Kidney Transplantation in Highly Sensitized Patients
Conditions
Keywords
Highly sensitized, Kidney transplantation, Renal transplantation
Brief summary
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.
Detailed description
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.
Interventions
DRUGImlifidase
Imlifidase is an immunoglobulin G (IgG)-degrading enzyme of Streptococcus pyogenes that is highly specific for IgG.
Sponsors
Hansa Biopharma AB
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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: * cPRA ≥ 99.9% * cPRA ≥ 98% and have been in kidney paired donation or kidney paired exchange programs for at least 1 year * A positive crossmatch towards a living donor * Willingness and ability to comply with the protocol
Exclusion criteria
* Previous treatment with imlifidase * Previous high dose IVIg treatment (2 g/kg) within 28 days prior to imlifidase treatment * Breast-feeding or pregnancy * Women of child-bearing potential not willing or able to practice FDA-approved forms of contraception. Two medically acceptable methods of highly effective contraception must be used for the duration of the study (e.g. oral, transdermal, intravaginal, injectable or implantable contraceptive; intrauterine device; intrauterine hormone-releasing system; vasectomized partner; bilateral tubal occlusion; or double-barrier method). For a woman to be considered postmenopausal this ascertainment must be made according to medical records and clinical history and may be aided by measurement of elevated postmenopausal serum gonadotropin levels (FSH). * ABO blood group incompatible transplantations (A2 and A2B kidneys will not be accepted for B recipients) * Positive serology for HIV * Clinical signs of HBV, HCV, CMV, or EBV infection * EBV seronegative or with unknown EBV serostatus * Positive SARS-CoV-2 tests at any time point from screening to transplantation * Active tuberculosis * Ongoing serious infections as judged by the investigator * Severe other conditions requiring treatment and close monitoring e.g. cardiac failure ≥ grade 4 (New York Heart Association), unstable coronary disease or oxygen dependent respiratory disease * A history of a proven hypercoagulable condition * Present, or history of, thrombotic thrombocytopenic purpura (TTP) or known familial history of TTP * Intake of investigational drugs (other than imlifidase) within 5 half-lives * Contemporaneous participation in a medical device study * Known allergy/sensitivity (except local reactions) to imlifidase or to any drug (or the excipients) specified in the protocol * Known mental incapacity or language barriers precluding adequate understanding of the Informed Consent information and the trial activities * Inability by the judgement of the investigator to participate in the trial for any other reason
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With DSA Rebound | Up to 3 months after transplantation | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patient With DSA Rebound | Up to 6 months after transplantation | See description to primary outcome measure |
| Proportion of Patients With Negative FCXM | Up to 24 hours after imlifidase treatment | Imlifidase is highly efficacious in converting a positive crossmatch to a negative |
| Levels of DSA | Within 4 hours before imlifidase until Day 181 | Analysis of DSAs before and after imlifidase will be done. The mean fluorescence intensity (MFI) will be presented for the individual patients' DSAs. |
| Levels of Complement Binding (C1q) DSA | Within 4 hours before imlifidase until Day 181 | 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. |
| Number of Participants With Graft Survival | 6 months after transplantation | Graft survival will be summarized by end of trial. |
| Patients Survival | 6 months after transplantation | Patient survival will be summarized by end of trial. |
| Number of Participants With Adverse Events (AEs) | Up to 6 months after transplantation | 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) |
| Kidney Function Assessed by Creatinine | Up to 6 months after transplantation | P-creatinine is a measure of kidney function. |
