Extension Study of the Efficacy and Safety of Deferasirox Treatment in Beta-thalassemia Patients With Transfusional Hemosiderosis (Study Amended to 2-year Duration) (ESCALATOR)

• ClinicalTrials.gov Identifier: NCT00171301
• Recruitment Status: Completed
• First Posted: September 15, 2005
• Results First Posted: July 29, 2011
• Last Update Posted: August 31, 2011
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

• Study Type: Interventional
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Beta-thalassemia Major; Hemosiderosis; Iron Overload; Rare Anemia
• Intervention: Drug: Deferasirox
• Enrollment: 233

Participant Flow

Recruitment Details	This is an Extension to Core Study CICL670A2402 (NCT00171171). 233 participants completed the core study and entered this extension study.
Pre-assignment Details	2 participants from the 16 and older group did not receive deferasirox. Thus, the 16 and older group comprises of 69 treated participants.

Arm/Group Title	Deferasirox (Between 2 <16 Years )	Deferasirox (16 Years or Older)
Arm/Group Description	Participants age 2 years up to 16 years received a daily oral dose of deferasirox. Dose selection was based on the dose last received in the core study. The individual daily doses of deferasirox and the exact amount of tablets (125, 250, or 500 mg) contributing to each dose were calculated by the investigator based on the patient's body weight.	Participants age 16 years or older received a daily oral dose of deferasirox. Dose selection was based on the dose last received in the core study. The individual daily doses of deferasirox and the exact amount of tablets (125, 250, or 500 mg) contributing to each dose were calculated by the investigator based on the patient's body weight.
Period Title: Overall Study
Started	162	71 [1]
Received Deferasirox	162	69
Completed	154	62
Not Completed	8	9
Reason Not Completed
Death	1	2
Adverse Event	1	2
Lost to Follow-up	6	2
Protocol Violation	0	2
Withdrawal by Subject	0	1
[1] 2 participants in this group never received deferasirox.

Baseline Characteristics

Arm/Group Title		Deferasirox (Between 2 <16 Years )	Deferasirox (16 Years or Older)	Total
Arm/Group Description		Participants age 2 years up to 16 years received a daily oral dose of deferasirox. Dose selection was based on the dose last received in the core study. The individual daily doses of deferasirox and the exact amount of tablets (125, 250, or 500 mg) contributing to each dose were calculated by the investigator based on the patient's body weight.	Participants age 16 years or older received a daily oral dose of deferasirox. Dose selection was based on the dose last received in the core study. The individual daily doses of deferasirox and the exact amount of tablets (125, 250, or 500 mg) contributing to each dose were calculated by the investigator based on the patient's body weight.	Total of all reporting groups
Overall Number of Baseline Participants		162	71	233
Baseline Analysis Population Description		[Not Specified]
Age Continuous [1]; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	162 participants	71 participants	233 participants
		9.5 (3.59)	21.2 (5.82)	13.0 (6.93)
		[1] Measure Description: Safety Population consisting of all participants who received study drug in the Extension study n= 231.
Sex/Gender, Customized [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	162 participants	71 participants	233 participants
Female		80	35	115
Male		82	36	118
		[1] Measure Description: Safety Population consisting of all participants who received study drug in the Extension study n=231.

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Treatment Success From Core Baseline (BL) to Extension End of Study, by Baseline LIC Level and Age
Description	Success was defined as the percentage of participants with decreased liver iron content (LIC) at the end of extension study compared to core baseline (BL) LIC. Success Criteria: For participants with Baseline LIC from 1 - <7 mg Fe/g dw, success was achieved if LIC level maintained at 1 - <7 mg Fe/g dw. For participants with Baseline LIC ≥7 - <10 mg Fe/g dw, success was achieved if LIC dropped to between 1 and < 7 mg Fe/g dw. For participants with Baseline LIC ≥10 mg Fe/g dw, success was achieved if LIC dropped by at least 3 mg Fe/g dw. LIC was measured by biopsy or magnetic resonance imaging.
Time Frame	From Core Study Baseline, to Extension End of Study, Up to 3 Years

Outcome Measure Data

Analysis Population Description

The primary analysis will be on the intent-to-treat (ITT) population. ITT population includes all participants who performed the core end of study (EOS) visit evaluation and assessments and were included in the extension study. "n" is the number of participants analyzed in each category.

