Efficacy and Safety Study of Deferasirox in Patients With Non-transfusion Dependent Thalassemia (THETIS)

An Open Label, Multi-center, Efficacy and Safety Study of Deferasirox in Iron Overloaded Patients With Non-transfusion Dependent Thalassemia

Assessed the efficacy of deferasirox in patients with non-transfusion dependent thalassemia based on change in liver iron concentration from baseline after 52 weeks of treatment. Provided further assessment of the long-term efficacy and safety of deferasirox in NTDT patients with iron overload (LIC ≥ 5 mg Fe/g liver dw and SF ≥ 300 ng/mL) for up to 260 weeks.

Study Overview

• Status: Completed
• Conditions: Non-transfusion Dependent Thalassemia
• Intervention / Treatment: Drug: deferasirox

• Study Type: Interventional
• Enrollment (Actual): 134
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Guangxi
    • Nanning, Guangxi, China, 530021
      • Novartis Investigative Site
• Greece
  • GR
    • Goudi-Athens, GR, Greece, 115 27
      • Novartis Investigative Site
• Italy
  • CA
    • Cagliari, CA, Italy, 09121
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20122
      • Novartis Investigative Site
• Lebanon
  • Beirut
    • Hazmiyeh, Beirut, Lebanon, PO BOX 213
      • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10700
    • Novartis Investigative Site
• Tunisia
  • Tunis, Tunisia, 1006
    • Novartis Investigative Site
• Turkey
  • Adana, Turkey, 01330
    • Novartis Investigative Site
  • Istanbul, Turkey, 34093
    • Novartis Investigative Site
  • Izmir, Turkey, 35040
    • Novartis Investigative Site
• United Kingdom
  • London, United Kingdom, NW1 2PJ
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Non-transfusion dependent congenital or chronic anemia inclusive of beta-thalassemia intermedia, HbE beta-thalassemia or alpha-thalassemia intermedia (HbH disease)/ Liver iron concentration >/= 5 mg Fe/g dw Serum Ferritin >/= 300 ng/mL

Exclusion Criteria:

HbS-beta Thalassemia, anticipated regular transfusion program during the study, blood transfusion 6 months prior to study start, significant proteinuria, creatinine clearance </= 40 ml/min, serum creatinine > ULN, ALT >5 x ULN, active hepatitis B or C, cirrhosis

Pediatrics Only:

A patient's weight of at least 20 kg is required to allow dosing of 5 mg/kg with one tablet of 125 mg

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Deferasirox; All patients were treated with 10mg/kg/day deferasirox with dose adjustments after 4 weeks of treatment according to baseline Liver Iron Concentration (LIC).	Drug: deferasirox; Deferasirox dispersible tablets at strengths of 125 mg, 250 mg, and 500 mg were administered by oral daily dosing.; Other Names: ICL670

