Study Of Efficacy,Safety of Combined Deferasirox and Deferiprone Versus Combined Deferiprone and Desferal In Conditions of Iron Overload

Study Overview
=================
Brief Summary
-----------------
Interventional Allocation: Randomized Endpoint Classification: Safety/Efficacy Study of combined chelation therapy Masking: Open Label Primary Purpose: Treatment of transfusional iron overload Primary Outcome Measures: • The primary outcome measure is to assess efficacy in lowering serum ferritin level(the change in serum ferritin compared to baseline) with combining DFP and deferasirox compared to combined DFP and DFO in conditions with severe chronic iron overload; showing an up-trend of SF over previous 12 months on single chelator. Secondary Outcome Measures: • The secondary outcome measure is to determine the number of patients who will develop adverse events in order to assess safety upon administering the drugs in combination (DFP and DFX) compared to the combination of DFO and DFP.

Detailed Description
-----------------
Study population: Beta-thalassemia major patients; Patients with high iron stores Serum ferritin consistently > 2500 mcg/l and or increasing trend over previous 12 months Liver iron >14 mg/g dry weight- by R2 MRI Other causes of transfusional hemosiderosis Estimated Enrollment: 30 patients in each arm Study Start Date: January 1st ; 2011 enrollment period 8 weeks Estimated Study Completion Date: End of February 1212 Arms Assigned Interventions Arm 1: Patients will be treated with combined DFP and deferasirox. Drug: Ferriprox It will be given orally in the morning Other Name: DFP Initial dose 25/mg/kg in 3 divided doses (better tolerated if started and then built up over 4 weeks). Dose may be increased up to 100mg/kg/day guided by serum ferritin. Agranulocytosis risk 1-2%. Monitor TLC and granulocytic count / 2weeks. Patients need to be continually educated about this risk, know that they must stop DFP if they have a fever or infection. Drug: Deferasirox will be orally administered at a dose of 20 mg/kg once daily at evening for 5 days. Other Name: ICL670 Arm 2: Patients will be treated for 6 days with a combination of deferoxamine and DFP. Interventions: Drug: Deferoxamine Drug: DFP Drug: Deferoxamine Deferoxamine will be administered subcutaneously over 8 hours for 5 days at a dose of 40 mg/kg. Other Name: Desferal, DFO Drug: DFP DFP: will be orally administered at a dose of 75mg/kg orally in 3 divided doses for 7 days Eligibility Ages Eligible for Study : 6 to 18Years Genders Eligible for Study: Both Inclusion Criteria: Subjects with transfusional iron overload after Approval of Ethical committee giving written informed consent. Subjects must have a serum ferritin greater than >2500 ng/mL, a platelet count greater than 100,000/mm3, and a serum creatinine within the normal range. A woman of childbearing potential must have a negative serum pregnancy test at screening. She must use a medically acceptable form of birth control during the study and for 1 month afterward. The subjects must also have a level of understanding and willingness to cooperate with the confinement and procedures described in the consent form and scheduled by the study site. In addition, he/she must be able to provide voluntary written informed consent. Exclusion Criteria: Subjects with a past history of agranulocytosis, history of clinically significant gastrointestinal, renal, hepatic ALT > 10 times high normal, OR > 50% increase of serum creatinine from basal value, pulmonary or cardiovascular disease. Patients with a history of tuberculosis, epilepsy, psychosis, glaucoma or any other condition, which in the opinion of the investigators, would jeopardize the safety of the subject or impact the validity of the study results. Subjects with HIV positive or have active HCV. A history of serious immunologic hypersensitivity to any medication, such as prophylaxis or angioedema. Participation in a previous investigational drug study within the 30 days preceding screening.. Women who are pregnant, or breast-feeding. Current alcohol or drug abuse. An inability to adhere to the designated procedures and restrictions of this protocol. Subjects receiving warfarin, digoxin, or anti-arrhythmic or anti-seizure medications. Subjects with a known allergy to Exjade or DFP that prevents chronic administration.

