Not provided
Not provided
Not provided
Not provided
Not provided
Company decision, not due to any safety reason
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
The purpose of this study is to assess whether imlifidase in combination with bortezomib, belatacept, rituximab and IVIg can suppress donor specific antibodies (DSA) and the occurrence of antibody-mediated rejection (AMR) in highly sensitized patients with chronic kidney disease with a positive crossmatch towards their living donor during a period of 3 months from transplantation.
Imlifidase is an immunoglobulin G (IgG)-degrading enzyme of Streptococcus pyogenes that is highly specific for IgG. The cleavage of IgG generates one F(ab')2- and one homodimeric Fc-fragment and efficiently neutralizes Fc-mediated activities of IgG. Clinical studies with imlifidase have demonstrated that the treatment enables transplantation in patients otherwise highly unlikely to be transplanted, by converting a positive crossmatch to a negative.
However, as with other desensitization methods, DSA tend to reappear within weeks after treatment and transplantation, which may cause AMR and increased risk of graft loss. In this study, treatment with imlifidase in combination with approved drugs that prevent or suppress DSA rebound by targeting antibody-producing plasma-cells and their B-cell precursors is suggested. These drugs include (i) bortezomib, a proteasome inhibitor which has activity against mature plasma cells, the source of DSA, (ii) belatacept, a fusion protein which is crucial in blocking T-cell co-stimulation and which is effective in reducing de novo DSA generation in humans, (iii) rituximab, an anti-CD20 monoclonal antibody that targets B-cells and which is an immunomodulatory agent, and (iv) intravenous immunoglobulin (IVIg) which is commonly used in desensitization regimens and for the treatment of AMR.
After being informed about the study and potential risks, all patients giving written informed consent will undergo a 2-week screening period to determine eligibility for study entry. Patients who meet the eligibility requirements will then start treatment with belatacept and bortezomib about 3 weeks prior to the imlifidase infusion and transplantation. Rituximab will be initiated 8 days after transplantation and IVIg 10 days after transplantation. Induction and maintenance immunosuppression will also be administered. The patients will be hospitalized for approximately 2 weeks following transplantation and after that 9 follow-up visits to the clinic will take place up to 6 months after transplantation.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Imlifidase | Experimental | Imlifidase is administered intravenously as one dose of 0.25 mg/kg over 15 minutes within the 24-hour period prior to transplantation. (A second dose may be given if the crossmatch test at 4 hours after the first dose remains positive.) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Imlifidase | Drug | Imlifidase is an immunoglobulin G (IgG)-degrading enzyme of Streptococcus pyogenes that is highly specific for IgG. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Proportion of Patients With DSA Rebound | The recurrence of DSA may cause AMR and increased risk of graft loss. Due to the early termination of the trial the primary endpoint was assessed as the incidence of DSA rebound of either immunodominant or total DSA to a mean fluorescence intensity (MFI) level that was ≥50% of the pre-imlifidase value up to 3 months after transplantation (trial day 91). | Up to 3 months after transplantation |
| Measure | Description | Time Frame |
|---|---|---|
| Proportion of Patients With Kidney Biopsy Proven AMR | The standardized international Banff classification 2019 for assessment of renal allograft biopsies will be used to assess AMRs reported from the study based on for cause and protocol biopsies. | Up to 6 months after transplantation |
| Proportion of Patient With DSA Rebound |
Not provided
Inclusion Criteria:
Signed Informed Consent obtained before any trial-related procedures
Male or female age 18 to 70 years at the time of screening
Highly sensitized patients registered on the UNOS waiting list for kidney transplantation, with either of the following:
A positive crossmatch towards a living donor
Willingness and ability to comply with the protocol
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Clinical Operations | Hansa Biopharma AB | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| NYU Langone Health Transplant Institute | New York | New York | 10016 | United States |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
The Sponsor decided to prematurely terminate the trial after 3 of the 12 patients had been treated and transplanted in the trial due to prioritization of internal resources. This decision was unrelated to either safety or efficacy, no safety issues were raised during the conduct of the trial.
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Imlifidase | Imlifidase is administered intravenously as one dose of 0.25 mg/kg over 15 minutes within the 24-hour period prior to transplantation. (A second dose may be given if the crossmatch test at 4 hours after the first dose remains positive.) |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Imlifidase | Imlifidase is administered intravenously as one dose of 0.25 mg/kg over 15 minutes within the 24-hour period prior to transplantation. (A second dose may be given if the crossmatch test at 4 hours after the first dose remains positive.) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Proportion of Patients With DSA Rebound | The recurrence of DSA may cause AMR and increased risk of graft loss. Due to the early termination of the trial the primary endpoint was assessed as the incidence of DSA rebound of either immunodominant or total DSA to a mean fluorescence intensity (MFI) level that was ≥50% of the pre-imlifidase value up to 3 months after transplantation (trial day 91). | Posted | Count of Participants | Participants | No | Up to 3 months after transplantation |
|
AEs were collected on the AE CRF for each patient, from the time of signing of the informed consent and throughout the trial including the follow-up period. 35 Days in screening phase plus 181 Days in trial, a total of 216 Days.
