Thalassemia, Non-transfusional-dependent Thalassemia (NTDT), Myeloplastic Dysplasia (MDS), Other AnemiaPhase 4NCT01736540
An Epidemiological Study to Assess Iron Overload Using MRI in Patients With Transfusional Siderosis (TIMES Study)
A Phase 4 study testing MRI scan in people with Thalassemia, Non-transfusional-dependent Thalassemia (NTDT), Myeloplastic Dysplasia (MDS), Other Anemia, run by Novartis Pharmaceuticals at 13 sites in Australia.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Thalassemia, Non-transfusional-dependent Thalassemia (NTDT), Myeloplastic Dysplasia (MDS), Other Anemia
- What is being tested?
- MRI scan
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 243 participants
- Where
- 13 sitesAustralia
- Study dates
- Feb 2013to May 2015
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
13 sites in 1 country.
13 sites in 1 country
Australia13 sites
Novartis Investigative Site
Adelaide, South Australia, 5000
Novartis Investigative Site
Bedford Park, South Australia, 5042
Novartis Investigative Site
Camperdown, New South Wales, 2050
Novartis Investigative Site
East Bentleigh, Victoria, 3165
Novartis Investigative Site
Hobart, Tasmania, 7000
Novartis Investigative Site
Kogarah, New South Wales, 2217
Novartis Investigative Site
Liverpool, New South Wales, 2170
Novartis Investigative Site
Nedlands, Western Australia, 6009
Novartis Investigative Site
Perth, Western Australia, 6000
Novartis Investigative Site
South Brisbane, Queensland, 4101
Novartis Investigative Site
St Leonards, New South Wales, 2065
Novartis Investigative Site
Wollongong, New South Wales, 2500
Novartis Investigative Site
Woolloongabba, Queensland, 4102
About this study
Official title: An Epidemiological Study to Assess the Prevalence of Iron Overload Using MRI in Patients With Transfusional Siderosis (TIMES Study)
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.
Read more
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).
Read the detailed description
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.
- Being tested
- MRI scan
- Keywords
- iron overload, liver iron concentration (LIC), cardiac siderosis, transfusional siderosis, magnetic resonance imaging (MRI)
- Medical subject headings
- Thalassemia, Iron Overload
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MRI scanDevice
MRI was used to measure both liver and cardiac iron loading (R2 by FerriScan and T2*, respectively).
| Study group | Role | What they receive |
|---|---|---|
| Magnetic Resonance Imaging (MRI) | Other | All participants were subjected to a non-invasive hepatic and cardiac MRI within 60 days of enrollment to measure iron overload. Receives: Device: MRI scan |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 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.
Measured: 2 months
Secondary outcomes (13)
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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 1 month
Percentage of Participants Transfused With Erythrocytes
Transfusion requirement in participants with acquired anaemias with history of receiving chelation therapy was assessed.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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?".
Measured: 2 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Nov 2012 (estimated)
- Study startFeb 2013
- Primary completionMay 2015
- Study completionMay 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Thalassemia, Non-transfusional-dependent Thalassemia (NTDT), Myeloplastic Dysplasia (MDS), Other AnemiaStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Other
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 243 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01736540
- Sponsor's protocol ID
- CICL670AAU05
- Status last verified
- Mar 2017
- First submitted
- 26 Nov 2012
- Last updated
- 12 Apr 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Ho PJ, Hiwase D, Ramakrishna R, Viiala N, Solterbeck A, Traficante R, Zor E, Gervasio OL, High LM, Ross DM, Bowden DK. Cardiac and hepatic siderosis in myelodysplastic syndrome, thalassemia and diverse causes of transfusion-dependent anemia: the TIMES study. Hemasphere. 2019 Jun 4;3(3):e224. doi: 10.1097/HS9.0000000000000224. eCollection 2019 Jun.
PubMed 31723837
Study at a glance
From the registry record, last updated by the sponsor on 12 Apr 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Epidemiological Study to Assess the Prevalence of Iron Overload Using MRI in Patients With Transfusional Siderosis (TIMES Study)
- ClinicalTrials.gov ID
- NCT01736540
- Acronym / sponsor ID
- CICL670AAU05
- Keywords
- iron overload, liver iron concentration (LIC), cardiac siderosis, transfusional siderosis, magnetic resonance imaging (MRI)
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 243 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- Feb 2013
- Primary completion
- May 2015 (actual)
- Study completion
- May 2015 (actual)
- First posted
- 29 Nov 2012 (estimated)
- Results
- Posted 19 Sep 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Detailed description
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 design
- Primary purpose
- Other
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Magnetic Resonance Imaging (MRI) | Other | Device: MRI scanAll participants were subjected to a non-invasive hepatic and cardiac MRI within 60 days of enrollment to measure iron overload. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (1 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MRI scanMRI was used to measure both liver and cardiac iron loading (R2 by FerriScan and T2*, respectively). | Device | Magnetic Resonance Imaging (MRI) |
Primary outcome
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.
13 secondary outcomes
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
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
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 Retrospective Hepatic Events
Time frame: 12 months - retrospective
Mean Cardiac T2* According to the Presence or Absence of Retrospective Cardiac Events
Time frame: 12 months - retrospective
Mean LIC According to the Presence or Absence of Retrospective Hepatic Events
Time frame: 12 months - retrospective
Mean Blood Magnetic Susceptibility (BMS)
Time frame: 1 month
Percentage of Participants Transfused With Erythrocytes
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
Time frame: 12 months - retrospective
Mean Number of Erythrocyte Units Transfused in Last 12 Months
Time frame: 12 months - retrospective
Mean Quality of Life (QOL) Scores
Time frame: 1 month
Percentage of Participants With Low Medium or High Adherence to Iron Chelator Therapy
Time frame: 1 month
Investigator Treatment Decisions Based on MRI Results
Time frame: 2 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Apr 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 31723837Ho PJ, Hiwase D, Ramakrishna R, Viiala N, Solterbeck A, Traficante R, Zor E, Gervasio OL, High LM, Ross DM, Bowden DK. Cardiac and hepatic siderosis in myelodysplastic syndrome, thalassemia and diverse causes of transfusion-dependent anemia: the TIMES study. Hemasphere. 2019 Jun 4;3(3):e224. doi: 10.1097/HS9.0000000000000224. eCollection 2019 Jun.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
13 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing MRI scan in people with Thalassemia, Non-transfusional-dependent Thalassemia (NTDT), Myeloplastic Dysplasia (MDS), Other Anemia, run by Novartis Pharmaceuticals at 13 sites in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Apr 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 13 sites in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 19 Sep 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of Participants With Cardiac and Liver Iron Overload. (time frame: 2 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01736540, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Apr 2017.