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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01459718
• Collaborator: (none)
• Enrollment: 32
• Locations: 4
• Arm: 1
• Duration (Months): 41
• Patients Per Site: 8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: N/A
• 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: Jan 1, 2011
• Actual Primary Completion Date: Jun 1, 2014
• Actual Study Completion Date: Jun 1, 2014

Arms and Interventions

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 Names: ICL670, Exjade ; Drug: Deferoxamine (DFO); 40 mg/kg/day subcutaneous (sc) infusion, 3-4 days per week; Other Names: DFO, Desferal

Outcome Measures

Primary Outcome Measures

1. Number of Patients Achieving a Complete Response (CR) [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) [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) [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 [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 [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) [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 [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) [6, 12, 18, 24 months]

   LVEF % was measured by cardiac magnetic resonance (CMR).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Athens	GR	Greece	GR-115 27
2	Novartis Investigative Site	Athens		Greece	11527
3	Novartis Investigative Site	Athens		Greece	GR
4	Novartis Investigative Site	Patras		Greece	265 00

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01459718
• Other Study ID Numbers: CICL670AGR02; 2009-018091-34
• First Posted: Oct 26, 2011
• Last Update Posted: Oct 23, 2019
• Last Verified: Oct 1, 2019

• Keywords provided by Novartis Pharmaceuticals: Severe cardiac iron overload; deferasirox; β-thalassaemia; cardiac dysfunction
• Additional relevant MeSH terms: Thalassemia; beta-Thalassemia; Iron Overload; Deferasirox; Deferoxamine

Study Results

Participant Flow

Recruitment Details	In this open-label, single arm study 31 participants were enrolled (one participant was screened twice and was assigned 2 screening numbers; therefore the number enrolled = 32). Of these enrolled participants, 13 were randomized.

Arm/Group Title	Deferasirox / Deferasirox + Deferoxamine (DFO)
Arm/Group Description	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.
Period Title: Overall Study
STARTED	13
Safety Analysis Set	13
COMPLETED	10
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Deferasirox / Deferasirox + Deferoxamine (DFO)
Arm/Group Description	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.
Overall Participants	13
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	32.7 (4.0)
Sex: Female, Male (Count of Participants)
Female	8 61.5%
Male	5 38.5%

Outcome Measures

1. Primary Outcome

Title	Number of Patients Achieving a Complete Response (CR)
Description	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.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

The full analysis set included all the participants entered in the study with at least a valid post-baseline assessment of the primary efficacy variable.

Arm/Group Title	Deferasirox / Deferasirox + Deferoxamine (DFO)
Arm/Group Description	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.
Measure Participants	12
Count of Participants [Participants]	4 30.8%

2. Primary Outcome

Title	Number of Patients Achieving a Partial Response (PR)
Description	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.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

The full analysis set included all the participants entered in the study with at least a valid post-baseline assessment of the primary efficacy variable.

Arm/Group Title	Deferasirox / Deferasirox + Deferoxamine (DFO)
Arm/Group Description	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.
Measure Participants	12
Count of Participants [Participants]	0 0%

3. Primary Outcome

Title	Number of Patients With Stable Disease (SD)
Description	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.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

The full analysis set included all the participants entered in the study with at least a valid post-baseline assessment of the primary efficacy variable.

Arm/Group Title	Deferasirox / Deferasirox + Deferoxamine (DFO)
Arm/Group Description	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.
Measure Participants	12
Count of Participants [Participants]	8 61.5%

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The full analysis set included all the participants entered in the study with at least a valid post-baseline assessment of the primary efficacy variable. Here 'n' number analyzed signifies number of participants evaluable at each time point.

Arm/Group Title	Deferasirox / Deferasirox + Deferoxamine (DFO)
Arm/Group Description	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.
Measure Participants	12
6 months	0.1 (1.4)
12 months	0.7 (1.9)
18 months	1.3 (2.4)
24 months	2.4 (3.9)

5. Secondary Outcome

Title	Time to Response
Description	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]).
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

The full analysis set included all participants entered in the study with at least a valid post-baseline assessment of the primary efficacy variable. Here 'N' (overall number of participants analyzed) signifies number of participants evaluable for this outcome measure at the specified time-point.

Arm/Group Title	Deferasirox / Deferasirox + Deferoxamine (DFO)
Arm/Group Description	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.
Measure Participants	5
Mean (Standard Deviation) [ms]	13.0 (1.1)

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The full analysis set included all the participants entered in the study with at least a valid post-baseline assessment of the primary efficacy variable. Here 'n' number analyzed signifies number of participants evaluable at each time point.

Arm/Group Title	Deferasirox / Deferasirox + Deferoxamine (DFO)
Arm/Group Description	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.
Measure Participants	12
6 months	-5 (7.7)
12 months	-10.3 (9.2)
18 months	-10.2 (10.7)
24 months	-12.4 (10.1)

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Full analysis set included all participants entered in study with at least a valid post-baseline assessment of the primary efficacy variable. Here 'N' (overall number of participants analyzed) signifies number of participants evaluable for this outcome measure and 'n' (number analyzed) signifies number of participants evaluable at each time point.

Arm/Group Title	Deferasirox / Deferasirox + Deferoxamine (DFO)
Arm/Group Description	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.
Measure Participants	11
6 months	0.091
12 months	-0.033
18 months	0.347
24 months	0.273

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The full analysis set included all the participants entered in the study with at least a valid post-baseline assessment of the primary efficacy variable. Here 'n' number analyzed signifies number of participants evaluable at each time point.