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Imlifidase | Imlifidase is administered intravenously as one dose of 0.25 mg/kg over 15 minutes within the 24-hour period prior to transplantation. (A second dose may be given if the crossmatch test at 4 hours after the first dose remains positive.) |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal pain | Gastrointestinal disorders | MedDRA version 26.0 | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA version 26.0 | Non-systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Hansa Biopharma AB | +46 46 16 56 70 | clinicalstudyinfo@hansabiopharma.com |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 23, 2022 | Mar 5, 2025 | Prot_SAP_001.pdf |
Not provided
Not provided
Not provided
| ID | Term |
|---|---|
| C442815 | Mac-1-like protein, Streptococcus |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
See description to primary outcome measure |
| Up to 6 months after transplantation |
| Proportion of Patients With Negative FCXM | Imlifidase is highly efficacious in converting a positive crossmatch to a negative | Up to 24 hours after imlifidase treatment |
| Levels of DSA | Analysis of DSAs before and after imlifidase will be done. The mean fluorescence intensity (MFI) will be presented for the individual patients' DSAs. | Within 4 hours before imlifidase until Day 181 |
| Levels of Complement Binding (C1q) DSA | Analysis of C1q DSAs before and after imlifidase will be done. The mean fluorescence intensity (MFI) will be presented for the individual patients' C1q DSAs. | Within 4 hours before imlifidase until Day 181 |
| Number of Participants With Graft Survival | Graft survival will be summarized by end of trial. | 6 months after transplantation |
| Patients Survival | Patient survival will be summarized by end of trial. | 6 months after transplantation |
| Number of Participants With Adverse Events (AEs) | Safety is assessed as type, frequency and intensity of adverse events (AEs)/serious adverse events (SAEs) including clinically relevant changes in clinical laboratory tests, vital signs and ECG) | Up to 6 months after transplantation |
| Kidney Function Assessed by Creatinine | P-creatinine is a measure of kidney function. | Up to 6 months after transplantation |
| Kidney Function Assessed by Estimated Glomerular Filtration Rate (eGFR) | Estimated glomerular filtration rate (eGFR) is a measure of kidney function. eGFR will be calculated as described by the modification of diet in renal disease (MDRD) equation. eGFR for a kidney with normal function is 90 mL/min/1.73m2. Kidney disease is characterized by a decreased eGFR value. | Up to 6 months after transplantation |
| Kidney Function Assessed by Protein/Creatinine Ratio in Urine | The protein/creatinine ratio in urine is a measure of kidney function. Will be measured unless patients are anuric. | Up to 6 months after transplantation |
| Imlifidase Pharmacokinetics (AUC) | AUC = Area under the imlifidase plasma concentration versus time curve | Within 4 hours before imlifidase dose until Day 15 |
| Imlifidase Pharmacokinetics (Cmax) | Cmax = Maximum observed plasma concentration of imlifidase following dosing | Within 4 hours before imlifidase dose until Day 15 |
| Imlifidase Pharmacokinetics (Tmax) | tmax = Time point for maximum observed plasma concentration of imlifidase following dosing | Within 4 hours before imlifidase dose until Day 15 |
| Imlifidase Pharmacokinetics (t1/2) | t1/2 = Terminal half-life of imlifidase, the time taken for concentration of imlifidase to decrease from its maximum concentration (Cmax) to half of Cmax in the blood plasma. t1/2 alpha = alpha phase (distribution/elimination) half-life, an initial phase of rapid decrease in plasma concentration. t1/2 beta = beta phase (elimination) half-life, a phase of gradual decrease in plasma concentration after the alpha phase. | Within 4 hours before imlifidase dose until Day 15 |
| Imlifidase Pharmacokinetics (CL) | CL = Clearance of imlifidase | Within 4 hours before imlifidase dose until Day 15 |
| Imlifidase Pharmacokinetics (Vz) | Vz = Apparent volume of distribution during terminal phase | Within 4 hours before imlifidase dose until Day 15 |
| Pharmacodynamics | Concentration of IgG in patient serum will be measured. Scoring of IgG fragments will be done. | Within 4 hours before imlifidase dose until Day 10 |
| Anti-drug Antibodies (ADA) Levels | Immunogenicity towards imlifidase will be assessed by the measurement of ADA levels in patient serum using a customized ImmunoCAP analysis. | Up to 6 months after imlifidase |
