Kidney Transplant Rejection
Conditions
Brief summary
The aim of this trial is to collect data and provide a better understanding of the long-term outcome of imlifidase treatment on active or chronic active antibody-mediated rejection (AMR) in kidney transplant recipients. This is done by collecting data during an extended follow-up period of 3 years of clinical study trial 16-HMedIdeS-12, in which patients received either imlifidase or plasma exchange (PE) as AMR treatment. Data for parameters such as kidney graft survival, patient survival, kidney function, treatment of rebound of donor specific antibodies (DSA) and anti-drug antibodies (ADAs) are collected.
Detailed description
AMR is one of the most challenging adverse events following kidney transplantation and a major cause of graft dysfunction and graft loss. AMR is triggered by donor-specific antibodies (DSA).Transplant glomerulopathy is a known consequence of persistent DSA positivity which results in graft failure and return to dialysis with attendant consequences for the patient and financial costs for the health care system. The time from transplantation to onset of clinical symptoms of AMR varies largely between individuals. An early AMR (\<30 days post-transplant) is commonly classified as active AMR and most often triggered by an immunological recall response with pre-existing DSA. A late AMR (\>30 days post-transplant) is classified as either active or chronic active AMR and is caused by either a recall DSA response or newly developing naïve immune response associated with de novo DSA production. There is no currently approved therapy for AMR and patients are often treated with a combination of therapies i.e., high dose IVIg +/- rituximab, PE with low dose IVIg +/- rituximab, and eculizumab which makes analysis of efficacy of any single agent difficult. Hence, there is a large unmet clinical need for new therapies to treat AMR. Imlifidase is an IgG-degrading enzyme of Streptococcus pyogenes that cleaves all four human subclasses of IgG with high efficacy and specificity. The rapidity of the IgG cleavage by imlifidase is considered a major advantage as compared with PE, which often requires several rounds over several days to achieve a sufficient DSA reduction. Within a few hours after imlifidase dosing, the entire pool of IgG is completely cleaved and thereby a window where IgG levels are kept very low for approximately one week is created. The short-term efficacy and safety of imlifidase in active and chronic active AMR is being investigated in a randomized, open-label, multi-centre trial, using PE as an active control (i.e. the feeder study: 16-HMedIdeS-12). A total of 30 subjects will be included in this study (20 in the imlifidase arm and 10 in the plasma exchange arm). The primary objective is to investigate the efficacy of imlifidase in removing DSA in patients who are experiencing an AMR episode after kidney transplantation. While a rapid removal of DSA by imlifidase might be expected, DSA is likely to rebound unless well-controlled by concomitant immunosuppressive therapy. Therefore, there is also a need to address the long-term outcome of imlifidase as an AMR therapy. This will be studied during an extended follow-up period of 3 years in this study. Data for parameters such as kidney graft survival, patient survival, kidney function, treatment of rebound of donor specific antibodies (DSA) and anti-drug antibodies (ADAs) will be collected.
Interventions
DRUGImlifidase
Immunoglobulin G degrading enzyme of Streptococcus pyogenes
Sponsors
Hansa Biopharma AB
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed Informed Consent obtained before any trial-related procedures * Willingness and ability to comply with the protocol * Previous treatment with imlifidase or plasma exchange in the trial 16-HMedIdeS-12 Note: The primary objective of this trial is overall graft survival after treatment with imlifidase or plasma exchange. Therefore, subjects can also be included even if the subject did not fully complete the feeder trial follow up but was dosed with imlifidase or plasma exchange in the trial 16-HMedIdeS-12.
