A Study With Imlifidase in Anti-GBM Disease

Phase 3Active Not RecruitingNCT05679401

Hansa Biopharma AB50 enrolled

Overview

An open-label, controlled, randomised, multi-centre Phase 3 trial evaluating renal function in patients with severe anti-GBM disease comparing imlifidase and standard of care (SoC) with SoC alone. All patients will remain in the trial for 24 months.

After being informed about the study and potential risks, all patients giving written informed consent will undergo screening to determine eligibility for study entry. Patients will be randomised to treatment in a 1:1 ratio to either imlifidase and SoC or SoC only. SoC consists of a combination of plasma exchange (PLEX), cyclophosphamide (CYC), and glucocorticoids. For patients randomised to the imlifidase arm the first PLEX immediately after randomisation is replaced by administration of imlifidase. Kidney function, anti-GBM antibody levels, pulmonary symptoms, safety, pharmacokinetic/pharmacodynamic (PK/PD) and health related quality of life (HRQoL) among others, will be assessed.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Anti-Glomerular Basement Membrane Disease Anti-Glomerular Basement Membrane Antibody Disease Goodpasture Syndrome Good Pasture Syndrome

Interventions

ImlifidaseDRUG

Imlifidase is an immunoglobulin G (IgG)-degrading enzyme of Streptococcus pyogenes that is highly selective towards IgG. The cleavage of IgG generates one F(ab')2- and one homodimeric Fc-fragment and efficiently neutralizes Fc-mediated activities of IgG.

Plasma exchange (PLEX)PROCEDURE

PLEX removes the patient's pathogenic anti-GBM antibodies, by replacement of deficient plasma with a replacement fluid.

Cyclophosphamide (CYC)DRUG

Cyclophosphamide's main mechanism of action (i.e. crosslinking of strands of DNA and RNA) results in inhibition of protein synthesis. Hence treatment prevents formation of new anti-GBM antibodies.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Anti-GBM antibodies constituting an indication for PLEX as judged by the Investigator 2. Haematuria on dipstick and/or urinary sediment 3. eGFR(MDRD) \<20 mL/min/1.73 m\^2 4. Patients aged ≥18 years 5. Willing and able to give written Informed Consent and to comply with the requirements of the study protocol Exclusion Criteria: 1. Diagnosis of anti-GBM disease more than 14 days prior to randomisation 2. Anuria during the last 24-hour 3. Any constituent of SoC given more than 10 days prior to randomisation 4. IVIg within 4 weeks before randomisation 5. History or presence of any medical condition or disease which, in the opinion of the investigator, may place the patient at unacceptable risk, or jeopardise the purpose of the study 6. Patients previously randomised in the study 7. Unsuitable to participate in the trial for any other reason in the opinion of the investigator 8. Pregnancy or breast feeding 9. Contraception: 1. Men who are not vasectomised or abstinent or with a partner (of child-bearing potential) not willing to use one of the highly effective contraceptives listed below from screening to 6 months following discontinuation of CYC 2. Men who are not willing to refrain from donating sperm from screening to 6 months following discontinuation of CYC 3. Men who are not willing to use a condom during any form of sexual intercourse, regardless of a partner being of child-bearing potential from screening to 6 months following discontinuation of CYC 4. Women of child-bearing potential not willing or not able to use at least one highly effective contraceptive method from screening to 12 months following discontinuation of CYC. In the context of this trial, a highly effective method is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly such as: * combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral/intravaginal/transdermal) * progestogen-only hormonal contraception associated with inhibition of ovulation (oral/injectable/implantable) * intrauterine device (IUD) * intrauterine hormone-releasing system (IUS) * bilateral tubal occlusion * vasectomised partner * true abstinence: When this is in line with the preferred and usual lifestyle of the patient. \[Periodic abstinence (such as calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception\] 10. Previous imlifidase treatment or known hypersensitivity to any of the excipients

Locations (48)

Outcomes

Primary Outcomes

Renal function as evaluated by estimated glomerular filtration rate (eGFR) at 6 months

Time frame: At 6 months after randomisation

Secondary Outcomes

Proportion of patients with functioning kidney at 6 months

Time frame: At 6 months after randomisation

Time to non-toxic level of anti-GBM antibodies

Time frame: During the study from screening up to 6 months

Exposure to toxic level of anti-GBM antibodies

Exposure to anti-GBM antibodies will be assessed by evaluation of the area under the anti-GBM antibody concentration versus time curve.

