Familial Mediterranean FevermiRinFMFNCT06033339
Assessment of microRNAs Role in Familial Mediterranean Fever FMF Pathophysiology
A study testing Blood sampling in people with Familial Mediterranean Fever, run by University Hospital, Montpellier at 4 sites in France.
Trial summary
Familial Mediterranean Fever (FMF) genetic diagnosis is well established for homozygous patients. On the other hand, although heterozygous individuals are theoretically healthy carriers, 1/3 of them will develop clinical symptoms of FMF and could benefit from prophylactic treatment. Read more about this study
- Who is it for?
- Ages 1 year and olderHealthy volunteers can take part
- Conditions the study is for
- Familial Mediterranean Fever
- What is being tested?
- Blood sampling
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 40 participants
- Where
- 4 sitesFrance
- Study dates
- 2 Oct 2023to 2 Oct 2025
- Phase
- Interventional
- 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 1 year and older
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Who may be able to join
- Patient aged ≥1 year
- Body weight ≥ 10kg
- Homozygous patients group: patients homozygous for MEFV (M694V, M694I, M680I, V726A)
- Symptomatic heterozygous patients group: patients heterozygous for the MEFV gene (M694V, M694I, M680I, V726A) meeting the Yalcinkaya criteria for FMF diagnosis (Fever lasting 6 to 72 hours with at least 3 attacks - Abdominal pain of 6 to 72 hours duration with at least 3 attacks - Chest pain of 6 to 72 hours duration with at least 3 attacks - Arthritis of 6 to 72 hours duration with at least 3 attacks- FMF Family History of FMF)
- Asymptomatic heterozygous patients group: patients heterozygous for the MEFV gene (M694V, M694I, M680I, V726A) who do not meet the Yalcinkaya criteria for FMF diagnosis
- Control subjects group: absence of identified auto-inflammatory disorder
Who cannot join
- Absence of collection of informed consent of participant or absence of informed consent of the legal representatives/guardians of pediatric participant
- Subjects not registered in Social Security system
Trial locations and contacts
4 sites in 1 country.
France4 sites
University Hospital of Nîmes
Nîmes
Tu Anh TRAN, MD
Tu Anh TRAN, MD
Robert Debré University Hospital of Paris
Paris
Ulrich MEINZER, MD
Ulrich MEINZER, MD
University Hospital of Paris Kremlin Bicêtre
Paris
Isabelle KONE-PAUT, MD
Isabelle KONE-PAUT, MD
University Hospital of Toulouse
Toulouse
Karine BROCHARD-PAYET, MD
Karine BROCHARD-PAYET, MD
About this study
Official title: Etude du rôle Des microARNs Dans la Physiopathologie de la fièvre méditerranéenne Familiale
Familial Mediterranean Fever (FMF) genetic diagnosis is well established for homozygous patients. On the other hand, although heterozygous individuals are theoretically healthy carriers, 1/3 of them will develop clinical symptoms of FMF and could benefit from prophylactic treatment. This suggests that the disorder expression mechanisms are not fully elucidated to date. The preliminary results obtained at the Institute for Regenerative Medicine and Biotherapy (IRMB) suggest the involvement of an epigenetic mechanism in FMF pathogenesis, and our laboratory has strong arguments as to the involvement of microRNAs (in particular miR-326) which are negative regulators of gene expression.
This study is exploratory and aims to validate the role of miRNAs in the clinical expression of FMF in patients, thus to explore the epigenetic mechanisms that may explain the variability of expression of this disorder.
Read the detailed description
Familial Mediterranean fever (FMF) is a rare autoinflammatory disorder due to mutations in the MEFV (MEditerranean FeVer) gene, that causes recurrent episodes of fever and acute serositis (peritoneum, pleura, synovium) beginning in early childhood.
MEFV gene identification allowed the development of a genomic sequencing test to confirm the diagnosis. The most frequent mutations are M680I, M694V, V726A and M694I, located in exon 10. This gene encodes the protein pyrin, which, following a pro-inflammatory stimulus, is capable of assembling a multi-protein complex to form the pyrin inflammasome. MEFV gene mutations lead to an alteration of its expression in innate immune system cells in FMF patients, causing a dysregulation of the immune response, which results in the abnormal secretion of certain proinflammatory cytokines such as IL-1β and IL-18.
