Acute Liver FailureNCT04621812
Role of Fecal Microbiota in Predicting Graft Rejection and Sepsis Among Recipients of Living Donor Liver Transplant in First Year.
An observational study of Acute Liver Failure and Acute-On-Chronic Liver Failure, run by Institute of Liver and Biliary Sciences, India at 1 site in India.
Trial summary
Efficient immunosuppressive therapy and improved surgical techniques have developed liver transplantation as a well-established and life-saving treatment. The 1-year survival rate of approximately 85-90%. Read more about this study
- Who is it for?
- Ages 12 to 75 years
- Conditions the study is for
- Acute Liver Failure, Acute-On-Chronic Liver Failure, Liver Cirrhosis
- How many people
- 100 participants
- Where
- 1 siteIndia
- Study dates
- 8 Nov 2020to 10 Oct 2022
- 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 12 to 75 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: Consecutive 100 patients fulfilling the eligibility criteria and undergoing living donor liver transplant in ILBS between April 2020 to March 2022.
Who may be able to join
- Living donor Liver transplantation for ALF, ACLF, cirrhosis and its complications.
- Age 12-75 years
- Valid consent
Who cannot join
- Deceased Donor Liver Transplants
- Re-transplants
- Simultaneous Liver-Kidney Transplants (SLKT)
Trial locations and contacts
1 site in 1 country.
India1 site, 1 recruiting
- Recruiting
Institute of Liver & Biliary Sciences
New Delhi, National Capital Territory of Delhi, 110070
Dr Navin Kumar, MD, 01146300000, navinktanvi10@gmail.com
About this study
Official title: Role of Fecal Microbiota in Predicting Graft Rejection and Sepsis Among Recipients of Living Donor Liver Transplant in First Year - An Observational Study.
Efficient immunosuppressive therapy and improved surgical techniques have developed liver transplantation as a well-established and life-saving treatment. The 1-year survival rate of approximately 85-90%. Acute cellular rejection (ACR) is one of the main causes of liver dysfunction (LD) after liver trans- plantation, occurring 30% to 70% of transplanted patients and potentially leading to allograft failure. In addition to ACR, presence of sepsis, drug injury, viral infections like CMV or recurrence of viral hepatitis is also other causes of graft dysfunction. Laboratory tests are commonly used as less invasive methods of monitoring allograft rejection, but they are not specific to rejection and are often elevated in other types of graft dysfunction too.
Till date the immunosuppressive regimen in liver transplant recipient is considered as an art in absence of an objective measures of the immune state. Therapeutic drug monitoring has little value in the assessment of the immune state and is always used as a supportive guide. The development of specific immune monitoring assays to measure the net immunosuppressive state in a transplant recipient would allow a more individualized therapeutic regimen Patients with altered gut microbiota had more chances of infection and longer course of hospital stay. Probiotics could mediate beneficial effects in graft rejection. Dysbiosis activates T cells through PAMPS and causes the inflammatory injury in the graft liver. The studies shown that lower Eubacteria, Bifidobacterium, Faecal bacterium and Lactobacillus with abundance of Enterococcus and Enterobacteriaceae. They restored to near normal after transplant in majority.
Read more
This is known that there is a dysbiosis in the natural history of ACLF or decompensated cirrhosis, and often correlated to complications like-endotoxemia, sepsis, worsening liver failure and poor survival. This has led to consider fecal microbiota modulation as an emerging therapy. Liver transplant and consequent recovery, there is over all change in the recipient homeostatic milieu as well as the immune milieu and the same may be happening to the gut flora too.It's well known that liver has animprint of resident gut flora. The preliminary rat model showed alteration of gut flora to predict the development acute cellular rejection before it happens. Similarly the risk of infection is more among transplant recipients with decreased microbial diversity after liver transplant. However the data is scanty and there is an urgent need to understand the mechanism..
The present study was necessitated in view of emerging role of gut microflora and its influence on immune remodeling for the prediction of infection, rejection and may be an early biomarker for the graft dysfunction. This may be of varied cause in liver transplant recipients along with its impact on overall immune status. Uniqueness of the present study will be to understand the mechanism of development of sepsis or graft dysfunction in due course of time using high-throughput tools of single cell analysis in whole blood and gut microbiota alterations among liver transplant recipient as a cause for graft dysfunction in first year of live donor liver transplant.
