Donor-derived Cell-free DNA for Early Diagnosis of Antibody-mediated Rejection (cfDNA-DSA)

• ClinicalTrials.gov Identifier: NCT04897438
• Recruitment Status: Active, not recruiting
• First Posted: May 21, 2021
• Last Update Posted: January 30, 2024
• Sponsor: Charite University, Berlin, Germany
• Information provided by (Responsible Party): Klemens Budde, Charite University, Berlin, Germany

Tracking Information

• First Submitted Date: May 18, 2021
• First Posted Date: May 21, 2021
• Last Update Posted Date: January 30, 2024
• Actual Study Start Date: June 1, 2021
• Actual Primary Completion Date: July 18, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 28, 2024)

Time from study inclusion to diagnosis of antibody-mediated rejection [ Time Frame: 12 months after inclusion ]

Time from study inclusion date to biopsy-proven diagnosis of active or chronic active antibody-mediated rejection

Original Primary Outcome Measures (submitted: May 18, 2021)

Time to diagnosis of antibody-mediated rejection [ Time Frame: 12 months after inclusion ]

Time from first detection of donor-specific anti-HLA antibodies to biopsy-proven diagnosis of active or chronic active antibody-mediated rejection

Current Secondary Outcome Measures (submitted: January 28, 2024)

• Sensitivity of absolute dd-cfDNA for detection of ABMR [ Time Frame: 12 Months ]
  Sensitivity of dd-cfDNA > 50 copies/ml to predict the occurence of active or chronic active ABMR in patients with DSA.
• Specificity of absolute dd-cfDNA for detection of ABMR [ Time Frame: 12 Months ]
  Specificity of dd-cfDNA > 50 copies/ml to predict the occurence of active or chronic active ABMR in patients with DSA.
• Receiver operating characteristics (ROC) analysis of absolute dd-cfDNA for detection of ABMR [ Time Frame: 12 Months ]
  ROC analysis for dd-cfDNA to predict the occurence of active or chronic active ABMR in patients with DSA.
• Sensitivity of intraindividual dd-cfDNA changes for detection of ABMR [ Time Frame: 12 Months ]
  Sensitivity of dd-cfDNA increase of > 25% to predict the occurence of active or chronic active ABMR in patients with DSA.
• Sensitivity of combined dd-cfDNA criterion for detection of ABMR [ Time Frame: 12 Months ]
  Sensitivity of the combination of "dd-cfDNA increase of > 25%" OR "absolute dd-cfDNA > 50 copies/ml" to predict the occurence of active or chronic active ABMR in patients with DSA.
• Clinical Outcome - estimated glomerular filtration rate (eGFR) 12 Months [ Time Frame: 12 Months ]
  Difference between eGFR decline after 12 months between control group and intervention group.
• Clinical Outcome - eGFR 24 Months [ Time Frame: 24 Months ]
  Difference between eGFR decline after 24 months between control group and intervention group.
• Clinical Outcome - albuminuria 12 Months [ Time Frame: 12 Months ]
  Difference between albuminuria after 12 months between control group and intervention group.
• Clinical Outcome - albuminuria 24 Months [ Time Frame: 24 Months ]
  Difference between albuminuria after 24 months between control group and intervention group.
• Clinical Outcome - Death-censored Graft Failure 12 Months [ Time Frame: 12 Months ]
  Difference in Death-censored Graft Failure after 12 months between control group and intervention group.
• Clinical Outcome - Death-censored Graft Failure 24 Months [ Time Frame: 24 Months ]
  Difference in Death-censored Graft Failure after 24 months between control group and intervention group.
• Clinical Outcome - Mortality 12 Months [ Time Frame: 12 Months ]
  Difference in Mortality after 12 months between control group and intervention group.
• Clinical Outcome - Mortality 24 Months [ Time Frame: 24 Months ]
  Difference in Mortality after 24 months between control group and intervention group.
• Clinical Outcome - Severe Infection 12 Months [ Time Frame: 12 Months ]
  Difference in occurence of severe infections (hospitalization, organ failure, death) during 12 months between control group and intervention group.
• Clinical Outcome - Severe Infection 24 Months [ Time Frame: 24 Months ]
  Difference in occurence of severe infections (hospitalization, organ failure, death) during 24 months between control group and intervention group.
• Adverse Events of Kidney Transplant Biopsy [ Time Frame: 12 Months ]
  Occurence of Complications from Kidney Transplant Biopsies, including Duration and potential therapy to treat the adverse event.
• Rate of ABMR [ Time Frame: 12 Months ]
  Number of biopsy proven active or chronic active ABMR in the cohort.
• DSA Levels 0 Months [ Time Frame: at inclusion ]
  Mean fluorescence intensity of immunodominant DSA
• DSA Levels 12 Months [ Time Frame: 12 months ]
  Mean fluorescence intensity of immunodominant DSA at 12 months
• DSA Levels 24 Months [ Time Frame: 24 months ]
  Mean fluorescence intensity of immunodominant DSA at 24 months
• Immunosuppressive Regimen [ Time Frame: 24 months ]
  Report of immunosuppressive medication at the following time points: 0,1,3,6,9,12,24 months, changes of medication, additional therapies such as plasmapheresis, or experimental therapies.
• Time from first DSA occurrence to diagnosis of antibody-mediated rejection [ Time Frame: 12 months after inclusion ]
  Time from first DSA occurrence to biopsy-proven diagnosis of active or chronic active antibody-mediated rejection

