Diabetes type2NADRANK-1NCT03968354
NASH and Type 2 Diabetes: Role of the Receptor Activator of Nuclear Factor-κB (RANK) and Its Ligand (RANKL)
An observational study of Diabetes type2 and NASH - Nonalcoholic Steatohepatitis, run by Assistance Publique - Hôpitaux de Paris.
Trial summary
Non-alcoholic fatty liver diseases (NAFLD) include several entities ranging from simple steatosis to hepatic fibrosis or cirrhosis. Steatosis, considered benign and the first stage of the disease, is characterized by the accumulation of triglycerides in the liver. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Diabetes type2, NASH - Nonalcoholic Steatohepatitis, NAFLD
- What is being tested?
- "Collection of additional blood tubes; Biobanking (plasma, liver tissue).
- How many people
- 50 participants
- Where
- No sites listed yet
- Study dates
- Feb 2020to Oct 2021
- Phase
- Observational
- 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
Study population: We will constitute 5 groups of patients very well phenotyped and with liver biopsy (with at our disposal frozen liver tissue, paraffin-embedded liver tissue and serum for all the patients): 1. steatosis group (n=10); 2. NASH group without fibrosis (n=10); 3. moderate fibrosis (n=10); 4. advanced fibrosis (n=10); 5. Control group (n=10).
Who may be able to join
- Patients adults with type 2 diabetes
- Patients with one of the following criteria:
- Steatosis, defined on biopsy as either steatosis alone (≥5% hepatocytes with fat) or steatosis without evidence of ballooning, with spotty lobular inflammation of grade 1 maximum (<2 foci/sox power field) and no fibrosis (Steatosis group) OR
- Patients with NASH, defined on biopsy, as steatosis (≥5%) co-existing with hepatocellular ballooning and lobular necroinflammation, without fibrosis (NASH group) OR
- Fibrosis on biopsy, where fibrosis will be defined as moderate if fibrosis is perisiunsoidal or periportal fibrosis (F1) or perisinusoidal and periportal/portal (F2) (Moderate fibrosis) OR
- Fibrosis on biopsy, where fibrosis will be defined as advanced if there is bridging fibrosis (F3) or cirrhosis (F4) (Advanced fibrosis group) OR
Show all 9Show fewer
- Patients without NAFLD: control population. Patients for whom a biopsy was performed due to liver biological abnormalities but without NAFLD criteria on biopsy OR patients with abdominal surgery during which a liver biopsy was performed and without NAFLD criteria on biopsy. (Control group).
- Patient affiliated to social security;
- Signed informed consent.
Who cannot join
- Patients with liver diseases other than NAFLD (drug-induced hepatotoxicity, chronic hepatitis B or C, genetic hemochromatosis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, α1-antitrypsin deficiency, Wilson's disease, etc.)
- Patients with daily alcohol consumption higher than 30 g/d (men) and 20 g/d (women)
- Patients exposed to drugs that can induce secondary NAFLD (corticosteroids, amiodarone, tamoxifen)
- Patient unable or unwilling to understand and sign an informed consent form.
- Patient deprived of liberty or under legal protection measure
- Weight ≤ 40 kg
- Patients with hemoglobin < 7 g/dL or 9 g/dL if existence of respiratory or cardiac disorder
Trial locations and contacts
No sites are listed yet.
About this study
Non-alcoholic fatty liver diseases (NAFLD) include several entities ranging from simple steatosis to hepatic fibrosis or cirrhosis. Steatosis, considered benign and the first stage of the disease, is characterized by the accumulation of triglycerides in the liver. It may in some cases progress to nonalcoholic steatohepatitis (NASH), which is characterized by the presence of a marked inflammation with or without fibrosis. NAFLD is the most common liver disease in the world and is particularly associated with type 2 diabetes (T2D) (80% in the diabetic population). While NASH is characterized by a higher prevalence of mortality from a cardiac and hepatic (cirrhosis and cancer) origin, therapeutic resources are almost non-existent.
RANK (receptor activator of NF-kB) and its ligand RANKL (a member of the TNFalpha family) have emerged in recent years as new players in bone pathophysiology. By binding to its receptor, RANKL induces a number of signaling pathway and in particular the NF-kB pathway (Nuclear factor-kB), a major player in inflammation. Recent literature shows that the role of RANK / RANKL is not confined to the bone but may be involved in the genesis of inflammation in other tissues. It has been shown recently that a high circulating level of RANKL was a risk factor predictor of T2DM. Furthermore, the invalidation of RANK specifically in hepatocytes protects from insulin resistance and hepatic steatosis induced by a high fat diet in mice.
