Hemochromatosis, Type 4Phase 2NCT01949467
Analysis of the Modulation of Serum Hepcidin Level in Response to Iron Oral Intake: Potential Interest for the Differential Diagnosis Between Ferroportin Disease and Dysmetabolic Hepatosiderosis.
A Phase 2 study testing iron fumarate in people with Hemochromatosis, Type 4 and Ferroportin Disease, run by Rennes University Hospital at 4 sites in France.
Trial summary
The diagnosis of iron overload is a common problem. It is important to optimize the diagnosis to ensure support for patients and their relatives especially regarding genetic disease. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Hemochromatosis, Type 4, Ferroportin Disease, Dysmetabolic Hepatosiderosis
- What is being tested?
- iron fumarate
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 62 participants
- Where
- 4 sitesFrance
- Study dates
- 10 Feb 2014to 26 Dec 2018
- Phase
- Phase 2
- Are there results?
- None posted in the registry
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
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Man or woman older than 18 years
- Subject having a liver iron overload greater than or equal to 100 umol /g dry liver weight, confirmed by MRI (done performed with body antenna and complete deactivation of the surface antenna) and / or by biochemical assay on liver biopsy, and related to dysmetabolic hepatosiderosis or ferroportin disease.
- The ferroportin disease will be retained when patients will present an hyperferritinemia without elevated transferrin saturation and a heterozygote mutation in the gene encoding ferroportin.
- A dysmetabolic hepatosiderosis will be retained following the usual diagnostic investigation including sequencing of the gene for ferroportin (mutation proven negative), if patients do not show any other cause of iron overload and hyperferritinemia is not related to excessive alcohol intake, non-metabolic liver cytolysis (hepatitis C virus, wilson, autoimmune hepatitis, ...), hemolysis, or inflammatory syndrome.
- Status towards the iron-depletive treatment : either no venesection performed (Dysmetabolic HepatoSiderosis and Ferroportin disease groups) or attack iron depletive treatment completed (Treated Dysmetabolic Hepatosiderosis and Treated Ferroportin Disease groups) with ferritin level less than 100 ng / ml, without anemia and with no venesection in the two last months.
- Having given a free and informed consent in writing
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- Affiliate to the social security system.
- Man or woman older than 18 years.
- Body Mass Index between 18 and 25 kg/m².
- Non smoker or quit smoking for more than 6 months
- Examen clinique normal. Normal clinical examination
- Normal ECG.
- Normal values for routine laboratory tests : serum iron, tranferrin saturation, CBC, ferritin, blood cell count C-reactive protein, AST, ALT, GGT, HDL and LDL cholesterol, triglycerides.
- Having given a free and informed consent in writing
- Affiliate or beneficiary to the social security system.
Who cannot join
- Alcohol consumption greater than 30g/d
- Chronic inflammatory disease.
- HIV, HCV or HBV Infection.
- Blood donation in the last three months.
- Infection during the previous seven days before testing
- Staying in altitude (>1500 m) dating less than 2 months
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- Night occupation or shift work.
- Pregnancy
- Exclusion period in the national register of persons suitable for biomedical research.
- Protected adults (judicial protection, guardianship and trusteeship) and persons deprived of liberty
- Progressive and/or chronic disease.
- Infection during the previous seven days before testing
- Drug use under 6 months.
- Alcohol consumption greater than 30g/d
- Medication ongoing or stopped from less than a week (except contraceptives).
- History of blood transfusion or martial treatment.
- Staying in altitude (>1500 m) dating less than 2 months
- Night occupation or shift work.
- Known infection by hepatitis B or C.
- Positive serology for HIV.
- Blood donation in the last three months.
- Pregnancy.
- Exclusion period in the national register of persons suitable for biomedical research.
- Protected adults (judicial protection, guardianship and trusteeship) and persons deprived of liberty.
Trial locations and contacts
4 sites in 1 country.