| Change in Patient-reported Life Participation, as Measured PROMIS-SF-8a | The PROMIS Social Health domain "Ability to participate in social roles & activities PROMIS-SF-8" will be used as a measure of the patients' health related quality of life. | At screening and Day 181 |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Units | Counts |
|---|
| Participants |
|
|
| Secondary | Proportion of Patients With Kidney Biopsy Proven AMR | The standardized international Banff classification 2019 for assessment of renal allograft biopsies will be used to assess AMRs reported from the study based on for cause and protocol biopsies. | Posted | Count of Participants | Participants | No | Up to 6 months after transplantation |
|
|
|
| Secondary | Proportion of Patient With DSA Rebound | See description to primary outcome measure | Posted | Count of Participants | Participants | No | Up to 6 months after transplantation |
|
|
|
| Secondary | Proportion of Patients With Negative FCXM | Imlifidase is highly efficacious in converting a positive crossmatch to a negative | Posted | Count of Participants | Participants | No | Up to 24 hours after imlifidase treatment |
|
|
|
| Secondary | Levels of DSA | Analysis of DSAs before and after imlifidase will be done. The mean fluorescence intensity (MFI) will be presented for the individual patients' DSAs. | Only 2 of 3 patients had data for DSA collected at the Day 181 timepoint, for patient 2 data from an unscheduled visit at day 139 is presented. | Posted | Number | MFI | Within 4 hours before imlifidase until Day 181 |
|
|
|
| Secondary | Levels of Complement Binding (C1q) DSA | Analysis of C1q DSAs before and after imlifidase will be done. The mean fluorescence intensity (MFI) will be presented for the individual patients' C1q DSAs. | Samples for assessment of DSA, including Cq1 DSA, were collected. However, the central laboratory assigned to Cq1 DSA analyzes was never activated due to the premature trial termination, hence analysis of Cq1 DSA was not performed. | Posted | Within 4 hours before imlifidase until Day 181 |
|
|
| Secondary | Number of Participants With Graft Survival | Graft survival will be summarized by end of trial. | Posted | Count of Participants | Participants | No | 6 months after transplantation |
|
|
|
| Secondary | Patients Survival | Patient survival will be summarized by end of trial. | Posted | Count of Participants | Participants | No | 6 months after transplantation |
|
|
|
| Secondary | Number of Participants With Adverse Events (AEs) | Safety is assessed as type, frequency and intensity of adverse events (AEs)/serious adverse events (SAEs) including clinically relevant changes in clinical laboratory tests, vital signs and ECG) | Results for adverse events is presented in the section Reported Adverse Events. | Posted | Count of Participants | Participants | No | Up to 6 months after transplantation |
|
|
|
| Secondary | Kidney Function Assessed by Creatinine | P-creatinine is a measure of kidney function. | Posted | Median | Full Range | μmol/L | Up to 6 months after transplantation |
|
|
|
| Secondary | Kidney Function Assessed by Estimated Glomerular Filtration Rate (eGFR) | Estimated glomerular filtration rate (eGFR) is a measure of kidney function. eGFR will be calculated as described by the modification of diet in renal disease (MDRD) equation. eGFR for a kidney with normal function is 90 mL/min/1.73m2. Kidney disease is characterized by a decreased eGFR value. | Posted | Median | Full Range | mL/min/1.73m2 | Up to 6 months after transplantation |
|
|
|
| Secondary | Kidney Function Assessed by Protein/Creatinine Ratio in Urine | The protein/creatinine ratio in urine is a measure of kidney function. Will be measured unless patients are anuric. | Only 2 of the 3 patients had data collected at the Day 181 timepoint. | Posted | Median | Full Range | mg/g | Up to 6 months after transplantation |
|
|
|
| Secondary | Imlifidase Pharmacokinetics (AUC) | AUC = Area under the imlifidase plasma concentration versus time curve | Posted | Median | Full Range | h×μg/mL | Within 4 hours before imlifidase dose until Day 15 |
|
|
|
| Secondary | Imlifidase Pharmacokinetics (Cmax) | Cmax = Maximum observed plasma concentration of imlifidase following dosing | Posted | Median | Full Range | μg/mL | Within 4 hours before imlifidase dose until Day 15 |
|
|
|
| Secondary | Imlifidase Pharmacokinetics (Tmax) | tmax = Time point for maximum observed plasma concentration of imlifidase following dosing | Posted | Median | Full Range | h | Within 4 hours before imlifidase dose until Day 15 |
|
|
|
