A Phase 2 interventional study of IdeS and Kidney transplantation in Kidney Failure, Chronic, sponsored by Hansa Biopharma AB. Completed at 5 sites in 3 countries. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2021-05-20.
Sponsored by Hansa Biopharma AB · Phase 2, Interventional, and Treatment
The purpose of this study is to evaluate the effectiveness of the study drug IdeS in patients who are on the waiting list for kidney transplant and have previously undergone desensitization unsuccessfully or in whom effective desensitization will be highly unlikely. At study entry, the patients will have an available deceased or live donor with a positive crossmatch test. The study will assess IdeS efficacy and safety in removing Donor Specific Antibodies (DSAs) and thereby convert a positive crossmatch test to negative.
The study will assess the IdeS efficacy in creating a negative crossmatch test (XM) in patients who exhibit donor specific antibodies (DSA) and have a positive crossmatch test to their available live or deceased donors. The first 3 patients in this study will receive a kidney from a deceased donor. The study will primarily examine the efficacy of IdeS in creating a negative XM. The first 3 patients will receive one dose of 0.25 mg/kg BW IdeS on study day 0. If it is considered safe and negative crossmatch test is not achieved after the first dose, an additional IdeS infusion can be given within 2 days of the first infusion. The dose schedule may be increased to 0.5 mg/kg BW given once or twice after the first 3 patients have been tested. The decision to escalate the dose will be done after evaluation of safety and efficacy.
1,995 studies on the registry are indexed under Renal Insufficiency; 173 are open to participants now.
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Exclusion Criteria:
IdeS intravenous infusion
Drug: IdeS · Procedure: Kidney transplantation
One dose of 0.25 mg/kg BW IdeS on study day 0. If negative crossmatch is not achieved, a second dose can be given within 2 days of the first infusion.
Also known as: IgG endopeptidase
Performed following IdeS treatment
Number of Patients With Crossmatch Conversion (Positive to Negative)
IdeS ability to create a negative crossmatch (XM) test in patients who before treatment exhibit Donor Specific Antibodies (DSAs) and have a positive XM test to their available live or deceased donor kidney. XM was assessed using both FACS and CDC XM tests. FACS XM is a multi-staining procedure where the recipient's serum is used to stain donor cells to identify presence of DSAs in recipient's serum. T- and B-cells are identified using conjugated antibodies against CD3 and CD19. DSAs are identified using a conjugated anti-human antibody. CDC XM evaluates the cytotoxic capacity of the DSAs. The recipient's serum is mixed with donor cells prior to addition of complement. Fluorescent dyes are added and the live/dead cells (%) is scored using a fluorescent microscope. CDC XM amplified with anti-human globulin is not compatible with imlifidase and should not be used. The endpoint was met if at least one XM test was positive pre-dose and the last test within 24 h was negative.
Time frame: Within 24 hours of IdeS dosing
Number of Patients With Donor Specific Antibodies With an MFI Value >3000
Donor specific antibodies (DSA) level at different time points within 180 days after administration of IdeS. DSA levels were measured using the single antigen beads (SAB) anti-HLA assay. The levels were determined as mean fluorescence intensity (MFI). Positive DSA (i.e. HLA antibodies) were defined as having a MFI value \>3000.
Time frame: Within 180 days after administration of IdeS.
Time to Create a Negative CDC Crossmatch Test
Time to create a negative CDC crossmatch (XM) was defined as the first timepoint all CDC XM results were negative.
Time frame: 2h, 6h, 24h after administration of IdeS.
Time to Create a Negative FACS Crossmatch Test
Time to create a negative FACS crossmatch (XM) was defined as the first timepoint all FACS XM results were negative.
Time frame: 2h, 6h, and 24h after administration of IdeS
Kidney Function After IdeS Treatment Assessed by eGFR
Estimated glomerular filtration rate (eGFR) was calculated as described by the 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: Within 180 days after administration of IdeS
Serum IgG Concentration After Administration of IdeS
The patient's immunoglobulin G (IgG) is cleaved by IdeS in two steps. The first cut separates one of the heavy chains from the Fc part, generating so called single-cleaved IgG (scIgG), and the second cut separates the other heavy chain from the Fc part, thus generating one F(ab')2 fragment and one Fc fragment. The IgG concentration measured for this outcome is the sum of intact and scIgG because the assay used cannot discriminate between the two. A decrease in IgG concentration therefore represents complete cleavage of the IgG molecules to Fc and F(ab')2 fragments. Please note that intravenous IgG (IVIg) was administered Day 7.