| Kidney Function Assessed by Estimated Glomerular Filtration Rate (eGFR) | Up to 6 months after transplantation | 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. |
| Proportion of Patients With Kidney Biopsy Proven AMR | Up to 6 months after transplantation | 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. |
| Imlifidase Pharmacokinetics (AUC) | Within 4 hours before imlifidase dose until Day 15 | AUC = Area under the imlifidase plasma concentration versus time curve |
| Imlifidase Pharmacokinetics (Cmax) | Within 4 hours before imlifidase dose until Day 15 | Cmax = Maximum observed plasma concentration of imlifidase following dosing |
| Imlifidase Pharmacokinetics (Tmax) | Within 4 hours before imlifidase dose until Day 15 | tmax = Time point for maximum observed plasma concentration of imlifidase following dosing |
| Imlifidase Pharmacokinetics (t1/2) | Within 4 hours before imlifidase dose until Day 15 | 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. |
| Imlifidase Pharmacokinetics (CL) | Within 4 hours before imlifidase dose until Day 15 | CL = Clearance of imlifidase |
| Imlifidase Pharmacokinetics (Vz) | Within 4 hours before imlifidase dose until Day 15 | Vz = Apparent volume of distribution during terminal phase |
| Pharmacodynamics | Within 4 hours before imlifidase dose until Day 10 | Concentration of IgG in patient serum will be measured. Scoring of IgG fragments will be done. |
| Anti-drug Antibodies (ADA) Levels | Up to 6 months after imlifidase | Immunogenicity towards imlifidase will be assessed by the measurement of ADA levels in patient serum using a customized ImmunoCAP analysis. |
| Change in Patient-reported Life Participation, as Measured PROMIS-SF-8a | At screening and Day 181 | 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. |
| Kidney Function Assessed by Protein/Creatinine Ratio in Urine | Up to 6 months after transplantation | The protein/creatinine ratio in urine is a measure of kidney function. Will be measured unless patients are anuric. |
Countries
United States
Participant flow
Recruitment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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.) | 3 |
| Total | 3 |
Baseline characteristics
| Characteristic | Imlifidase |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Region of Enrollment United States | 3 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 3 |
| other Total, other adverse events | 3 / 3 |
| serious Total, serious adverse events | 2 / 3 |
Outcome results
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).
Time frame: Up to 3 months after transplantation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Imlifidase | Proportion of Patients With DSA Rebound | 0 Participants |
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.
Time frame: Up to 6 months after imlifidase
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Imlifidase | Anti-drug Antibodies (ADA) Levels | Pre-dose | 4.1 mg/L |
| Imlifidase | Anti-drug Antibodies (ADA) Levels | Day 181 | 20.5 mg/L |
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.
Time frame: At screening and Day 181
Population: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Imlifidase | Change in Patient-reported Life Participation, as Measured PROMIS-SF-8a | Screening | 53.6 score on a scale |
| Imlifidase | Change in Patient-reported Life Participation, as Measured PROMIS-SF-8a | Day 181 | 65.4 score on a scale |
Secondary
Imlifidase Pharmacokinetics (AUC)
AUC = Area under the imlifidase plasma concentration versus time curve
Time frame: Within 4 hours before imlifidase dose until Day 15
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imlifidase | Imlifidase Pharmacokinetics (AUC) | 71.9 h×μg/mL |
Secondary
Imlifidase Pharmacokinetics (CL)
CL = Clearance of imlifidase
Time frame: Within 4 hours before imlifidase dose until Day 15
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imlifidase | Imlifidase Pharmacokinetics (CL) | 3.48 mL/h/kg |
Secondary
Imlifidase Pharmacokinetics (Cmax)
Cmax = Maximum observed plasma concentration of imlifidase following dosing
Time frame: Within 4 hours before imlifidase dose until Day 15
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imlifidase | Imlifidase Pharmacokinetics (Cmax) | 3.70 μg/mL |
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.