Original Secondary Outcome Measures (submitted: May 18, 2021)

• Sensitivity of absolute dd-cfDNA for detection of ABMR [ Time Frame: 12 Months ]
  Sensitivity of dd-cfDNA > 50 copies/ml to predict the occurence of active or chronic active ABMR in patients with DSA.
• Specificity of absolute dd-cfDNA for detection of ABMR [ Time Frame: 12 Months ]
  Specificity of dd-cfDNA > 50 copies/ml to predict the occurence of active or chronic active ABMR in patients with DSA.
• ROC analysis of absolute dd-cfDNA for detection of ABMR [ Time Frame: 12 Months ]
  ROC analysis for dd-cfDNA to predict the occurence of active or chronic active ABMR in patients with DSA.
• Sensitivity of intraindividual dd-cfDNA changes for detection of ABMR [ Time Frame: 12 Months ]
  Sensitivity of dd-cfDNA increase of > 25% to predict the occurence of active or chronic active ABMR in patients with DSA.
• Sensitivity of combined dd-cfDNA criterion for detection of ABMR [ Time Frame: 12 Months ]
  Sensitivity of the combination of "dd-cfDNA increase of > 25%" OR "absolute dd-cfDNA > 50 copies/ml" to predict the occurence of active or chronic active ABMR in patients with DSA.
• Clinical Outcome - eGFR 12 Months [ Time Frame: 12 Months ]
  Difference between eGFR decline after 12 months between control group and intervention group.
• Clinical Outcome - eGFR 24 Months [ Time Frame: 24 Months ]
  Difference between eGFR decline after 24 months between control group and intervention group.
• Clinical Outcome - albuminuria 12 Months [ Time Frame: 12 Months ]
  Difference between albuminuria after 12 months between control group and intervention group.
• Clinical Outcome - albuminuria 24 Months [ Time Frame: 24 Months ]
  Difference between albuminuria after 24 months between control group and intervention group.
• Clinical Outcome - Death-censored Graft Failure 12 Months [ Time Frame: 12 Months ]
  Difference in Death-censored Graft Failure after 12 months between control group and intervention group.
• Clinical Outcome - Death-censored Graft Failure 24 Months [ Time Frame: 24 Months ]
  Difference in Death-censored Graft Failure after 24 months between control group and intervention group.
• Clinical Outcome - Mortality 12 Months [ Time Frame: 12 Months ]
  Difference in Mortality after 12 months between control group and intervention group.
• Clinical Outcome - Mortality 24 Months [ Time Frame: 24 Months ]
  Difference in Mortality after 24 months between control group and intervention group.
• Clinical Outcome - Severe Infection 12 Months [ Time Frame: 12 Months ]
  Difference in occurence of severe infections (hospitalization, organ failure, death) during 12 months between control group and intervention group.
• Clinical Outcome - Severe Infection 24 Months [ Time Frame: 24 Months ]
  Difference in occurence of severe infections (hospitalization, organ failure, death) during 24 months between control group and intervention group.
• Adverse Events of Kidney Transplant Biopsy [ Time Frame: 12 Months ]
  Occurence of Complications from Kidney Transplant Biopsies, including Duration and potential therapy to treat the adverse event.
• Rate of ABMR [ Time Frame: 12 Months ]
  Number of biopsy proven active or chronic active ABMR in the cohort.
• DSA Levels 0 Months [ Time Frame: at inclusion ]
  Mean fluorescence intensity of immunodominant donor-specific anti-HLA antibodies
• DSA Levels 12 Months [ Time Frame: 12 months ]
  Mean fluorescence intensity of immunodominant donor-specific anti-HLA antibodies at 12 months
• DSA Levels 24 Months [ Time Frame: 24 months ]
  Mean fluorescence intensity of immunodominant donor-specific anti-HLA antibodies at 24 months
• Immunosuppressive Regimen [ Time Frame: 24 months ]
  Report of immunsuppressive medication at the following time points: 0,1,3,6,9,12,24 months, changes of medication, additional therapies such as plasmapheresis, or experimental therapies.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Donor-derived Cell-free DNA for Early Diagnosis of Antibody-mediated Rejection
• Official Title: Donor-derived Cell-free DNA for Early Diagnosis of Antibody-mediated Rejection in Kidney Transplant Recipient With Donor-specific Antibodies
• Brief Summary: Patients after kidney transplantation who develop donor-specific antibodies (DSA) are at high risk for antibody-mediated rejection (ABMR). Donor-derived cell-free DNA (dd-cfDNA) levels have been shown to be increased in patients with active or chronic active ABMR. This study aims to evaluate if repeated analysis of dd-cfDNA in patients with DSA and kidney allograft biopsy which is triggered by increased levels of dd-cfDNA can lead to early diagnosis of active or chronic active ABMR among these patients.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Diagnostic