Official Title
-----------------
A Prospective Randomized Comparative Study of Efficacy and Safety of Combined Deferiprone (DFP) and Deferasirox Versus DFP and Desferrioxamine (DFO) Therapy in Diseases With Severe Iron Overload

Conditions
-----------------
Beta-thalassemia Major, Sickle Cell Disease, Iron Hemosiderosis

Intervention / Treatment
-----------------
* Drug: DFP (ferriprox) and deferasirox (ICL 670)
* Drug: DFP, DFO


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects with transfusional iron overload secondary to thalassemia major , sickle cell disease showing up-trend in SF aged 6 Years or older, may participate after Approval of Ethical committee giving written informed consent. Subjects must have a serum ferritin greater than >2500 ng/mL, a platelet count greater than 100,000/mm3, and a serum creatinine within the normal range. A woman of childbearing potential must have a negative serum pregnancy test at screening. She must use a medically acceptable form of birth control during the study and for 1 month afterward. The subjects must also have a level of understanding and willingness to cooperate with the confinement and procedures described in the consent form and scheduled by the study site. In addition, he/she must be able to provide voluntary written informed consent. Exclusion Criteria: Subjects with a past history of agranulocytosis, history of clinically significant gastrointestinal, renal, hepatic ALT > 10 times high normal, OR > 50% increase of serum creatinine from basal value, pulmonary or cardiovascular disease. Patients with a history of tuberculosis, epilepsy, psychosis, glaucoma or any other condition, which in the opinion of the investigators, would jeopardize the safety of the subject or impact the validity of the study results. Subjects with HIV positive or have active HCV. A history of serious immunologic hypersensitivity to any medication, such as anaphylaxis or angioedema. Participation in a previous investigational drug study within the 30 days preceding screening.. Women who are pregnant, or breast-feeding. Current alcohol or drug abuse. An inability to adhere to the designated procedures and restrictions of this protocol. Subjects receiving warfarin, digoxin, or anti-arrhythmic or anti-seizure medications. Subjects with a known allergy to Exjade or DFP that prevents chronic administration.

Ages Eligible for Study
-----------------
Minimum Age: 6 Years
Maximum Age: 18 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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: arm 1<br>30 Patients will be treated with combined DFP and deferasirox. | Drug: DFP (ferriprox) and deferasirox (ICL 670)<br>* Drug: Ferriprox It will be given orally in the morning Other Name: DFP Initial dose 25/mg/kg 3 times/d (better tolerated if started and then built up over 4 weeks). Dose may be increased up to 100mg/kg/day guided by serum ferritin. Agranulocytosis risk 1-2%. Monitor TLC and granulocytic count / 2weeks. Patients need to be continually educated about this risk, know that they must stop DFP if they have a fever or infection. Drug: Deferasirox will be orally administered at a dose of 20 mg/kg once daily at evening for 5 days. Other Name: ICL670<br>|
| Active Comparator: arm 2<br>Patients will be treated for 6 days with a combination of deferoxamine and DFP | Drug: DFP, DFO<br>* Drug: Deferoxamine It will be administered subcutaneously over 8 hours for 5 days at a dose of 40 mg/kg. Other Name: Desferal, DFO Drug: DFP DFP: will be orally administered at a dose of 75mg/kg orally in 3 divided doses for 7 days<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| to assess efficacy of combining DFP and deferasirox compared to combined DFP and DFO in decreasing the serum ferritin level in conditions with severe chronic iron overload. | • The primary outcome measure is to measure the change in serum ferritin level from baseline in the 2 combination therapy. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| to determine the safety upon administering the drugs in combination (DFP and DFX) compared to the combination of DFO and DFP. | • The secondary outcome measure is to determine the number of patients who will develop adverse reactions upon administering the drugs in combination. | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Iron chelation, Iron balance, Secondary iron overload, deferoxamine, deferasirox, Deferiprone, 1- Beta-thalassemia major patients;, Patients with high iron stores, Serum ferritin consistently > 2500 mcg/l and or increasing trend over previous 12 months, Liver iron >14 mg/g dry weight- by R2 MRI, 2- Sickle cell disease, 3- Other causes of transfusional iron hemosiderosis