Safety and Efficacy of Deferasirox in Combination With Desferoxamine in β-thalassaemia Patients With Severe Cardiac Iron Overload
Condition: Transfusion-dependent β-thalassemia Patients; Cardiac Iron Overload
MeSH terms: Thalassemia; beta-Thalassemia; Iron Overload
Intervention: Deferasirox; Deferoxamine (DFO)
Intervention description: 20-40 mg/kg/day orally, once daily; 40 mg/kg/day subcutaneous (sc) infusion, 3-4 days per week
Intervention MeSH terms: Deferasirox; Deferoxamine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 32.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Severe cardiac iron overload; deferasirox; β-thalassaemia; cardiac dysfunction

Summary:

      The primary efficacy endpoint of this interventional study was to evaluate the number of
      patients achieving a complete response (CR), defined as patients switching from intensive
      deferasirox -DFO treatment, at any time point during the 24 months of study, to deferasirox
      monotherapy based on improvement in the cardiac magnetic resonance imaging (MRI) T2* value to
      >10ms, and continue to maintain their MRI T2* to values >10 msec.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or female patients with β-thalassemia major, at least 18 years old, having given
             written consent to participate in the study.

          -  Cardiac MRI T2* value ranging from <=4 to <=10 ms.

          -  LVEF ≥ 56 % as determined by CMR.

          -  Patients with LIC > 10mg Fe/g dw will be included in the protocol. Study will evaluate
             the first 10 patients at 6 months, and if no safety signals are present, patients with
             LIC>5 mg Fe/g dw will be allowed to be included.

          -  Prior iron chelation treatment with DFO, DFP, DFX or combination DFO-DFP

        Exclusion Criteria:

          -  Patients with symptoms of cardiac dysfunction symptoms (shortness of breath at rest or
             exertion, orthopnea, exercise intolerance, lower extremity edema, arrhythmias).

          -  Patients with cardiac T2* MRI < 4 or > 10 ms.

          -  Patients not compliant to intensive iron chelation therapy regimens such i.v DFO 24 hr
             infusions or DFO-DFP combination.

          -  Patients with documented liver failure (presence of portal hypertension, hepatic
             edemas, ascites).

          -  Patients unable to undergo study assessments, including blood sampling, MRI, e.g., are
             claustrophobic to MRI, have a pacemaker, ferromagnetic metal implants other than those
             approved as safe for use in MRI scanners (e.g., some types of aneurysm clips, shrapnel
             in proximity to vital organs such as the retina), are obese (exceeding the equipment
             limits).

          -  Patients with serum creatinine > ULN or with significant proteinuria as indicated by a
             urinary protein/creatinine ratio ≥ 1.0 in a non-first void urine sample at baseline.
             Patients with creatinine clearance <60 ml/min will be excluded.

          -  Patients with ALT (SGPT) levels > 5 x ULN.

          -  Patients with considerable impaired gastrointestinal (GI) function or GI disease that
             may significantly alter the absorption of oral deferasirox / ICL670 (e.g., ulcerative
             diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small
             bowel resection.

          -  History or clinical evidence of pancreatic injury or pancreatitis.

          -  Patients with a known hypersensitivity to any of the study drugs or the drug's
             excipients.

          -  History of clinically relevant ocular and/or auditor toxicity related to iron
             chelation therapy.

          -  Patients with psychiatric or addictive disorders which prevent them from giving their
             informed consent or undergoing any of the treatment options or patients unwilling or
             unable to comply with the protocol.

          -  Patients with a known history of HIV seropositivity (Elisa or Western blot).

          -  History of malignancy of any organ system, treated or untreated, within the past 5
             years whether or not there is evidence of local recurrence or metastases, with the
             exception of localized basal cell carcinoma of the skin.

          -  Female patients who are pregnant or breast feeding.

          -  Female patients of reproductive potential not employing an effective method of birth
             control. Women of childbearing potential must have a negative serum pregnancy test ≤
             48 hours prior to the study drugs.

          -  Patients participating in another clinical trial or receiving an investigational drug.

          -  History of non-compliance with medical regimens or patients who are considered
             potentially unreliable and/or not cooperative, unwilling or unable to comply with the
             protocol.

        Other protocol-defined inclusion/exclusion criteria may apply