An Epidemiological Study to Assess Iron Overload Using MRI in Patients With Transfusional Siderosis (TIMES Study)

• ClinicalTrials.gov Identifier: NCT01736540
• Recruitment Status: Completed
• First Posted: November 29, 2012
• Results First Posted: September 19, 2016
• Last Update Posted: April 12, 2017
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: November 26, 2012
• First Posted Date: November 29, 2012
• Results First Submitted Date: May 28, 2016
• Results First Posted Date: September 19, 2016
• Last Update Posted Date: April 12, 2017
• Study Start Date: February 2013
• Actual Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 29, 2016)

• 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.

Original Primary Outcome Measures (submitted: November 28, 2012)

Prevalence and severity of liver and cardiac iron overload in patients with transfusional siderosis (MDS, thalassaemia major and other anaemias). [ Time Frame: 12 months - retrospective ]

Hepatic and cardiac iron overload in patients with transfusional siderosis (MDS, thalassaemia major and other anaemias) will be measured using MRI to measure both liver and cardiac iron loading (R2 by FerriScan and T2*, respectively). Values will be compared to published thresholds of iron overload to determine severity of transfusion siderosis in the patient population studied.

Current Secondary Outcome Measures (submitted: March 14, 2017)

• 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?".

Original Secondary Outcome Measures (submitted: November 28, 2012)

• Measurement of iron overload due to transfusion therapy comparing chelation-naïve and chelation-treated patient subgroups. [ Time Frame: 12 months - retrospective ]
  The severity of iron overload due to transfusion therapy will be assessed based on chelation status of each patient (i.e. chelation-naïve and chelation-treated patient subgroups).
• Levels of cardiac and liver siderosis in different populations of patients requiring regular blood transfusions (e.g. thalassaemia major vs. NTDT, thalassaemia major vs. MDS). [ Time Frame: 12 months ]
  Levels of cardiac and liver siderosis will be compared between patient subgroups, according to their primary diagnosis leading to anaemia (e.g. thalassaemia major vs. NTDT, thalassaemia major vs. MDS).
• Relationship between serum ferritin, cardiac and liver iron with cardiac and hepatic events. [ Time Frame: 12 months - retrospective ]
  The relationship between serum ferritin, cardiac and liver iron with cardiac and hepatic events will be assessed all patient subgroups.
• Relationship between BMS and cardiac T2*. [ Time Frame: 1 month ]
  Relationship between BMS and cardiac T2* will be assessed comparing all patient groups.
• Haematologic parameters and transfusion requirement in patients with acquired anaemias with history of receiving chelation therapy. [ Time Frame: 12 months - retrospective ]
  haematologic parameters and transfusion requirement in patients with acquired anaemias with history of receiving chelation therapy will be assessed, in order to evaluate possible impact of chelation on transfusion independence.
• Quality of life and different disease states, levels of iron overload and different chelation regimens. [ Time Frame: 1 month ]
  Quality of life will be assessed comparing different disease states, levels of iron overload and different chelation regimens.
• Adherence of patients according to different chelation regimens. [ Time Frame: 1 month ]
  Adherence of patients according to different chelation regimens (adherence questionnaire will only be recorded for patients receiving chelating agents).
• Treatment decisions based on MRI results. [ Time Frame: 1 month ]
  Treatment decisions will be recorded after the investigator evaluates the MRI results, in order to assess the impact of such diagnostic test on the overall clinical management of patients with iron overload.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: An Epidemiological Study to Assess Iron Overload Using MRI in Patients With Transfusional Siderosis (TIMES Study)
• Official Title: An Epidemiological Study to Assess the Prevalence of Iron Overload Using MRI in Patients With Transfusional Siderosis (TIMES Study)

Brief 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. 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 Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Other
• Condition: Thalassemia, Non-transfusional-dependent Thalassemia (NTDT), Myeloplastic Dysplasia (MDS), Other Anemia

Intervention

Device: MRI scan

MRI was used to measure both liver and cardiac iron loading (R2 by FerriScan and T2*, respectively).

Study Arms

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.

Intervention: Device: MRI scan

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 29, 2016): 243
• Original Estimated Enrollment (submitted: November 28, 2012): 350
• Actual Study Completion Date: May 2015
• Actual Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia

Administrative Information

• NCT Number: NCT01736540
• Other Study ID Numbers: CICL670AAU05
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: March 2017