An Epidemiological Study to Assess Iron Overload Using MRI in Patients With Transfusional Siderosis (TIMES Study)
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| ClinicalTrials.gov Identifier: NCT01736540 |
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Recruitment Status :
Completed
First Posted : November 29, 2012
Results First Posted : September 19, 2016
Last Update Posted : April 12, 2017
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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).
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Thalassemia, Non-transfusional-dependent Thalassemia (NTDT), Myeloplastic Dysplasia (MDS), Other Anemia | Device: MRI scan | Phase 4 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 243 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Other |
| Official Title: | An Epidemiological Study to Assess the Prevalence of Iron Overload Using MRI in Patients With Transfusional Siderosis (TIMES Study) |
| Study Start Date : | February 2013 |
| Actual Primary Completion Date : | May 2015 |
| Actual Study Completion Date : | May 2015 |
| Arm | Intervention/treatment |
|---|---|
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Magnetic Resonance Imaging (MRI)
All participants were subjected to a non-invasive hepatic and cardiac MRI within 60 days of enrollment to measure iron overload.
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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. [ Time Frame: 2 months ]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).
- Cardiac Siderosis Severity [ Time Frame: 2 months ]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.
- Comparison of T2* Levels to Evaluate the Severity of Iron Overload Due to Transfusion Therapy in Chelation-naïve and Chelation-treated Participant Subgroups [ Time Frame: 2 months ]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).
- Comparison of Liver Iron Concentration (LIC) Levels to Evaluate Iron Overload Due to Transfusion Therapy in Chelation-naïve and Chelation-treated Participant Subgroups [ Time Frame: 2 months ]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.
- Mean Serum Ferritin According to the Presence or Absence of Retrospective Cardiac Events [ Time Frame: 12 months - retrospective ]Mean serum ferritin according to the presence or absence of cardiac events was assessed for all participant subgroups.
- Mean Serum Ferritin According to the Presence or Absence of Retrospective Hepatic Events [ Time Frame: 12 months - retrospective ]Mean serum ferritin according to the presence or absence of hepatic events was assessed for all participant subgroups.
- Mean Cardiac T2* According to the Presence or Absence of Retrospective Cardiac Events [ Time Frame: 12 months - retrospective ]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.
- Mean LIC According to the Presence or Absence of Retrospective Hepatic Events [ Time Frame: 12 months - retrospective ]Mean LIC according to the presence or absence of hepatic events was assessed for all participant subgroups.
- Mean Blood Magnetic Susceptibility (BMS) [ Time Frame: 1 month ]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.
- Percentage of Participants Transfused With Erythrocytes [ Time Frame: 12 months - retrospective ]Transfusion requirement in participants with acquired anaemias with history of receiving chelation therapy was assessed.
- 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 [ Time Frame: 12 months - retrospective ]Transfusion requirement in participants with acquired anaemias with history of receiving chelation therapy was assessed.
- Mean Number of Erythrocyte Units Transfused in Last 12 Months [ Time Frame: 12 months - retrospective ]Transfusion requirement in participants with acquired anaemias with history of receiving chelation therapy was assessed.
- Mean Quality of Life (QOL) Scores [ Time Frame: 1 month ]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.
- Percentage of Participants With Low Medium or High Adherence to Iron Chelator Therapy [ Time Frame: 1 month ]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.
- Investigator Treatment Decisions Based on MRI Results [ Time Frame: 2 months ]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?".
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Age ≥18 years
- Confirmed clinical diagnosis of one of the following disease states: 1. Myelodysplastic syndromes, 2. Thalassaemia major, 3.Other anaemias (e.g. NTDT, SCD, Diamond-Blackfan anaemia, aplastic anaemia, myeloproliferative disease)
- Lifetime history of at least 20 units of red blood cell transfusions AND serum ferritin level > 500 ng/ml; patients with NTDT are not required to have a minimum of 20 units of red blood cell transfusions, but must have serum ferritin level > 300 ng/ml (serum ferritin for all patients must be measured up to 1 month prior to enrollment)
- Written informed consent obtained prior to any procedure required by this protocol
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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01736540
| Australia, New South Wales | |
| Novartis Investigative Site | |
| Camperdown, New South Wales, Australia, 2050 | |
| Novartis Investigative Site | |
| Kogarah, New South Wales, Australia, 2217 | |
| Novartis Investigative Site | |
| Liverpool, New South Wales, Australia, 2170 | |
| Novartis Investigative Site | |
| St Leonards, New South Wales, Australia, 2065 | |
| Novartis Investigative Site | |
| Wollongong, New South Wales, Australia, 2500 | |
| Australia, Queensland | |
| Novartis Investigative Site | |
| South Brisbane, Queensland, Australia, 4101 | |
| Novartis Investigative Site | |
| Woolloongabba, Queensland, Australia, 4102 | |
| Australia, South Australia | |
| Novartis Investigative Site | |
| Adelaide, South Australia, Australia, 5000 | |
| Novartis Investigative Site | |
| Bedford Park, South Australia, Australia, 5042 | |
| Australia, Tasmania | |
| Novartis Investigative Site | |
| Hobart, Tasmania, Australia, 7000 | |
| Australia, Victoria | |
| Novartis Investigative Site | |
| East Bentleigh, Victoria, Australia, 3165 | |
| Australia, Western Australia | |
| Novartis Investigative Site | |
| Nedlands, Western Australia, Australia, 6009 | |
| Novartis Investigative Site | |
| Perth, Western Australia, Australia, 6000 | |
| Study Director: | Novartis Pharmaceuticals | Novartis Pharmaceuticals |
| Responsible Party: | Novartis Pharmaceuticals |
| ClinicalTrials.gov Identifier: | NCT01736540 |
| Other Study ID Numbers: |
CICL670AAU05 |
| First Posted: | November 29, 2012 Key Record Dates |
| Results First Posted: | September 19, 2016 |
| Last Update Posted: | April 12, 2017 |
| Last Verified: | March 2017 |
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iron overload, liver iron concentration (LIC), cardiac siderosis, transfusional siderosis, magnetic resonance imaging (MRI) |
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Siderosis Thalassemia Iron Overload Anemia, Hemolytic, Congenital Anemia, Hemolytic Anemia Hematologic Diseases Hemoglobinopathies Genetic Diseases, Inborn |
Iron Metabolism Disorders Metabolic Diseases Pneumoconiosis Lung Diseases, Interstitial Lung Diseases Respiratory Tract Diseases Lung Injury Occupational Diseases |