Condition category
Urological and Genital Diseases
Date applied
20/05/2011
Date assigned
14/06/2011
Last edited
08/09/2016
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
The aim of this study is to use a technique called magnetic resonance imaging (MRI) to measure the iron content of the liver, spleen and heart of patients who are undergoing hemodialysis or peritoneal dialysis and who are being treated with intravenous iron and erythropoiesis stimulating agents (ESA). The study will also find out about the risk factors of iron overload, and especially the role of iron therapy.

Who can participate?
Patients undergoing hemodialysis or peritoneal dialysis three times a week for at least 3 months.

What does the study involve?
MRI will be used to determine the iron content of the participants' liver, spleen and heart. The participants' medical records and dialysis charts will be reviewed by clinical research technicians. Blood samples will be taken and the patients will be tested for measurement of biochemical markers of iron metabolism and for a genetic defect of the HFE genes. A test will be carried out to determine the participants' alcohol consumption and to detect alcohol addiction. Patients will be followed for analysis of relevant clinical events (illness and death).

What are the possible benefits and risks of participating?
Careful monitoring of iron therapy will allow the safe use of intravenous iron, avoiding iron overload. The risks of participating are anxiety related to MRI exams and genetic testing.

Where is the study run from?
Private hospital Claude Galien (Quincy sous Sénart), Hôpital de Melun, Groupe hospitalier Pitié salpétrière (Paris), Groups hospitalier Kremlin Bicêtre (Le kremlin Bicêtre), Hôpital de Creil, Association AURA (Paris) (France)

When is the study starting and how long is it expected to run for?
January 2005 to January 2020

Who is funding the study?
The Physicians' Association of Claude Galien Hospital (Association Quincy Recherche Clinique et Thérapeutique) (France)

Who is the main contact?
Dr Guy Rostoker
rostotom@orange.fr

Trial website

Contact information

Type

Scientific

Primary contact

Dr Guy Rostoker

ORCID ID

http://orcid.org/0000-0002-4383-3825

Contact details

Service de Néphrologie et de Dialyse
Hopital Privé Claude Galien
2 Rue de Boussy
Quincy Sous Senart
91480
France
-
rostotom@orange.fr

Type

Scientific

Additional contact

Dr Mireille Griuncelli

ORCID ID

Contact details

Nephrology and Hemodialysis
Private Hospital Claude Galien
20
route de Boussy
Quincy-sous-Sénart
91480
France
-
rostotom@orange.fr

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

N/A

Study information

Scientific title

Analysis of hepatic iron stores of haemodialysis patients by magnetic resonance imaging: a cross-sectional and longitudinal study

Acronym

Study hypothesis

The aim of this study was to determine hepatic iron content, using magnetic resonance imaging (MRI) and the Rennes University algorithm, in a cohort of haemodialysis patients receiving both intravenous iron and erythropoiesis stimulating agents (ESA), in keeping with current guidelines.

Ethics approval

1. COMEDIMS (Drug, Devices and Clinical Trials Committee) CHP Claude Galien, 09/12/2004, ref: 2004-2
2. COMEDIMS (Drug, Devices and Clinical Trials Committee) CHP Claude Galien, 15/02/2013, ref 2013-2

Study design

Prospective cross-sectional longitudinal multicenter study

Primary study design

Observational

Secondary study design

Cross-sectional longitudinal study

Trial setting

Hospitals

Trial type

Diagnostic

Patient information sheet

Not available in web format, please contact rostotom@orange.fr to request a patient information sheet