| Secondary | Imlifidase Pharmacokinetics (t1/2) | t1/2 = Terminal half-life of imlifidase, the time taken for concentration of imlifidase to decrease from its maximum concentration (Cmax) to half of Cmax in the blood plasma. t1/2 alpha = alpha phase (distribution/elimination) half-life, an initial phase of rapid decrease in plasma concentration. t1/2 beta = beta phase (elimination) half-life, a phase of gradual decrease in plasma concentration after the alpha phase. | Posted | Median | Full Range | h | Within 4 hours before imlifidase dose until Day 15 |
|
|
|
| Secondary | Imlifidase Pharmacokinetics (CL) | CL = Clearance of imlifidase | Posted | Median | Full Range | mL/h/kg | Within 4 hours before imlifidase dose until Day 15 |
|
|
|
| Secondary | Imlifidase Pharmacokinetics (Vz) | Vz = Apparent volume of distribution during terminal phase | Posted | Median | Full Range | L/kg | Within 4 hours before imlifidase dose until Day 15 |
|
|
|
| Secondary | Pharmacodynamics | Concentration of IgG in patient serum will be measured. Scoring of IgG fragments will be done. | Posted | Median | Full Range | g/L | Within 4 hours before imlifidase dose until Day 10 |
|
|
|
| Secondary | Anti-drug Antibodies (ADA) Levels | Immunogenicity towards imlifidase will be assessed by the measurement of ADA levels in patient serum using a customized ImmunoCAP analysis. | Posted | Median | Full Range | mg/L | Up to 6 months after imlifidase |
|
|
|
| Secondary | Change in Patient-reported Life Participation, as Measured PROMIS-SF-8a | The PROMIS Social Health domain "Ability to participate in social roles & activities PROMIS-SF-8" will be used as a measure of the patients' health related quality of life. | PROMIS-SF-8 sores are calculate using the PROMIS® Short Form v2.0-Ability to Participate in Social Roles and Activities 8a scoring manual. The total scale raw score was translated into a T-score for each participant. The T-score rescales the raw score into a standardized score with a mean of 50 and a standard deviation (SD) of 10, i.e. a T-score of 40 is one SD below the mean. The lowest possible T-score is 25.9 and the highest possible score is 65.4, a higher score means a better outcome. | Posted | Median | Full Range | score on a scale | At screening and Day 181 |
|
|
|
| 0 |
| 3 |
| 2 |
| 3 |
| 3 |
| 3 |
| Post procedural discharge | Injury, poisoning and procedural complications | MedDRA version 26.0 | Non-systematic Assessment |
|
| Wound evisceration | Infections and infestations | MedDRA version 26.0 | Non-systematic Assessment |
|
| Donor specific antibody present | Investigations | MedDRA version 26.0 | Non-systematic Assessment |
|
| International normalised ratio increased | Investigations | MedDRA version 26.0 | Non-systematic Assessment |
|
| Hypotension | Vascular disorders | MedDRA version 26.0 | Non-systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA version 26.0 | Non-systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA version 26.0 | Non-systematic Assessment |
|
| Haemorrhoids | Gastrointestinal disorders | MedDRA version 26.0 | Non-systematic Assessment |
|
| Small intestinal obstruction | Gastrointestinal disorders | MedDRA version 26.0 | Non-systematic Assessment |
|
| Abdominal infection | Infections and infestations | MedDRA version 26.0 | Non-systematic Assessment |
|
| Delayed graft function | Injury, poisoning and procedural complications | MedDRA version 26.0 | Non-systematic Assessment |
|
| Infusion related reaction | Injury, poisoning and procedural complications | MedDRA version 26.0 | Non-systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA version 26.0 | Non-systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | MedDRA version 26.0 | Non-systematic Assessment |
|
| Neutrophil count decreased | Investigations | MedDRA version 26.0 | Non-systematic Assessment |
|
| White blood cell count decreased | Investigations | MedDRA version 26.0 | Non-systematic Assessment |
|
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA version 26.0 | Non-systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA version 26.0 | Non-systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA version 26.0 | Non-systematic Assessment |
|
| Paraesthesia | Nervous system disorders | MedDRA version 26.0 | Non-systematic Assessment |
|
| Renal infarct | Renal and urinary disorders | MedDRA version 26.0 | Non-systematic Assessment |
|
| Deep vein thrombosis | Vascular disorders | MedDRA version 26.0 | Non-systematic Assessment |
|
Not provided
Not provided
|
| Patient 2, pre-dose |
|
|
| Patient 2, Day 139 |
|
|
| Patient 3, pre-dose |
|
|
| Patient 3, Day 181 |
|
|
|