Lung Transplant RejectionNGS-ACRLNCT05260372
Next Generation Sequencing to Detect Acute Rejection in Lung Transplant Patients.
An observational study of Lung Transplant Rejection, run by Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico at 1 site in Italy.
Trial summary
Lung transplantation is a consolidated treatment in selected patients with end-stage respiratory diseases; however, acute rejection remains an important cause of lung allograft loss and a risk factor for chronic allograft dysfunction. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Lung Transplant Rejection
- What is being tested?
- Quantification of donor-derived cell-free DNA
- How many people
- 55 participants
- Where
- 1 siteItaly
- Study dates
- 4 Oct 2018to Dec 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 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Patients undergoing lung transplantation at Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Who may be able to join
- Patients undergoing lung transplantation at our centre
- Patients aged 18 to 65 years old
- Written informed consent to partecipate in the study
Who cannot join
- Patients undergoing retransplantation
- Patients with a history of prior solid organ transplantation
Trial locations and contacts
1 site in 1 country.
Italy1 site
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Milan, 20122
About this study
Official title: Next Generation Sequencing for the Diagnosis of Acute Rejection in Patients Undergoing Lung Transplantation. Pilot Study for Comparative Longitudinal Descriptive Trial.
Lung transplantation is a consolidated treatment in selected patients with end-stage respiratory diseases; however, acute rejection remains an important cause of lung allograft loss and a risk factor for chronic allograft dysfunction. Histopathological examination of lung tissue is the gold standard for the diagnosis of acute rejection, therefore recipients undergo surveillance transbronchial biopsy and bronchoalveolar lavage after transplantation. However, the obtained tissue is sometimes inadequate for histopathology, and the endoscopic procedure can lead to complications (bleeding, pneumothorax). The quantification of donor-derived cell-free DNA (ddcfDNA) in the recipient plasma has shown to be increased in case of acute rejection, and could represent an early and non-invasive diagnostic marker to detect acute rejection. We planned to enroll all patients aged 18 to 65 years old enlisted for lung transplantation at our centre. Patients undergoing retransplantation and patients with a history of prior solid organ transplantation were excluded. The quantification of donor-derived cell-free DNA was performed 15 days and 3, 6, and 12 months after transplantation, concurrently with the routine surveillance bronchoscopies as per our protocol; the same analysis was also conducted in case of suspected clinical rejection.
Read the detailed description
The purpose of the study is the identification of a non-invasive post-transplantation acute lung rejection monitoring method, by identification of donor derived cell free DNA (ddcf-DNA) in the recipient's plasma. At the time of transplantation, the ddcf-DNA derived from lymphocytes present in the peripheral blood of the donor and recipient will be genotyped by analysis of about 300 single nucleotide polymorphisms (SNPs) with a high probability of being differently homozygous between donor and recipient, according to the frequencies in the population reported on genomic databases. During the post-transplant follow-up, the presence of ddcf-DNA will be monitored by identification of the donor's SNP in the free DNA extracted from the recipient's plasma using the next-generation sequencing (NGS) method. Levels of ddcfDNA in the recipient will be correlated with clinical and histological data obtained from routine 3, 6 and 12 month post-transplant surveillance lung biopsies. All patients enrolled in the study will sign a study-specific written informed consent.
-Timeline: T-1 (before lung transplantation): DNA genotyping of the recipient; T0 (lung transplantation): genotyping of donor DNA; T1, T2, T3, T4 (15 days, 3, 6, 12 months after lung transplantation): ddcfDNA research on recipient serum; Tr: in any case of clinical suspicion of acute cellular rejection. At T2, T3, T4 and Tr, surveillance trans-bronchial lung biopsies (TBBs) are also performed, as per our centre's standard post-transplant lung follow-up protocol.
-Sample size and statistical analysis: Proportion of ddcfDNA/recipient DNA: stable patients (pA): 0.01, patients with graft damage (pB): 0.30, proportion nA/nB: 3, Power (1-beta): 0.80, Alpha: 5%, Margin of non inferiority δ: 0.05. Population (A+B) : 48; for possible exit from the study we add 7 cases for a total of 55 patients.