Read the detailed description
Primary Objective:
To characterize the fecal microbiota changes over one year after living donor liver transplantation and its association with graft rejection and sepsis.
Secondary objectives :
- Incidence of graft dysfunction attributable to sepsis, rejection and CMV infection in first year of LDLT.
- To study the pre-LT immunological profile and its correlation with post-transplant rejection, immunosuppression requirements and restoration of immunosenescence.
- To correlate the dynamic changes in immune cells and cytokines in predicting graft rejection and sepsis.
STUDY DESIGN Type of study - Single centre, prospective, observational study Study population - consecutive 100 patients fulfilling the eligibility criteria and undergoing living donor liver transplant in ILBS between April 2020 to March 2022.
Study duration - 24 months from the date of approval of IEC
Methodology:
Identification of gut microbiota:
DNA extraction All subjects will undergo serum and stool collection the same day. About 5-8g of fecal materialwill be collected .The QIAamp Fast DNA Stool Mini Kit for stool samples will be used for DNA extraction.
PCR Amplification of the 16s RNA Gene Briefly, PCR amplification of the V3-V4 hypervariable regions will be done by using the 341F and 806R primers containing the sample specific barcode. Purified amplified product (QIAGEN), will be run on the MiSeq platform with custom sequencing primer reads 1 (R1), read 2 (R2) and index.
Whole blood: Whole blood will be (5-10ml) will be collected. Plasma will be separated by centrifugation at 2500rpm. Plasma will be stored at -80C in biobank (NLDB) until processed for cytokines array. Remaining blood will be treated with RBC lysis buffer and will be processed for immune cells analysis.
Immunophenotyping for frequency/absolute number of immune cells: The cells in the whole blood will be stained with specific flurochrome labelled monoclonal antibodies for the surface markers for T cells subsets (Th1,Th2, Th17, Tregs), B regulatory cells using Flowcytometry and analysis will be done by FCS express software.
Cytokine Array: The pro-inflammatory (IL-1β) and anti-inflammatory cytokines (IL-10)will be measured in plasma of the patients under study. The cytokine array kit will be procured commercially and will be done according to the manufacturer's instructions.
STATISTICAL ANALYSIS
- Data will be reported as mean + SD
- Categorical variables will be compared using the chi-square test or Fisher exact test
- Normal continuous variables will be compared using the Student t test
- Non normal continuous variables will be compared using the Mann-Whitney rank-sum test (unpaired data) or the Wilcoxon test (paired data).
- Comparison between groups on quantitative variables will be analyzed by ANOVA A Cox regression analysis will be performed to identify independent prognostic factors for graft function.
STUDY END POINTS Primary End point
- Development of sepsis, rejection, CMV infection
- Death
Secondary End points
- Post LT complications requiring surgical interventions
- Retransplantation
Expected outcome of the project:
- This will help us in designing simple diagnostic tools based on microbial profiling or immune cells signatures for diagnosis of graft dysfunction and sepsis.
- This will also give us insight about mechanism of immune pathogenesis during the development of severe conditions and this will pave way for newer therapeutic options.
Ethical issues in the study and plans to address these issues - None
- Medical subject headings
- Liver Failure, Acute, Acute-On-Chronic Liver Failure, Liver Cirrhosis
What is being measured
The primary outcome is the main question the study is designed to answer.
Development of sepsis
Sepsis diagnosis is based on positive cultures of the patient (Blood, urine, tip of catheter ), foci of infection by cross sectional imaging at any point of time
Measured: 1 years
Development of rejection
Rejection dosgnosis is based on graft biopsy and histology - assessed by REJECTION ACTIVITY INDEX (RAI)
Measured: 1 years
Development of CMV infection
CMV DNA diagnosis is by RT PCR technique
Measured: 1 years
Death
Measured: 1 years
Secondary outcomes (2)
Post LT complications requiring surgical interventions
Measured: 1 years
Number of patients who will undergo Retransplantation
Measured: 1 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Nov 2020
- Study start8 Nov 2020
- Primary completion10 Oct 2022 (estimated)
- Study completion10 Oct 2022 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Acute Liver FailureStudies of the same condition, open and under way.
