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

Primary Purpose

Kidney Failure, Chronic

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
IdeS
Kidney transplantation
Sponsored by
Hansa Biopharma AB
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Kidney Failure, Chronic

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Cedars-Sinai Medical Center
  • The Johns Hopkins Hospital
  • New York University School of Medicine
  • Necker Hospital
  • Uppsala University Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment IdeS

Arm Description

IdeS intravenous infusion

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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 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 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.
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.
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.
Pharmacokinetics - Cmax (First Dose)
Cmax = Maximum observed plasma concentration of IdeS following dosing (Non-compartmental PK analysis)
Pharmacokinetics - Cmax (Second Dose)
Cmax = Maximum observed plasma concentration of IdeS following dosing (Non-compartmental PK analysis)
Pharmacokinetics - Tmax (First Dose)
Tmax = Time point for maximum observed plasma concentration of IdeS following dosing (Non-compartmental PK analysis)
Pharmacokinetics - Tmax (Second Dose)
Tmax = Time point for maximum observed plasma concentration of IdeS following dosing (Non-compartmental PK analysis)
Pharmacokinetics - AUC
AUC = Area under the plasma concentration versus time curve (Non-compartmental PK analysis)
Pharmacokinetics - t1/2
Alpha-t1/2 = Half-life during distribution phase Beta-t1/2 = Half-life during elimination phase Non-compartmental PK analysis
Pharmacokinetics - CL
CL = Clearance Non compartmental PK analysis
Pharmacokinetics - Vss
Vss = Volume of distribution at steady state Non compartmental PK analysis
Pharmacokinetics - Vz
Vz = Volume of distribution during the elimination phase Non compartmental PK analysis

Full Information

First Posted
May 30, 2016
Last Updated
April 28, 2021
Sponsor
Hansa Biopharma AB
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1. Study Identification

Unique Protocol Identification Number
NCT02790437
Brief Title
A Phase II Study to Evaluate the Efficacy of IdeS to Desensitize Transplant Patients With a Positive Crossmatch Test
Acronym
Highdes
Official Title
A Phase II Study to Evaluate the Efficacy of IdeS (IgG Endopeptidase) to Desensitize Transplant Patients With a Positive Crossmatch Test
Study Type
Interventional

2. Study Status

Record Verification Date
April 2021
Overall Recruitment Status
Completed
Study Start Date
June 2016 (undefined)
Primary Completion Date
December 12, 2017 (Actual)
Study Completion Date
July 3, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hansa Biopharma AB

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Kidney Failure, Chronic

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
19 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment IdeS
Arm Type
Experimental
Arm Description
IdeS intravenous infusion
Intervention Type
Drug
Intervention Name(s)
IdeS
Other Intervention Name(s)
IgG endopeptidase
Intervention Description
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.
Intervention Type
Procedure
Intervention Name(s)
Kidney transplantation
Intervention Description
Performed following IdeS treatment
Primary Outcome Measure Information:
Title
Number of Patients With Crossmatch Conversion (Positive to Negative)
Description
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
Secondary Outcome Measure Information:
Title
Number of Patients With Donor Specific Antibodies With an MFI Value >3000
Description
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.
Title
Time to Create a Negative CDC Crossmatch Test
Description
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.
Title
Time to Create a Negative FACS Crossmatch Test
Description
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
Title
Kidney Function After IdeS Treatment Assessed by eGFR
Description
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
Title
Serum IgG Concentration After Administration of IdeS
Description
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.
Title
Pharmacokinetics - Cmax (First Dose)
Description
Cmax = Maximum observed plasma concentration of IdeS following dosing (Non-compartmental PK analysis)
Time Frame
Pre-dose to Day 14 after administration of IdeS.
Title
Pharmacokinetics - Cmax (Second Dose)
Description
Cmax = Maximum observed plasma concentration of IdeS following dosing (Non-compartmental PK analysis)
Time Frame
Pre-dose until Day 14 after administration of IdeS
Title
Pharmacokinetics - Tmax (First Dose)
Description
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
Title
Pharmacokinetics - Tmax (Second Dose)
Description
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
Title
Pharmacokinetics - AUC
Description
AUC = Area under the plasma concentration versus time curve (Non-compartmental PK analysis)
Time Frame
Pre-dose to Day 14 after administration of IdeS.
Title
Pharmacokinetics - t1/2
Description
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.
Title
Pharmacokinetics - CL
Description
CL = Clearance Non compartmental PK analysis
Time Frame
Pre-dose to Day 14
Title
Pharmacokinetics - Vss
Description
Vss = Volume of distribution at steady state Non compartmental PK analysis
Time Frame
Pre-dose to Day 14 after administration of IdeS
Title
Pharmacokinetics - Vz
Description
Vz = Volume of distribution during the elimination phase Non compartmental PK analysis
Time Frame
Pre-dose to Day 14 after administration of IdeS.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lena Winstedt, PhD
Organizational Affiliation
Hansa Biopharma AB
Official's Role
Study Director
Facility Information:
Facility Name
Cedars-Sinai Medical Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90048
Country
United States
Facility Name
The Johns Hopkins Hospital
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21205
Country
United States
Facility Name
New York University School of Medicine
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
Necker Hospital
City
Paris
ZIP/Postal Code
75743
Country
France
Facility Name
Uppsala University Hospital
City
Uppsala
ZIP/Postal Code
75185
Country
Sweden

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
34236770
Citation
Kjellman C, Maldonado AQ, Sjoholm K, Lonze BE, Montgomery RA, Runstrom A, Lorant T, Desai NM, Legendre C, Lundgren T, von Zur Muhlen B, Vo AA, Olsson H, Jordan SC. Outcomes at 3 years posttransplant in imlifidase-desensitized kidney transplant patients. Am J Transplant. 2021 Dec;21(12):3907-3918. doi: 10.1111/ajt.16754. Epub 2021 Jul 19.
Results Reference
derived
PubMed Identifier
33093408
Citation
Jordan SC, Legendre C, Desai NM, Lorant T, Bengtsson M, Lonze BE, Vo AA, Runstrom A, Laxmyr L, Sjoholm K, Schiott A, Sonesson E, Wood K, Winstedt L, Kjellman C, Montgomery RA. Imlifidase Desensitization in Crossmatch-positive, Highly Sensitized Kidney Transplant Recipients: Results of an International Phase 2 Trial (Highdes). Transplantation. 2021 Aug 1;105(8):1808-1817. doi: 10.1097/TP.0000000000003496.
Results Reference
derived

Learn more about this trial

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

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