- Conditions
- Lung Transplant Rejection
- Being tested
- Quantification of donor-derived cell-free DNA
- Keywords
- Acute rejection, Donor-derived cell-free DNA, Lung transplantation, Next-generation sequencing
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Quantification of donor-derived cell-free DNADiagnostic test
Quantification of ddcfDNA on serial plasma samples during follow-up after lung transplantation
| Study group | Role | What they receive |
|---|---|---|
| Lung transplantation recipients | Recipients aged 18 to 65 years old undergoing lung transplantation at Fondazione IRCCS Ospedale Policlinico Milano undergoing quantification of donor-derived cell-free DNA on serial plasma samples Receives: Diagnostic Test: Quantification of donor-derived cell-free DNA |
What is being measured
The primary outcome is the main question the study is designed to answer.
Proportion ddcfDNA
Proportion of the ddcfDNA on the recipient's plasma cell free DNA
Measured: 1 year
Secondary outcomes (1)
ddcfDNA-clinical data correlation
Clinical data on trans-bronchial lung biopsies, pulmonary functional tests, culture of bronchoalveolar lavage fluid, donor-specific anti-human leukocyte antigen antibodies.
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Mar 2022
- Study start4 Oct 2018
- Primary completionNov 2022 (estimated)
- Study completionDec 2022 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (13)Papers the sponsor has linked to this study.
- Other trials for Lung Transplant RejectionStudies of the same condition, open and under way.
- More trials run by Fondazione IRCCS Ca' Granda, Ospedale Maggiore PoliclinicoThe 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
- 55 participants (estimated)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Collaborators
- University of Milan
- Responsible party
- Principal investigator, Mario Nosotti, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
- Investigators
- Mario Nosotti, MD, Professor, Principal investigator, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05260372
- Sponsor's protocol ID
- 1883/2018
- Acronym
- NGS-ACRL
- Status last verified
- Feb 2022
- First submitted
- 19 Feb 2022
- Last updated
- 2 Mar 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Report CRT, Italy, Rete nazionale trapianti, 2017
Chambers DC, Yusen RD, Cherikh WS, Goldfarb SB, Kucheryavaya AY, Khusch K, Levvey BJ, Lund LH, Meiser B, Rossano JW, Stehlik J; International Society for Heart and Lung Transplantation. The Registry of the International Society for Heart and Lung Transplantation: Thirty-fourth Adult Lung And Heart-Lung Transplantation Report-2017; Focus Theme: Allograft ischemic time. J Heart Lung Transplant. 2017 Oct;36(10):1047-1059. doi: 10.1016/j.healun.2017.07.016. Epub 2017 Jul 19. No abstract available.
PubMed 28784324Lande JD, Patil J, Li N, Berryman TR, King RA, Hertz MI. Novel insights into lung transplant rejection by microarray analysis. Proc Am Thorac Soc. 2007 Jan;4(1):44-51. doi: 10.1513/pats.200605-110JG.
PubMed 17202291Tosi D, Carrinola R, Morlacchi LC, Tarsia P, Rossetti V, Mendogni P, Rosso L, Righi I, Damarco F, Nosotti M. Surveillance Transbronchial Biopsy Program to Evaluate Acute Rejection After Lung Transplantation: A Single Institution Experience. Transplant Proc. 2019 Jan-Feb;51(1):198-201. doi: 10.1016/j.transproceed.2018.04.073. Epub 2018 Jun 28.
PubMed 30655138Rademacher J, Suhling H, Greer M, Haverich A, Welte T, Warnecke G, Gottlieb J. Safety and efficacy of outpatient bronchoscopy in lung transplant recipients - a single centre analysis of 3,197 procedures. Transplant Res. 2014 May 27;3:11. doi: 10.1186/2047-1440-3-11. eCollection 2014.