- More trials run by Institute of Liver and Biliary Sciences, IndiaThe 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
- Case only
- Time perspective
- Prospective
- Enrolment
- 100 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Institute of Liver and Biliary Sciences, India
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04621812
- Sponsor's protocol ID
- ILBS-FMT-02
- Status last verified
- Oct 2021
- First submitted
- 16 Oct 2020
- Last updated
- 5 Oct 2021
- 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 5 Oct 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Role of Fecal Microbiota in Predicting Graft Rejection and Sepsis Among Recipients of Living Donor Liver Transplant in First Year - An Observational Study.
- ClinicalTrials.gov ID
- NCT04621812
- Acronym / sponsor ID
- ILBS-FMT-02
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 100 participants (estimated)
- Lead sponsor
- Institute of Liver and Biliary Sciences, IndiaUniversity, hospital or other
- Study start
- 8 Nov 2020 (actual)
- Primary completion
- 10 Oct 2022 (estimated)
- Study completion
- 10 Oct 2022 (estimated)
- First posted
- 9 Nov 2020 (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.
Efficient immunosuppressive therapy and improved surgical techniques have developed liver transplantation as a well-established and life-saving treatment. The 1-year survival rate of approximately 85-90%. Acute cellular rejection (ACR) is one of the main causes of liver dysfunction (LD) after liver trans- plantation, occurring 30% to 70% of transplanted patients and potentially leading to allograft failure. In addition to ACR, presence of sepsis, drug injury, viral infections like CMV or recurrence of viral hepatitis is also other causes of graft dysfunction. Laboratory tests are commonly used as less invasive methods of monitoring allograft rejection, but they are not specific to rejection and are often elevated in other types of graft dysfunction too.
Till date the immunosuppressive regimen in liver transplant recipient is considered as an art in absence of an objective measures of the immune state. Therapeutic drug monitoring has little value in the assessment of the immune state and is always used as a supportive guide. The development of specific immune monitoring assays to measure the net immunosuppressive state in a transplant recipient would allow a more individualized therapeutic regimen Patients with altered gut microbiota had more chances of infection and longer course of hospital stay. Probiotics could mediate beneficial effects in graft rejection. Dysbiosis activates T cells through PAMPS and causes the inflammatory injury in the graft liver. The studies shown that lower Eubacteria, Bifidobacterium, Faecal bacterium and Lactobacillus with abundance of Enterococcus and Enterobacteriaceae. They restored to near normal after transplant in majority.
This is known that there is a dysbiosis in the natural history of ACLF or decompensated cirrhosis, and often correlated to complications like-endotoxemia, sepsis, worsening liver failure and poor survival. This has led to consider fecal microbiota modulation as an emerging therapy. Liver transplant and consequent recovery, there is over all change in the recipient homeostatic milieu as well as the immune milieu and the same may be happening to the gut flora too.It's well known that liver has animprint of resident gut flora. The preliminary rat model showed alteration of gut flora to predict the development acute cellular rejection before it happens. Similarly the risk of infection is more among transplant recipients with decreased microbial diversity after liver transplant. However the data is scanty and there is an urgent need to understand the mechanism..
The present study was necessitated in view of emerging role of gut microflora and its influence on immune remodeling for the prediction of infection, rejection and may be an early biomarker for the graft dysfunction. This may be of varied cause in liver transplant recipients along with its impact on overall immune status. Uniqueness of the present study will be to understand the mechanism of development of sepsis or graft dysfunction in due course of time using high-throughput tools of single cell analysis in whole blood and gut microbiota alterations among liver transplant recipient as a cause for graft dysfunction in first year of live donor liver transplant.
Detailed description
Primary Objective:
To characterize the fecal microbiota changes over one year after living donor liver transplantation and its association with graft rejection and sepsis.
Secondary objectives :
- Incidence of graft dysfunction attributable to sepsis, rejection and CMV infection in first year of LDLT.
- To study the pre-LT immunological profile and its correlation with post-transplant rejection, immunosuppression requirements and restoration of immunosenescence.
- To correlate the dynamic changes in immune cells and cytokines in predicting graft rejection and sepsis.