Time frame: Within 4 hours before imlifidase dose until Day 15
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Imlifidase | Imlifidase Pharmacokinetics (t1/2) | t1/2 alpha | 6.40 h |
| Imlifidase | Imlifidase Pharmacokinetics (t1/2) | t1/2 beta | 28.3 h |
Secondary
Imlifidase Pharmacokinetics (Tmax)
tmax = Time point for maximum observed plasma concentration of imlifidase following dosing
Time frame: Within 4 hours before imlifidase dose until Day 15
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imlifidase | Imlifidase Pharmacokinetics (Tmax) | 1.13 h |
Secondary
Imlifidase Pharmacokinetics (Vz)
Vz = Apparent volume of distribution during terminal phase
Time frame: Within 4 hours before imlifidase dose until Day 15
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imlifidase | Imlifidase Pharmacokinetics (Vz) | 0.142 L/kg |
Secondary
Kidney Function Assessed by Creatinine
P-creatinine is a measure of kidney function.
Time frame: Up to 6 months after transplantation
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Imlifidase | Kidney Function Assessed by Creatinine | Day 181 | 180 μmol/L |
| Imlifidase | Kidney Function Assessed by Creatinine | Pre-dose | 506 μmol/L |
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.
Time frame: Up to 6 months after transplantation
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Imlifidase | Kidney Function Assessed by Estimated Glomerular Filtration Rate (eGFR) | Pre-dose | 11 mL/min/1.73m2 |
| Imlifidase | Kidney Function Assessed by Estimated Glomerular Filtration Rate (eGFR) | Day 181 | 35 mL/min/1.73m2 |
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.
Time frame: Up to 6 months after transplantation
Population: Only 2 of the 3 patients had data collected at the Day 181 timepoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Imlifidase | Kidney Function Assessed by Protein/Creatinine Ratio in Urine | 24h post-dose | 2158 mg/g |
| Imlifidase | Kidney Function Assessed by Protein/Creatinine Ratio in Urine | Day 181 | 1233 mg/g |
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.
Time frame: Within 4 hours before imlifidase until Day 181
Population: 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.
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.
Time frame: Within 4 hours before imlifidase until Day 181
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imlifidase | Levels of DSA | Patient 1, Day 181 | 8619 MFI |
| Imlifidase | Levels of DSA | Patient 2, pre-dose | 8526 MFI |
| Imlifidase | Levels of DSA | Patient 2, Day 139 | 2172 MFI |
| Imlifidase | Levels of DSA | Patient 3, pre-dose | 9994 MFI |
| Imlifidase | Levels of DSA | Patient 3, Day 181 | 149 MFI |
| Imlifidase | Levels of DSA | Patient 1, pre-dose | 22311 MFI |
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)
Time frame: Up to 6 months after transplantation
Population: Results for adverse events is presented in the section Reported Adverse Events.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Imlifidase | Number of Participants With Adverse Events (AEs) | 3 Participants |
Secondary
Number of Participants With Graft Survival
Graft survival will be summarized by end of trial.
Time frame: 6 months after transplantation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Imlifidase | Number of Participants With Graft Survival | 3 Participants |
Secondary
Patients Survival
Patient survival will be summarized by end of trial.
Time frame: 6 months after transplantation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Imlifidase | Patients Survival | 3 Participants |
Secondary
Pharmacodynamics
Concentration of IgG in patient serum will be measured. Scoring of IgG fragments will be done.
Time frame: Within 4 hours before imlifidase dose until Day 10
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Imlifidase | Pharmacodynamics | Pre-dose | 11.6 g/L |
| Imlifidase | Pharmacodynamics | Day 10 | 1.0 g/L |
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.
Time frame: Up to 6 months after transplantation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Imlifidase | Proportion of Patients With Kidney Biopsy Proven AMR | 1 Participants |
Secondary
Proportion of Patients With Negative FCXM
Imlifidase is highly efficacious in converting a positive crossmatch to a negative
Time frame: Up to 24 hours after imlifidase treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Imlifidase | Proportion of Patients With Negative FCXM | 3 Participants |
Secondary
Proportion of Patient With DSA Rebound
See description to primary outcome measure
Time frame: Up to 6 months after transplantation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Imlifidase | Proportion of Patient With DSA Rebound | 0 Participants |