PubMed 24917927De Vlaminck I, Martin L, Kertesz M, Patel K, Kowarsky M, Strehl C, Cohen G, Luikart H, Neff NF, Okamoto J, Nicolls MR, Cornfield D, Weill D, Valantine H, Khush KK, Quake SR. Noninvasive monitoring of infection and rejection after lung transplantation. Proc Natl Acad Sci U S A. 2015 Oct 27;112(43):13336-41. doi: 10.1073/pnas.1517494112. Epub 2015 Oct 12.
PubMed 26460048Agbor-Enoh S, Jackson AM, Tunc I, Berry GJ, Cochrane A, Grimm D, Davis A, Shah P, Brown AW, Wang Y, Timofte I, Shah P, Gorham S, Wylie J, Goodwin N, Jang MK, Marishta A, Bhatti K, Fideli U, Yang Y, Luikart H, Cao Z, Pirooznia M, Zhu J, Marboe C, Iacono A, Nathan SD, Orens J, Valantine HA, Khush K. Late manifestation of alloantibody-associated injury and clinical pulmonary antibody-mediated rejection: Evidence from cell-free DNA analysis. J Heart Lung Transplant. 2018 Jul;37(7):925-932. doi: 10.1016/j.healun.2018.01.1305. Epub 2018 Jan 31.
PubMed 29500138De Vlaminck I, Valantine HA, Snyder TM, Strehl C, Cohen G, Luikart H, Neff NF, Okamoto J, Bernstein D, Weisshaar D, Quake SR, Khush KK. Circulating cell-free DNA enables noninvasive diagnosis of heart transplant rejection. Sci Transl Med. 2014 Jun 18;6(241):241ra77. doi: 10.1126/scitranslmed.3007803.
PubMed 24944192Rizopoulos, D. Joint Models for Longitudinal and Time-to-Event Data, with Applications in R. Boca Raton: Chapman & Hall/CRC. 2012.
Wu, L. Mixed Effects Models for Complex Data. Boca Raton: Chapman & Hall/CRC, Chapter 8. 2009
Rizopoulos, D. The R package JMbayes for fitting joint models for longitudinal and timeto-event data using MCMC. Journal of Statistical Software 72(7), 1-45. doi:10.18637/jss.v072.i07. 2016
Rizopoulos D. Dynamic predictions and prospective accuracy in joint models for longitudinal and time-to-event data. Biometrics. 2011 Sep;67(3):819-29. doi: 10.1111/j.1541-0420.2010.01546.x. Epub 2011 Feb 9.
PubMed 21306352R Foundation for Statistical Computing, Vienna, Austria(2015)
Study at a glance
From the registry record, last updated by the sponsor on 2 Mar 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Next Generation Sequencing for the Diagnosis of Acute Rejection in Patients Undergoing Lung Transplantation. Pilot Study for Comparative Longitudinal Descriptive Trial.
- ClinicalTrials.gov ID
- NCT05260372
- Acronym / sponsor ID
- NGS-ACRL / 1883/2018
- Conditions
- Lung Transplant Rejection
- Keywords
- Acute rejection, Donor-derived cell-free DNA, Lung transplantation, Next-generation sequencing
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 55 participants (estimated)
- Lead sponsor
- Fondazione IRCCS Ca' Granda, Ospedale Maggiore PoliclinicoUniversity, hospital or other
- Collaborators
- University of Milan
- Study start
- 4 Oct 2018 (actual)
- Primary completion
- Nov 2022 (estimated)
- Study completion
- Dec 2022 (estimated)
- First posted
- 2 Mar 2022 (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.
Lung transplantation is a consolidated treatment in selected patients with end-stage respiratory diseases; however, acute rejection remains an important cause of lung allograft loss and a risk factor for chronic allograft dysfunction. Histopathological examination of lung tissue is the gold standard for the diagnosis of acute rejection, therefore recipients undergo surveillance transbronchial biopsy and bronchoalveolar lavage after transplantation. However, the obtained tissue is sometimes inadequate for histopathology, and the endoscopic procedure can lead to complications (bleeding, pneumothorax). The quantification of donor-derived cell-free DNA (ddcfDNA) in the recipient plasma has shown to be increased in case of acute rejection, and could represent an early and non-invasive diagnostic marker to detect acute rejection. We planned to enroll all patients aged 18 to 65 years old enlisted for lung transplantation at our centre. Patients undergoing retransplantation and patients with a history of prior solid organ transplantation were excluded. The quantification of donor-derived cell-free DNA was performed 15 days and 3, 6, and 12 months after transplantation, concurrently with the routine surveillance bronchoscopies as per our protocol; the same analysis was also conducted in case of suspected clinical rejection.
