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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00171301
• Collaborator: (none)
• Enrollment: 233
• Locations: 5
• Arm: 1
• Duration (Months): 35
• Patients Per Site: 46.6
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

To allow patients treated with deferasirox in the core study to continue iron chelation therapy for 2 years or until the drug became locally commercially available. To evaluate the long-term safety and efficacy of deferasirox by measuring treatment success, change in liver iron content (LIC) and change in serum ferritin levels. Safety was mainly assessed by incidence of adverse events (AEs)and clinically significant lab parameters.

Condition or Disease	Intervention/Treatment	Phase
Beta-thalassemia Major; Hemosiderosis; Iron Overload; Rare Anemia	Drug: Deferasirox	Phase 4

Detailed Description

Iron accumulation is an inevitable consequence of chronic blood transfusions and results in serious complications in the absence of chelation treatment to remove excess iron. Deferasirox (Exjade, ICL670) is an oral chelator with high iron-binding potency and selectivity. This extension study aimed at collecting efficacy and safety data during 2 years of treatment with deferasirox in the extension study or until deferasirox became commercially available in the countries where the centers were located, whichever came first. The population comprised of β-thalassemia patients with transfusional hemosiderosis who could not be satisfactorily treated with deferoxamine or deferiprone.

Study Design

• Study Type: Interventional
• Actual Enrollment: 233 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 1-year Extension to CICL670A2402 an Open-label, Multi-center Trial of the Efficacy and Safety of Long-term Treatment With Deferasirox (10 to 20 mg/kg/Day) in Beta-thalassemia Patients With Transfusional Hemosiderosis (Study Amended to 2- Year Duration)
• Study Start Date: Jun 1, 2005
• Actual Primary Completion Date: May 1, 2008
• Actual Study Completion Date: May 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Deferasirox Deferasirox was given orally once daily (10 to 20 mg/kg) to participants 2 years and older based on participant's body weight.	Drug: Deferasirox; Deferasirox was administered orally once daily. Deferasirox was available as 125 mg, 250 mg, and 500 mg tablets.; Other Names: Exjade

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Treatment Success From Core Baseline (BL) to Extension End of Study, by Baseline LIC Level and Age [From Core Study Baseline, to Extension End of Study, Up to 3 Years]

   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.

2. 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 [From Baseline of Core Study to End of Extension Study, up to 3 years]

   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.

Secondary Outcome Measures

1. Absolute Change in Serum Ferritin Level Measured From Core Study Baseline (BL) to End of Extension Study [From Baseline of Core Study to End of Extension Study, up to 3 years]

   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).

2. 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) [From Baseline of Core Study to End of Extension Study, up to 3 years]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients completing the planned 12-month core study (NCT00171171)

• Female patients who have reached menarche and who are sexually active must use an effective method of contraception, or must have undergone clinically documented total hysterectomy and/or ovariectomy, or tubal ligation

• Written informed consent obtained from the patient and/or legal guardian on the patient's behalf in accordance with the national legislation

Exclusion Criteria:

• Pregnant or breast feeding patients.

• Patients being considered by the investigator potentially unreliable and/or not cooperative with regard to the core study protocol, or the planned extension protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Cairo		Egypt
2	Novartis Investigative Site	Beirut		Lebanon
3	Novartis Investigative Site	Muscat		Oman
4	Novartis Investigative Site	Riyadh		Saudi Arabia
5	Novartis Investigative Site	Damascus		Syrian Arab Republic

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: NCT00171301
• Other Study ID Numbers: CICL670A2402E1
• First Posted: Sep 15, 2005
• Last Update Posted: Aug 31, 2011
• Last Verified: Aug 1, 2011

• Keywords provided by Novartis Pharmaceuticals: Transfusional hemosiderosis; Beta-thalassemia major; Deferasirox; iron overload; rare anemia; iron overload due to transfusion
• Additional relevant MeSH terms: Thalassemia; beta-Thalassemia; Hemochromatosis; Iron Overload; Hemosiderosis; Deferasirox

Study Results

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 Detail	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
Received Deferasirox	162	69
COMPLETED	154	62
NOT COMPLETED	8	9

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 Participants	162	71	233
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	9.5 (3.59)	21.2 (5.82)	13.0 (6.93)
Sex/Gender, Customized (participants) [Number]
Female	80 49.4%	35 49.3%	115 49.4%
Male	82 50.6%	36 50.7%	118 50.6%

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.
Measure Participants	162	71
Core Baseline LIC 1-<7 mg Fe/g dw (n=20, 2)	75.0 46.3%	100 140.8%
Core Baseline LIC 7-<10 mg Fe/g dw (n=18, 8)	72.2 44.6%	50.0 70.4%
Core Baseline LIC ≥10 mg Fe/g dw (n=124, 61)	76.6 47.3%	73.8 103.9%

