A Phase 4 interventional study of deferasirox in Non-transfusion Dependent Thalassemia, sponsored by Novartis Pharmaceuticals. Completed at 11 sites in 8 countries. Open to participants aged 10 Years and older. Per ClinicalTrials.gov, last updated 2019-10-02.
Sponsored by Novartis Pharmaceuticals · Phase 4, Interventional, and Treatment
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.
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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
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.
Also known as: ICL670
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
Time frame: Baseline, 52 weeks
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
Time frame: 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
Time frame: 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
Time frame: 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 \[0 (worst possible health state measured by the questionnaire) to 100 (best possible health state)\].
Time frame: 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 \[0 (worst possible health state measured by the questionnaire) to 100 (best possible health state)\].
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 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)
Time frame: 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
Time frame: 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).
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: Weeks 12 & 24: pre-dose (0hr), 2hr & 4hr post-dose
At least 117 patients were planned to be enrolled; 134 patients were enrolled.
| Milestone | Deferasirox |
|---|---|
| Started | 134 |
| Completed | 67 |
| Not completed | 67 |
| Withdrew: Withdrawal by subject | 21 |
| Withdrew: Lost to follow-up | 16 |
| Withdrew: Pregnancy | 10 |
| Withdrew: Subject/guardian decision | 8 |
| Withdrew: Adverse event | 4 |
| Withdrew: Physician decision | 4 |
| Withdrew: Death | 3 |
| Withdrew: Protocol violation | 1 |
Absolute change in liver iron concentration measured by MRI from baseline after 52 weeks of treatment
| mg Fe/g dw | Deferasirox |
|---|---|
| Absolute Change in Liver Iron Content (LIC) at 52 Weeks From Baseline | -6.68 ± 7.018 |
The percentage of participants with baseline LIC\>15 mg Fe/g dw achieving an LIC \<5 mg Fe/g dw during the study
| percentage of participants | Deferasirox |
|---|---|
| Percentage of Participants With Baseline LIC>15 Achieving LIC<5 mg Fe/g dw | 51.0 |
Time to achieving LIC \<5 mg Fe/g dw for participants with baseline LIC\>15 mg Fe/g dw during the study
| months | Deferasirox |
|---|---|
| Time to Achieving LIC <5 mg Fe/g dw | 36.3 (28.55 to 48.30) |
Time from the target LIC \<3 mg Fe/g dw to the first LIC ≥5 mg Fe/g dw in the follow-up period
| days | Deferasirox |
|---|---|
| Time From Target LIC of 3 mg Fe/g dw to the First LIC ≥5 mg Fe/g dw in the Follow up Period | 27.4 (17.68 to NA) |
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 \[0 (worst possible health state measured by the questionnaire) to 100 (best possible health state)\].
| scores on a scale | Deferasirox |
|---|---|
| Physical Functioning Week 52 | -0.5 ± 5.5 |
| Physical Functioning Week 104 | -0.7 ± 4.9 |
| Physical Functioning Week 156 | 0.6 ± 6.1 |
| Role Physical Week 52 | 0.9 ± 9.1 |
| Role Physical Week 104 | -1.0 ± 10.2 |
| Role Physical Week 156 | 1.0 ± 10.9 |
| Bodily Pain Week 52 | -0.0 ± 11.6 |
| Bodily Pain Week 104 | -1.3 ± 10.8 |
| General Health Week 52 | -2.3 ± 9.1 |
| Bodily Pain Week 156 | 0.9 ± 12.2 |
| General Health Pain Week 104 | -1.9 ± 9.2 |
| General Health Week 156 | -1.1 ± 8.6 |
| Vitality Week 52 | 1.1 ± 9.7 |
| Vitality Week 104 | -0.2 ± 8.7 |
| Vitality Week 156 | 2.1 ± 9.6 |
| Social Functioning Week 52 | 0.9 ± 9.8 |
| Social Functioning Week 104 | -1.2 ± 9.6 |
| Social Functioning Week 156 | 1.6 ± 10.6 |
| Role Emotional Week 52 | -0.1 ± 11.3 |
| Role Emotional Week 104 | -2.5 ± 12.2 |
| Role Emotional Week 156 | 0.7 ± 11.2 |
| Mental Health Week 52 | 1.5 ± 11.7 |
| Mental Health Week 104 | -0.6 ± 11.4 |
| Mental Health Week 156 | 2.8 ± 10.9 |
| Physical Component Week 52 | -0.8 ± 7.2 |
| Physical Component Week 104 | -1.0 ± 7.4 |
| Physical Component Week 156 | -0.1 ± 7.9 |
| Mental Component Week 104 | -1.3 ± 11.1 |
| Mental Component Week 52 | 1.1 ± 10.9 |
| Mental Component Week 156 | 2.2 ± 10.8 |
| SF6D Health Utility Index Week 52 | 0.0 ± 0.1 |
| SF6D Health Utility Index Week 104 | -0.0 ± 0.1 |
| SF6D Health Utility Index Week 156 | 0.0 ± 0.1 |
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 \[0 (worst possible health state measured by the questionnaire) to 100 (best possible health state)\].