FMF is an autosomal recessive disorder. Thus, heterozygous individuals are theoretically healthy carriers. Nevertheless, in nearly 1/3 of patients with clinical symptoms of FMF, a single heterozygous mutation is found. To date, there is no biological marker to distinguish heterozygous individuals who will develop the disease from those who remain healthy carriers, hence diagnostic errors and delays in treatment. Several hypotheses have been put forward to explain this variation in mutation expression, whether it is the environment, the involvement of other genes, or the involvement of epigenetic modifiers.
Among the mechanisms that regulate gene expression, microRNAs (miRNAs),which are small non-coding RNAs, negatively regulate gene expression at the post-transcriptional level by binding to sequences located mainly in the region 3'UTR of gene mRNA. Many publications report that they are abnormally expressed in various pathologies. Very recently, this has been reported for FMF. Several studies have focused on miRNAs as biomarkers of FMF, without evaluating their role in FMF pathogenesis.
Assessing the role of miRNAs specifically targeting the MEFV gene in myeloid cells (especially monocytes), and the functional impact of their modulation in these cells, would deepen our understanding of FMF physiopathology. If a miRNA specifically targeting MEFV has a proven role in FMF pathophysiology, it could ultimately prove to be a prognostic biomarker of the disorder for heterozygous patients, or even a future therapeutic target.
- Conditions
- Familial Mediterranean Fever
- Being tested
- Blood sampling
- Keywords
- MEditerranean FeVer MEFV gene, micro ribonucleic acid miRNA
- Medical subject headings
- Familial Mediterranean Fever
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Blood samplingOther
Collection of 10 ml of blood on EDTA tubes per patient. Once collected, the blood tubes will be transported within 24 hours to the IRB (Biotherapy Research Institute) of Montpellier University Hospital, where the monocytes will be isolated by magnetic sorting on the basis of expression of surface marker CD14+, after a preliminary step of Ficoll. Monocytes will then be frozen in nitrogen at -196°C until use (biobank).Gain-of-function experiments will then be performed on monocytes by transfecting them with the microRNA of interest or control. The expression of the pyrin protein and its phosphorylation rate will be evaluated after induction by immunoprecipitation experiments followed by western blot. The activity of the pyrin inflammasome will also be studied by looking at pyroptosis and toxicity rate using LDH test. All these experiments will be carried out in the absence and in the presence of the microRNA in order to study its role in the pathophysiology of FMF.
| Study group | Role | What they receive |
|---|---|---|
| Blood Sampling | Other | Collection of 10 ml of blood on EDTA tube during:
* Standard check-up visit as a part of the standard monitoring of the disorder for homozygous and symptomatic heterozygous patients
* Specific study visit for asymptomatic heterozygous patients
* Presurgery blood test for control subjects Receives: Other: Blood sampling |
What is being measured
The primary outcome is the main question the study is designed to answer.
miR-326 expression level quantification
Analyze the expression levels (quantification) of miRNA miR-326 in blood monocytes within the 4 groups of individuals: homozygous, symptomatic heterozygous, asymptomatic heterozygous for MEFV and control subjects, in order to determine whether or not miR-326 influences the inflammatory response of monocytes.
Measured: 1 day (at enrollment)
MEFV expression level quantification
Analyze the expression levels (quantification) of MEFV gene in blood monocytes within the 4 groups of individuals: homozygous, symptomatic heterozygous, asymptomatic heterozygous for MEFV and control subjects
Measured: 1 day (at enrollment)
Secondary outcomes (4)
miR-326 expression level comparison
Compare the expression levels of miR-326 between symptomatic and asymptomatic heterozygous groups.
Measured: 1 day (at enrollment)
MEFV expression level comparison
Compare the expression levels of MEFV between symptomatic and asymptomatic heterozygous groups.
Measured: 1 day (at enrollment)
Blood samples collection
Create a biobank (freezing monocytes extracted from patient samples) in order to subsequently study other miRNAs
Measured: 1 day (at enrollment)
Expression levels of other candidate miRNAs targeting MEFV
Quantification of the the expression levels of other candidate miRNAs targetting MEFV within the 4 groups of participants. 5 miRNAs will be selected using a methylome study currently being carried out.
Measured: 1 day (at enrollment)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Sep 2023
- Study start2 Oct 2023 (estimated)
- Primary completion2 Oct 2025 (estimated)
- Study completion2 Oct 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Familial Mediterranean FeverStudies of the same condition, open and under way.