Arm/Group Title	Deferasirox (Between 2 <16 Years)	Deferasirox (16 Years or Older)
Arm/Group Description:	Participants age 2 years up to 16 years received a daily oral dose of deferasirox. Dose selection was based on the dose last received in the core study. The individual daily doses of deferasirox and the exact amount of tablets (125, 250, or 500 mg) contributing to each dose were calculated by the investigator based on the patient's body weight.	Participants age 16 years or older received a daily oral dose of deferasirox. Dose selection was based on the dose last received in the core study. The individual daily doses of deferasirox and the exact amount of tablets (125, 250, or 500 mg) contributing to each dose were calculated by the investigator based on the patient's body weight.
Overall Number of Participants Analyzed	162	71
Mean (95% Confidence Interval); Unit of Measure: percentage of participants
Core Baseline LIC 1-<7 mg Fe/g dw (n=20, 2)	75.0; (56.0 to 94.0)	100; (15.8 to 100)
Core Baseline LIC 7-<10 mg Fe/g dw (n=18, 8)	72.2; (51.5 to 92.9)	50.0; (15.7 to 84.3)
Core Baseline LIC ≥10 mg Fe/g dw (n=124, 61)	76.6; (69.2 to 84.1)	73.8; (62.7 to 84.8)

2. Primary Outcome

Title	Absolute Change in Liver Iron Concentration (LIC)Measured by Liver MRI or Liver Biopsy From Core Study Baseline (BL) to End of Extension Study, by LIC Category
Description	Liver MRI or Liver Biopsy was performed at the core study baseline (BL) and then 1 year and 2 years in the core study, baseline of the extension study and time of discontinuation from the extension visit (end of study). Liver iron content (LIC) is reported in milligram Iron per gram dry weight (mg Fe/g dw). Absolute change in LIC from core study baseline to the end of the extension study is presented for participants with the following two core study baseline LIC levels: 1-<7 mg Fe/g dw and ≥7 mg Fe/g dw.
Time Frame	From Baseline of Core Study to End of Extension Study, up to 3 years

Outcome Measure Data

Analysis Population Description

Participants from the Intent-to-Treat (ITT) population for whom LIC data was available at Core Study baseline and at the End of Extension Study. "n" is the number of participants analyzed in each category.

Arm/Group Title	Deferasirox (Between 2 <16 Years)	Deferasirox (16 Years or Older)
Arm/Group Description:	Participants age 2 years up to 16 years received a daily oral dose of deferasirox. Dose selection was based on the dose last received in the core study. The individual daily doses of deferasirox and the exact amount of tablets (125, 250, or 500 mg) contributing to each dose were calculated by the investigator based on the patient's body weight.	Participants age 16 years or older received a daily oral dose of deferasirox. Dose selection was based on the dose last received in the core study. The individual daily doses of deferasirox and the exact amount of tablets (125, 250, or 500 mg) contributing to each dose were calculated by the investigator based on the patient's body weight.
Overall Number of Participants Analyzed	119	41
Mean (Standard Deviation); Unit of Measure: mg Fe/g dw
Core Baseline LIC 1-<7 mg Fe/g dw (n=12, 0)	-1.32 (3.125)	NA [1] (NA)
Core Baseline LIC ≥7 mg Fe/g dw (n=107, 41)	-9.03 (9.260)	-8.39 (11.312)

[1]

No participants in this category for this group.

3. Secondary Outcome

Title	Absolute Change in Serum Ferritin Level Measured From Core Study Baseline (BL) to End of Extension Study
Description	Serum Levels were assessed at core study baseline (BL), 1 year, 2 years in core study, baseline of extension study and time of discontinuation from the extension visit (end of study) in monthly intervals. Serum Ferritin is reported in micrograms per Liter (µg/L).
Time Frame	From Baseline of Core Study to End of Extension Study, up to 3 years

Outcome Measure Data

Analysis Population Description

Participants from the Intent-to-Treat (ITT) population for whom Serum Ferritin data was available at Core Study baseline and at the End of Extension Study.

