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

• ClinicalTrials.gov Identifier: NCT01459718
• Recruitment Status: Terminated
• First Posted: October 26, 2011
• Results First Posted: October 23, 2019
• Last Update Posted: October 23, 2019
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: July 20, 2011
• First Posted Date: October 26, 2011
• Results First Submitted Date: July 28, 2015
• Results First Posted Date: October 23, 2019
• Last Update Posted Date: October 23, 2019
• Study Start Date: January 2011
• Actual Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 21, 2019)

• 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.
• 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.
• 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.

Original Primary Outcome Measures (submitted: October 24, 2011)

• 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 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 ]
  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 onotherapy, 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 ]
  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.

Current Secondary Outcome Measures (submitted: October 21, 2019)

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

Original Secondary Outcome Measures (submitted: October 24, 2011)

• 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 ]
  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 ]
  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 ]
• Reduction in Liver iron concentration (LIC) [ Time Frame: screening, 6, 12, 18, 24 months ]
  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 ferrtin levels and LIC [ Time Frame: 6, 12, 18, 24 months ]
  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 ]
  Determined as change in cardiac magnetic resonance (CMR) measured left ventricular ejection fraction (LVEF) (%) at 6, 12, 18, 24 months.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Transfusion-dependent β-thalassemia Patients
• Cardiac Iron Overload

Intervention

• 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

Study Arms

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.

Interventions:

• Drug: Deferasirox
• Drug: Deferoxamine (DFO)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: February 9, 2015): 32
• Original Estimated Enrollment (submitted: October 24, 2011): 52
• Actual Study Completion Date: June 2014
• Actual Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Greece

Administrative Information

• NCT Number: NCT01459718
• Other Study ID Numbers: CICL670AGR02; 2009-018091-34 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: October 2019