- More trials run by University Hospital, MontpellierThe 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 N/A
- Primary purpose
- Other
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Among the 40 subjects to be enrolled: 10 are MEFV homozygous patients, 10 are symptomatic MEFV heterozygous patients, 10 are asymptomatic MEFV heterozygous patients and 10 are control subjects. All enrolled patients receive the same intervention (biological sample collection).
- Masking
- None (open label)
- Enrolment
- 40 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Hospital, Montpellier
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Eric JEZIORSKI, MD, Principal investigator, University Hospital, Montpellier
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06033339
- Sponsor's protocol ID
- RECHMPL22_0296 - UF 8310
- Acronym
- miRinFMF
- Status last verified
- Sep 2023
- First submitted
- 5 Sep 2023
- Last updated
- 14 Sep 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 14 Sep 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Etude du rôle Des microARNs Dans la Physiopathologie de la fièvre méditerranéenne Familiale
- ClinicalTrials.gov ID
- NCT06033339
- Acronym / sponsor ID
- miRinFMF / RECHMPL22_0296 - UF 8310
- Conditions
- Familial Mediterranean Fever
- Keywords
- MEditerranean FeVer MEFV gene, micro ribonucleic acid miRNA
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 40 participants (estimated)
- Lead sponsor
- University Hospital, MontpellierUniversity, hospital or other
- Study start
- 2 Oct 2023 (estimated)
- Primary completion
- 2 Oct 2025 (estimated)
- Study completion
- 2 Oct 2025 (estimated)
- First posted
- 13 Sep 2023 (actual)
- 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.
Familial Mediterranean Fever (FMF) genetic diagnosis is well established for homozygous patients. On the other hand, although heterozygous individuals are theoretically healthy carriers, 1/3 of them will develop clinical symptoms of FMF and could benefit from prophylactic treatment. This suggests that the disorder expression mechanisms are not fully elucidated to date. The preliminary results obtained at the Institute for Regenerative Medicine and Biotherapy (IRMB) suggest the involvement of an epigenetic mechanism in FMF pathogenesis, and our laboratory has strong arguments as to the involvement of microRNAs (in particular miR-326) which are negative regulators of gene expression.
This study is exploratory and aims to validate the role of miRNAs in the clinical expression of FMF in patients, thus to explore the epigenetic mechanisms that may explain the variability of expression of this disorder.
Detailed description
Familial Mediterranean fever (FMF) is a rare autoinflammatory disorder due to mutations in the MEFV (MEditerranean FeVer) gene, that causes recurrent episodes of fever and acute serositis (peritoneum, pleura, synovium) beginning in early childhood.
MEFV gene identification allowed the development of a genomic sequencing test to confirm the diagnosis. The most frequent mutations are M680I, M694V, V726A and M694I, located in exon 10. This gene encodes the protein pyrin, which, following a pro-inflammatory stimulus, is capable of assembling a multi-protein complex to form the pyrin inflammasome. MEFV gene mutations lead to an alteration of its expression in innate immune system cells in FMF patients, causing a dysregulation of the immune response, which results in the abnormal secretion of certain proinflammatory cytokines such as IL-1β and IL-18.
FMF is an autosomal recessive disorder. Thus, heterozygous individuals are theoretically healthy carriers. Nevertheless, in nearly 1/3 of patients with clinical symptoms of FMF, a single heterozygous mutation is found. To date, there is no biological marker to distinguish heterozygous individuals who will develop the disease from those who remain healthy carriers, hence diagnostic errors and delays in treatment. Several hypotheses have been put forward to explain this variation in mutation expression, whether it is the environment, the involvement of other genes, or the involvement of epigenetic modifiers.
Among the mechanisms that regulate gene expression, microRNAs (miRNAs),which are small non-coding RNAs, negatively regulate gene expression at the post-transcriptional level by binding to sequences located mainly in the region 3'UTR of gene mRNA. Many publications report that they are abnormally expressed in various pathologies. Very recently, this has been reported for FMF. Several studies have focused on miRNAs as biomarkers of FMF, without evaluating their role in FMF pathogenesis.
Assessing the role of miRNAs specifically targeting the MEFV gene in myeloid cells (especially monocytes), and the functional impact of their modulation in these cells, would deepen our understanding of FMF physiopathology. If a miRNA specifically targeting MEFV has a proven role in FMF pathophysiology, it could ultimately prove to be a prognostic biomarker of the disorder for heterozygous patients, or even a future therapeutic target.