Exclusion criteria
• Inability by the judgement of the investigator to participate in the trial for any other reason
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Graft Survival at Year 3 | 3 years after start of AMR treatment in feeder study (16-HMedIdeS-12) | Graft survival is defined as time from start of AMR treatment in feeder study (16-HMedIdeS-12) to graft loss. Graft loss is defined as permanent return to dialysis for at least 6 weeks, re-transplantation, or nephrectomy. Data table show number of patients with a functioning graft at Year 3. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Graft Survival at Year 2 | 2 years after start of AMR treatment in feeder study (16-HMedIdeS-12) | Graft survival is defined as time from start of AMR treatment in feeder study (16-HMedIdeS-12) to graft loss. Graft loss is defined as permanent return to dialysis for at least 6 weeks, re-transplantation, or nephrectomy. |
| Overall Graft Survival at Year 1 | 1 year after start of AMR treatment in feeder study (16-HMedIdeS-12) | Graft survival is defined as time from start of AMR treatment in feeder study (16-HMedIdeS-12) to graft loss. Graft loss is defined as permanent return to dialysis for at least 6 weeks, re-transplantation, or nephrectomy. |
| Patient Survival at Year 3 | 3 years after start of AMR treatment in feeder study (16-HMedIdeS-12) | Overall patient survival is defined as time from start of AMR treatment in feeder study (16-HMedIdeS-12) to death for any cause. |
| Kidney Function as Evaluated by eGFR | 1, 2 and 3 years after start of AMR treatment in feeder study (16-HMedIdeS-12) | Estimated glomerular filtration rate (eGFR) was calculated as described by the Modification of Diet in Renal Disease Study (MDRD) equation. eGFR is a measure of kidney function. eGFR for a kidney with normal function is 90 mL/min/1.72m2. Kidney disease is characterised by a decreased eGFR value. |
| Kidney Function as Evaluated by S/P-creatinine | 1, 2 and 3 years after start of AMR treatment in feeder study (16-HMedIdeS-12) | S/P-creatinine is a measure of kidney function. Kidney disease is characterized by an increased S/P-creatinine level. |
| Number of Participants With Presumed or Biopsy Proven AMR Episodes | 3 years after start of AMR treatment in feeder study (16-HMedIdeS-12) | Information about rejection episodes will be collected, according to Banff 2017 or later classification. For-cause biopsies together with contemporaneous local DSA analyses, kidney function parameters (creatinine, albumin/creatinine ratio in urine) and treatments (e.g. plasma exchange and IVIg) will be collected to assess the rejection episodes. |
| Number of Participants With Presumed or Biopsy-proven Rejection Episodes (Other Than AMR Episodes) | 3 years after start of AMR treatment in feeder study (16-HMedIdeS-12) | Information about rejection episodes will be collected, according to Banff 2017 or later classification. For-cause biopsies together with contemporaneous local DSA analyses, kidney function parameters (creatinine, albumin/creatinine ratio in urine) and treatments (e.g. plasma exchange and IVIg) will be collected to assess the rejection episodes. |
| DSA Levels | 1, 2 and 3 years after start of AMR treatment in feeder study (16-HMedIdeS-12) | DSA levels will be measured using single antigen bead human leukocyte antigen (SAB-HLA) assay |
| ADA Levels | 1,2 and 3 years after start of AMR treatment in feeder study (16-HMedIdeS-12) | The immunogenicity of imlifidase will be assessed by measuring ADA levels. |
Countries
Austria, France, Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 No treatment is given in this long-term follow-up study. In the feeder study (16-HMedIdeS-12) the patients in this group were treated with imlifidase.
Imlifidase: Immunoglobulin G degrading enzyme of Streptococcus pyogenes | 11 |
| Plasma Exchange (PE) Treatment in Feeder Study 16-HMedIdeS-12 No treatment is given in this long-term follow-up study. In the feeder study (16-HMedIdeS-12) the patients in this group were treated with PE. | 7 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Graft loss | 2 | 1 |
| Overall Study | Patient not eligible as no AMR in feeder trial | 1 | 0 |
| Overall Study | Sponsor decision | 0 | 2 |
| Overall Study | Study terminated by sponsor | 5 | 3 |
Baseline characteristics
| Characteristic | Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | Plasma Exchange (PE) Treatment in Feeder Study 16-HMedIdeS-12 | Total |
|---|---|---|---|
| Age, Continuous | 45.9 years STANDARD_DEVIATION 17.6 | 48.0 years STANDARD_DEVIATION 13.5 | 46.7 years STANDARD_DEVIATION 15.8 |
| BMI | 27.1 kg/m^2 STANDARD_DEVIATION 6.9 | 29.0 kg/m^2 STANDARD_DEVIATION 7.1 | 27.8 kg/m^2 STANDARD_DEVIATION 6.8 |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 8 Participants | 6 Participants | 14 Participants |
| Region of Enrollment Austria | 1 participants | 3 participants | 4 participants |
| Region of Enrollment France | 8 participants | 2 participants | 10 participants |
| Region of Enrollment Germany | 2 participants | 2 participants | 4 participants |
| Sex: Female, Male Female | 5 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Male | 6 Participants | 3 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 7 |
| other Total, other adverse events | 0 / 11 | 0 / 7 |
| serious Total, serious adverse events | 0 / 11 | 0 / 7 |
Outcome results
Primary
Overall Graft Survival at Year 3
Graft survival is defined as time from start of AMR treatment in feeder study (16-HMedIdeS-12) to graft loss. Graft loss is defined as permanent return to dialysis for at least 6 weeks, re-transplantation, or nephrectomy. Data table show number of patients with a functioning graft at Year 3.