| scores on a scale | Deferasirox |
|---|---|
| Physical Functioning - Teenager Wk 52 | 2.3 ± 13.7 |
| Physical Functioning - Teenager Wk 104 | 1.0 ± 19.3 |
| Physical Functioning - Teenager Wk 156 | -0.9 ± 15.4 |
| Emotional Functioning - Teenager Wk 52 | 0.7 ± 17.8 |
| Emotional Functioning - Teenager Wk 104 | 3.1 ± 27.6 |
| Emotional Functioning - Teenager Wk 156 | 10.9 ± 25.9 |
| Social Functioning - Teenager Wk 52 | -9.3 ± 17.5 |
| Social Functioning - Teenager Wk 104 | -10.0 ± 17.8 |
| Social Functioning - Teenager Wk 156 | -5.0 ± 20.1 |
| School Functioning - Teenager Wk 52 | 0.7 ± 12.4 |
| School Functioning - Teenager Wk 104 | -3.8 ± 16.4 |
| School Functioning - Teenager Wk 156 | 1.0 ± 21.4 |
| Physical Health - Teenager Wk 52 | 2.3 ± 13.7 |
| Physical Health - Teenager Wk 104 | 1.0 ± 19.3 |
| Physical Health - Teenager Wk 156 | -0.9 ± 15.4 |
| Psychosocial Health - Teenager Wk 52 | -3.3 ± 13.0 |
| Psychosocial Health - Teenager Wk 104 | -4.0 ± 16.9 |
| Psycholosocial Health - Teenager Wk 156 | 2.0 ± 19.1 |
| Total Score - Teenager Wk 52 | -1.0 ± 10.6 |
| Total Score - Teenager Wk 104 | -1.9 ± 14.4 |
| Total Score - Teenager Wk 156 | 1.2 ± 15.8 |
| Physical Functioning - Parent Wk 52 | -2.9 ± 19.0 |
| Physical Functioning - Parent Wk 104 | 0.0 ± 18.6 |
| Physical Functioning - Parent Wk 156 | -0.3 ± 15.6 |
| Emotional Functioning - Parent Wk 52 | -8.7 ± 19.1 |
| Emotional Functioning - Parent Wk 104 | -3.8 ± 20.8 |
| Emotional Functioning - Parent Wk 156 | 2.0 ± 20.6 |
| Social Functioning - Parent Wk 52 | -3.7 ± 15.5 |
| Social Functioning - Parent Wk 104 | -4.6 ± 18.0 |
| Social Functioning - Parent Wk 156 | -6.0 ± 20.9 |
| School Functioning - Parent Wk 52 | -3.6 ± 20.6 |
| School Functioning - Parent Wk 104 | 0.0 ± 11.7 |
| School Functioning - Parent Wk 156 | -0.6 ± 21.1 |
| Physical Health - Parent Wk 52 | -2.9 ± 19.0 |
| Physical Health - Parent Wk 104 | 0.0 ± 18.6 |
| Physical Health - Parent Wk 156 | -0.3 ± 15.6 |
| Psychosocial Health - Parent Wk 52 | -5.5 ± 15.0 |
| Psychosocial Health - Parent Wk 104 | -3.2 ± 12.3 |
| Psychosocial Health - Parent Wk 156 | -1.8 ± 14.1 |
| Total Score - Parent Wk 52 | -4.6 ± 14.8 |
| Total Score - Parent Wk 104 | -1.9 ± 12.0 |
| Total Score - Parent Wk 156 | -1.1 ± 12.9 |
Absolute change in serum ferritin from baseline over time up to 260 weeks
| mg Fe/g dw | Deferasirox |
|---|---|
| Week 24 | -3.67 ± 3.778 |
| Week 52 | -7.02 ± 7.132 |
| Week 76 | -8.93 ± 8.922 |
| Week 104 | -9.63 ± 9.474 |
| Week 128 | -10.03 ± 9.445 |
| Week 156 | -10.20 ± 9.746 |
| Week 180 | -9.94 ± 9.838 |
| Week 208 | -10.04 ± 10.010 |
| Week 232 | -10.58 ± 10.045 |
| Week 260 | -10.57 ± 10.366 |
Correlation between serum ferritin and LIC is assessed using scatter plots with pearson correlation coefficient and simple linear model.
