Effect of Deferasirox on Endocrine Complications in Subjects With Transfusion Dependent Thalassemia

Study Overview
=================
Brief Summary
-----------------
The CENTAurus trial is a prospective clinical study designed to address systematically some of the relevant endocrine complications in an iron overloaded thalassemic population, primary objective being the assessment of the effect of deferasirox therapy on glucose metabolism/homeostasis. Other endocrine parameters complementary or supportive to the primary objective will be assessed and analyzed during this study. A number of lab parameters related to other axes of the endocrine system will be collected and analyzed.

Official Title
-----------------
A Multicenter, Open-label, Single Arm, Interventional Phase IV Study, to Evaluate the Effect of Deferasirox on Endocrine Complications in Subjects With Transfusion Dependent Thalassemia

Conditions
-----------------
Thalassemia (Transfusion Delendent)

Intervention / Treatment
-----------------
* Drug: deferasirox


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 1. Beta thalassemia major and severe intermedia patients transfusion dependent and with transfusional iron overload 2. Patients with diagnosis of impaired fasting glucose or impaired glucose tolerance 4.Patients naïve to deferasirox or patients who already receive deferasirox at sub-optimal doses 5.Cardiac MRI T2* >10 msec; 7.normal cardiac function (LVEF > 56%); Exclusion Criteria: Non transfusional hemosiderosis; Patients with diabetes mellitus (genetic or secondary) or history of diabetes mellitus in 1st degree relatives; 4.Patients who received organ transplant; 5.Patients with galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption; 6.Patients unable to tolerate (or who have unacceptable toxicities to) prior treatment with deferasirox; 7.History of hypersensitivity to the study drug or any of its excipients; 8. Renal impairment 10. Liver impairment; 11.Patients with active chronic hepatitis B infection, active hepatitis C infection; Other protocol-defined inclusion/exclusion criteria may apply at the end

Ages Eligible for Study
-----------------
Minimum Age: 2 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: Supportive Care
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: deferasirox<br>single arm. all patients will receive deferasirox | Drug: deferasirox<br>* 125, 250, 500 mg dispersable tablets<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline of glucose blood level measured after 2 h after receiving a glucose-equivalent oral challenge | The primary efficacy variable is the change (mg/dl) from baseline to 36 months of glucose plasma levels measured 2 hr post glusose equivalent oral challange. After a 12-hour overnight fasting, at zero time (baseline) blood sample will be drawn and afterwards patients will receive a glucose-equivalent oral challenge (75 grams). After glucose loading plasma samples will be drawn at 30, 60, 90, 120 minutes for determination of plasma glucose. This will be repeated every 6 month till end of study | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucose of OGTT ( AUC) | change in of glucose metabolism during deferasirox treatment measuring the change versus baseline of 2-hr and fasting glucose plasma level of OGTT.After a 12-hour overnight fasting, at zero time (baseline) blood sample will be drawn and afterwards patients will receive a glucose-equivalent oral challenge (75 grams). After glucose loading plasma samples will be drawn at 30, 60, 90, 120 minutes for determination of plasma glucose . This will be repeated every 6 months till end of study | baseline and every 6 months measurement of 2hour Glocose of OGTT | 
| change on insulin secretion and sensitivity | Change in insulin secretion and insulin sensitivity at every measurement versus screening. Stumvol Formula will be applied to values of 2hr glucose OCTT to calucolate insulin secretion and insulin sensitivity. After a 12-hour overnight fasting, at zero time (baseline) blood sample will be drawn and afterwards patients will receive a glucose-equivalent oral challenge (75 grams). After glucose loading plasma samples will be drawn at 30, 60, 90, 120 minutes for determination of insulin concentration. | baseline and every 6 months measurement of 2hr Glucose OGTT | 
| Measurement of thyroid hormones TSH and FT4 | Changes in plasma levels of TSH and FT4 at every measurement versus screening. Blood samples will be drawn from the patient at baseline and every 12 month till end of study and plansa concentration of thyroid hormons TSH and FT4 will be assessed. | baseline and every 12 months | 
| Risk factors for the impairment of glucose homeostasis | information on age, sex, ethnicity, BMI, metabolic syndrome (hypertension, dyslipidemia, hypertrygliceridemia), chronic use of steroids, use of immunosuppressive drugs, growth hormonal deficit will be collected on a monthly basis till end of study | baseline and monthly till End of Study | 
| Changes in endocrine funcionts parameters | - Female patients will be assessed for the presence or absence of menses every month versus baseline .Use of current hormonal replacing therapy, if any (e.g. thyroxin therapy for patients with non-compensated hypothyroidism, hormonal replacement drugs for hypogonadal patients) will be checked on a monthly basis versus baseline | baseline and monthly till EOS | 
| Changes in parameters of bone metabolism | - Blood samples wiil be drawn to measure levels of serum calcium, phosphorus, alkaline phosphatase, vitamin D levels (25-hydroxycholecalciferol), serum calcium, parathormone (intact 1-84 PTH) from baseline to the end of study. Blood samples will be drawn to assess also Vitamin D and parathormone at baseline and then every six months. The intact parathormone will be assessed by evaluating the 1-84 PTH form. Inorganic phosphorus, serum calcium will be assessed at baseline and then monthly; alkaline phosphatase will be evaluated at baseline, every two weeks during the first month of treatment and monthly thereafter till EOS. | baseline, monthly or every 6 months till end of study | 
| Iron overload status | Blood samples will be drawn to assess Serum Ferriting. Liver and cardiac iron will be assessed by MRI (MRI R2 annual measurements for liver, MRI T2* annual measurements for cardiac); -Relationship between changes in SF, LIC and cardiac T2* and changes in primary (OGTT) and secondary endpoints (glucose metabolism trend, insulin secretion and insulin sensitivity); | baseline and regularly till end of study (monthly or yearly as specified) | 
| Safety of deferasirox therapy | Clinical and laboratory monitoring of AEs and SAEs (in particular changes in hepatic, renal, audiometric and ophthalmology parameters). Blood samples will be drawn to assess liver functions, renal funtions. Urine test will be performed to assess renal functions. An audiometric and ophalmologic visit will be done to assess eyes and ears functions. | baseline and at every scheduled visit (weekly for the first months or after dose escalation and monthly thereafter or yearly till EOS | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Endocrine complications, transfusion dependent thalassemia