France4 sites
CHU Clermont-Ferrand
Clermont-Ferrand
CHU Limoges
Limoges
CHU Montpellier
Montpellier
CHU Pontchaillou
Rennes, 35000
About this study
Official title: Prospective, Comparative (5 Groups), Non-randomized, Multicenter, Physiopathological Study, Evaluating Pharmacokinetic Characteristics of Serum Hepcidin Level in Response to Iron Oral Intake in Order to Evaluate Their Interest to Discriminate Patients With Dysmetabolic Hepatosiderosis or Ferroportin Disease.
The diagnosis of iron overload is a common problem. It is important to optimize the diagnosis to ensure support for patients and their relatives especially regarding genetic disease.
Iron overload revealed by a high level of serum ferritin and confirmed by the presence of an excessive amount of iron in the liver is a frequent situation. In a lot of case there is no increase in serum iron and transferrin saturation. This situation may arise in particular in patients with:
Read more
- a genetic iron overload related to mutation in the ferroportine gene, leading to a ferroportin disease. The diagnosis is based on the sequencing of the gene,
- a dysmetabolic hepatosiderosis, the most frequent situation , where iron overload is associated with abnormalities in the metabolism of carbohydrates and fats, whereas no genetic cause is identified.
However, patients often have similar biological signs and despite the implementation of strict algorithm regarding the diagnostic procedure, it appears that a large number of patients are tested for the mutation in the ferroportin gene, and that mutation is not found in most cases. It is therefore essential to optimize the diagnosis process by introducing additional criteria.
The investigators' hypothesis, based on the known elements, is that the response to a single dose of iron will modulate differently the iron parameters measured in serum, including hepcidin level which controls iron metabolism and metals associated with iron. This could be helpful for diagnosis procedure in patients with ferroportin disease or dysmetabolic hepatosiderosis.
Read the detailed description
The quantification of serum hepcidin level is a potential method of investigation in iron metabolism disorders. However, apart from some extreme situations, the assay achieved solely is not helpful. This is due to the varying levels encountered from one subject to another for the same disease. This is related to the facts that values considered to be normal cover a wide range and that a value obtained for a given patient at a given time, can be influenced by many factors.
It has been reported that a a single oral iron dose induced an increase of serum hepcidin level in healthy subjects which is abolished in subjects with genetic hemochromatosis linked to insufficient hepcidin expression related to mutations in the HFE or TFR2 genes.
In patients with a dysmetabolic hepatosiderosis, it was suggested that the expected hepcidinemia increase found after an iron intake was altered, likely due to a slight inflammatory signal responsible for hepcidin induction.
The investigators hypothesize that a dynamic response of iron parameters, including modulation of hepcidin level, to an iron intake will allow to discriminate patients with ferroportin disease or dysmetabolic hepatosiderosis, situations whose clinicobiological presentation is often confusing.
Thus, the three objectives in this study will be :
- To define pharmacokinetic characteristics of serum hepcidin in response to iron oral intake and to determine the ability of this pharmacokinetic to discriminate dysmetabolic hepatosiderosis and ferroportin disease.
- To correlate amplitude of this response to the iron parameters modulation
- To correlate amplitude of this response to the concentration of divalent cations whose metabolism uses common genes to those involved in iron metabolism.
- Being tested
- iron fumarate
- Keywords
- ferroportin disease, dysmetabolic hepatosiderosis, genetic hemochromatosis, hyperferritinemia, hepcidin, iron fumarate, physiopathological study, diagnosis, HFE gene, TRF2 gene, iron parameters, divalent cations
- Medical subject headings
- Hemochromatosis, type 4, Disease, Hemochromatosis, Hyperferritinemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
iron fumarateDrug
All patients will receive a tablet of 66mg of iron, in the form of iron fumarate (Fumafer®) with 50 ml water.