Time frame: 3 years after start of AMR treatment in feeder study (16-HMedIdeS-12)
Population: Due to the premature termination of the trial, 7 patients in the Imlifidase treatment group and 6 patients in the Plasma exchange treatment group had no graft survival data for the 3 year timepoint
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | Overall Graft Survival at Year 3 | Number of patients with a functioning graft | 2 Participants |
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | Overall Graft Survival at Year 3 | Number of patients with graft loss | 2 Participants |
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | Overall Graft Survival at Year 3 | Censored (patients being censored up to the time point) | 7 Participants |
| Plasma Exchange (PE) Treatment in Feeder Study 16-HMedIdeS-12 | Overall Graft Survival at Year 3 | Number of patients with a functioning graft | 0 Participants |
| Plasma Exchange (PE) Treatment in Feeder Study 16-HMedIdeS-12 | Overall Graft Survival at Year 3 | Number of patients with graft loss | 1 Participants |
| Plasma Exchange (PE) Treatment in Feeder Study 16-HMedIdeS-12 | Overall Graft Survival at Year 3 | Censored (patients being censored up to the time point) | 6 Participants |
Secondary
ADA Levels
The immunogenicity of imlifidase will be assessed by measuring ADA levels.
Time frame: 1,2 and 3 years after start of AMR treatment in feeder study (16-HMedIdeS-12)
Population: Only patients exposed to imlifidase were assessed for anti-imlifidase antibodies (ADA).~Due to premature termination of the trial by the Sponsor, some imlifidase treated patients have no ADA assessments done at Year 1, Year 2 and Year 3
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | ADA Levels | 1 year post dosing | 75 mg/L | Geometric Coefficient of Variation 405 |
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | ADA Levels | 2 years post dosing | 41 mg/L | Geometric Coefficient of Variation 1426 |
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | ADA Levels | 3 years post dosing | 15 mg/L | — |
Secondary
DSA Levels
DSA levels will be measured using single antigen bead human leukocyte antigen (SAB-HLA) assay
Time frame: 1, 2 and 3 years after start of AMR treatment in feeder study (16-HMedIdeS-12)
Population: Due to premature termination of the trial by the Sponsor, some patients have no DSA assessments done at Year 1, Year 2 and Year 3 and no data were collected for Year 3 in the Plasma exchange treatment in feeder Study 16-HMedIdeS-12 arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | DSA Levels | 2 years post dosing | 2156 Mean Fluorescence Intensity | Standard Deviation 1025 |
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | DSA Levels | 1 year post dosing | 5964 Mean Fluorescence Intensity | Standard Deviation 5539 |
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | DSA Levels | 3 years post dosing | 974 Mean Fluorescence Intensity | — |
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | DSA Levels | Visit 2 - feeder trial pre-treatment | 10764 Mean Fluorescence Intensity | Standard Deviation 7603 |
| Plasma Exchange (PE) Treatment in Feeder Study 16-HMedIdeS-12 | DSA Levels | 1 year post dosing | 3672 Mean Fluorescence Intensity | Standard Deviation 643 |
| Plasma Exchange (PE) Treatment in Feeder Study 16-HMedIdeS-12 | DSA Levels | Visit 2 - feeder trial pre-treatment | 15794 Mean Fluorescence Intensity | Standard Deviation 5897 |
| Plasma Exchange (PE) Treatment in Feeder Study 16-HMedIdeS-12 | DSA Levels | 2 years post dosing | 12362 Mean Fluorescence Intensity | — |
Secondary
Kidney Function as Evaluated by eGFR
Estimated glomerular filtration rate (eGFR) was calculated as described by the Modification of Diet in Renal Disease Study (MDRD) equation. eGFR is a measure of kidney function. eGFR for a kidney with normal function is 90 mL/min/1.72m2. Kidney disease is characterised by a decreased eGFR value.
