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Safety and Efficacy of Deferasirox in Combination With Desferoxamine in β-thalassaemia Patients With Severe Cardiac Iron Overload

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01459718
Recruitment Status : Terminated (The study terminated due to low enrollment.)
First Posted : October 26, 2011
Results First Posted : October 23, 2019
Last Update Posted : October 23, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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.

Condition or disease Intervention/treatment Phase
Transfusion-dependent β-thalassemia Patients Cardiac Iron Overload Drug: Deferasirox Drug: Deferoxamine (DFO) Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 32 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : January 2011
Actual Primary Completion Date : June 2014
Actual Study Completion Date : June 2014

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Iron Thalassemia

Arm Intervention/treatment
Experimental: Deferasirox / Deferasirox + Deferoxamine (DFO)
During Phase A, the induction treatment at entry, participants received Deferasirox -DFO combination. During Phase B, when participants transitioned to less intensive chelation therapy, participants received Deferasirox monotherapy.
Drug: Deferasirox
20-40 mg/kg/day orally, once daily
Other Name: ICL670, Exjade

Drug: Deferoxamine (DFO)
40 mg/kg/day subcutaneous (sc) infusion, 3-4 days per week
Other Name: DFO, Desferal




Primary Outcome Measures :
  1. Number of Patients Achieving a Complete Response (CR) [ Time Frame: 24 months ]
    Complete Response is defined as patients that stop intensive deferasirox -DFO treatment, at any time point during the 24 months of study, based on an improvement in the cardiac Magnetic Resonance Imaging T2 star technique (MRI T2*) value being >10ms, and continue to be treated with deferasirox monotherapy without any further need for reverting back to intensive iron chelation treatment during the 24 months of study.

  2. Number of Patients Achieving a Partial Response (PR) [ Time Frame: 24 months ]
    Partial Response is defined as patients that stop intensive deferasirox -DFO treatment at any time point during the 24 months study and transition to receive deferasirox monotherapy, but due to a deterioration in cardiac MRI T2* to a value < 10 ms revert back to intensive deferasirox -DFO iron chelation therapy during the 24 months of study.

  3. Number of Patients With Stable Disease (SD) [ Time Frame: 24 months ]
    Stable Disease is defined as those patients that never achieved an improvement in the cardiac MRI T2* to values >10ms during the 24 months of study.


Secondary Outcome Measures :
  1. Change From Baseline in Cardiac Iron Overload of Patients in Intensive Iron Chelation Therapy Consisting of Deferasirox-DFO and After Transition to Deferasirox Monotherapy [ Time Frame: Baseline, 6, 12, 18, 24 months ]
    Cardiac iron overload was determined by cardiac MRI T2*. Cardiac iron overload also was measured by the monthly velocity of heart MRI T2*.

  2. Time to Response [ Time Frame: 24 months ]
    Time to response was defined as the time from baseline when the participant had severe cardiac iron overload to the time when the participant achieved mild/moderate cardiac overload (T2*>10 milliseconds [ms]).

  3. Change From Baseline in Liver Iron Concentration (LIC) [ Time Frame: Baseline, 6, 12, 18, 24 months ]
    Change from baseline in LIC was determined by change in liver MRI T2*.

  4. Correlation Between Change From Baseline in Serum Ferritin and LIC Levels [ Time Frame: Baseline, 6, 12, 18, 24 months ]
    Spearman correlation coefficients between serum ferritin and LIC changes from baseline levels were reported.

  5. Left Ventricular Ejection Fraction (LVEF) [ Time Frame: 6, 12, 18, 24 months ]
    LVEF % was measured by cardiac magnetic resonance (CMR).



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01459718


Locations
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Greece
Novartis Investigative Site
Athens, GR, Greece, GR-115 27
Novartis Investigative Site
Athens, Greece, 11527
Novartis Investigative Site
Athens, Greece, GR
Novartis Investigative Site
Patras, Greece, 265 00
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

Additional Information:
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01459718    
Other Study ID Numbers: CICL670AGR02
2009-018091-34 ( EudraCT Number )
First Posted: October 26, 2011    Key Record Dates
Results First Posted: October 23, 2019
Last Update Posted: October 23, 2019
Last Verified: October 2019
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Severe cardiac iron overload
deferasirox
β-thalassaemia
cardiac dysfunction
Additional relevant MeSH terms:
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Thalassemia
beta-Thalassemia
Iron Overload
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Iron Metabolism Disorders
Metabolic Diseases
Deferasirox
Deferoxamine
Iron Chelating Agents
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action
Siderophores