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NCT Number: NCT02790437

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

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.

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Key information

Conditions

Kidney Failure, Chronic Chronic Disease Disease Attributes Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Kidney Diseases Male Urogenital Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms Renal Insufficiency Renal Insufficiency, Chronic Urogenital Diseases Urologic Diseases

Age range

18 year–70 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Necker Hospital, Paris, France

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

IdeS

Drug

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.

Other names: IgG endopeptidase

Kidney transplantation

Procedure

Performed following IdeS treatment

Primary outcomes

  1. Number of Patients With Crossmatch Conversion (Positive to Negative)

    Time frame: 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 outcomes

  1. Number of Patients With Donor Specific Antibodies With an MFI Value >3000

    Time frame: 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.

  2. Time to Create a Negative CDC Crossmatch Test

    Time frame: 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.

  3. Time to Create a Negative FACS Crossmatch Test

    Time frame: 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.

  4. Kidney Function After IdeS Treatment Assessed by eGFR

    Time frame: 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.

  5. Serum IgG Concentration After Administration of IdeS

    Time frame: 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.

  6. Pharmacokinetics - Cmax (First Dose)

    Time frame: Pre-dose to Day 14 after administration of IdeS.

    Cmax = Maximum observed plasma concentration of IdeS following dosing (Non-compartmental PK analysis)

  7. Pharmacokinetics - Cmax (Second Dose)

    Time frame: Pre-dose until Day 14 after administration of IdeS

    Cmax = Maximum observed plasma concentration of IdeS following dosing (Non-compartmental PK analysis)

  8. Pharmacokinetics - Tmax (First Dose)

    Time frame: 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)

  9. Pharmacokinetics - Tmax (Second Dose)

    Time frame: 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)

  10. Pharmacokinetics - AUC

    Time frame: Pre-dose to Day 14 after administration of IdeS.

    AUC = Area under the plasma concentration versus time curve (Non-compartmental PK analysis)

  11. Pharmacokinetics - t1/2

    Time frame: 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

  12. Pharmacokinetics - CL

    Time frame: Pre-dose to Day 14

    CL = Clearance Non compartmental PK analysis

  13. Pharmacokinetics - Vss

    Time frame: Pre-dose to Day 14 after administration of IdeS

    Vss = Volume of distribution at steady state Non compartmental PK analysis

  14. Pharmacokinetics - Vz

    Time frame: Pre-dose to Day 14 after administration of IdeS.

    Vz = Volume of distribution during the elimination phase Non compartmental PK analysis

Sponsors and collaborators

Lead sponsor

Hansa Biopharma AB

Industry

Registry information

Official study title

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

Acronym: Highdes

Important dates

Study start
2016
Primary completion
2017
Study completion
2018
First posted
Jun 3, 2016
Registry last updated
May 20, 2021

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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