Study design
- Primary purpose
- Other
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Among the 40 subjects to be enrolled: 10 are MEFV homozygous patients, 10 are symptomatic MEFV heterozygous patients, 10 are asymptomatic MEFV heterozygous patients and 10 are control subjects. All enrolled patients receive the same intervention (biological sample collection).
| Arm | Type | Receives |
|---|---|---|
| Blood Sampling | Other | Other: Blood samplingCollection of 10 ml of blood on EDTA tube during: * Standard check-up visit as a part of the standard monitoring of the disorder for homozygous and symptomatic heterozygous patients * Specific study visit for asymptomatic heterozygous patients * Presurgery blood test for control subjects |
Who may qualify
- Ages
- 1 year and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (6 listed)
- Patient aged ≥1 year
- Body weight ≥ 10kg
- Homozygous patients group: patients homozygous for MEFV (M694V, M694I, M680I, V726A)
- Symptomatic heterozygous patients group: patients heterozygous for the MEFV gene (M694V, M694I, M680I, V726A) meeting the Yalcinkaya criteria for FMF diagnosis (Fever lasting 6 to 72 hours with at least 3 attacks - Abdominal pain of 6 to 72 hours duration with at least 3 attacks - Chest pain of 6 to 72 hours duration with at least 3 attacks - Arthritis of 6 to 72 hours duration with at least 3 attacks- FMF Family History of FMF)
- Asymptomatic heterozygous patients group: patients heterozygous for the MEFV gene (M694V, M694I, M680I, V726A) who do not meet the Yalcinkaya criteria for FMF diagnosis
Key exclusion criteria (2 listed)
- Absence of collection of informed consent of participant or absence of informed consent of the legal representatives/guardians of pediatric participant
- Subjects not registered in Social Security system
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 |
|---|---|---|
| Blood samplingCollection of 10 ml of blood on EDTA tubes per patient. Once collected, the blood tubes will be transported within 24 hours to the IRB (Biotherapy Research Institute) of Montpellier University Hospital, where the monocytes will be isolated by magnetic sorting on the basis of expression of surface marker CD14+, after a preliminary step of Ficoll. Monocytes will then be frozen in nitrogen at -196°C until use (biobank).Gain-of-function experiments will then be performed on monocytes by transfecting them with the microRNA of interest or control. The expression of the pyrin protein and its phosphorylation rate will be evaluated after induction by immunoprecipitation experiments followed by western blot. The activity of the pyrin inflammasome will also be studied by looking at pyroptosis and toxicity rate using LDH test. All these experiments will be carried out in the absence and in the presence of the microRNA in order to study its role in the pathophysiology of FMF. | Other | Blood Sampling |
Primary outcome
miR-326 expression level quantification
Time frame: 1 day (at enrollment)
Analyze the expression levels (quantification) of miRNA miR-326 in blood monocytes within the 4 groups of individuals: homozygous, symptomatic heterozygous, asymptomatic heterozygous for MEFV and control subjects, in order to determine whether or not miR-326 influences the inflammatory response of monocytes.
MEFV expression level quantification
Time frame: 1 day (at enrollment)
Analyze the expression levels (quantification) of MEFV gene in blood monocytes within the 4 groups of individuals: homozygous, symptomatic heterozygous, asymptomatic heterozygous for MEFV and control subjects
4 secondary outcomes
miR-326 expression level comparison
Time frame: 1 day (at enrollment)
MEFV expression level comparison
Time frame: 1 day (at enrollment)
Blood samples collection
Time frame: 1 day (at enrollment)
Expression levels of other candidate miRNAs targeting MEFV
Time frame: 1 day (at enrollment)
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Sep 2023.
- Individual participant dataSharing planned: No
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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.
Eric JEZIORSKI, MD principal investigator
University Hospital, Montpellier
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Blood sampling in people with Familial Mediterranean Fever, run by University Hospital, Montpellier 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 6 inclusion and 2 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: status not confirmed, as of the sponsor's last update on 14 Sep 2023. 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.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Anna DEGUET, MD (0033669107224, a-deguet@chu-montpellier.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
miR-326 expression level quantification (time frame: 1 day (at enrollment)). The study lists 2 primary outcomes in all. 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 14 Sep 2023.