Condition

Chronic kidney disease

Intervention

Current interventions as of 08/09/2016:
1. Non-randomised measurement of hepatic iron content by means of T1 and T2 contrast magnetic resonance imaging (MRI) on a Sigma MRI unit (GE Medical Systems, Milwaukee, WI, USA) operating at a field strength of 1.5 Tesla
2. Five weighted gradient-recalled-echo sequences of the liver (GRE T1, DP, T2, T2+ and T2++) with a repetition time of 120 ms will be acquired
3. Measurements will be made in five regions of interest larger than 1 cm2 (usually 3 on the right liver and 2 on paraspinal muscles on the same slice), and calculated the liver-to-muscle ratio
4. Areas of cyst-free liver will be examined in patients with renal and hepatic polycystosis
5. We will used the software algorithm provided by Rennes University (http://www.radio.univ-rennes1.fr) to determine hepatic iron content (expressed in micromol/g of dry liver)
6. Duration of MRI examination is about 20 minutes
7. Measurements of biochemical markers of iron metabolism:
7.1. Serum ferritin
7.2. Serum iron
7.3. Transferrin
7.4. Transferrin saturation (TSAT)
7.5. Soluble transferrin receptors (sTfR)
7.6. Serum hepcidin-25
7.7. Screening for the C282Y HFE gene mutation
7.8. Serum hepcidin-20, 22, and 24
7.9. Serum erythroferrone
7.10. Serum glycosylated ferritin
7.11. Serum non bound transferrin iron (NBTI) and serum labile iron
7.12. Plasma FGF23 C-terminal, plasma FGF23 Intact, soluble alpha Klotho, sclerotin
8. Use of The Alcohol Use Disorder Identification Test (AUDIT) to quantify alcohol consumption and to detect addiction
9. Measurement of iron content in spleen and heart will be performed simultaneously to determination of liver iron content by R2* relaxometry
10. Follow-up of patients for relevant clinical events (morbidity and mortality)

Previous interventions from 01/03/2013 to 08/09/2016:
1. Non-randomised measurement of hepatic iron content by means of T1 and T2 contrast magnetic resonance imaging (MRI) on a Sigma MRI unit (GE Medical Systems, Milwaukee, WI, USA) operating at a field strength of 1.5 Tesla
2. Five weighted gradient-recalled-echo sequences of the liver (GRE T1, DP, T2, T2+ and T2++) with a repetition time of 120 ms will be acquired
3. Measurements will be made in five regions of interest larger than 1 cm2 (usually 3 on the right liver and 2 on paraspinal muscles on the same slice), and calculated the liver-to-muscle ratio
4. Areas of cyst-free liver will be examined in patients with renal and hepatic polycystosis
5. We will used the software algorithm provided by Rennes University (http://www.radio.univ-rennes1.fr) to determine hepatic iron content (expressed in micromol/g of dry liver)
6. Duration of MRI examination is about 20 minutes
7. Measurements of biochemical markers of iron metabolism:
7.1. Serum ferritin
7.2. Serum iron
7.3. Transferrin
7.4. Transferrin saturation (TSAT)
7.5. Soluble transferrin receptors (sTfR)
7.6. Serum hepcidin-25
7.7. Screening for the C282Y HFE gene mutation
8. Use of The Alcohol Use Disorder Identification Test (AUDIT) to quantify alcohol consumption and to detect addiction
9. Measurement of iron content in spleen and heart will be performed simultaneously to determination of liver iron content by R2* relaxometry
10. Follow-up of patients for relevant clinical events (morbidity and mortality)

Previous interventions from 07/12/2012 to 01/03/2013:
1. Non-randomised measurement of hepatic iron content by means of T1 and T2 contrast magnetic resonance imaging (MRI) on a Sigma MRI unit (GE Medical Systems, Milwaukee, WI, USA) operating at a field strength of 1.5 Tesla
2. Five weighted gradient-recalled-echo sequences of the liver (GRE T1, DP, T2, T2+ and T2++) with a repetition time of 120 ms will be acquired
3. Measurements will be made in five regions of interest larger than 1 cm2 (usually 3 on the right liver and 2 on paraspinal muscles on the same slice), and calculated the liver-to-muscle ratio
4. Areas of cyst-free liver will be examined in patients with renal and hepatic polycystosis
5. We will used the software algorithm provided by Rennes University (http://www.radio.univ-rennes1.fr) to determine hepatic iron content (expressed in micromol/g of dry liver)
6. Duration of MRI examination is about 20 minutes
7. Measurements of biochemical markers of iron metabolism:
7.1. Serum ferritin
7.2. Serum iron
7.3. Transferrin
7.4. Transferrin saturation (TSAT)
7.5. Soluble transferrin receptors (sTfR)
7.6. Serum hepcidin-25
7.7. Screening for the C282Y HFE gene mutation
8. Use of The Alcohol Use Disorder Identification Test (AUDIT) to quantify alcohol consumption and to detect addiction
9. Measurement of iron content in spleen and heart will be performed simultaneously to determination of liver iron content by T2*/R2* sequences

