Safety and Efficacy of Deferasirox in Combination With Desferoxamine in β-thalassaemia Patients With Severe Cardiac Iron Overload (MACS1097)

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Novartis
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01459718
First received: July 20, 2011
Last updated: June 24, 2014
Last verified: June 2014
  Purpose

The primary efficacy endpoint of this interventional study is 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 Intervention Phase
Transfusion-dependent β-thalassemia Patients
Cardiac Iron Overload
Drug: Deferasirox
Drug: Deferasirox + Deferoxamine
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Number of patients achieving a complete response (CR) [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    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 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.

  • Number of patients achieving a partial response (PR) [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    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.

  • Number of patients with stable disease (SD [ Time Frame: 24 nmonths ] [ Designated as safety issue: No ]
    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:
  • Safety and tolerability will be measured by the number of post baseline adverse events (AEs) (clinical and laboratory abnormalities), severity and relationship to study i.e ocular/ auditory exams [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]

    Laboratory abnormalities qualifying as AEs include occurrence of post baseline abnormal parameters of serum creatinine, creatinine clearance, liver transaminases (AST/ALT), bilirubin and proteinuria and by the patients who discontinue the study due to AEs.

    Patients who discontinue the study due to AEs for each of the treatment regimens, i.e., deferasirox-DFO combination and deferasirox monotherapy


  • Reduction in cardiac iron overload of patients in intensive iron chelation therapy consisting of deferasirox-DFO and after transition to deferasirox monotherapy [ Time Frame: screening, 6, 12, 18, 24 months ] [ Designated as safety issue: No ]

    Reduction in cardiac iron overload will be determined by the changes in cardiac MRI T2* from screening, at 6, 12, 18 and 24 months for each response group.

    Reduction in cardiac iron overload will also be measured by the monthly velocity of heart T2* for each response group.


  • Time for a patient with severe cardiac iron receiving intensive deferasirox-DFO regimen to achieve a cardiac MRI T2* > 10 ms [ Time Frame: 24 months ] [ Designated as safety issue: No ]
  • Reduction in Liver iron concentration (LIC) [ Time Frame: screening, 6, 12, 18, 24 months ] [ Designated as safety issue: No ]
    Reduction in LIC will be determined by change in liver MRI T2* from screening, at 6, 12, 18 and 24 months for each response group

  • Trends and associations between serum ferritin levels and LIC [ Time Frame: 6, 12, 18, 24 months ] [ Designated as safety issue: No ]
    Trends and associations will be evaluated by the observed changes at 6, 12, 18, 24 months at a given time point for each response group

  • Improvement in cardiac function [ Time Frame: 6, 12, 18, 24 months ] [ Designated as safety issue: No ]
    Determined as change in cardiac magnetic resonance (CMR) measured left ventricular ejection fraction (LVEF) (%) at 6, 12, 18, 24 months.


Estimated Enrollment: 50
Study Start Date: January 2011
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Deferasirox
Monotherapy of deferasirox
Drug: Deferasirox
Deferasirox monotherapy treatment of intensive iron chelation treatment. Medication label will comply with the Greek legal requirements and be printed in Greek. A subject identifier will be entered on the medication label.
Other Name: ICL670
Active Comparator: Deferasirox + Deferioxamine (DFO)
Combination Therapy: Deferasirox-DFO
Drug: Deferasirox + Deferoxamine
Deferasirox-DFO regimen for intensive iron chelation treatment. Medication labels will comply with the Greek legal requirements and will be printed in Greek. A subject identifier will be entered on the medication label.
Other Names:
  • ICL670
  • DFO

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01459718

Contacts
Contact: Novartis Pharmaceuticals +41613241111
Contact: Novartis Pharmaceuticals

Locations
Greece
Novartis Investigative Site Recruiting
Athens, GR, Greece, 11527
Novartis Investigative Site Recruiting
Athens, Greece, GR
Novartis Investigative Site Recruiting
Athens, Greece, GR-115 27
Novartis Investigative Site Recruiting
Patras, Greece, 26500
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01459718     History of Changes
Other Study ID Numbers: CICL670AGR02, 2009-018091-34
Study First Received: July 20, 2011
Last Updated: June 24, 2014
Health Authority: United States: Food and Drug Administration
Greece:Hellenic National Health Authorities (EOF, NEC)

Keywords provided by Novartis:
Severe cardiac iron overload
deferasirox
β-thalassaemia
cardiac dysfunction

Additional relevant MeSH terms:
Beta-Thalassemia
Iron Overload
Thalassemia
Anemia
Anemia, Hemolytic
Anemia, Hemolytic, Congenital
Genetic Diseases, Inborn
Hematologic Diseases
Hemoglobinopathies
Iron Metabolism Disorders
Metabolic Diseases
Deferasirox
Deferoxamine
Chelating Agents
Iron Chelating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Sequestering Agents
Siderophores

ClinicalTrials.gov processed this record on October 29, 2014