Clinical trial NCT01736540: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Thalassemia, Non-transfusional-dependent Thalassemia (NTDT), Myeloplastic Dysplasia (MDS), Other Anemia
Keywords: iron overload, liver iron concentration (LIC), cardiac siderosis, transfusional siderosis, magnetic resonance imaging (MRI)
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-11-29
Enrollment: 243
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

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.

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

Primary outcomes:
measure: Percentage of Participants With Cardiac and Liver Iron Overload.
timeFrame: 2 months
measure: Cardiac Siderosis Severity
timeFrame: 2 months
Secondary outcomes:
measure: Comparison of T2* Levels to Evaluate the Severity of Iron Overload Due to Transfusion Therapy in Chelation-naïve and Chelation-treated Participant Subgroups
timeFrame: 2 months
measure: Comparison of Liver Iron Concentration (LIC) Levels to Evaluate Iron Overload Due to Transfusion Therapy in Chelation-naïve and Chelation-treated Participant Subgroups
timeFrame: 2 months
measure: Mean Serum Ferritin According to the Presence or Absence of Retrospective Cardiac Events
timeFrame: 12 months - retrospective
measure: Mean Serum Ferritin According to the Presence or Absence of Retrospective Hepatic Events
timeFrame: 12 months - retrospective
measure: Mean Cardiac T2* According to the Presence or Absence of Retrospective Cardiac Events
timeFrame: 12 months - retrospective
measure: Mean LIC According to the Presence or Absence of Retrospective Hepatic Events
timeFrame: 12 months - retrospective
measure: Mean Blood Magnetic Susceptibility (BMS)
timeFrame: 1 month
measure: Percentage of Participants Transfused With Erythrocytes
timeFrame: 12 months - retrospective
measure: 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
timeFrame: 12 months - retrospective
measure: Mean Number of Erythrocyte Units Transfused in Last 12 Months
timeFrame: 12 months - retrospective
measure: Mean Quality of Life (QOL) Scores
timeFrame: 1 month
measure: Percentage of Participants With Low Medium or High Adherence to Iron Chelator Therapy
timeFrame: 1 month
measure: Investigator Treatment Decisions Based on MRI Results
timeFrame: 2 months
Other outcomes:
Locations:
city: Camperdown
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Kogarah
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Liverpool
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: St Leonards
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Wollongong
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: South Brisbane
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Woolloongabba
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Adelaide
country: Australia
facility: Novartis Investigative Site
state: South Australia
city: Bedford Park
country: Australia
facility: Novartis Investigative Site
state: South Australia
city: Hobart
country: Australia
facility: Novartis Investigative Site
state: Tasmania
city: East Bentleigh
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Nedlands
country: Australia
facility: Novartis Investigative Site
state: Western Australia
city: Perth
country: Australia
facility: Novartis Investigative Site
state: Western Australia
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.