Previous interventions until 07/12/2012:
1. Non-randomised measurement of hepatic iron content by means of T1 and T2 contrast magnetic resonance imaging (MRI) on a Sigma MRI unit (GE Medical Systems, Milwaukee, WI, USA) operating at a field strength of 1.5 Tesla
2. Five weighted gradient-recalled-echo sequences of the liver (GRE T1, DP, T2, T2+ and T2++) with a repetition time of 120 ms will be acquired
3. Measurements will be made in five regions of interest larger than 1 cm2 (usually 3 on the right liver and 2 on paraspinal muscles on the same slice), and calculated the liver-to-muscle ratio
4. Areas of cyst-free liver will be examined in patients with renal and hepatic polycystosis
5. We will used the software algorithm provided by Rennes University (http://www.radio.univ-rennes1.fr) to determine hepatic iron content (expressed in micromol/g of dry liver)
6. Duration of MRI examination is about 20 minutes
7. Measurements of biochemical markers of iron metabolism:
7.1. Serum ferritin
7.2. Serum iron
7.3. Transferrin
7.4. Transferrin saturation (TSAT)
7.5. Soluble transferrin receptors (sTfR)
7.6. Serum hepcidin-25
7.7. Screening for the C282Y HFE gene mutation
8. Use of The Alcohol Use Disorder Identification Test (AUDIT) to quantify alcohol consumption and to detect addiction

Intervention type

Other

Phase

Not Applicable

Drug names

Primary outcome measures

1. Determination of iron content (micromol/g/dry weight)
2. Percentage of patients with abnormal iron liver content (mild, moderate and severe overload)
3. As hepatic MRI accurately detects liver iron overload exceeding 50 micromol/g, the upper limit of normal was set at 50 micromol/g for this study
4. Values between 51 and 100 micromol/g will be considered to represent mild iron overload, values between 101 and 200 micromol/g moderate iron overload; and values >201 micromol/g severe iron overload.
5. MRI for quantification of hepatic iron stores will be performed at least seven days after iron infusion

Added 18/07/2013:
6. Spleen involvement
7. Heart (cardiac) involvement

Secondary outcome measures

1. Analysis of factors determining iron content:
1.1. Demographic characteristics
1.2. Clinical variables
1.3. Dialysis vintage
1.4. Erythropoiesis-stimulating agents (ESA) and iron therapies
1.5. AUDIT score
1.6. Mutation of HFE gene
2. Relationship between hepatic iron content and biochemical makers of iron status and hepcidine-25

Overall trial start date

31/01/2005

Overall trial end date

31/01/2020

Reason abandoned

Eligibility

Participant inclusion criteria

Current inclusion criteria as of 18/07/2013:
1. Patients of either sex
2. Undergoing chronic intermittent bipuncture bicarbonate hemodialysis (with ultrapure dialysate
single use biocompatible membranes) three times a week
3. or peritoneal dialysis

Previous inclusion criteria:
1. Patients of either sex
2. Undergoing chronic intermittent bipuncture bicarbonate hemodialysis (with ultrapure dialysate single use biocompatible membranes) three times a week

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

600

Participant exclusion criteria

1. Refusal to participate in the study
2. Poor compliance with the dialysis therapy schedule
3. Age < 18 years
4. Severe cognitive impairment
5. Claustrophobia
6. Hepatic cirrhosis
7. Overt inflammatory or infectious disease
8. Malnutrition
9. Recent major bleeding (< 3 months), major surgery (< 3 months), transfusion dependency, recent transfusion (< 3 months)
10. Intractable malignancy
11. Cardiac pacemakers and metallic cardiac valves