Arm/Group Title	Deferasirox / Deferasirox + Deferoxamine (DFO)
Arm/Group Description	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.
Measure Participants	12
Baseline	65 (4.4)
6 months	65.4 (5)
12 months	64.8 (4.6)
18 months	65.1 (4.8)
24 months	66.2 (4.6)

Adverse Events

Arm/Group Title	Deferasirox / Deferasirox + Deferoxamine (DFO)
Arm/Group Description	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.
All Cause Mortality
	Deferasirox / Deferasirox + Deferoxamine (DFO)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Deferasirox / Deferasirox + Deferoxamine (DFO)
	Affected / at Risk (%)	# Events
Total	5/13 (38.5%)
Blood and lymphatic system disorders
Haemolysis	1/13 (7.7%)
Cardiac disorders
Cardiac discomfort	1/13 (7.7%)
Sinus tachycardia	1/13 (7.7%)
Gastrointestinal disorders
Abdominal discomfort	1/13 (7.7%)
Abdominal pain	1/13 (7.7%)
Gastritis	1/13 (7.7%)
Pancreatitis acute	1/13 (7.7%)
Rectal haemorrhage	1/13 (7.7%)
Vomiting	1/13 (7.7%)
General disorders
Chest pain	1/13 (7.7%)
Fatigue	1/13 (7.7%)
Pyrexia	1/13 (7.7%)
Immune system disorders
Hypersensitivity	1/13 (7.7%)
Infections and infestations
Sepsis	1/13 (7.7%)
Urinary tract infection	1/13 (7.7%)
Renal and urinary disorders
Nephrolithiasis	1/13 (7.7%)
Renal colic	2/13 (15.4%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/13 (7.7%)
Surgical and medical procedures
Lithotripsy	1/13 (7.7%)
Other (Not Including Serious) Adverse Events
	Deferasirox / Deferasirox + Deferoxamine (DFO)
	Affected / at Risk (%)	# Events
Total	12/13 (92.3%)
Blood and lymphatic system disorders
Thrombocytosis	1/13 (7.7%)
Cardiac disorders
Angina pectoris	1/13 (7.7%)
Atrial fibrillation	1/13 (7.7%)
Sinus tachycardia	1/13 (7.7%)
Ear and labyrinth disorders
Ear pain	1/13 (7.7%)
Hypoacusis	1/13 (7.7%)
Tinnitus	1/13 (7.7%)
Endocrine disorders
Hyperthyroidism	1/13 (7.7%)
Gastrointestinal disorders
Abdominal discomfort	1/13 (7.7%)
Abdominal distension	1/13 (7.7%)
Abdominal pain	3/13 (23.1%)
Abdominal pain lower	2/13 (15.4%)
Abdominal pain upper	2/13 (15.4%)
Constipation	2/13 (15.4%)
Diarrhoea	6/13 (46.2%)
Gastric disorder	1/13 (7.7%)
Gastrointestinal disorder	3/13 (23.1%)
Nausea	2/13 (15.4%)
Toothache	1/13 (7.7%)
Vomiting	1/13 (7.7%)
General disorders
Chest pain	1/13 (7.7%)
Discomfort	1/13 (7.7%)
Fatigue	1/13 (7.7%)
Gait disturbance	1/13 (7.7%)
Malaise	1/13 (7.7%)
Pyrexia	4/13 (30.8%)
Immune system disorders
Hypersensitivity	2/13 (15.4%)
Seasonal allergy	1/13 (7.7%)
Infections and infestations
Abscess	1/13 (7.7%)
Bronchitis	1/13 (7.7%)
Ear infection	1/13 (7.7%)
Gastroenteritis	2/13 (15.4%)
Nasopharyngitis	1/13 (7.7%)
Respiratory tract infection	2/13 (15.4%)
Rhinitis	2/13 (15.4%)
Tooth abscess	1/13 (7.7%)
Upper respiratory tract infection	3/13 (23.1%)
Viral infection	2/13 (15.4%)
Viral upper respiratory tract infection	2/13 (15.4%)
Injury, poisoning and procedural complications
Arthropod bite	1/13 (7.7%)
Muscle contusion	1/13 (7.7%)
Investigations
Blood pressure increased	1/13 (7.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	5/13 (38.5%)
Back pain	3/13 (23.1%)
Bone pain	1/13 (7.7%)
Musculoskeletal pain	1/13 (7.7%)
Myalgia	2/13 (15.4%)
Nervous system disorders
Dizziness	2/13 (15.4%)
Facial neuralgia	1/13 (7.7%)
Headache	4/13 (30.8%)
Hypotonia	1/13 (7.7%)
Presyncope	1/13 (7.7%)
Sciatica	1/13 (7.7%)
Syncope	1/13 (7.7%)
Reproductive system and breast disorders
Dysmenorrhoea	1/13 (7.7%)
Genital burning sensation	1/13 (7.7%)
Menstrual disorder	1/13 (7.7%)
Respiratory, thoracic and mediastinal disorders
Catarrh	3/13 (23.1%)
Cough	4/13 (30.8%)
Dysphonia	1/13 (7.7%)
Paranasal sinus discomfort	1/13 (7.7%)
Respiratory distress	1/13 (7.7%)
Rhinitis allergic	1/13 (7.7%)
Skin and subcutaneous tissue disorders
Photosensitivity reaction	1/13 (7.7%)
Surgical and medical procedures
Tooth extraction	2/13 (15.4%)
Tooth repair	1/13 (7.7%)
Wisdom teeth removal	1/13 (7.7%)

Limitations/Caveats

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

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.