A Phase II Study to Evaluate the Efficacy of IdeS to Desensitize Transplant Patients With a Positive Crossmatch Test

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase II Study to Evaluate the Efficacy of IdeS (IgG Endopeptidase) to Desensitize Transplant Patients With a Positive Crossmatch Test

Conditions
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Kidney Failure, Chronic

Intervention / Treatment
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* Drug: IdeS
* Procedure: Kidney transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients on the kidney transplant waitlist who have previously undergone desensitization unsuccessfully or in whom effective desensitization will be highly unlikely. The breadth and strength of sensitization will predict an extremely low likelihood of successful desensitization or kidney paired donation. Patients with a live or deceased donor with a positive crossmatch test. Exclusion Criteria: Previous treatment with IdeS Previous high dose IVIg treatment (2 g/kg BW) within 28 days prior to IdeS treatment Lactating or pregnant females Women of child-bearing age who are not willing or able to practice FDA-approved forms of contraception HIV-positive patients Patients with clinical signs of HBV or HCV infection Patients with active tuberculosis A significantly abnormal general serum screening lab result according to the investigator's judgement. Hgb cannot be < 6.0 g/dL Severe other conditions requiring treatment and close monitoring, e.g. cardiac failure > NYHA (New York Heart Association) grade 3, unstable coronary disease or oxygen dependent COPD Individuals deemed unable to comply with the protocol Patients with clinical signs of CMV or EBV infection Patients with a history of major thrombotic events, patients with active peripheral vascular disease or patients with proven hypercoagulable conditions Patients should not have received investigational drugs within 4 half-lives (or similar) Known allergy/sensitivity to IdeS infusions Patients who have a live donor and test positive for ImmunoCap anti-IdeS IgE

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment IdeS<br>IdeS intravenous infusion | Drug: IdeS<br>* 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.<br>* Other names: IgG endopeptidase;Procedure: Kidney transplantation<br>* Performed following IdeS treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Within 24 hours of IdeS dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | Within 180 days after administration of IdeS. | 
| Pharmacokinetics - Cmax (First Dose) | Cmax = Maximum observed plasma concentration of IdeS following dosing (Non-compartmental PK analysis) | 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) | 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) | 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) | Pre-dose to Day 14 after administration of IdeS | 
| Pharmacokinetics - AUC | AUC = Area under the plasma concentration versus time curve (Non-compartmental PK analysis) | 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 | Pre-dose to Day 14 after administration of IdeS. | 
| Pharmacokinetics - CL | CL = Clearance Non compartmental PK analysis | Pre-dose to Day 14 | 
| Pharmacokinetics - Vss | Vss = Volume of distribution at steady state Non compartmental PK analysis | Pre-dose to Day 14 after administration of IdeS | 
| Pharmacokinetics - Vz | Vz = Volume of distribution during the elimination phase Non compartmental PK analysis | Pre-dose to Day 14 after administration of IdeS. |