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Change in Liver Iron Content (LIC) at 52 Weeks From Baseline	Absolute change in liver iron concentration measured by MRI from baseline after 52 weeks of treatment	Baseline, 52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Baseline LIC>15 Achieving LIC<5 mg Fe/g dw	The percentage of participants with baseline LIC>15 mg Fe/g dw achieving an LIC <5 mg Fe/g dw during the study	5 years
Time to Achieving LIC <5 mg Fe/g dw	Time to achieving LIC <5 mg Fe/g dw for participants with baseline LIC>15 mg Fe/g dw during the study	5 years
Time From Target LIC of 3 mg Fe/g dw to the First LIC ≥5 mg Fe/g dw in the Follow up Period	Time from the target LIC <3 mg Fe/g dw to the first LIC ≥5 mg Fe/g dw in the follow-up period	post-baseline, up to 260 weeks
Absolute Change in Health-related Outcomes Using Medical Outcomes Study Form 36 (SF-36v2)	The SF-36 is a self-administered questionnaire for adults (from 18 years of age) and contains 36 items which measure: Physical functioning, Role limitation due to physical health problems, Bodily pain, General health perceptions, Vitality, Social functioning, Role limitations due to emotional problems and General mental health . The higher values indicate a better evaluation of health. Range: 0 to 100 [0 (worst possible health state measured by the questionnaire) to 100 (best possible health state)].	Baseline, 52, 104 & 156 Weeks
Absolute Change in Health-related Outcomes Using the Pediatric Quality of Life Questionnaire (PedsQL™)	The PedsQL™ is a modular approach to measuring health-related quality of life (HRQOL) in children and adolescents. The 23-item PedsQL™ Generic Core Scales encompass the essential core domains for pediatric HRQOL measurement: 1) Physical Functioning (8 items), 2) Emotional Functioning (5 items), 3) Social Functioning (5 items), and 4) School Functioning (5 items). The Generic Core Scales are designed to enable comparisons across patient and healthy populations. The higher values indicate a better evaluation of health. Range: 0 to 100 [0 (worst possible health state measured by the questionnaire) to 100 (best possible health state)].	Baseline, 52, 104 & 156 Weeks
Absolute Change in LIC From Baseline Over Time	Absolute change in serum ferritin from baseline over time up to 260 weeks	24, 52, 76, 104, 128, 156, 180, 208, 232, 260 Weeks
Serum Ferritin (SF) vs LIC at Baseline and EOS (Week 260 + 30 Days Follow-up)	Correlation between serum ferritin and LIC is assessed using scatter plots with pearson correlation coefficient and simple linear model.	Baseline, End of Study (EOS): Week 260 + 30 days follow up
Correlation Analysis for Absolute Change in LIC and Serum Ferritin at Week 24 and EOS (Week 260 + 30 Days Follow-up)	Correlation for absolute change between LIC and serum ferritin was assessed using scatter plots with pearson correlation coefficient and simple linear model.	Week 24, End of Study (EOS): Week 260 + 30 days follow up
Absolute Change in LIC From Baseline After 52 Weeks of Treatment by Underlying Non-transfusion Dependent Thalassemia (NTDT) Syndrome	Absolute change in liver iron concentration measured by MRI from baseline after 52 weeks of treatment by underlying NTDT syndrome. The 4 underlying disease types: Beta-thalassemia intermedia (N =69), HbE beta-thalassemia (N = 24), Alpha-thalassemia intermedia (HbH disease) (N = 40), Other, specify (N = 1)	Baseline, 52 Weeks
Absolute Change in Serum Ferritin From Baseline After 52 Weeks	Absolute change in serum ferritin from baseline after 52 weeks of treatment	Baseline, 52 weeks
PK Parameters: AUCtau	The pharmacokinetic parameter, AUCtau was determined using non-compartmental method(s) for deferasirox and its iron complex. AUC=area under the concentration-time curve during a dosing interval at steady state (amount × time × volume).	pre-dose (0 hour), and at 2, and 4 hours at Week 4
PK Parameters: Cmax	The pharmacokinetic parameter, Cmax, was determined using non-compartmental method(s) for deferasirox and its iron complex. Cmax (maximum/peak plasma drug concentration after drug administration)=amount × volume	pre-dose (0 hour), and at 2, and 4 hours at Week 4
PK Parameters: Tmax	The pharmacokinetic parameter, Tmax, may be determined using non-compartmental method(s) for deferasirox and its iron complex. Tmax=time to reach maximum/peak concentration following drug administration.	pre-dose (0 hour), and at 2, and 4 hours at Week 4
Plasma Pharmacokinetics (PK) Deferasirox Concentrations	Blood samples for PK evaluation were collected for a sub-group of patients. The patient had to have been on treatment without dose adjustment or treatment interruption (for any reason) for at least 4 consecutive days prior to scheduled PK sampling visit. If there was a dosage change or interruption within 4 days of the visit, no PK blood samples was collected, and an appropriate comment had to be made on the PK CRF page.	Weeks 12 & 24: pre-dose (0hr), 2hr & 4hr post-dose

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): December 6, 2012
• Primary Completion (Actual): January 3, 2015
• Study Completion (Actual): January 17, 2019

Study Registration Dates

• First Submitted: October 16, 2012
• First Submitted That Met QC Criteria: October 17, 2012
• First Posted (Estimate): October 18, 2012

Study Record Updates

• Last Update Posted (Actual): October 2, 2019
• Last Update Submitted That Met QC Criteria: September 19, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: deferasirox; NTDT; ICL670; Non-transfusion dependent thalassemia; LIC; Liver Iron Concentration
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Thalassemia; Molecular Mechanisms of Pharmacological Action; Chelating Agents; Sequestering Agents; Iron Chelating Agents; Deferasirox
• Other Study ID Numbers: CICL670E2419; 2012-000650-64 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No