental treatment, this group will receive the traditional treatment of hydroxyurea, Folic acid, pain killer plus regular blood transfusion with a dose de-escalation methods till efficacy of experimental treatment proved.<br>* Other names: Zinc tablet medication;Drug: Hydroxy Urea<br>* 50 patients from each participating hospital that will receive the ordinary treatment of Hydroxyurea (20 mg/kg/day) with monitoring blood count every 2 weeks maximum daily dose: (40 mg/kg/day) for 8 consecutive months up to 10 months.<br>* Other names: Hydroxy Urea tablet medication 20mg/kg/day;Drug: Folic Acid Supplementation<br>* Folic Acid dose of 0.5 to 1 mg daily for 3 to 4 weeks until definite hematologic response<br>* Other names: Folic Acid tablet medication 1mg/day;Drug: Morphine Sulfate<br>* Morphine medication as a pain killer is administered, if Patient weight <50 kg: Opioid naïve: Initial: 0.05 mg/kg/dose; usual maximum initial dose: 1 to 2 mg/dose.<br>* Other names: Morphine Sulfate intra venous medication;Procedure: blood transfusion session<br>* Regular blood transfusion session based on patient hematological profile starts from one session every 2 weeks.<br>|
| Experimental: Statin experimental group<br>50 patients from each participating hospital that will receive Simvastatin orally (20 mg to 40 mg ) per day for 8 consecutive months up to 10 months. in addition to the experimental treatment, this group will receive the traditional treatment of hydroxyurea, Folic acid, pain killer plus regular blood transfusion with a dose de-escalation methods till efficacy of experimental treatment proved. | Drug: Statins (Cardiovascular Agents)<br>* 50 patients from each participating hospital that will receive Simvastatin orally (20 mg to 40 mg ) per day for 8 consecutive months up to 10 months. in addition to the experimental treatment, this group will receive the traditional treatment of hydroxyurea, Folic acid, pain killer plus regular blood transfusion with a dose de-escalation methods till efficacy of experimental treatment proved.<br>* Other names: Simvastatin 20mg;Drug: Hydroxy Urea<br>* 50 patients from each participating hospital that will receive the ordinary treatment of Hydroxyurea (20 mg/kg/day) with monitoring blood count every 2 weeks maximum daily dose: (40 mg/kg/day) for 8 consecutive months up to 10 months.<br>* Other names: Hydroxy Urea tablet medication 20mg/kg/day;Drug: Folic Acid Supplementation<br>* Folic Acid dose of 0.5 to 1 mg daily for 3 to 4 weeks until definite hematologic response<br>* Other names: Folic Acid tablet medication 1mg/day;Drug: Morphine Sulfate<br>* Morphine medication as a pain killer is administered, if Patient weight <50 kg: Opioid naïve: Initial: 0.05 mg/kg/dose; usual maximum initial dose: 1 to 2 mg/dose.<br>* Other names: Morphine Sulfate intra venous medication;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 Hydroxyurea (20 mg/kg/day) with monitoring blood count every 2 weeks maximum daily dose: (40 mg/kg/day) for 8 consecutive months up to 10 months. in addition, Folic Acid dose of 0.5 to 1 mg daily for 3 to 4 weeks until definite hematologic response in addition, Morphine medication as a pain killer is administered, if Patient weight <50 kg: Opioid naïve: Initial: 0.05 mg/kg/dose; usual maximum initial dose: 1 to 2 mg/dose. This group received regular blood transfusion session. | Drug: Hydroxy Urea<br>* 50 patients from each participating hospital that will receive the ordinary treatment of Hydroxyurea (20 mg/kg/day) with monitoring blood count every 2 weeks maximum daily dose: (40 mg/kg/day) for 8 consecutive months up to 10 months.<br>* Other names: Hydroxy Urea tablet medication 20mg/kg/day;Drug: Folic Acid Supplementation<br>* Folic Acid dose of 0.5 to 1 mg daily for 3 to 4 weeks until definite hematologic response<br>* Other names: Folic Acid tablet medication 1mg/day;Drug: Morphine Sulfate<br>* Morphine medication as a pain killer is administered, if Patient weight <50 kg: Opioid naïve: Initial: 0.05 mg/kg/dose; usual maximum initial dose: 1 to 2 mg/dose.<br>* Other names: Morphine Sulfate intra venous medication;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?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| C-reactive protein mg/L | C-reactive protein milligrams per deciliter | 10 months | 
| Hematocrit % | Hematocrit level in percentage value | 10 months | 
| Fibrinogen mg/dl | Fibrinogen concentration in milligrams per deciliter | 10 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 | 
| leukocytes count μl | leukocytes in microliter | 10 months | 
| hemoglobin (Hbg) g/dL | hemoglobin (Hbg) gram/deciliter | 10 months | 
| White blood cells count | White blood cells count in a cubic milliliter of blood | 10 months | 
| Lactic acid dehydrogenase U/L | Lactic acid dehydrogenase unit per litter | 10 months | 
| Reticulocyte count % | Reticulocyte count percentage | 10 months | 
| Red blood cell (erythrocyte ) sedimentation rate mm/hr | erythrocyte sedimentation rate in millimeters (mm) per one hour(hr) | 10 months | 
| lymphocyte count µL | lymphocyte count in 1 microliter (µL) of blood | 10 months | 
| Granulocyte absolute count cells/microliter | Granulocyte cells numbers in microliter | 10 months | 
| Granulocytes,percentage (GR, pct) | percentage of white blood cells with granules in percentage | 10 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
omega3, Vaso-occlusive painful crisis, Pediatric sickle cell anemia, comparative effective analysis in VOC, Anti-inflammatory effect of Vit-D, Anti-hemolytic effect of Vit-D, Anti-hyperlipidemia of Vit-D, effect of omega-3 on blood rheology, effect of omega-3 on blood viscosity, Antiaggregation effect of omega-3, Anti-inflammatory effect of statins, Anti-inflammatory effect of zinc supplements, effect of zinc supplements on blood viscosity, effect of zinc supplements on blood rheology, Antiaggregation effect of zinc supplements, pediatric sickle cell disease