Arm/Group Title	Deferasirox (Between 2 <16 Years)	Deferasirox (16 Years or Older)
Arm/Group Description:	Participants age 2 years up to 16 years received a daily oral dose of deferasirox. Dose selection was based on the dose last received in the core study. The individual daily doses of deferasirox and the exact amount of tablets (125, 250, or 500 mg) contributing to each dose were calculated by the investigator based on the patient's body weight.	Participants age 16 years or older received a daily oral dose of deferasirox. Dose selection was based on the dose last received in the core study. The individual daily doses of deferasirox and the exact amount of tablets (125, 250, or 500 mg) contributing to each dose were calculated by the investigator based on the patient's body weight.
Overall Number of Participants Analyzed	120	43
Mean (Standard Deviation); Unit of Measure: µg/L
	-1432.51 (1969.622)	-1791.91 (2712.334)

4. Secondary Outcome

Title	Absolute Change in Serum Ferritin Level for All Participants Measured From Core Study Baseline (BL) to End of Extension Study, by Baseline Liver Iron Content (LIC)
Description	Serum Levels were assessed at core study baseline (BL) and then 1 year and 2 years in core study, baseline of extension study and time of discontinuation from the extension visit (end of study). Serum Ferritin is reported in micrograms per Liter. Absolute change in Serum Ferritin from core study baseline to the end of the extension study is presented for participants with the following two core study baseline LIC levels: 1-<7 mg Fe/g dw and ≥7 mg Fe/g dw.
Time Frame	From Baseline of Core Study to End of Extension Study, up to 3 years

Outcome Measure Data

Analysis Population Description

Participants from the Intent-to-Treat (ITT) population for whom Serum Ferritin data was available at Core Study baseline and at the End of Extension Study. "n" is the number of participants analyzed in each category.

Arm/Group Title	Deferasirox (All Participants)
Arm/Group Description:	Participants received a daily oral dose of deferasirox. Dose selection was based on the dose last received in the core study. The individual daily doses of deferasirox and the exact amount of tablets (125, 250, or 500 mg) contributing to each dose were calculated by the investigator based on the patient's body weight.
Overall Number of Participants Analyzed	163
Mean (Standard Deviation); Unit of Measure: µg/L
Core Baseline LIC 1-<7 mg Fe/g dw (n=12)	-369.83 (1349.57)
Core Baseline LIC ≥ 7 mg Fe/g dw (n=151)	-1619.31 (2217.104)