Time frame: 1, 2 and 3 years after start of AMR treatment in feeder study (16-HMedIdeS-12)
Population: Due to the premature termination of the trial a large proportion of the patients did not complete the trial and no data were collected for Year 3 in the Plasma exchange treatment in feeder Study 16-HMedIdeS-12 arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | Kidney Function as Evaluated by eGFR | Year 1 | 30.1 mL/min/1.73 m^2 | Standard Deviation 20.9 |
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | Kidney Function as Evaluated by eGFR | Year 2 | 41.2 mL/min/1.73 m^2 | Standard Deviation 6.4 |
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | Kidney Function as Evaluated by eGFR | Year 3 | 30.5 mL/min/1.73 m^2 | — |
| Plasma Exchange (PE) Treatment in Feeder Study 16-HMedIdeS-12 | Kidney Function as Evaluated by eGFR | Year 1 | 36.6 mL/min/1.73 m^2 | Standard Deviation 12.3 |
| Plasma Exchange (PE) Treatment in Feeder Study 16-HMedIdeS-12 | Kidney Function as Evaluated by eGFR | Year 2 | 39.7 mL/min/1.73 m^2 | — |
Secondary
Kidney Function as Evaluated by S/P-creatinine
S/P-creatinine is a measure of kidney function. Kidney disease is characterized by an increased S/P-creatinine level.
Time frame: 1, 2 and 3 years after start of AMR treatment in feeder study (16-HMedIdeS-12)
Population: Due to premature termination of the trial by the Sponsor, only very few patients had assessments at Year 2 and Year 3 and no data were collected for Year 3 in the Plasma exchange treatment in feeder Study 16-HMedIdeS-12 arm.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | Kidney Function as Evaluated by S/P-creatinine | Year 1 | 297 umol/L |
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | Kidney Function as Evaluated by S/P-creatinine | Year 2 | 130 umol/L |
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | Kidney Function as Evaluated by S/P-creatinine | Year 3 | 144 umol/L |
| Plasma Exchange (PE) Treatment in Feeder Study 16-HMedIdeS-12 | Kidney Function as Evaluated by S/P-creatinine | Year 1 | 187 umol/L |
| Plasma Exchange (PE) Treatment in Feeder Study 16-HMedIdeS-12 | Kidney Function as Evaluated by S/P-creatinine | Year 2 | 187 umol/L |
Secondary
Number of Participants With Presumed or Biopsy Proven AMR Episodes
Information about rejection episodes will be collected, according to Banff 2017 or later classification. For-cause biopsies together with contemporaneous local DSA analyses, kidney function parameters (creatinine, albumin/creatinine ratio in urine) and treatments (e.g. plasma exchange and IVIg) will be collected to assess the rejection episodes.
Time frame: 3 years after start of AMR treatment in feeder study (16-HMedIdeS-12)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | Number of Participants With Presumed or Biopsy Proven AMR Episodes | 9 Participants |
| Plasma Exchange (PE) Treatment in Feeder Study 16-HMedIdeS-12 | Number of Participants With Presumed or Biopsy Proven AMR Episodes | 6 Participants |
Secondary
Number of Participants With Presumed or Biopsy-proven Rejection Episodes (Other Than AMR Episodes)
Information about rejection episodes will be collected, according to Banff 2017 or later classification. For-cause biopsies together with contemporaneous local DSA analyses, kidney function parameters (creatinine, albumin/creatinine ratio in urine) and treatments (e.g. plasma exchange and IVIg) will be collected to assess the rejection episodes.