| correlation coefficient | Deferasirox |
|---|---|
| At Baseline | 0.730 |
| Change from Baseline at EOS | 0.531 |
Correlation for absolute change between LIC and serum ferritin was assessed using scatter plots with pearson correlation coefficient and simple linear model.
| correlation coefficient | Deferasirox |
|---|---|
| Week 24 | 0.299 |
| Change from Baseline at EOS | 0.740 |
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)
| mg Fe/g dw | Deferasirox |
|---|---|
| Beta-thalassemia intermedia | -6.11 ± 6.481 |
| HbE beta-thalassemia | -6.18 ± 7.572 |
| Alpha-thalassemia intermedia (HbH disease) | -7.97 ± 7.652 |
| Other, specify | -6.00 ± NA |
Absolute change in serum ferritin from baseline after 52 weeks of treatment
| ng/mL | Deferasirox |
|---|---|
| Absolute Change in Serum Ferritin From Baseline After 52 Weeks | -494.64 ± 760.782 |
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).
| hr*umol/L | Deferasirox |
|---|---|
| PK Parameters: AUCtau | 678.2 ± 61.9 |
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
| umol/L | Deferasirox |
|---|---|
| PK Parameters: Cmax | 53.367 ± 60.960 |
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.
| hr | Deferasirox |
|---|---|
| PK Parameters: Tmax | 2.5131 ± 33.9321 |
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.
| hr*umol/L | Deferasirox |
|---|---|
| 4 weeks: 0hr pre-dose | 6.513 ± 75.891 |
| 4 weeks: 2hr post-dose | 48.556 ± 58.006 |
| 4 weeks: 4hr post-dose | 44.652 ± 69.392 |
Collected over Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 63.2 months.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Chinese | 2/68 (2.9%) | 15/68 (22.1%) | 26/68 (38.2%) |
| Non-Chinese | 0/66 (0%) | 30/66 (45.5%) | 58/66 (87.9%) |
| All Patients | 2/134 (1.5%) | 45/134 (33.6%) | 84/134 (62.7%) |
| Event | Chinese | Non-Chinese | All Patients |
|---|---|---|---|
| AnaemiaBlood and lymphatic system disorders | 2/68 | 4/66 | 6/134 |
| GastroenteritisInfections and infestations | 0/68 | 4/66 | 4/134 |
| PneumoniaInfections and infestations | 3/68 | 4/66 | 7/134 |
| PyrexiaGeneral disorders | 0/68 | 3/66 | 3/134 |
| CholelithiasisHepatobiliary disorders | 1/68 | 3/66 | 4/134 |
| Urinary tract infectionInfections and infestations | 0/68 | 3/66 | 3/134 |
| Extramedullary haemopoiesisBlood and lymphatic system disorders | 0/68 | 2/66 | 2/134 |
| Abdominal painGastrointestinal disorders | 0/68 | 2/66 | 2/134 |
| FatigueGeneral disorders | 0/68 | 2/66 | 2/134 |
| PharyngitisInfections and infestations | 0/68 | 2/66 | 2/134 |
| Event | Chinese | Non-Chinese | All Patients |
|---|---|---|---|
| Upper respiratory tract infectionInfections and infestations | 7/68 | 27/66 | 34/134 |
| HeadacheNervous system disorders | 0/68 | 27/66 | 27/134 |
| DiarrhoeaGastrointestinal disorders | 1/68 | 19/66 | 20/134 |
| Back painMusculoskeletal and connective tissue disorders | 0/68 | 16/66 | 16/134 |
| Oropharyngeal painRespiratory, thoracic and mediastinal disorders | 0/68 | 16/66 | 16/134 |
| Abdominal painGastrointestinal disorders | 0/68 | 15/66 | 15/134 |
| PyrexiaGeneral disorders | 3/68 | 14/66 | 17/134 |
| Platelet count increasedInvestigations | 13/68 | 1/66 | 14/134 |
| FatigueGeneral disorders | 1/68 | 12/66 | 13/134 |
| TonsillitisInfections and infestations | 0/68 | 12/66 | 12/134 |
The Full Analysis Set (FAS) consisted of all patients who were assigned at least one dose of study drug.
| Age, Continuous(years) | Deferasirox |
|---|---|
| Mean | 28.0 ± 11.10 |
| Age, Customized(participants) | Deferasirox |
|---|---|
| < 18 years | 25 |
| 18 - < 50 years | 104 |
| 50 - < 65 years | 5 |
| Sex: Female, Male(Participants) | Deferasirox |
|---|---|
| Female | 58 |
| Male | 76 |
| Race/Ethnicity, Customized(Participants) | Deferasirox |
|---|---|
| Asian | 85 |
| Caucasian | 48 |
| Other | 1 |
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