Adverse Events

Time Frame	From baseline to end of study, up to 2 years
Adverse Event Reporting Description	Adverse Events were calculated for the Safety Population consisting of all participants who received study drug in this Extension study. (162 participants between 2 < 16 years, 69 participants 16 years or older. Total 231 participants in Safety Population.)
Arm/Group Title	Deferasirox (Between 2 <16 Years)	Deferasirox (16 Years or Older)
Arm/Group Description	Participants age 2 years up to 16 years received a daily oral dose of deferasirox. Dose selection was based on the dose last received in the core study. The individual daily doses of deferasirox and the exact amount of tablets (125, 250, or 500 mg) contributing to each dose were calculated by the investigator based on the patient's body weight.	Participants age 16 years and older received a daily oral dose of deferasirox. Dose selection was based on the dose last received in the core study. The individual daily doses of deferasirox and the exact amount of tablets (125, 250, or 500 mg) contributing to each dose were calculated by the investigator based on the patient's body weight.
All-Cause Mortality
	Deferasirox (Between 2 <16 Years)	Deferasirox (16 Years or Older)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	Deferasirox (Between 2 <16 Years)	Deferasirox (16 Years or Older)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	5/162 (3.09%)	12/69 (17.39%)
Cardiac disorders
Arrhythmia † 1	0/162 (0.00%)	1/69 (1.45%)
Cardiac failure † 1	1/162 (0.62%)	0/69 (0.00%)
Cardiac failure congestive † 1	0/162 (0.00%)	1/69 (1.45%)
Cardio-respiratory arrest † 1	1/162 (0.62%)	0/69 (0.00%)
Gastrointestinal disorders
Abdominal pain upper † 1	0/162 (0.00%)	3/69 (4.35%)
Intestinal obstruction † 1	0/162 (0.00%)	1/69 (1.45%)
Melaena † 1	0/162 (0.00%)	1/69 (1.45%)
Peptic ulcer perforation † 1	0/162 (0.00%)	1/69 (1.45%)
Vomiting † 1	1/162 (0.62%)	1/69 (1.45%)
General disorders
Pyrexia † 1	0/162 (0.00%)	1/69 (1.45%)
Hepatobiliary disorders
Cholecystitis † 1	0/162 (0.00%)	1/69 (1.45%)
Infections and infestations
Appendicitis † 1	0/162 (0.00%)	1/69 (1.45%)
Lower respiratory tract infection † 1	1/162 (0.62%)	0/69 (0.00%)
Otitis media † 1	1/162 (0.62%)	0/69 (0.00%)
Perinephric abscess † 1	0/162 (0.00%)	1/69 (1.45%)
Pneumonia streptococcal † 1	1/162 (0.62%)	0/69 (0.00%)
Sepsis † 1	0/162 (0.00%)	1/69 (1.45%)
Subdiaphragmatic abscess † 1	1/162 (0.62%)	0/69 (0.00%)
Wound infection † 1	0/162 (0.00%)	1/69 (1.45%)
Injury, poisoning and procedural complications
Fall † 1	0/162 (0.00%)	1/69 (1.45%)
Femur fracture † 1	0/162 (0.00%)	1/69 (1.45%)
Hip fracture † 1	0/162 (0.00%)	1/69 (1.45%)
Perinephric collection † 1	0/162 (0.00%)	1/69 (1.45%)
Road traffic accident † 1	0/162 (0.00%)	2/69 (2.90%)
Upper limb fracture † 1	0/162 (0.00%)	3/69 (4.35%)
Investigations
Blood creatinine increased † 1	0/162 (0.00%)	1/69 (1.45%)
Nervous system disorders
Cerebral haemorrhage † 1	0/162 (0.00%)	1/69 (1.45%)
Coma † 1	0/162 (0.00%)	1/69 (1.45%)
Convulsion † 1	1/162 (0.62%)	0/69 (0.00%)
Headache † 1	1/162 (0.62%)	1/69 (1.45%)
Subarachnoid haemorrhage † 1	0/162 (0.00%)	1/69 (1.45%)
Respiratory, thoracic and mediastinal disorders
Adenoidal hypertrophy † 1	1/162 (0.62%)	0/69 (0.00%)
Dyspnoea † 1	0/162 (0.00%)	1/69 (1.45%)
Vascular disorders
Aneurysm † 1	0/162 (0.00%)	1/69 (1.45%)
Haemorrhage † 1	0/162 (0.00%)	1/69 (1.45%)
Hypotension † 1	0/162 (0.00%)	1/69 (1.45%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Deferasirox (Between 2 <16 Years)	Deferasirox (16 Years or Older)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	54/162 (33.33%)	33/69 (47.83%)
Gastrointestinal disorders
Nausea † 1	1/162 (0.62%)	5/69 (7.25%)
Vomiting † 1	17/162 (10.49%)	5/69 (7.25%)
General disorders
Pain † 1	0/162 (0.00%)	5/69 (7.25%)
Pyrexia † 1	3/162 (1.85%)	6/69 (8.70%)
Infections and infestations
Gastroenteritis † 1	1/162 (0.62%)	4/69 (5.80%)
Influenza † 1	26/162 (16.05%)	3/69 (4.35%)
Upper respiratory tract infection † 1	3/162 (1.85%)	8/69 (11.59%)
Investigations
Alanine aminotransferase increased † 1	13/162 (8.02%)	4/69 (5.80%)
Blood calcium decreased † 1	0/162 (0.00%)	4/69 (5.80%)
Blood creatinine increased † 1	5/162 (3.09%)	9/69 (13.04%)
Musculoskeletal and connective tissue disorders
Osteoporosis † 1	1/162 (0.62%)	4/69 (5.80%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA

Limitations and Caveats

An internal review revealed major Good Clinical Practice violations at 2 sites in Saudi Arabia: 602 for core + extension, 601 for 2-yr extension. Therefore data was excluded (completely for 602 + partly for 601) from analyses.

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

• Name/Title: Study Director
• Organization: Novartis Pharmaceuticals
• Phone: 862-778-8300

• Responsible Party: Novartis ( Novartis Pharmaceuticals )
• ClinicalTrials.gov Identifier: NCT00171301
• Other Study ID Numbers: CICL670A2402E1
• First Submitted: September 12, 2005
• First Posted: September 15, 2005
• Results First Submitted: January 12, 2011
• Results First Posted: July 29, 2011
• Last Update Posted: August 31, 2011