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

NCT01459718 | Terminated Phase 2 Results

• 2 other identifiers: CICL670AGR022009-018091-34
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 4

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.

Conditions

Transfusion-dependent β-thalassemia Patients; Cardiac Iron Overload

Keywords

Severe cardiac iron overload; deferasirox; β-thalassaemia; cardiac dysfunction

Outcome Measures

Primary Outcomes (3)

• Number of Patients Achieving a Complete Response (CR)

  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.

  24 months

• Number of Patients Achieving a Partial Response (PR)

  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.

  24 months

• Number of Patients With Stable Disease (SD)

  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.

  24 months

Secondary Outcomes (5)

• Change From Baseline in Cardiac Iron Overload of Patients in Intensive Iron Chelation Therapy Consisting of Deferasirox-DFO and After Transition to Deferasirox Monotherapy

  Baseline, 6, 12, 18, 24 months

• Time to Response

  24 months

• Change From Baseline in Liver Iron Concentration (LIC)

  Baseline, 6, 12, 18, 24 months

• Correlation Between Change From Baseline in Serum Ferritin and LIC Levels

  Baseline, 6, 12, 18, 24 months

• Left Ventricular Ejection Fraction (LVEF)

  6, 12, 18, 24 months

Study Arms (1)

Deferasirox / Deferasirox + Deferoxamine (DFO)

EXPERIMENTAL

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; Drug: Deferoxamine (DFO)

Interventions

Deferasirox DRUG

20-40 mg/kg/day orally, once daily

Also known as: ICL670, Exjade

Deferasirox / Deferasirox + Deferoxamine (DFO)

Deferoxamine (DFO) DRUG

40 mg/kg/day subcutaneous (sc) infusion, 3-4 days per week

Also known as: DFO, Desferal

Deferasirox / Deferasirox + Deferoxamine (DFO)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (4)

Novartis Investigative Site

Athens, GR, GR-115 27, Greece

Location

Novartis Investigative Site

Athens, 11527, Greece

Location

Novartis Investigative Site

Athens, GR, Greece

Location

Novartis Investigative Site

Pátrai, 265 00, Greece

Location

MeSH Terms

Interventions

Deferasirox; Deferoxamine

Intervention Hierarchy (Ancestors)

Benzoates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Hydroxamic Acids; Hydroxylamines; Amines; Hydroxy Acids

Limitations and Caveats

Study was terminated. Efficacy was not powered for analysis due to the low enrollment of only 13 patients.

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

862-778-1873

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 20, 2011
• First Posted: October 26, 2011
• Study Start: January 1, 2011
• Primary Completion: June 1, 2014
• Study Completion: June 1, 2014
• Last Updated: October 23, 2019
• Results First Posted: October 23, 2019

Record last verified: 2019-10

Locations

GR (4)