Time frame: Within 180 days after administration of IdeS.
Pharmacokinetics - Cmax (First Dose)
Cmax = Maximum observed plasma concentration of IdeS following dosing (Non-compartmental PK analysis)
Time frame: Pre-dose to Day 14 after administration of IdeS.
Pharmacokinetics - Cmax (Second Dose)
Cmax = Maximum observed plasma concentration of IdeS following dosing (Non-compartmental PK analysis)
Time frame: Pre-dose until Day 14 after administration of IdeS
Pharmacokinetics - Tmax (First Dose)
Tmax = Time point for maximum observed plasma concentration of IdeS following dosing (Non-compartmental PK analysis)
Time frame: Pre-dose to Day 14 after administration of IdeS
Pharmacokinetics - Tmax (Second Dose)
Tmax = Time point for maximum observed plasma concentration of IdeS following dosing (Non-compartmental PK analysis)
Time frame: Pre-dose to Day 14 after administration of IdeS
Pharmacokinetics - AUC
AUC = Area under the plasma concentration versus time curve (Non-compartmental PK analysis)
Time frame: Pre-dose to Day 14 after administration of IdeS.
Pharmacokinetics - t1/2
Alpha-t1/2 = Half-life during distribution phase Beta-t1/2 = Half-life during elimination phase Non-compartmental PK analysis
Time frame: Pre-dose to Day 14 after administration of IdeS.
Pharmacokinetics - CL
CL = Clearance Non compartmental PK analysis
Time frame: Pre-dose to Day 14
Pharmacokinetics - Vss
Vss = Volume of distribution at steady state Non compartmental PK analysis
Time frame: Pre-dose to Day 14 after administration of IdeS
Pharmacokinetics - Vz
Vz = Volume of distribution during the elimination phase Non compartmental PK analysis
Time frame: Pre-dose to Day 14 after administration of IdeS.
| Milestone | One Dose of IdeS (0.25 mg/kg BW) | Two Doses of IdeS (2 x 0.25 mg/kg BW) |
|---|---|---|
| Started | 16 | 3 |
| Completed | 13 | 3 |
| Not completed | 3 | 0 |
| Withdrew: Patient graft failure - nephrectomy | 1 | 0 |
| Withdrew: Adverse event | 1 | 0 |
| Withdrew: Withdrawal by subject | 1 | 0 |
IdeS ability to create a negative crossmatch (XM) test in patients who before treatment exhibit Donor Specific Antibodies (DSAs) and have a positive XM test to their available live or deceased donor kidney. XM was assessed using both FACS and CDC XM tests. FACS XM is a multi-staining procedure where the recipient's serum is used to stain donor cells to identify presence of DSAs in recipient's serum. T- and B-cells are identified using conjugated antibodies against CD3 and CD19. DSAs are identified using a conjugated anti-human antibody. CDC XM evaluates the cytotoxic capacity of the DSAs. The recipient's serum is mixed with donor cells prior to addition of complement. Fluorescent dyes are added and the live/dead cells (%) is scored using a fluorescent microscope. CDC XM amplified with anti-human globulin is not compatible with imlifidase and should not be used. The endpoint was met if at least one XM test was positive pre-dose and the last test within 24 h was negative.
| Patients | FAS - One or Two Doses of 0.25 mg/kg BW IdeS |
|---|---|
| XM conversion within 24 h | 17 |
| No XM conversion within 24 h | 2 |
Donor specific antibodies (DSA) level at different time points within 180 days after administration of IdeS. DSA levels were measured using the single antigen beads (SAB) anti-HLA assay. The levels were determined as mean fluorescence intensity (MFI). Positive DSA (i.e. HLA antibodies) were defined as having a MFI value \>3000.