STUDY DESIGN Type of study - Single centre, prospective, observational study Study population - consecutive 100 patients fulfilling the eligibility criteria and undergoing living donor liver transplant in ILBS between April 2020 to March 2022.
Study duration - 24 months from the date of approval of IEC
Methodology:
Identification of gut microbiota:
DNA extraction All subjects will undergo serum and stool collection the same day. About 5-8g of fecal materialwill be collected .The QIAamp Fast DNA Stool Mini Kit for stool samples will be used for DNA extraction.
PCR Amplification of the 16s RNA Gene Briefly, PCR amplification of the V3-V4 hypervariable regions will be done by using the 341F and 806R primers containing the sample specific barcode. Purified amplified product (QIAGEN), will be run on the MiSeq platform with custom sequencing primer reads 1 (R1), read 2 (R2) and index.
Whole blood: Whole blood will be (5-10ml) will be collected. Plasma will be separated by centrifugation at 2500rpm. Plasma will be stored at -80C in biobank (NLDB) until processed for cytokines array. Remaining blood will be treated with RBC lysis buffer and will be processed for immune cells analysis.
Immunophenotyping for frequency/absolute number of immune cells: The cells in the whole blood will be stained with specific flurochrome labelled monoclonal antibodies for the surface markers for T cells subsets (Th1,Th2, Th17, Tregs), B regulatory cells using Flowcytometry and analysis will be done by FCS express software.
Cytokine Array: The pro-inflammatory (IL-1β) and anti-inflammatory cytokines (IL-10)will be measured in plasma of the patients under study. The cytokine array kit will be procured commercially and will be done according to the manufacturer's instructions.
STATISTICAL ANALYSIS
- Data will be reported as mean + SD
- Categorical variables will be compared using the chi-square test or Fisher exact test
- Normal continuous variables will be compared using the Student t test
- Non normal continuous variables will be compared using the Mann-Whitney rank-sum test (unpaired data) or the Wilcoxon test (paired data).
- Comparison between groups on quantitative variables will be analyzed by ANOVA A Cox regression analysis will be performed to identify independent prognostic factors for graft function.
STUDY END POINTS Primary End point
- Development of sepsis, rejection, CMV infection
- Death
Secondary End points
- Post LT complications requiring surgical interventions
- Retransplantation
Expected outcome of the project:
- This will help us in designing simple diagnostic tools based on microbial profiling or immune cells signatures for diagnosis of graft dysfunction and sepsis.
- This will also give us insight about mechanism of immune pathogenesis during the development of severe conditions and this will pave way for newer therapeutic options.
Ethical issues in the study and plans to address these issues - None
Study design
- Observational model
- Case only
- Time perspective
- Prospective
Who may qualify
- Ages
- 12 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Consecutive 100 patients fulfilling the eligibility criteria and undergoing living donor liver transplant in ILBS between April 2020 to March 2022.
Key inclusion criteria (3 listed)
- Living donor Liver transplantation for ALF, ACLF, cirrhosis and its complications.
- Age 12-75 years
- Valid consent
Key exclusion criteria (3 listed)
- Deceased Donor Liver Transplants
- Re-transplants
- Simultaneous Liver-Kidney Transplants (SLKT)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Development of sepsis
Time frame: 1 years
Sepsis diagnosis is based on positive cultures of the patient (Blood, urine, tip of catheter ), foci of infection by cross sectional imaging at any point of time
Development of rejection
Time frame: 1 years
Rejection dosgnosis is based on graft biopsy and histology - assessed by REJECTION ACTIVITY INDEX (RAI)
Development of CMV infection
Time frame: 1 years
CMV DNA diagnosis is by RT PCR technique
Death
Time frame: 1 years
2 secondary outcomes
Post LT complications requiring surgical interventions
Time frame: 1 years
Number of patients who will undergo Retransplantation
Time frame: 1 years
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Oct 2021.
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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.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Acute Liver Failure and Acute-On-Chronic Liver Failure, run by Institute of Liver and Biliary Sciences, India at 1 site in India.
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 3 inclusion and 3 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 5 Oct 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in India. 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 Dr Navin Kumar M, MD (01146300000, navinktanvi10@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Development of sepsis (time frame: 1 years). The study lists 4 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 5 Oct 2021.