Time frame: 3 years after start of AMR treatment in feeder study (16-HMedIdeS-12)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | Number of Participants With Presumed or Biopsy-proven Rejection Episodes (Other Than AMR Episodes) | 3 Participants |
| Plasma Exchange (PE) Treatment in Feeder Study 16-HMedIdeS-12 | Number of Participants With Presumed or Biopsy-proven Rejection Episodes (Other Than AMR Episodes) | 4 Participants |
Secondary
Overall Graft Survival at Year 1
Graft survival is defined as time from start of AMR treatment in feeder study (16-HMedIdeS-12) to graft loss. Graft loss is defined as permanent return to dialysis for at least 6 weeks, re-transplantation, or nephrectomy.
Time frame: 1 year after start of AMR treatment in feeder study (16-HMedIdeS-12)
Population: Due to the premature termination of the trial, 1 patient in each treatment group have no data for Year 1.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | Overall Graft Survival at Year 1 | Number of patients with a functioning graft | 8 Participants |
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | Overall Graft Survival at Year 1 | Number of patients with graft loss | 2 Participants |
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | Overall Graft Survival at Year 1 | Censored (patients being censored up to the time point) | 1 Participants |
| Plasma Exchange (PE) Treatment in Feeder Study 16-HMedIdeS-12 | Overall Graft Survival at Year 1 | Number of patients with a functioning graft | 5 Participants |
| Plasma Exchange (PE) Treatment in Feeder Study 16-HMedIdeS-12 | Overall Graft Survival at Year 1 | Number of patients with graft loss | 1 Participants |
| Plasma Exchange (PE) Treatment in Feeder Study 16-HMedIdeS-12 | Overall Graft Survival at Year 1 | Censored (patients being censored up to the time point) | 1 Participants |
Secondary
Overall Graft Survival at Year 2
Graft survival is defined as time from start of AMR treatment in feeder study (16-HMedIdeS-12) to graft loss. Graft loss is defined as permanent return to dialysis for at least 6 weeks, re-transplantation, or nephrectomy.
Time frame: 2 years after start of AMR treatment in feeder study (16-HMedIdeS-12)
Population: Due to the premature termination of the trial, 6 patients in the Imlifidase treatment group and 4 patients in the Plasma exchange treatment group have no graft survival data for Year 2.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | Overall Graft Survival at Year 2 | Number of patients with a functioning graft | 3 Participants |
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | Overall Graft Survival at Year 2 | Number of patients with graft loss | 2 Participants |
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | Overall Graft Survival at Year 2 | Censored (patients being censored up to the time point) | 6 Participants |
| Plasma Exchange (PE) Treatment in Feeder Study 16-HMedIdeS-12 | Overall Graft Survival at Year 2 | Number of patients with a functioning graft | 2 Participants |
| Plasma Exchange (PE) Treatment in Feeder Study 16-HMedIdeS-12 | Overall Graft Survival at Year 2 | Number of patients with graft loss | 1 Participants |
| Plasma Exchange (PE) Treatment in Feeder Study 16-HMedIdeS-12 | Overall Graft Survival at Year 2 | Censored (patients being censored up to the time point) | 4 Participants |
Secondary
Patient Survival at Year 3
Overall patient survival is defined as time from start of AMR treatment in feeder study (16-HMedIdeS-12) to death for any cause.
Time frame: 3 years after start of AMR treatment in feeder study (16-HMedIdeS-12)
Population: Due to the premature termination of the trial, 9 patients in the Imlifidase treatment group and 7 patients in the Plasma exchange treatment group have no survival data for the 3 year timepoint.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | Patient Survival at Year 3 | At risk (patients being at risk for event at the time point) | 2 Participants |
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | Patient Survival at Year 3 | Event (patients having events up to the time point) | 0 Participants |
| Imlifidase Treatment in Feeder Study 16-HMedIdeS-12 | Patient Survival at Year 3 | Censored (patients being censored up to the time point) | 9 Participants |
| Plasma Exchange (PE) Treatment in Feeder Study 16-HMedIdeS-12 | Patient Survival at Year 3 | At risk (patients being at risk for event at the time point) | 0 Participants |
| Plasma Exchange (PE) Treatment in Feeder Study 16-HMedIdeS-12 | Patient Survival at Year 3 | Event (patients having events up to the time point) | 0 Participants |
| Plasma Exchange (PE) Treatment in Feeder Study 16-HMedIdeS-12 | Patient Survival at Year 3 | Censored (patients being censored up to the time point) | 7 Participants |