| Patients with DSA (MFI>3000) | PP - One or Two Doses of 0.25 mg/kg BW IdeS |
|---|---|
| Pre-dose | 17 |
| 2 h | 7 |
| 6 h | 3 |
| 24 h | 3 |
| 48 h | 3 |
| 96 h | 6 |
| Day 7 | 9 |
| Day 14 | 13 |
| Day 28 | 10 |
| Day 90 | 8 |
| Day 180 | 7 |
Time to create a negative CDC crossmatch (XM) was defined as the first timepoint all CDC XM results were negative.
| Participants | FAS - One or Two Doses of 0.25 mg/kg BW IdeS |
|---|---|
| All CDC XM tests negative at 2h | 6 |
| All CDC XM tests negative already pre-dose | 3 |
Time to create a negative FACS crossmatch (XM) was defined as the first timepoint all FACS XM results were negative.
| Participants | FAS - One or Two Doses of 0.25 mg/kg BW IdeS |
|---|---|
| All FACS XM tests negative at 2h | 8 |
| All FACS XM tests negative at 6h | 2 |
| All FACS XM tests negative at 24h | 7 |
| Remained positive | 2 |
Estimated glomerular filtration rate (eGFR) was calculated as described by the 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.
| Participants | PP - One or Two Doses of 0.25 mg/kg BW IdeS |
|---|---|
| Day 28 — eGFR: <30 ml/min/1.72m2 | 5 |
| Day 28 — eGFR: 30-59 ml/min/1.72m2 | 9 |
| Day 28 — eGFR: >60 ml/min/1.72m2 | 4 |
| Day 90 — eGFR: <30 ml/min/1.72m2 | 4 |
| Day 90 — eGFR: 30-59 ml/min/1.72m2 | 7 |
| Day 90 — eGFR: >60 ml/min/1.72m2 | 6 |
| Day 180 — eGFR: <30 ml/min/1.72m2 | 2 |
| Day 180 — eGFR: 30-59 ml/min/1.72m2 | 11 |
| Day 180 — eGFR: >60 ml/min/1.72m2 | 4 |
The patient's immunoglobulin G (IgG) is cleaved by IdeS in two steps. The first cut separates one of the heavy chains from the Fc part, generating so called single-cleaved IgG (scIgG), and the second cut separates the other heavy chain from the Fc part, thus generating one F(ab')2 fragment and one Fc fragment. The IgG concentration measured for this outcome is the sum of intact and scIgG because the assay used cannot discriminate between the two. A decrease in IgG concentration therefore represents complete cleavage of the IgG molecules to Fc and F(ab')2 fragments. Please note that intravenous IgG (IVIg) was administered Day 7.
| mg/mL | PP - One Dose of 0.25 mg/kg BW IdeS | PP - Two Doses of 0.25 mg/kg BW IdeS | PP - One or Two Doses of 0.25 mg/kg BW IdeS |
|---|---|---|---|
| IgG concentration (pre-dose) | 10.11 ± 85.92 | 8.35 ± 55.37 | 9.79 ± 79.73 |
| IgG concentration (2 h) | 1.19 ± 91.05 | 0.68 ± 165.87 | 1.08 ± 100.51 |
| IgG concentration (6 h) | 0.55 ± 83.44 | 0.38 ± 109.18 | 0.52 ± 85.49 |
| IgG concentration (24 h) | 0.37 ± 79.14 | 0.15 ± 42.46 | 0.32 ± 83.92 |
| IgG concentration (48 h) | 0.51 ± 129.17 | 0.17 ± 45.57 | 0.43 ± 132.55 |
| IgG concentration (Day 7 before IVIg) | 0.64 ± 107.44 | 0.2 ± 96.88 | 0.53 ± 122.3 |
| IgG concentration (Day 7 after IVIg) | 16.52 ± 49.9 | 18.47 ± 23.91 | 16.89 ± 45.05 |
| IgG concentration (Day 9) | 15.34 ± 85.32 | 26.94 ± 50.82 | 16.85 ± 83 |
| IgG concentration (Day 14) | 13.48 ± 55.67 | 10.85 ± 53.42 | 13 ± 54.34 |
| IgG concentration (Day 21) | 10.57 ± 58.67 | 5.88 ± 88.3 | 9.58 ± 66.04 |