| Study group | Role | What they receive |
|---|---|---|
| TDHS | Other | 20 Patients with Treated Dysmetabolic Hepatosiderosis (TDHS) Receives: Drug: iron fumarate |
| UDHS | Other | 20 patients with untreated Dysmetabolic Hepatosiderosis (UDHS) Receives: Drug: iron fumarate |
| TFPD | Other | 20 patients with treated Ferroportin Disease (TFPD) Receives: Drug: iron fumarate |
| UFPD | Other | 20 patients with untreated Ferroportin Disease (UFPD) Receives: Drug: iron fumarate |
| HV | Other | 20 Healthy volunteers (HV) patients Receives: Drug: iron fumarate |
What is being measured
The primary outcome is the main question the study is designed to answer.
hepcidemia rate
The primary endpoint is the maximum variation, of hepcidemia rate (Δmax) after iron oral intake. This variation will be compared between the different groups of included subjects
Measured: Day 1
Secondary outcomes (2)
ratios between serum hepcidin level and iron parameters
Differential modulation, induced by the iron intake, of ratios between serum hepcidin level and iron parameters (serum iron, transferrin, ferritin) between the different groups.
Measured: Day 1
serum level of other divalent cations
Modulation of serum level of other divalent cations.
Measured: day 1
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Sep 2013 (estimated)
- Study start10 Feb 2014
- Primary completion19 Dec 2017
- Study completion26 Dec 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Hemochromatosis, Type 4Studies of the same condition, open and under way.
- More trials run by Rennes University HospitalThe 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 2
- Primary purpose
- Diagnosis
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 62 participants (actual)
Sponsor and investigators
- Lead sponsor
- Rennes University Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01949467
- Sponsor's protocol ID
- FERHEP
- Status last verified
- Aug 2018
- First submitted
- 20 Sep 2013
- Last updated
- 27 Mar 2019
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 27 Mar 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prospective, Comparative (5 Groups), Non-randomized, Multicenter, Physiopathological Study, Evaluating Pharmacokinetic Characteristics of Serum Hepcidin Level in Response to Iron Oral Intake in Order to Evaluate Their Interest to Discriminate Patients With Dysmetabolic Hepatosiderosis or Ferroportin Disease.
- ClinicalTrials.gov ID
- NCT01949467
- Acronym / sponsor ID
- FERHEP
- Keywords
- ferroportin disease, dysmetabolic hepatosiderosis, genetic hemochromatosis, hyperferritinemia, hepcidin, iron fumarate, physiopathological study, diagnosis
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 62 participants (actual)
- Lead sponsor
- Rennes University HospitalUniversity, hospital or other
- Study start
- 10 Feb 2014 (actual)
- Primary completion
- 19 Dec 2017 (actual)
- Study completion
- 26 Dec 2018 (actual)
- First posted
- 24 Sep 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The diagnosis of iron overload is a common problem. It is important to optimize the diagnosis to ensure support for patients and their relatives especially regarding genetic disease.
Iron overload revealed by a high level of serum ferritin and confirmed by the presence of an excessive amount of iron in the liver is a frequent situation. In a lot of case there is no increase in serum iron and transferrin saturation. This situation may arise in particular in patients with:
- a genetic iron overload related to mutation in the ferroportine gene, leading to a ferroportin disease. The diagnosis is based on the sequencing of the gene,
- a dysmetabolic hepatosiderosis, the most frequent situation , where iron overload is associated with abnormalities in the metabolism of carbohydrates and fats, whereas no genetic cause is identified.
However, patients often have similar biological signs and despite the implementation of strict algorithm regarding the diagnostic procedure, it appears that a large number of patients are tested for the mutation in the ferroportin gene, and that mutation is not found in most cases. It is therefore essential to optimize the diagnosis process by introducing additional criteria.
The investigators' hypothesis, based on the known elements, is that the response to a single dose of iron will modulate differently the iron parameters measured in serum, including hepcidin level which controls iron metabolism and metals associated with iron. This could be helpful for diagnosis procedure in patients with ferroportin disease or dysmetabolic hepatosiderosis.