Read more
The aim of our project is to provide a proof of concept that the RANKL / RANK system plays an important role in the pathogenesis of NAFLD and in the progression of this disease to NASH. The aim of our project is to provide a proof of concept that the RANKL / RANK system plays an important role in the pathogenesis of NAFLD and in the progression of this disease to NASH.
The investigator propose to study the RANKL / RANK expression in serum and liver biopsies of type 2 diabetic patients at different stages of NAFLD.
Read the detailed description
Objectives:
To show that (i) expression of mRNA and proteins of the RANKL pathway (RANK, RANKL, OPG) in liver and (ii) serum concentration of RANKL/OPG proteins are correlated with the gravity of the NAFLD.
Study protocol:
Identify patients with different stages of NAFLD (mere steatosis, NASH, and moderate or advanced fibrosis) from the database of patients who have undergone liver biopsy in the hepatology department of the Pitié-Salpêtrière Hospital . From the hepatic tissue, the paraffin-embedded liver biopsies and the serum of these patients, study of the expression of mRNA (quantitative RtPCR) and proteins (immunohistochemistry, western blots) of the RANKL pathway (RANK, RANKL, OPG) in liver. In the serum of these patients, measure of concentration of RANKL and OPG proteins as described above.
Study Type: monocentric, observational, case-control, analytical study Study duration: 18 months (time for data collection, for cellular biological experimentations and for data analysis)
Patient Population:
5 groups of patients very well phenotyped and with liver biopsy (with at our disposal frozen liver tissue, paraffin-embedded liver tissue and serum for all the patients):
- 1) steatosis group (n=10)
- 2) NASH group without fibrosis (n=10)
- 3) moderate fibrosis (n=10)
- 4) advanced fibrosis (n=10)
- 5) healthy control group without liver disease (n=10) Comprehensive clinical and laboratory data were observed at the time of the liver biopsy and are available for all the patients.
- Conditions
- Diabetes type2, NASH - Nonalcoholic Steatohepatitis, NAFLD
- Being tested
- "Collection of additional blood tubes; Biobanking (plasma, liver tissue).
- Keywords
- NAFLD, NASH, Diabetes type2
- Medical subject headings
- Non-alcoholic Fatty Liver Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
"Collection of additional blood tubes; Biobanking (plasma, liver tissue).Biological
- Preservation of liver tissue obtain by liver biopsy, constitution of a collection
- Sampling of additional blood tubes for a biological collection (serum): Serum biomarker research and genetic research
| Study group | Role | What they receive |
|---|---|---|
| Steatosis group - Experimental1 | Steatosis group Receives: Biological: "Collection of additional blood tubes; Biobanking (plasma, liver tissue). | |
| NASH group without fibrosis - Experimental 2 | NASH group without fibrosis Receives: Biological: "Collection of additional blood tubes; Biobanking (plasma, liver tissue). | |
| Moderate fibrosis - Experimental 3 | Moderate fibrosis Receives: Biological: "Collection of additional blood tubes; Biobanking (plasma, liver tissue). | |
| Advanced fibrosis - Experimental 4 | Advanced fibrosis Receives: Biological: "Collection of additional blood tubes; Biobanking (plasma, liver tissue). | |
| Control group - Active Comparator | Control group Receives: Biological: "Collection of additional blood tubes; Biobanking (plasma, liver tissue). |
What is being measured
The primary outcome is the main question the study is designed to answer.
Measure of RANKL mRNA expression in the liver
Expression of RANKL mRNA in liver of patients with NASH or NAFLD with fibrosis comparatively to patients with mere steatosis.
Measured: Baseline
Secondary outcomes (9)
Serum concentrations of RANKL
Measure of Serum RANKL concentration in patients with NASH or NAFLD with fibrosis comparatively to patients with mere steatosis and in NAFLD patients comparatively to healthy controls.
Measured: Baseline
Serum osteoprotegerin concentrations
Measure of serum osteoprotegerin concentrations in type 2 diabetic patients with NASH or NAFLD with fibrosis compared to type 2 diabetic patients with simple steatosis and in patients with type 2 diabetes with NAFLD compared to healthy controls.
Measured: Baseline
HOMA-IR
Correlation between RANK and RANKL protein expression and insulin resistance and correlation between serum concentrations of RANKL / osteoprotegerin and insulin resistance in type 2 diabetic patients with NASH and NAFLD with fibrosis compared to type 2 diabetic patients with simple steatosis and in patients with type 2 diabetes with NAFLD compared to healthy controls
Measured: Baseline
Measure of RANKL mRNA
Expression of RANKL mRNA and RANKL protein in liver tissue of NAFLD patients comparatively to healthy controls.
Measured: Baseline
Measure of RANKL protein levels
Expression of RANKL protein in liver of patients with NASH or NAFLD with fibrosis comparatively to patients with mere steatosis.