Recruitment start date

01/03/2005

Recruitment end date

31/01/2020

Locations

Countries of recruitment

France

Trial participating centre

Hopital Privé Claude Galien
-
France

Trial participating centre

Hôpital de Melun
-
France

Trial participating centre

Groupe Hospitalier Pitié-Salpétrière
-
France

Trial participating centre

Groupe Hospitalier Kremlin Bicêtre
-
France

Trial participating centre

Centre Nephrocare Marne la Vallée
-
France

Trial participating centre

Polyclinique des Mousseaux
-
France

Trial participating centre

Clinique du Landy
-
France

Trial participating centre

Polyclinique les Fleurs
-
France

Trial participating centre

Hôpital de Mulhouse
-
France

Trial participating centre

Hôpital de Valenciennes
-
France

Trial participating centre

Clinique Saint-Anne de Strasbourg
-
France

Trial participating centre

CHU de Nancy
-
France

Sponsor information

Organisation

Quincy Association of Clinical Research and Therapeutics (France)

Sponsor details

Association Quincy Recherche Clinique et Therapeutique (QRCT) (France)
2 Rue du Moulin de Jarcy
Quincy Sous Senart
91480
France
-
qrct@orange.fr

Sponsor type

Research council

Website

Funders

Funder type

Hospital/treatment centre

Funder name

Physicians Association of Claude Galien Hospital (Association Quincy Recherche Clinique et Thérapeutique - QRCT) (France)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Participant-level data are already available as supplemental file of our published article: http://www.ncbi.nlm.nih.gov/pubmed/25506921
These participant-level data are common with our other published article: http://www.ncbi.nlm.nih.gov/pubmed/26182077
We also wish to make available participant-level data for our next planned publications.

We plan to publish in 2016:
1. A study on iron stores in peritoneal dialysis patients (last patient included in December 2015)
2. A study on the relationship between liver iron concentration at MRI and HFE mutations C282Y, H63D and S65C

We plan to publish in 2017 :
1. A replication multicentre study on iron overload in hemodialysis patients (replication of the original monocenter study published in the Am J Med in 2012)
2. A multicentre study for research of heart iron deposits in hemodialysis patients

Intention to publish date

Participant level data

Available on request

Results - basic reporting

Publication summary

2012 results in: http://www.ncbi.nlm.nih.gov/pubmed/22998881
2014 results in: http://www.ncbi.nlm.nih.gov/pubmed/25506921
2015 results in: http://www.ncbi.nlm.nih.gov/pubmed/26182077

Publication citations

  1. Results

    Rostoker G, Griuncelli M, Loridon C, Couprie R, Benmaadi A, Bounhiol C, Roy M, Machado G, Janklewicz P, Drahi G, Dahan H, Cohen Y, Hemodialysis-associated hemosiderosis in the era of erythropoiesis-stimulating agents: a MRI study., Am. J. Med., 2012, 125, 10, 991-999.e1, doi: 10.1016/j.amjmed.2012.01.015.

  2. Results

    Rostoker G, Griuncelli M, Loridon C, Magna T, Machado G, Drahi G, Dahan H, Janklewicz P, Cohen Y, Reassessment of Iron Biomarkers for Prediction of Dialysis Iron Overload: An MRI Study, PLoS One, 2015, 10, 7, e0132006, doi: 10.1371/journal.pone.0132006.

  3. Results

    Rostoker G, Griuncelli M, Loridon C, Magna T, Janklewicz P, Drahi G, Dahan H, Cohen Y, Maximal standard dose of parenteral iron for hemodialysis patients: an MRI-based decision tree learning analysis, PLoS One, 2014, 9, 12, e115096, doi: 10.1371/journal.pone.0115096.

Additional files

Editorial Notes

30/11/2012: the following changes were made to the trial record: 1. The overall trial end date was updated from 31/01/2012 to 31/01/2014. 2. The target number of participants was updated from 200 to 300. 18/07/2013: the following changes were made to the trial record: 1. The study design was changed from "Prospective cross-sectional longitudinal study" to "Prospective cross-sectional longitudinal multicenter study". 2. The overall trial end date was updated from 31/01/2014 to 31/01/2015. 3. The target number of participants was updated from 300 to 400. 04/11/2015: the following changes were made to the trial record: 1. The overall trial end date was changed from 31/01/2015 to 31/01/2020. 2. The target number of participants was changed from 400 to 600. 25/01/2016: Hôpital de Valenciennes, Clinique Saint-Anne de Strasbourg and CHU de Nancy (France) were added as trial participating centres.