An Long-term Follow-up Trial of Kidney Tx Patients Treated With Imlifidase or PE After an AMR

Study Overview
=================
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.

Official Title
-----------------
A Prospective, Observational Long-term Follow-up Trial of Kidney Transplant Patients Treated With Imlifidase or Plasma Exchange After an Active/Chronic Active Antibody-Mediated Rejection Episode

Conditions
-----------------
Kidney Transplant Rejection

Intervention / Treatment
-----------------
* Drug: Imlifidase


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Imlifidase treatment in feeder Study 16-HMedIdeS-12<br>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. | Drug: Imlifidase<br>* Immunoglobulin G degrading enzyme of Streptococcus pyogenes<br>* Other names: IdeS, HMED-IdeS;|
| Plasma exchange (PE) treatment in feeder Study 16-HMedIdeS-12<br>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. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 3 years after start of AMR treatment in feeder study (16-HMedIdeS-12) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall graft survival at Year 1 and 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. | 1 and 2 years after start of AMR treatment in feeder study (16-HMedIdeS-12) | 
| 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. | 3 years after start of AMR treatment in feeder study (16-HMedIdeS-12) | 
| 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. | 1, 2 and 3 years after start of AMR treatment in feeder study (16-HMedIdeS-12) | 
| 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. | 1, 2 and 3 years after start of AMR treatment in feeder study (16-HMedIdeS-12) | 
| Kidney function as evaluated by albumin/creatinine ratio (ACR) in urine | ACR in urine is a measure of kidney function. Kidney disease is characterized by an increased ACR in urine. | 1, 2 and 3 years after start of AMR treatment in feeder study (16-HMedIdeS-12) | 
| 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. | 3 years after start of AMR treatment in feeder study (16-HMedIdeS-12) | 
| 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. | 3 years after start of AMR treatment in feeder study (16-HMedIdeS-12) | 
| DSA levels | DSA levels will be measured using single antigen bead human leukocyte antigen (SAB-HLA) assay | 1, 2 and 3 years after start of AMR treatment in feeder study (16-HMedIdeS-12) | 
| ADA levels | The immunogenicity of imlifidase will be assessed by measuring ADA levels. | 1,2 and 3 years after start of AMR treatment in feeder study (16-HMedIdeS-12) |