| IgG concentration (Day 28) | 10.25 ± 69.85 | 11.53 ± 66.45 | 10.45 ± 67.16 |
| IgG concentration (Day 64) | 11.91 ± 71.52 | 7.77 ± 45.82 | 11.09 ± 69.02 |
| IgG concentration (Day 180) | 9.33 ± 42.58 | 8.99 ± 0 | 9.28 ± 39.21 |
Cmax = Maximum observed plasma concentration of IdeS following dosing (Non-compartmental PK analysis)
| microgram/mL | PP - One or Two Doses of 0.25 mg/kg BW IdeS |
|---|---|
| Pharmacokinetics - Cmax (First Dose) | 3.95 ± 25.2 |
Cmax = Maximum observed plasma concentration of IdeS following dosing (Non-compartmental PK analysis)
| micrograms/mL | PP - Two Doses of 0.25 mg/kg BW IdeS |
|---|---|
| Pharmacokinetics - Cmax (Second Dose) | 4.13 ± 29.4 |
Tmax = Time point for maximum observed plasma concentration of IdeS following dosing (Non-compartmental PK analysis)
| hours | PP - One or Two Doses of 0.25 mg/kg BW IdeS |
|---|---|
| Pharmacokinetics - Tmax (First Dose) | 2.21 ± 0.31 |
Tmax = Time point for maximum observed plasma concentration of IdeS following dosing (Non-compartmental PK analysis)
| hours | PP - Two Doses of 0.25 mg/kg BW IdeS |
|---|---|
| Pharmacokinetics - Tmax (Second Dose) | 15.98 ± 5.50 |
AUC = Area under the plasma concentration versus time curve (Non-compartmental PK analysis)
| hour*microgram/mL | PP - One Dose of 0.25 mg/kg BW IdeS | PP - Two Doses of 0.25 mg/kg BW IdeS |
|---|---|---|
| Pharmacokinetics - AUC | 156.09 ± 45.4 | — |
Alpha-t1/2 = Half-life during distribution phase Beta-t1/2 = Half-life during elimination phase Non-compartmental PK analysis
| hours | PP - One Dose of 0.25 mg/kg BW IdeS | PP - Two Doses of 0.25 mg/kg BW IdeS |
|---|---|---|
| t1/2 (alpha) | 4.58 ± 3.85 | — |
| t1/2 (beta) | 76.30 ± 42.76 | — |
CL = Clearance Non compartmental PK analysis
| mL/h/kg | PP - One Dose of 0.25 mg/kg BW IdeS | PP - Two Doses of 0.25 mg/kg BW IdeS |
|---|---|---|
| Pharmacokinetics - CL | 1.60 ± 45.4 | — |
Vss = Volume of distribution at steady state Non compartmental PK analysis
| L/kg | PP - One Dose of 0.25 mg/kg BW IdeS | PP - Two Doses of 0.25 mg/kg BW IdeS |
|---|---|---|
| Pharmacokinetics - Vss | 0.14 ± 26.9 | — |
Vz = Volume of distribution during the elimination phase Non compartmental PK analysis
| L/kg | PP - One Dose of 0.25 mg/kg BW IdeS | PP - Two Doses of 0.25 mg/kg BW IdeS |
|---|---|---|
| Pharmacokinetics - Vz | 0.19 ± 27.0 | — |
Collected over Adverse events (AEs) were collected for 6 months (i.e., from the timepoint the patient signed the informed consent form (ICF) until end of study, including the follow-up period).. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| SAS - One Dose of IdeS (0.25 mg/kg BW) | 0/16 (0%) | 12/16 (75%) | 15/16 (93.8%) |
| SAS - Two Doses of IdeS (2 x 0.25 mg/kg BW) | 0/3 (0%) | 3/3 (100%) | 3/3 (100%) |
| SAS - All Patients (One or Two Doses of IdeS (0.25 mg/kg BW)) | 0/19 (0%) | 15/19 (78.9%) | 18/19 (94.7%) |
| Event | SAS - One Dose of IdeS (0.25 mg/kg BW) | SAS - Two Doses of IdeS (2 x 0.25 mg/kg BW) | SAS - All Patients (One or Two Doses of IdeS (0.25 mg/kg BW)) |
