Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01736540
First received: November 26, 2012
Last updated: July 29, 2016
Last verified: July 2016
  Purpose

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 Intervention Phase
Thalassemia, Non-transfusional-dependent Thalassemia (NTDT), Myeloplastic Dysplasia (MDS), Other Anemia
Device: MRI scan
Phase 4

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Official Title: An Epidemiological Study to Assess the Prevalence of Iron Overload Using MRI in Patients With Transfusional Siderosis (TIMES Study)

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Percentage of Participants With Cardiac and Liver Iron Overload. [ Time Frame: 2 months ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    BMS was assessed, comparing all participant subgroups.

  • Percentage of Participants Transfused With Erythrocytes [ Time Frame: 12 months - retrospective ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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?".


Enrollment: 243
Study Start Date: February 2013
Study Completion Date: May 2015
Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Device: MRI scan
MRI was used to measure both liver and cardiac iron loading (R2 by FerriScan and T2*, respectively).

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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01736540

Locations
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
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01736540     History of Changes
Other Study ID Numbers: CICL670AAU05 
Study First Received: November 26, 2012
Results First Received: May 28, 2016
Last Updated: July 29, 2016
Health Authority: Australia: Human Research Ethics Committee
United States: Food and Drug Administration

Keywords provided by Novartis:
iron overload, liver iron concentration (LIC), cardiac siderosis, transfusional siderosis, magnetic resonance imaging (MRI)

Additional relevant MeSH terms:
Thalassemia
Iron Overload
Siderosis
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
Iron
Trace Elements
Micronutrients
Growth Substances
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 29, 2016