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

Phase 2

Completed

• Conditions: Kidney Failure, Chronic
• Interventions: Drug: IdeS; Procedure: Kidney transplantation

• Registration Number: NCT02790437
• Lead Sponsor: Hansa Biopharma AB

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2016-05-30
• Study Start: 2016-06
• Study First Submitted QC: 2016-06-02
• Study First Posted: 2016-06-03
• Primary Completion: 2017-12-12
• Study Completion: 2018-07-03
• Disposition First Submitted: 2019-03-01
• Disposition First Submitted QC: 2019-03-01
• Disposition First Posted: 2019-03-05
• Results First Submitted: 2021-02-22
• Status Verified: 2021-04
• Results First Submitted QC: 2021-04-28
• Last Update Submitted: 2021-04-28
• Results First Posted: 2021-05-20
• Last Update Posted: 2021-05-20

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 19

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment IdeS	Kidney transplantation	IdeS intravenous infusion
Treatment IdeS	IdeS	IdeS intravenous infusion

Primary Outcome Measures

Name	Time	Method
Number of Patients With Crossmatch Conversion (Positive to Negative)	Within 24 hours of IdeS dosing	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.

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetics - t1/2	Pre-dose to Day 14 after administration of IdeS.	Alpha-t1/2 = Half-life during distribution phase Beta-t1/2 = Half-life during elimination phase Non-compartmental PK analysis
Pharmacokinetics - Vss	Pre-dose to Day 14 after administration of IdeS	Vss = Volume of distribution at steady state Non compartmental PK analysis
Pharmacokinetics - Tmax (First Dose)	Pre-dose to Day 14 after administration of IdeS	Tmax = Time point for maximum observed plasma concentration of IdeS following dosing (Non-compartmental PK analysis)
Pharmacokinetics - Tmax (Second Dose)	Pre-dose to Day 14 after administration of IdeS	Tmax = Time point for maximum observed plasma concentration of IdeS following dosing (Non-compartmental PK analysis)
Pharmacokinetics - Cmax (First Dose)	Pre-dose to Day 14 after administration of IdeS.	Cmax = Maximum observed plasma concentration of IdeS following dosing (Non-compartmental PK analysis)
Pharmacokinetics - Vz	Pre-dose to Day 14 after administration of IdeS.	Vz = Volume of distribution during the elimination phase Non compartmental PK analysis
Kidney Function After IdeS Treatment Assessed by eGFR	Within 180 days after administration of IdeS	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.
Number of Patients With Donor Specific Antibodies With an MFI Value >3000	Within 180 days after administration of IdeS.	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 to Create a Negative CDC Crossmatch Test	2h, 6h, 24h after administration of IdeS.	Time to create a negative CDC crossmatch (XM) was defined as the first timepoint all CDC XM results were negative.
Time to Create a Negative FACS Crossmatch Test	2h, 6h, and 24h after administration of IdeS	Time to create a negative FACS crossmatch (XM) was defined as the first timepoint all FACS XM results were negative.
Serum IgG Concentration After Administration of IdeS	Within 180 days 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.
Pharmacokinetics - Cmax (Second Dose)	Pre-dose until Day 14 after administration of IdeS	Cmax = Maximum observed plasma concentration of IdeS following dosing (Non-compartmental PK analysis)
Pharmacokinetics - AUC	Pre-dose to Day 14 after administration of IdeS.	AUC = Area under the plasma concentration versus time curve (Non-compartmental PK analysis)
Pharmacokinetics - CL	Pre-dose to Day 14	CL = Clearance Non compartmental PK analysis

Trial Locations

Locations (5)

Cedars-Sinai Medical Center; 🇺🇸 Los Angeles, California, United States

Necker Hospital; 🇫🇷 Paris, France

Uppsala University Hospital; 🇸🇪 Uppsala, Sweden

The Johns Hopkins Hospital; 🇺🇸 Baltimore, Maryland, United States

New York University School of Medicine; 🇺🇸 New York, New York, United States