|---|---|---|---|
| Transplant rejectionImmune system disorders | 7/16 | 2/3 | 9/19 |
| Blood creatine increasedInvestigations | 1/16 | 1/3 | 2/19 |
| Thrombotic microangiopathyBlood and lymphatic system disorders | 0/16 | 1/3 | 1/19 |
| Abdominal pain upperGastrointestinal disorders | 0/16 | 1/3 | 1/19 |
| Nephropathy toxicRenal and urinary disorders | 1/16 | 1/3 | 2/19 |
| Tubulointerstitial nephritisRenal and urinary disorders | 0/16 | 1/3 | 1/19 |
| InfluenzaInfections and infestations | 0/16 | 1/3 | 1/19 |
| Urinary tract infectionInfections and infestations | 2/16 | 0/3 | 2/19 |
| Axillary vein thrombosisVascular disorders | 1/16 | 0/3 | 1/19 |
| Superior vena cava syndromeVascular disorders | 1/16 | 0/3 | 1/19 |
| Event | SAS - One Dose of IdeS (0.25 mg/kg BW) | SAS - Two Doses of IdeS (2 x 0.25 mg/kg BW) | SAS - All Patients (One or Two Doses of IdeS (0.25 mg/kg BW)) |
|---|---|---|---|
| HypertriglyceridaemiaMetabolism and nutrition disorders | 4/16 | 3/3 | 7/19 |
| HypomagnesaemiaMetabolism and nutrition disorders | 6/16 | 3/3 | 9/19 |
| HypogammaglobulinaemiaImmune system disorders | 2/16 | 2/3 | 4/19 |
| AnaemiaBlood and lymphatic system disorders | 9/16 | 2/3 | 11/19 |
| NeutropeniaBlood and lymphatic system disorders | 4/16 | 2/3 | 6/19 |
| ConstipationGastrointestinal disorders | 7/16 | 2/3 | 9/19 |
| HyperkalaemiaMetabolism and nutrition disorders | 5/16 | 2/3 | 7/19 |
| Metabolic acidosisMetabolism and nutrition disorders | 5/16 | 2/3 | 7/19 |
| Delayed graft functionInjury, poisoning and procedural complications | 7/16 | 1/3 | 8/19 |
| DiarrhoeaGastrointestinal disorders | 7/16 | 0/3 | 7/19 |
| Age, Categorical(Participants) | One Dose of IdeS (0.25 mg/kg BW) | Two Doses of IdeS (2 x 0.25 mg/kg BW) | Total |
|---|---|---|---|
| <=18 years | 0 | 0 | 0 |
| Between 18 and 65 years | 16 | 3 | 19 |
| >=65 years | 0 | 0 | 0 |
| Age, Continuous(years) | One Dose of IdeS (0.25 mg/kg BW) | Two Doses of IdeS (2 x 0.25 mg/kg BW) | Total |
|---|---|---|---|
| Median | 40 (20 to 64) | 45 (39 to 45) | 40 (20 to 64) |
| Sex: Female, Male(Participants) | One Dose of IdeS (0.25 mg/kg BW) | Two Doses of IdeS (2 x 0.25 mg/kg BW) | Total |
|---|---|---|---|
| Female | 5 | 1 | 6 |
| Male | 11 | 2 | 13 |
| Race/Ethnicity, Customized(participants) | One Dose of IdeS (0.25 mg/kg BW) | Two Doses of IdeS (2 x 0.25 mg/kg BW) | Total |
|---|---|---|---|
| Asian | 1 | 0 | 1 |
| Black or african american | 2 | 2 | 4 |
| Hispanic | 1 | 0 | 1 |
| Indian | 1 | 0 | 1 |
| White | 11 | 1 | 12 |
| Region of Enrollment(participants) | One Dose of IdeS (0.25 mg/kg BW) | Two Doses of IdeS (2 x 0.25 mg/kg BW) | Total |
|---|---|---|---|
| Sweden | 1 | 1 | 2 |
| United States | 12 | 2 | 14 |
| France | 3 | 0 | 3 |
| Weight(kg) | One Dose of IdeS (0.25 mg/kg BW) | Two Doses of IdeS (2 x 0.25 mg/kg BW) | Total |
|---|---|---|---|
| Median | 74.05 (45.1 to 107.4) | 68.0 (62.6 to 70.3) | 71.6 (45.1 to 107.4) |
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Hansa Biopharma AB