Detailed description
The purpose of the study is the identification of a non-invasive post-transplantation acute lung rejection monitoring method, by identification of donor derived cell free DNA (ddcf-DNA) in the recipient's plasma. At the time of transplantation, the ddcf-DNA derived from lymphocytes present in the peripheral blood of the donor and recipient will be genotyped by analysis of about 300 single nucleotide polymorphisms (SNPs) with a high probability of being differently homozygous between donor and recipient, according to the frequencies in the population reported on genomic databases. During the post-transplant follow-up, the presence of ddcf-DNA will be monitored by identification of the donor's SNP in the free DNA extracted from the recipient's plasma using the next-generation sequencing (NGS) method. Levels of ddcfDNA in the recipient will be correlated with clinical and histological data obtained from routine 3, 6 and 12 month post-transplant surveillance lung biopsies. All patients enrolled in the study will sign a study-specific written informed consent.
-Timeline: T-1 (before lung transplantation): DNA genotyping of the recipient; T0 (lung transplantation): genotyping of donor DNA; T1, T2, T3, T4 (15 days, 3, 6, 12 months after lung transplantation): ddcfDNA research on recipient serum; Tr: in any case of clinical suspicion of acute cellular rejection. At T2, T3, T4 and Tr, surveillance trans-bronchial lung biopsies (TBBs) are also performed, as per our centre's standard post-transplant lung follow-up protocol.
-Sample size and statistical analysis: Proportion of ddcfDNA/recipient DNA: stable patients (pA): 0.01, patients with graft damage (pB): 0.30, proportion nA/nB: 3, Power (1-beta): 0.80, Alpha: 5%, Margin of non inferiority δ: 0.05. Population (A+B) : 48; for possible exit from the study we add 7 cases for a total of 55 patients.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Lung transplantation recipients | – | Diagnostic Test: Quantification of donor-derived cell-free DNARecipients aged 18 to 65 years old undergoing lung transplantation at Fondazione IRCCS Ospedale Policlinico Milano undergoing quantification of donor-derived cell-free DNA on serial plasma samples |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Patients undergoing lung transplantation at Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Key inclusion criteria (3 listed)
- Patients undergoing lung transplantation at our centre
- Patients aged 18 to 65 years old
- Written informed consent to partecipate in the study
Key exclusion criteria (2 listed)
- Patients undergoing retransplantation
- Patients with a history of prior solid organ transplantation
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 |
|---|---|---|
| Quantification of donor-derived cell-free DNAQuantification of ddcfDNA on serial plasma samples during follow-up after lung transplantation | Diagnostic test | Lung transplantation recipients |
Primary outcome
Proportion ddcfDNA
Time frame: 1 year
Proportion of the ddcfDNA on the recipient's plasma cell free DNA
1 secondary outcome
ddcfDNA-clinical data correlation
Time frame: 1 year
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Mar 2022.
- BackgroundReport CRT, Italy, Rete nazionale trapianti, 2017
- Background: PubMed 28784324Chambers DC, Yusen RD, Cherikh WS, Goldfarb SB, Kucheryavaya AY, Khusch K, Levvey BJ, Lund LH, Meiser B, Rossano JW, Stehlik J; International Society for Heart and Lung Transplantation. The Registry of the International Society for Heart and Lung Transplantation: Thirty-fourth Adult Lung And Heart-Lung Transplantation Report-2017; Focus Theme: Allograft ischemic time. J Heart Lung Transplant. 2017 Oct;36(10):1047-1059. doi: 10.1016/j.healun.2017.07.016. Epub 2017 Jul 19. No abstract available.