Measured: Baseline
Measure of RANK mRNA
Expression of RANK mRNA and protein in liver of patients with NASH or NAFLD with fibrosis comparatively to patients with mere steatosis and in liver tissue of NAFLD patients comparatively to healthy controls
Measured: Baseline
Measure of RANK protein levels
Expression of RANK protein in liver of patients with NASH or NAFLD with fibrosis comparatively to patients with mere steatosis and in liver tissue of NAFLD patients comparatively to healthy controls.
Measured: Baseline
RANK/RANKL genes polymorphisms
Association between RANK/RANKL gene polymorphisms and NAFLD development To highlight association between RANK/RANKL genes polymorphisms and NAFLD development.
Measured: Baseline
NF-kB pathway in hepatocytes and Kupffer cells
Correlation of liver RANKL and RANK proteins expression with activation of NF-kB pathway in hepatocytes and Kupffer cells of patients with NASH or NAFLD with fibrosis comparatively to patients with mere steatosis and in NAFLD patients comparatively to healthy controls and correlation of serum RANKL and osteoprotegerin concentrations with activation of NF-kB pathway in hepatocytes and Kupffer cells in NAFLD patients comparatively to healthy controls and in NAFLD patients comparatively to patients with mere steatosis.
Measured: Baseline
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 May 2019
- Study startFeb 2020 (estimated)
- Primary completionJun 2021 (estimated)
- Study completionOct 2021 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Diabetes type2Studies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe 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
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 50 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Olivier MD, PHD Bourron, Principal investigator, Hopital Universitaire La Pitié-Salpêtrière
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03968354
- Sponsor's protocol ID
- K171105J
- Other IDs
- 2018-A02468-47
- Acronym
- NADRANK-1
- Status last verified
- Jan 2020
- First submitted
- 14 May 2019
- Last updated
- 28 Jan 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 28 Jan 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- NASH and Type 2 Diabetes: Role of the Receptor Activator of Nuclear Factor-κB (RANK) and Its Ligand (RANKL)
- ClinicalTrials.gov ID
- NCT03968354
- Acronym / sponsor ID
- NADRANK-1 / K171105J
- Conditions
- Diabetes type2, NASH - Nonalcoholic Steatohepatitis, NAFLD
- Keywords
- NAFLD, NASH, Diabetes type2
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 50 participants (estimated)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Study start
- Feb 2020 (estimated)
- Primary completion
- Jun 2021 (estimated)
- Study completion
- Oct 2021 (estimated)
- First posted
- 30 May 2019 (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.
Non-alcoholic fatty liver diseases (NAFLD) include several entities ranging from simple steatosis to hepatic fibrosis or cirrhosis. Steatosis, considered benign and the first stage of the disease, is characterized by the accumulation of triglycerides in the liver. It may in some cases progress to nonalcoholic steatohepatitis (NASH), which is characterized by the presence of a marked inflammation with or without fibrosis. NAFLD is the most common liver disease in the world and is particularly associated with type 2 diabetes (T2D) (80% in the diabetic population). While NASH is characterized by a higher prevalence of mortality from a cardiac and hepatic (cirrhosis and cancer) origin, therapeutic resources are almost non-existent.
RANK (receptor activator of NF-kB) and its ligand RANKL (a member of the TNFalpha family) have emerged in recent years as new players in bone pathophysiology. By binding to its receptor, RANKL induces a number of signaling pathway and in particular the NF-kB pathway (Nuclear factor-kB), a major player in inflammation. Recent literature shows that the role of RANK / RANKL is not confined to the bone but may be involved in the genesis of inflammation in other tissues. It has been shown recently that a high circulating level of RANKL was a risk factor predictor of T2DM. Furthermore, the invalidation of RANK specifically in hepatocytes protects from insulin resistance and hepatic steatosis induced by a high fat diet in mice.
The aim of our project is to provide a proof of concept that the RANKL / RANK system plays an important role in the pathogenesis of NAFLD and in the progression of this disease to NASH. The aim of our project is to provide a proof of concept that the RANKL / RANK system plays an important role in the pathogenesis of NAFLD and in the progression of this disease to NASH.
The investigator propose to study the RANKL / RANK expression in serum and liver biopsies of type 2 diabetic patients at different stages of NAFLD.
Detailed description
Objectives:
To show that (i) expression of mRNA and proteins of the RANKL pathway (RANK, RANKL, OPG) in liver and (ii) serum concentration of RANKL/OPG proteins are correlated with the gravity of the NAFLD.