Detailed description
The quantification of serum hepcidin level is a potential method of investigation in iron metabolism disorders. However, apart from some extreme situations, the assay achieved solely is not helpful. This is due to the varying levels encountered from one subject to another for the same disease. This is related to the facts that values considered to be normal cover a wide range and that a value obtained for a given patient at a given time, can be influenced by many factors.
It has been reported that a a single oral iron dose induced an increase of serum hepcidin level in healthy subjects which is abolished in subjects with genetic hemochromatosis linked to insufficient hepcidin expression related to mutations in the HFE or TFR2 genes.
In patients with a dysmetabolic hepatosiderosis, it was suggested that the expected hepcidinemia increase found after an iron intake was altered, likely due to a slight inflammatory signal responsible for hepcidin induction.
The investigators hypothesize that a dynamic response of iron parameters, including modulation of hepcidin level, to an iron intake will allow to discriminate patients with ferroportin disease or dysmetabolic hepatosiderosis, situations whose clinicobiological presentation is often confusing.
Thus, the three objectives in this study will be :
- To define pharmacokinetic characteristics of serum hepcidin in response to iron oral intake and to determine the ability of this pharmacokinetic to discriminate dysmetabolic hepatosiderosis and ferroportin disease.
- To correlate amplitude of this response to the iron parameters modulation
- To correlate amplitude of this response to the concentration of divalent cations whose metabolism uses common genes to those involved in iron metabolism.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| TDHS | Other | Drug: iron fumarate20 Patients with Treated Dysmetabolic Hepatosiderosis (TDHS) |
| UDHS | Other | Drug: iron fumarate20 patients with untreated Dysmetabolic Hepatosiderosis (UDHS) |
| TFPD | Other | Drug: iron fumarate20 patients with treated Ferroportin Disease (TFPD) |
| UFPD | Other | Drug: iron fumarate20 patients with untreated Ferroportin Disease (UFPD) |
| HV | Other | Drug: iron fumarate20 Healthy volunteers (HV) patients |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (15 listed)
- Man or woman older than 18 years
- Subject having a liver iron overload greater than or equal to 100 umol /g dry liver weight, confirmed by MRI (done performed with body antenna and complete deactivation of the surface antenna) and / or by biochemical assay on liver biopsy, and related to dysmetabolic hepatosiderosis or ferroportin disease.
- Status towards the iron-depletive treatment : either no venesection performed (Dysmetabolic HepatoSiderosis and Ferroportin disease groups) or attack iron depletive treatment completed (Treated Dysmetabolic Hepatosiderosis and Treated Ferroportin Disease groups) with ferritin level less than 100 ng / ml, without anemia and with no venesection in the two last months.
- Having given a free and informed consent in writing
- Affiliate to the social security system.
Key exclusion criteria (24 listed)
- Alcohol consumption greater than 30g/d
- Chronic inflammatory disease.
- HIV, HCV or HBV Infection.
- Blood donation in the last three months.
- Infection during the previous seven days before testing
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 |
|---|---|---|
| iron fumarateAll patients will receive a tablet of 66mg of iron, in the form of iron fumarate (Fumafer®) with 50 ml water. | Drug | HV, TDHS, TFPD, UDHS, UFPD |
Primary outcome
hepcidemia rate
Time frame: Day 1
The primary endpoint is the maximum variation, of hepcidemia rate (Δmax) after iron oral intake. This variation will be compared between the different groups of included subjects
2 secondary outcomes
ratios between serum hepcidin level and iron parameters
Time frame: Day 1
serum level of other divalent cations
Time frame: day 1
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Mar 2019.
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.
The record lists no contact. Use the official record to reach the sponsor.
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing iron fumarate in people with Hemochromatosis, Type 4 and Ferroportin Disease, run by Rennes University Hospital at 4 sites in France.
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 15 inclusion and 24 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 27 Mar 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in France. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
hepcidemia rate (time frame: Day 1). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 27 Mar 2019.