- Background: PubMed 17202291Lande JD, Patil J, Li N, Berryman TR, King RA, Hertz MI. Novel insights into lung transplant rejection by microarray analysis. Proc Am Thorac Soc. 2007 Jan;4(1):44-51. doi: 10.1513/pats.200605-110JG.
- Background: PubMed 30655138Tosi D, Carrinola R, Morlacchi LC, Tarsia P, Rossetti V, Mendogni P, Rosso L, Righi I, Damarco F, Nosotti M. Surveillance Transbronchial Biopsy Program to Evaluate Acute Rejection After Lung Transplantation: A Single Institution Experience. Transplant Proc. 2019 Jan-Feb;51(1):198-201. doi: 10.1016/j.transproceed.2018.04.073. Epub 2018 Jun 28.
- Background: PubMed 24917927Rademacher J, Suhling H, Greer M, Haverich A, Welte T, Warnecke G, Gottlieb J. Safety and efficacy of outpatient bronchoscopy in lung transplant recipients - a single centre analysis of 3,197 procedures. Transplant Res. 2014 May 27;3:11. doi: 10.1186/2047-1440-3-11. eCollection 2014.
- Background: PubMed 26460048De Vlaminck I, Martin L, Kertesz M, Patel K, Kowarsky M, Strehl C, Cohen G, Luikart H, Neff NF, Okamoto J, Nicolls MR, Cornfield D, Weill D, Valantine H, Khush KK, Quake SR. Noninvasive monitoring of infection and rejection after lung transplantation. Proc Natl Acad Sci U S A. 2015 Oct 27;112(43):13336-41. doi: 10.1073/pnas.1517494112. Epub 2015 Oct 12.
- Background: PubMed 29500138Agbor-Enoh S, Jackson AM, Tunc I, Berry GJ, Cochrane A, Grimm D, Davis A, Shah P, Brown AW, Wang Y, Timofte I, Shah P, Gorham S, Wylie J, Goodwin N, Jang MK, Marishta A, Bhatti K, Fideli U, Yang Y, Luikart H, Cao Z, Pirooznia M, Zhu J, Marboe C, Iacono A, Nathan SD, Orens J, Valantine HA, Khush K. Late manifestation of alloantibody-associated injury and clinical pulmonary antibody-mediated rejection: Evidence from cell-free DNA analysis. J Heart Lung Transplant. 2018 Jul;37(7):925-932. doi: 10.1016/j.healun.2018.01.1305. Epub 2018 Jan 31.
- Background: PubMed 24944192De Vlaminck I, Valantine HA, Snyder TM, Strehl C, Cohen G, Luikart H, Neff NF, Okamoto J, Bernstein D, Weisshaar D, Quake SR, Khush KK. Circulating cell-free DNA enables noninvasive diagnosis of heart transplant rejection. Sci Transl Med. 2014 Jun 18;6(241):241ra77. doi: 10.1126/scitranslmed.3007803.
- BackgroundRizopoulos, D. Joint Models for Longitudinal and Time-to-Event Data, with Applications in R. Boca Raton: Chapman & Hall/CRC. 2012.
- BackgroundWu, L. Mixed Effects Models for Complex Data. Boca Raton: Chapman & Hall/CRC, Chapter 8. 2009
- BackgroundRizopoulos, D. The R package JMbayes for fitting joint models for longitudinal and timeto-event data using MCMC. Journal of Statistical Software 72(7), 1-45. doi:10.18637/jss.v072.i07. 2016
- Background: PubMed 21306352Rizopoulos D. Dynamic predictions and prospective accuracy in joint models for longitudinal and time-to-event data. Biometrics. 2011 Sep;67(3):819-29. doi: 10.1111/j.1541-0420.2010.01546.x. Epub 2011 Feb 9.
- Individual participant dataSharing planned: Undecided
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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.
Mario Nosotti, MD, Professor principal investigator
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
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 Lung Transplant Rejection, run by Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico at 1 site in Italy.
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 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 2 Mar 2022. 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 Italy. 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?
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?
Proportion ddcfDNA (time frame: 1 year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05260372, which also lists 13 linked publications.
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 2 Mar 2022.