Study protocol:
Identify patients with different stages of NAFLD (mere steatosis, NASH, and moderate or advanced fibrosis) from the database of patients who have undergone liver biopsy in the hepatology department of the Pitié-Salpêtrière Hospital . From the hepatic tissue, the paraffin-embedded liver biopsies and the serum of these patients, study of the expression of mRNA (quantitative RtPCR) and proteins (immunohistochemistry, western blots) of the RANKL pathway (RANK, RANKL, OPG) in liver. In the serum of these patients, measure of concentration of RANKL and OPG proteins as described above.
Study Type: monocentric, observational, case-control, analytical study Study duration: 18 months (time for data collection, for cellular biological experimentations and for data analysis)
Patient Population:
5 groups of patients very well phenotyped and with liver biopsy (with at our disposal frozen liver tissue, paraffin-embedded liver tissue and serum for all the patients):
- 1) steatosis group (n=10)
- 2) NASH group without fibrosis (n=10)
- 3) moderate fibrosis (n=10)
- 4) advanced fibrosis (n=10)
- 5) healthy control group without liver disease (n=10) Comprehensive clinical and laboratory data were observed at the time of the liver biopsy and are available for all the patients.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| Steatosis group - Experimental1 | – | Biological: "Collection of additional blood tubes; Biobanking (plasma, liver tissue).Steatosis group |
| NASH group without fibrosis - Experimental 2 | – | Biological: "Collection of additional blood tubes; Biobanking (plasma, liver tissue).NASH group without fibrosis |
| Moderate fibrosis - Experimental 3 | – | Biological: "Collection of additional blood tubes; Biobanking (plasma, liver tissue).Moderate fibrosis |
| Advanced fibrosis - Experimental 4 | – | Biological: "Collection of additional blood tubes; Biobanking (plasma, liver tissue).Advanced fibrosis |
| Control group - Active Comparator | – | Biological: "Collection of additional blood tubes; Biobanking (plasma, liver tissue).Control group |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- We will constitute 5 groups of patients very well phenotyped and with liver biopsy (with at our disposal frozen liver tissue, paraffin-embedded liver tissue and serum for all the patients): 1. steatosis group (n=10); 2. NASH group without fibrosis (n=10); 3. moderate fibrosis (n=10); 4. advanced fibrosis (n=10); 5. Control group (n=10).
Key inclusion criteria (9 listed)
- Patients adults with type 2 diabetes
- Patients with one of the following criteria:
- Patient affiliated to social security;
- Signed informed consent.
Key exclusion criteria (7 listed)
- Patients with liver diseases other than NAFLD (drug-induced hepatotoxicity, chronic hepatitis B or C, genetic hemochromatosis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, α1-antitrypsin deficiency, Wilson's disease, etc.)
- Patients with daily alcohol consumption higher than 30 g/d (men) and 20 g/d (women)
- Patients exposed to drugs that can induce secondary NAFLD (corticosteroids, amiodarone, tamoxifen)
- Patient unable or unwilling to understand and sign an informed consent form.
- Patient deprived of liberty or under legal protection measure
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 |
|---|---|---|
| "Collection of additional blood tubes; Biobanking (plasma, liver tissue).* Preservation of liver tissue obtain by liver biopsy, constitution of a collection * Sampling of additional blood tubes for a biological collection (serum): Serum biomarker research and genetic research | Biological | Advanced fibrosis - Experimental 4, Control group - Active Comparator, Moderate fibrosis - Experimental 3, NASH group without fibrosis - Experimental 2, Steatosis group - Experimental1 |
Primary outcome
Measure of RANKL mRNA expression in the liver
Time frame: Baseline
Expression of RANKL mRNA in liver of patients with NASH or NAFLD with fibrosis comparatively to patients with mere steatosis.
9 secondary outcomes
Serum concentrations of RANKL
Time frame: Baseline
Serum osteoprotegerin concentrations
Time frame: Baseline
HOMA-IR
Time frame: Baseline
Measure of RANKL mRNA
Time frame: Baseline
Measure of RANKL protein levels
Time frame: Baseline
Measure of RANK mRNA
Time frame: Baseline
Measure of RANK protein levels
Time frame: Baseline
RANK/RANKL genes polymorphisms
Time frame: Baseline
NF-kB pathway in hepatocytes and Kupffer cells
Time frame: Baseline
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Jan 2020.
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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.
Olivier MD, PHD Bourron principal investigator
Hopital Universitaire La Pitié-Salpêtrière
Questions about this trial
What is this clinical trial studying?
An observational study of Diabetes type2 and NASH - Nonalcoholic Steatohepatitis, run by Assistance Publique - Hôpitaux de Paris.
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 9 inclusion and 7 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 28 Jan 2020. Status can change between updates, so confirm with the study contact before making plans.
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 Olivier MD, PHD Bourron (33142178118, olivier.bourron@aphp.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Measure of RANKL mRNA expression in the liver (time frame: Baseline). 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 28 Jan 2020.