Time frame: From randomisation up to Day 22 and to Day 29 respectively

Renal function as evaluated by eGFR at 3 months

Time frame: At 3 months after randomisation

Proportion of patients with functioning kidney at 3 months,

Time frame: At 3 months after randomisation

Proportion of patients experiencing end stage renal disease (ESRD) within 6 months

Time frame: During the study from randomisation up to 6 months

Proportion of patients experiencing death due to anti-GBM disease within 6 months

Time frame: During the study from randomisation up to 6 months

Change in urine creatinine clearance (CrCl) from randomisation to 3 and 6 months

Time frame: At randomisation and at 3 and 6 months

Data from ClinicalTrials.gov

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Glucocorticoids inhibit the inflammation process.

UCLA Medical Center Plaza

Los Angeles, California, United States

John Hopkins Medical Institution

Baltimore, Maryland, United States

Brigham and Women's Hospital

Boston, Massachusetts, United States

University of Minnesota Health Clinical Research Unit

Minneapolis, Minnesota, United States

UNC Kidney Center/Division of Nephrology & Hypertension

Chapel Hill, North Carolina, United States

The Ohio State University Wexner Medical Center

Columbus, Ohio, United States

Med Uni Graz / LKH-UNIV Klinikum Graz, Klinische Abteilung fuer Nephrologie

Graz, Stiermark, Austria

Medical University Innsbruck, Dept of Internal Medicine IV (Nephrology and Hypertension)

Innsbruck, Tyrol, Austria

Medical University of Vienna, Dept of Medicine III, Division of Nephrology and dialysis

Vienna, Austria

UZ Leuven

Leuven, Belgium

...and 38 more locations

U-albumin/creatinine ratio at 3 and 6 months (24h collection)

Time frame: At screening and at 3 and 6 months

U-albumin/creatinine ratio at screening and during study (morning urine void)

Time frame: During the study from screening up to 6 months

Renal function as evaluated by eGFR at screening and during study

Time frame: During the study from screening up to 6 months

Number of PLEX sessions within 3 months from randomisation

Time frame: During the study from randomisation up to 3 months

Number of days on dialysis within 3 and 6 months from randomisation

Time frame: During the study from randomisation to 3 months and 6 months

Proportion of patients being negative during study for anti-GBM antibodies/anti-neutrophilic cytoplasmic autoantibodies (ANCA)/anti-GBM antibodies+ANCA

Time frame: During the study from screening up to 6 months

Number of days with mechanical ventilation due to anti-GBM disease within 3 months from randomisation

Time frame: During the study from randomisation to 3 months

Number of days at intensive care unit (ICU) and number of days in hospitalisation from randomisation to 3 months

Time frame: During the study from randomisation to 3 months

Change in health related quality of life (HRQoL) from screening to 6 months

All patients will fill out the HRQoL questionnaire PROMIS-29 which is a universal rather than disease specific measure. The PROMIS-29 measure assesses pain intensity using a single 0-10 numeric pain rating item and seven health domains using four items each: physical functioning, fatigue, pain interference, depression, anxiety, ability to participate in social roles and activities, and sleep disturbance. The score of each domain is converted into a standardized score so called T-score reported for each patient. A T-score of 50 represent a person from a reference population. A T-score higher than 50 indicates more of what is measured and a T-score less than 50 indicates less of what is measured.

Time frame: At screening and at 6 months

Change in health status from screening to 6 months

All patients will fill out the EQ-5D-5L questionnarie that comprises 5 questions measuring 5 dimensions of health status (mobility, self-care, usual activities, pain/ discomfort, and anxiety/depression). Patients will be asked to select a response to each category that best describes their current health. The EQ-5D-5L also contains a visual analogue scale and the patients will be asked to rate their health on a scale of 0-100.

Time frame: At screening and at 6 months

Pharmacokinetic (PK) data (Cmax) from start of treatment to Day 15

Cmax = Maximum observed plasma concentration of imlifidase following dosing.

Time frame: During the study from before administration of imlifidase up to Day 15

Imlifidase pharmacodynamic (PD) profile (IgG levels in serum) from start of treatment to Day 15

Imlifidase cleaves IgG. PD of imlifidase will be assessed as IgG levels in serum. A validated electrochemiluminescence (ECL) method will be used for the analysis.

Time frame: During the study from before administration of imlifidase up to Day 15

Imlifidase pharmacodynamic (PD) profile (composition of different IgG fractions) from start of treatment to Day 15

Imlifidase cleaves IgG. PD of imlifidase will be assessed using a sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis to measure the composition of the following fractions of IgG: Intact IgG, single cleaved IgG (scIgG) and Fab'2 fraction.

Time frame: During the study from before administration of imlifidase up to Day 15

Anti-imlifidase antibody levels from start of imlifidase treatment to 6 months

Only applicable for patients who receive imlifidase.

Time frame: During the study from before administration of imlifidase up to 6 months