Condition

• Kidney Transplant Rejection
• Antibody-mediated Rejection
• Kidney Transplant Failure

Intervention

Procedure: Kidney allograft biopsy depending on donor-derived cell-free DNA levels

Kidney allograft biopsy is performed, when absolute levels of donor-derived cell-free DNA are above 50 copies/ml

Study Arms

• Experimental: Intervention
  Additionally to standard of care, measurements for donor-derived cell-free DNA (dd-cfDNA) are performed at months 0, 1, 3, 6, 9, and 12. If absolute levels of dd-cfDNA are > 50 copies/ml, the patients receive a kidney allograft biopsy. Additionally, kidney allograft biopsies are performed according to standard of care as determined by the treating physicians.
  Intervention: Procedure: Kidney allograft biopsy depending on donor-derived cell-free DNA levels
• No Intervention: Control
  Additionally to standard of care, measurements for donor-derived cell-free DNA (dd-cfDNA) are performed at months 0, 1, 3, 6, 9, and 12. These measurements are not used to guide kidney allograft biopsies. Those are performed according to standard of care as determined by the treating physicians.

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: May 18, 2021): 40
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: September 1, 2024
• Actual Primary Completion Date: July 18, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• patients 18 years or older
• patients provided written informed consent
• patients after kidney transplantation
• functioning kidney allograft, at least after 180 days after last transplantation
• estimated glomerular filtration rate above 20 ml/min/1.73m^2
• detection of DSA

Exclusion Criteria:

• patients younger than 18 years
• patients unable or did not provide written informed consent
• pregnant or breastfeeding persons
• patients with increased bleeding risk
• patients with multi-organ transplantation
• patients who underwent kidney allograft biopsy after first detection of DSA
• biopsy-proven antibody-mediated rejection
• participation in another interventional clinical trial

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT04897438
• Other Study ID Numbers: CHA-NTX-001
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Klemens Budde, Charite University, Berlin, Germany
• Original Responsible Party: Same as current
• Current Study Sponsor: Charite University, Berlin, Germany
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Klemens Budde, MD; Charite University, Berlin, Germany

• PRS Account: Charite University, Berlin, Germany
• Verification Date: September 2023