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.
Measure Participants	119	41
Core Baseline LIC 1-<7 mg Fe/g dw (n=12, 0)	-1.32 (3.125)	NA (NA)
Core Baseline LIC ≥7 mg Fe/g dw (n=107, 41)	-9.03 (9.260)	-8.39 (11.312)

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.
Measure Participants	120	43
Mean (Standard Deviation) [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.
Measure Participants	163
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 (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Deferasirox (Between 2 <16 Years)		Deferasirox (16 Years or Older)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/162 (3.1%)		12/69 (17.4%)
Cardiac disorders
Arrhythmia	0/162 (0%)		1/69 (1.4%)
Cardiac failure	1/162 (0.6%)		0/69 (0%)
Cardiac failure congestive	0/162 (0%)		1/69 (1.4%)
Cardio-respiratory arrest	1/162 (0.6%)		0/69 (0%)
Gastrointestinal disorders
Abdominal pain upper	0/162 (0%)		3/69 (4.3%)
Intestinal obstruction	0/162 (0%)		1/69 (1.4%)
Melaena	0/162 (0%)		1/69 (1.4%)
Peptic ulcer perforation	0/162 (0%)		1/69 (1.4%)
Vomiting	1/162 (0.6%)		1/69 (1.4%)
General disorders
Pyrexia	0/162 (0%)		1/69 (1.4%)
Hepatobiliary disorders
Cholecystitis	0/162 (0%)		1/69 (1.4%)
Infections and infestations
Appendicitis	0/162 (0%)		1/69 (1.4%)
Lower respiratory tract infection	1/162 (0.6%)		0/69 (0%)
Otitis media	1/162 (0.6%)		0/69 (0%)
Perinephric abscess	0/162 (0%)		1/69 (1.4%)
Pneumonia streptococcal	1/162 (0.6%)		0/69 (0%)
Sepsis	0/162 (0%)		1/69 (1.4%)
Subdiaphragmatic abscess	1/162 (0.6%)		0/69 (0%)
Wound infection	0/162 (0%)		1/69 (1.4%)
Injury, poisoning and procedural complications
Fall	0/162 (0%)		1/69 (1.4%)
Femur fracture	0/162 (0%)		1/69 (1.4%)
Hip fracture	0/162 (0%)		1/69 (1.4%)
Perinephric collection	0/162 (0%)		1/69 (1.4%)
Road traffic accident	0/162 (0%)		2/69 (2.9%)
Upper limb fracture	0/162 (0%)		3/69 (4.3%)
Investigations
Blood creatinine increased	0/162 (0%)		1/69 (1.4%)
Nervous system disorders
Cerebral haemorrhage	0/162 (0%)		1/69 (1.4%)
Coma	0/162 (0%)		1/69 (1.4%)
Convulsion	1/162 (0.6%)		0/69 (0%)
Headache	1/162 (0.6%)		1/69 (1.4%)
Subarachnoid haemorrhage	0/162 (0%)		1/69 (1.4%)
Respiratory, thoracic and mediastinal disorders
Adenoidal hypertrophy	1/162 (0.6%)		0/69 (0%)
Dyspnoea	0/162 (0%)		1/69 (1.4%)
Vascular disorders
Aneurysm	0/162 (0%)		1/69 (1.4%)
Haemorrhage	0/162 (0%)		1/69 (1.4%)
Hypotension	0/162 (0%)		1/69 (1.4%)
Other (Not Including Serious) Adverse Events
	Deferasirox (Between 2 <16 Years)		Deferasirox (16 Years or Older)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	54/162 (33.3%)		33/69 (47.8%)
Gastrointestinal disorders
Nausea	1/162 (0.6%)		5/69 (7.2%)
Vomiting	17/162 (10.5%)		5/69 (7.2%)
General disorders
Pain	0/162 (0%)		5/69 (7.2%)
Pyrexia	3/162 (1.9%)		6/69 (8.7%)
Infections and infestations
Gastroenteritis	1/162 (0.6%)		4/69 (5.8%)
Influenza	26/162 (16%)		3/69 (4.3%)
Upper respiratory tract infection	3/162 (1.9%)		8/69 (11.6%)
Investigations
Alanine aminotransferase increased	13/162 (8%)		4/69 (5.8%)
Blood calcium decreased	0/162 (0%)		4/69 (5.8%)
Blood creatinine increased	5/162 (3.1%)		9/69 (13%)
Musculoskeletal and connective tissue disorders
Osteoporosis	1/162 (0.6%)		4/69 (5.8%)

Limitations/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.

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.