Clinical trial NCT01459718: Safety and Efficacy of Deferasirox in Combination With Desferoxamine in β-thalassaemia Patients With Severe Cardiac Iron Overload
Official title: A Multicenter Open Label Phase II Study to Evaluate the Safety and Efficacy of Deferasirox in Combination With Deferoxamine Followed by Transitioning to Deferasirox Monotherapy in β-thalassemia Patients With Severe Cardiac Iron Overload
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Transfusion-dependent β-thalassemia Patients
Cardiac Iron Overload
Keywords: Severe cardiac iron overload
deferasirox
β-thalassaemia
cardiac dysfunction
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2011-10-26
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed description: This study was planned to recruit 52 transfusion-dependent β-thalassemia patients with severe cardiac iron overload. However only 13 patients participated in the study during a 3 year and 5 month timeframe. The study was terminated due to the slow enrollment rate due to scarcity of the patient population with severe cardiac iron overload.

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

Primary outcomes:
measure: Number of Patients Achieving a Complete Response (CR)
timeFrame: 24 months
measure: Number of Patients Achieving a Partial Response (PR)
timeFrame: 24 months
measure: Number of Patients With Stable Disease (SD)
timeFrame: 24 months
Secondary outcomes:
measure: Change From Baseline in Cardiac Iron Overload of Patients in Intensive Iron Chelation Therapy Consisting of Deferasirox-DFO and After Transition to Deferasirox Monotherapy
timeFrame: Baseline, 6, 12, 18, 24 months
measure: Time to Response
timeFrame: 24 months
measure: Change From Baseline in Liver Iron Concentration (LIC)
timeFrame: Baseline, 6, 12, 18, 24 months
measure: Correlation Between Change From Baseline in Serum Ferritin and LIC Levels
timeFrame: Baseline, 6, 12, 18, 24 months
measure: Left Ventricular Ejection Fraction (LVEF)
timeFrame: 6, 12, 18, 24 months
Other outcomes:
Locations:
city: Athens
country: Greece
facility: Novartis Investigative Site
state: GR
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Patras
country: Greece
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: