A Phase 4 interventional study of MRI scan in Thalassemia, Non-transfusional-dependent Thalassemia (NTDT), Myeloplastic Dysplasia (MDS), Other Anemia, sponsored by Novartis Pharmaceuticals. Completed at 13 sites in Australia. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2017-04-12.
Sponsored by Novartis Pharmaceuticals · Phase 4, Interventional, and Other
Iron, one of the most common elements in nature and the most abundant transition metal in the body, is readily capable of accepting and donating electrons. This capability makes iron a useful component of various, essential biochemical processes. Despite the essential role of iron, the excess of iron is toxic to the human body. It is critical for the human body to maintain iron balance, since humans have no physiologic mechanism for actively removing iron from the body.
The development of iron overload occurs when iron intake exceeds the body's capacity to safely store the iron in the liver, which is the primary store for iron. Long-term transfusion therapy, a life-giving treatment for patients with intractable chronic anemia is currently the most frequent cause of secondary iron overload.
The mounting evidence regarding the mortality and morbidity due to chronic iron overload in transfusion dependent anaemias has led to the establishment of guidelines that aim the improvement of patient outcomes. Further prospective studies are warranted in order to assess the impact of iron overload in patients with acquired anaemias.
In this study, non-invasive R2- and T2*-MRI techniques were applied to the liver and the heart, respectively, to complement the primary variable (serum ferritin) assessed in patients with various transfusion-dependent anaemias. The main objective of this study was to assess the prevalence and severity of cardiac and liver siderosis in patients with transfusional siderosis. This study was also aim to establish possible correlations between cardiac and liver iron levels with clinical effects in patients with different transfusion-dependent anaemias. Patients were eligible for enrollment irrespective of receiving chelation therapy or not (and irrespective of the chelating agent used).
This study was designed to collect information about a large cohort of patients with anaemias including MDS, aplastic anemia, Diamond-Blackfan, myeloproliferative disorder, as well as haemoglobinopathies (e.g. thalassaemia major, SCD) or other anaemias requiring chronic red blood cell transfusions.
Clinical data was collected retrospectively (if available), unless specified by this protocol (e.g. serum ferritin within less than one month prior to enrollment). All assessments required for this protocol were performed after the patient informed consent is signed. The data was gathered by all study centers and was combined in one central database.
Data was recorded using an electronic case report form (eCRF) at each study site. Adverse events and serious adverse events were recorded for all patients from the date of signed patient informed consent until the MRI tests are performed.
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This study's enrollment of 243 is above the median of 37 across 277 interventional studies indexed under Thalassemia.
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Exclusion Criteria:
Any condition that does not allow the MRI test to be performed: 1. Cardiac pacemaker, 2. Ferromagnetic metal implants other than those approved as safe for use in MR scanners (Example: some types of aneurysm clips, shrapnel), 3. Obesity (exceeding the equipment limits), 4. Patients who are claustrophobic to MR Women who are pregnant Unwillingness or being unable to give consent
All participants were subjected to a non-invasive hepatic and cardiac MRI within 60 days of enrollment to measure iron overload.
Device: MRI scan
MRI was used to measure both liver and cardiac iron loading (R2 by FerriScan and T2\*, respectively).
Percentage of Participants With Cardiac and Liver Iron Overload.
Hepatic iron overload (liver siderosis) and cardiac iron overload (cardiac siderosis) in patients with transfusional siderosis (Myelodysplastic syndrome (MDS), thalassaemia major, non-transfusion-dependent thalassaemia (NTDT) and other anaemias) were measured using MRI (R2 by FerriScan and T2\*, respectively).
Time frame: 2 months
Cardiac Siderosis Severity
Cardiac siderosis severity was measured by MRI (T2\*). The severity grade of siderosis was tiered in 3 levels: mild (T2\* \>= 20ms), moderate (T2\* from 10 to 20ms), and severe (T2\* \<10ms). Mild cardiac siderosis, by the definitions used in this study, were equivalent to not having cardiac siderosis. Values were compared to published thresholds of iron overload to determine severity of transfusion siderosis in the participant population studied.
Time frame: 2 months
Comparison of T2* Levels to Evaluate the Severity of Iron Overload Due to Transfusion Therapy in Chelation-naïve and Chelation-treated Participant Subgroups
Iron overload due to transfusion therapy was assessed based on chelation status of each participant (i.e. minimally exposed to chelator treatment and chelation-treated patient subgroups).
Time frame: 2 months
Comparison of Liver Iron Concentration (LIC) Levels to Evaluate Iron Overload Due to Transfusion Therapy in Chelation-naïve and Chelation-treated Participant Subgroups
Iron overload due to transfusion therapy was assessed based on chelation status of each participant (i.e. minimally exposed to chelator treatment and chelation-treated patient subgroups). The mean data presented are mean estimates of log transformed data.
Time frame: 2 months
Mean Serum Ferritin According to the Presence or Absence of Retrospective Cardiac Events
Mean serum ferritin according to the presence or absence of cardiac events was assessed for all participant subgroups.
Time frame: 12 months - retrospective
Mean Serum Ferritin According to the Presence or Absence of Retrospective Hepatic Events
Mean serum ferritin according to the presence or absence of hepatic events was assessed for all participant subgroups.
Time frame: 12 months - retrospective
Mean Cardiac T2* According to the Presence or Absence of Retrospective Cardiac Events
Mean cardiac T2\* according to the presence or absence of cardiac events was assessed for all participant subgroups. The mean data presented are mean estimates of log transformed data.
Time frame: 12 months - retrospective
Mean LIC According to the Presence or Absence of Retrospective Hepatic Events
Mean LIC according to the presence or absence of hepatic events was assessed for all participant subgroups.
Time frame: 12 months - retrospective
Mean Blood Magnetic Susceptibility (BMS)
Blood samples were collected to assess BMS. The measurement represents absolute magnetic susceptibility at 1 month. Whole blood magnetic susceptibility was calculated by the addition of the dry weight susceptibility and the contribution of the water driven from the sample.
Time frame: 1 month
Percentage of Participants Transfused With Erythrocytes
Transfusion requirement in participants with acquired anaemias with history of receiving chelation therapy was assessed.
Time frame: 12 months - retrospective
Percentage of Participants With Time Since Most Recent Transfuison of <7 Days, 7 to < 14 Days, 14 to < 30 Days, 30 to < 60 Days or >= 60 Days
Transfusion requirement in participants with acquired anaemias with history of receiving chelation therapy was assessed.
Time frame: 12 months - retrospective
Mean Number of Erythrocyte Units Transfused in Last 12 Months
Transfusion requirement in participants with acquired anaemias with history of receiving chelation therapy was assessed.
Time frame: 12 months - retrospective
Mean Quality of Life (QOL) Scores
Quality of life was assessed using the Short Form 36 (SF-36) Health Survey. The SF-36 consists of 8 sub-scales: vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning and mental health. The raw sores of the 8 scales are transformed to a 0 - 100 scale where 0 indicates maximum disability and 100 indicates no disability. There also are two physical and mental health summary measures. Each summary measure is the mean average of the 4 associated sub-scale scores. The range for each summary measure is 0 to 100 where 0 represents maximum disability and 100 represents no disability.
Time frame: 1 month
Percentage of Participants With Low Medium or High Adherence to Iron Chelator Therapy
Adherence of participants was assessed using an adherence questionnaire. Adherence questionnaires were completed only by participants who received chelating agents. Participants answered yes or no to 6 statements such as "Forgot to take pills". Based on the responses to these questions, adherence was classified as low, medium or high.
Time frame: 1 month
Investigator Treatment Decisions Based on MRI Results
Treatment decisions were recorded after the investigator evaluated the MRI results, in order to assess the impact of such diagnostic test on the overall clinical management of participants with iron overload. Investigators answered the following question: "Since the MRI scan, have you changed or are planning to change the management of iron in your subject?".
Time frame: 2 months
| Milestone | Magnetic Resonance Imaging (MRI) |
|---|---|
| Started | 243 |
| Completed | 228 |
| Not completed | 15 |
| Withdrew: Did not complete scan within 45 days | 2 |
| Withdrew: Death | 1 |
| Withdrew: Abnormal test procedure | 1 |
| Withdrew: Withdrawal by subject | 5 |
| Withdrew: Protocol violation | 1 |
| Withdrew: Unable to tolerate mri; claustrophobic | 1 |
| Withdrew: No show for mri appointment | 1 |
| Withdrew: Unable to make mri appointment | 3 |
Hepatic iron overload (liver siderosis) and cardiac iron overload (cardiac siderosis) in patients with transfusional siderosis (Myelodysplastic syndrome (MDS), thalassaemia major, non-transfusion-dependent thalassaemia (NTDT) and other anaemias) were measured using MRI (R2 by FerriScan and T2\*, respectively).
| Percentage of participants | Magnetic Resonance Imaging (MRI) | Thalassemia Major | Melodysplastic Syndrome (MDS) | Non-transfusion-dependent Anaemia (NTDT) | Other Anaemias |
|---|---|---|---|---|---|
| Cardiac | 10 | 22 | 4 | 0 | 3 |
| Liver | 48 | 33 | 55 | 50 | 57 |
Cardiac siderosis severity was measured by MRI (T2\*). The severity grade of siderosis was tiered in 3 levels: mild (T2\* \>= 20ms), moderate (T2\* from 10 to 20ms), and severe (T2\* \<10ms). Mild cardiac siderosis, by the definitions used in this study, were equivalent to not having cardiac siderosis. Values were compared to published thresholds of iron overload to determine severity of transfusion siderosis in the participant population studied.
| Percentage of participants | Magnetic Resonance Imaging (MRI) | Thalassemia Major | Melodysplastic Syndrome (MDS) | Non-transfusion-dependent Anaemia (NTDT) | Other Anaemias |
|---|---|---|---|---|---|
| None | 89.9 | 77.6 | 95.7 | 100.0 | 95.4 |
| Moderate | 4.4 | 11.8 | 0.0 | 0.0 | 1.5 |
| Severe | 5.7 | 10.5 | 4.3 | 0.0 | 3.1 |
Iron overload due to transfusion therapy was assessed based on chelation status of each participant (i.e. minimally exposed to chelator treatment and chelation-treated patient subgroups).
| ms | Magnetic Resonance Imaging (MRI) | Thalassemia Major | Melodysplastic Syndrome (MDS) | Non-transfusion-dependent Anaemia (NTDT) | Other Anaemias |
|---|---|---|---|---|---|
| Overall (n=228,76,69,18,65) | 30.2 (27.62 to 32.62) | 23.95 (21.46 to 26.72) | 30.13 (26.78 to 33.90) | 32.69 (25.94 to 41.19) | 30.76 (27.29 to 34.67) |
| Chelation naïve/minimally exposed(n=75,0,27,11,37) | 32.55 (28.71 to 36.91) | NA (NA to NA) | 32.05 (26.66 to 38.53) | 32.95 (24.70 to 43.97) | 32.66 (27.91 to 38.22) |
| Chelator exposed (n=153,76,42,7,28) | 28.25 (25.28 to 31.57) | 23.95 (21.46 to 26.72) | 28.32 (24.43 to 32.82) | 32.43 (22.59 to 46.55) | 28.96 (24.17 to 34.70) |
Iron overload due to transfusion therapy was assessed based on chelation status of each participant (i.e. minimally exposed to chelator treatment and chelation-treated patient subgroups). The mean data presented are mean estimates of log transformed data.
| mg Fe/g | Magnetic Resonance Imaging (MRI) | Thalassemia Major | Melodysplastic Syndrome (MDS) | Non-transfusion-dependent Anaemia (NTDT) | Other Anaemias |
|---|---|---|---|---|---|
| Overall (n=228,76,69,18,65) | 11.30 (9.42 to 13.17) | 8.09 (5.62 to 10.57) | 10.84 (8.18 to 13.50) | 12.38 (7.16 to 17.59) | 12.28 (9.58 to 14.98) |
| Chelation naïve/minimally exposed(n=75,0,27,11,37) | 8.73 (5.90 to 11.56) | NA (NA to NA) | 10.28 (6.13 to 14.43) | 5.00 (-1.50 to 11.50) | 10.92 (7.37 to 14.47) |
| Chelator exposed (n=153,76,42,7,28) | 13.22 (10.72 to 15.72) | 8.09 (5.62 to 10.57) | 11.40 (8.07 to 14.72) | 19.76 (11.60 to 27.91) | 13.64 (9.56 to 17.72) |
Mean serum ferritin according to the presence or absence of cardiac events was assessed for all participant subgroups.
| ng/mL | Magnetic Resonance Imaging (MRI) |
|---|---|
| Cardiac event in past 12 months = yes (n=12) | 2153.6 ± 1878.6 |
| Cardiac event in past 12 months = no (n=226) | 2150.2 ± 1914.5 |
Mean serum ferritin according to the presence or absence of hepatic events was assessed for all participant subgroups.
| ng/mL | Magnetic Resonance Imaging (MRI) |
|---|---|
| Hepatic event in the past 12 months = yes (n=8) | 3302.8 ± 2684.3 |
| Hepatic event in the past 12 months = no (n=231) | 2124.1 ± 1879.2 |
Mean cardiac T2\* according to the presence or absence of cardiac events was assessed for all participant subgroups. The mean data presented are mean estimates of log transformed data.
| log10 (ms) | Magnetic Resonance Imaging (MRI) |
|---|---|
| Cardiac event in past 12 months = yes (n=12) | 1.546 ± 0.0979 |
| Cardiac event in the past 12 months = no (n=226) | 1.445 ± 0.2188 |
Mean LIC according to the presence or absence of hepatic events was assessed for all participant subgroups.
| mg Fe/g | Magnetic Resonance Imaging (MRI) |
|---|---|
| Hepatic event in past 12 months = yes (n=7) | 17.51 ± 15.292 |
| Hepatic event in past 12 months = no (n=221) | 10.08 ± 10.950 |
Blood samples were collected to assess BMS. The measurement represents absolute magnetic susceptibility at 1 month. Whole blood magnetic susceptibility was calculated by the addition of the dry weight susceptibility and the contribution of the water driven from the sample.
| emu/g wet wt/Oe | Magnetic Resonance Imaging (MRI) |
|---|---|
| Mean Blood Magnetic Susceptibility (BMS) | -6.18 ± 0.147 |
Transfusion requirement in participants with acquired anaemias with history of receiving chelation therapy was assessed.
| Percentage of participants | Magnetic Resonance Imaging (MRI) | Thalassemia Major | Melodysplastic Syndrome (MDS) | Non-transfusion-dependent Anaemia (NTDT) | Other Anaemias |
|---|---|---|---|---|---|
| Percentage of Participants Transfused With Erythrocytes | 95.0 | 100.0 | 100.0 | 36.8 | 100.0 |
Transfusion requirement in participants with acquired anaemias with history of receiving chelation therapy was assessed.
| percentage of participants | Magnetic Resonance Imaging (MRI) | Thalassemia Major | Melodysplastic Syndrome (MDS) | Non-transfusion-dependent Anaemia (NTDT) | Other Anaemias |
|---|---|---|---|---|---|
| < 7 days | 43.1 | 72.8 | 31.0 | 14.3 | 22.7 |
| 7 - < 14 days | 12.9 | 2.5 | 28.2 | 14.3 | 9.1 |
| 14 - < 30 days | 20.0 | 22.2 | 14.1 | 0.0 | 25.8 |
| 30 - < 60 days | 5.8 | 2.5 | 9.9 | 14.3 | 4.5 |
| >= 60 days | 18.2 | 0.0 | 16.9 | 57.1 | 37.9 |
Transfusion requirement in participants with acquired anaemias with history of receiving chelation therapy was assessed.
| number of units transfused | Magnetic Resonance Imaging (MRI) | Thalassemia Major | Melodysplastic Syndrome (MDS) | Non-transfusion-dependent Anaemia (NTDT) | Other Anaemias |
|---|---|---|---|---|---|
| Mean Number of Erythrocyte Units Transfused in Last 12 Months | 33.3 ± 21.0 | 41.4 ± 9.5 | 34.7 ± 25.6 | 8.4 ± 12.2 | 24.8 ± 21.5 |
Quality of life was assessed using the Short Form 36 (SF-36) Health Survey. The SF-36 consists of 8 sub-scales: vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning and mental health. The raw sores of the 8 scales are transformed to a 0 - 100 scale where 0 indicates maximum disability and 100 indicates no disability. There also are two physical and mental health summary measures. Each summary measure is the mean average of the 4 associated sub-scale scores. The range for each summary measure is 0 to 100 where 0 represents maximum disability and 100 represents no disability.
| units on a scale | Magnetic Resonance Imaging (MRI) | Thalassemia Major | Melodysplastic Syndrome (MDS) | Non-transfusion-dependent Anaemia (NTDT) | Other Anaemias |
|---|---|---|---|---|---|
| Physical functioning | 43.10 ± 11.471 | 49.79 ± 9.144 | 35.67 ± 9.791 | 49.37 ± 7.576 | 41.56 ± 11.139 |
| Role physical | 42.54 ± 10.895 | 49.51 ± 8.836 | 36.71 ± 9.462 | 46.46 ± 8.717 | 39.44 ± 10.229 |
| Bodily pain | 48.41 ± 10.969 | 50.48 ± 11.084 | 45.52 ± 10.750 | 54.66 ± 7.773 | 47.60 ± 10.815 |
| General health | 41.65 ± 9.909 | 44.82 ± 9.365 | 39.48 ± 9.595 | 43.23 ± 8.893 | 39.80 ± 10.239 |
| Vitality | 45.59 ± 10.267 | 50.18 ± 9.277 | 42.41 ± 9.190 | 48.95 ± 8.424 | 42.67 ± 10.757 |
| Social functioning | 44.99 ± 11.075 | 48.98 ± 9.869 | 42.37 ± 10.486 | 46.43 ± 9.905 | 42.67 ± 12.043 |
| Role emotional | 43.83 ± 12.977 | 48.99 ± 11.236 | 40.11 ± 13.101 | 47.03 ± 10.552 | 40.89 ± 13.320 |
| Mental health | 47.84 ± 11.149 | 50.09 ± 11.240 | 46.69 ± 9.495 | 48.74 ± 9.846 | 46.12 ± 12.632 |
| Physical component summary | 43.48 ± 9.808 | 48.75 ± 7.809 | 37.55 ± 8.748 | 50.34 ± 6.392 | 41.93 ± 9.524 |
| Mental component summary | 46.76 ± 11.622 | 49.58 ± 10.354 | 45.91 ± 10.349 | 47.47 ± 10.832 | 44.08 ± 13.822 |
Adherence of participants was assessed using an adherence questionnaire. Adherence questionnaires were completed only by participants who received chelating agents. Participants answered yes or no to 6 statements such as "Forgot to take pills". Based on the responses to these questions, adherence was classified as low, medium or high.
| Percentage of participants | Magnetic Resonance Imaging (MRI) | Thalassemia Major | Melodysplastic Syndrome (MDS) | Non-transfusion-dependent Anaemia (NTDT) | Other Anaemias |
|---|---|---|---|---|---|
| Low | 27.7 | 32.1 | 11.8 | 75.0 | 28.0 |
| Medium | 61.7 | 57.7 | 73.5 | 25.0 | 64.0 |
| High | 10.6 | 10.3 | 14.7 | 0.0 | 8.0 |
Treatment decisions were recorded after the investigator evaluated the MRI results, in order to assess the impact of such diagnostic test on the overall clinical management of participants with iron overload. Investigators answered the following question: "Since the MRI scan, have you changed or are planning to change the management of iron in your subject?".
| Percentage of participants | Magnetic Resonance Imaging (MRI) |
|---|---|
| Answer = yes | 42.4 |
| Answer = no | 57.6 |
Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Thalassaemia Major | — | 2/81 (2.5%) | 7/81 (8.6%) |
| Myelodysplastic Syndrome (MDS) | — | 8/74 (10.8%) | 9/74 (12.2%) |
| Other Anaemia | — | 2/68 (2.9%) | 3/68 (4.4%) |
| Non-transfusion-dependent Anaemia (NTDT) | — | 0/20 (0%) | 0/20 (0%) |
| Event | Thalassaemia Major | Myelodysplastic Syndrome (MDS) | Other Anaemia | Non-transfusion-dependent Anaemia (NTDT) |
|---|---|---|---|---|
| Febrile neutropeniaBlood and lymphatic system disorders | 0/81 | 1/74 | 2/68 | 0/20 |
| DiarrhoeaGastrointestinal disorders | 0/81 | 2/74 | 1/68 | 0/20 |
| Eye swellingEye disorders | 0/81 | 0/74 | 1/68 | 0/20 |
| MalaiseGeneral disorders | 0/81 | 0/74 | 1/68 | 0/20 |
| PyrexiaGeneral disorders | 0/81 | 0/74 | 1/68 | 0/20 |
| NasopharyngitisInfections and infestations | 0/81 | 0/74 | 1/68 | 0/20 |
| PneumoniaInfections and infestations | 0/81 | 0/74 | 1/68 | 0/20 |
| C-reactive protein increasedInvestigations | 0/81 | 0/74 | 1/68 | 0/20 |
| Electrocardiogram QT prolongedInvestigations | 0/81 | 0/74 | 1/68 | 0/20 |
| Platelet count decreasedInvestigations | 0/81 | 0/74 | 1/68 | 0/20 |
| Event | Thalassaemia Major | Myelodysplastic Syndrome (MDS) | Other Anaemia | Non-transfusion-dependent Anaemia (NTDT) |
|---|---|---|---|---|
| Abdominal painGastrointestinal disorders | 0/81 | 3/74 | 1/68 | 0/20 |
| PalpitationsCardiac disorders | 0/81 | 2/74 | 0/68 | 0/20 |
| FatigueGeneral disorders | 0/81 | 2/74 | 1/68 | 0/20 |
| HeadacheNervous system disorders | 0/81 | 2/74 | 0/68 | 0/20 |
| Upper respiratory tract infectionInfections and infestations | 2/81 | 0/74 | 0/68 | 0/20 |
| AnaemiaBlood and lymphatic system disorders | 0/81 | 1/74 | 1/68 | 0/20 |
| Febrile neutropeniaBlood and lymphatic system disorders | 0/81 | 0/74 | 1/68 | 0/20 |
| ThrombocytopeniaBlood and lymphatic system disorders | 0/81 | 0/74 | 1/68 | 0/20 |
| HypoacusisEar and labyrinth disorders | 0/81 | 0/74 | 1/68 | 0/20 |
| Dry eyeEye disorders | 0/81 | 0/74 | 1/68 | 0/20 |
| Age, Continuous(Years) | Magnetic Resonance Imaging (MRI) |
|---|---|
| Mean | 52.8 ± 20.92 |
| Sex: Female, Male(Participants) | Magnetic Resonance Imaging (MRI) |
|---|---|
| Female | 109 |
| Male | 134 |
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Siderosis
Novartis Pharmaceuticals