A Study With Imlifidase in Anti-GBM Disease

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase 3 Open-label, Controlled, Randomised, Multi-centre Trial Comparing Imlifidase and Standard-of-care With Standard-of-care Alone in the Treatment of Severe Anti-GBM Antibody Disease (Goodpasture Disease)

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

Intervention / Treatment
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* Drug: Imlifidase
* Procedure: Plasma exchange (PLEX)
* Drug: Cyclophosphamide (CYC)
* Drug: Glucocorticoids


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Anti-GBM antibodies constituting an indication for PLEX as judged by the Investigator Haematuria on dipstick and/or urinary sediment eGFR(MDRD) <20 mL/min/1.73 m^2 Patients aged ≥18 years Willing and able to give written Informed Consent and to comply with the requirements of the study protocol Exclusion Criteria: Diagnosis of anti-GBM disease more than 14 days prior to randomisation Anuria during the last 24-hour Any constituent of SoC given more than 10 days prior to randomisation IVIg within 4 weeks before randomisation 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 Patients previously randomised in the study Unsuitable to participate in the trial for any other reason in the opinion of the investigator Pregnancy or breast feeding Contraception: 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 Men who are not willing to refrain from donating sperm from screening to 6 months following discontinuation of CYC 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 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] Previous imlifidase treatment or known hypersensitivity to any of the excipients

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open-label, controlled, randomised, multi-centre trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Imlifidase and Standard-of-Care (SoC)<br>Imlifidase is administered IV as one dose of 0.25 mg/kg over 15 minutes. SoC consists of a standardized combination of PLEX, CYC, and glucocorticoids. | Drug: Imlifidase<br>* 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.<br>* Other names: IdeS, HMED-IdeS;Procedure: Plasma exchange (PLEX)<br>* PLEX removes the patient's pathogenic anti-GBM antibodies, by replacement of deficient plasma with a replacement fluid.<br>* Other names: PE;Drug: Cyclophosphamide (CYC)<br>* 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.<br>Drug: Glucocorticoids<br>* Glucocorticoids inhibit the inflammation process.<br>|
| Active Comparator: Standard-of-Care (SoC)<br>SoC consists of a standardized combination of PLEX, CYC, and glucocorticoids. | Procedure: Plasma exchange (PLEX)<br>* PLEX removes the patient's pathogenic anti-GBM antibodies, by replacement of deficient plasma with a replacement fluid.<br>* Other names: PE;Drug: Cyclophosphamide (CYC)<br>* 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.<br>Drug: Glucocorticoids<br>* Glucocorticoids inhibit the inflammation process.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal function as evaluated by estimated glomerular filtration rate (eGFR) at 6 months |  | At 6 months after randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with functioning kidney at 6 months |  | At 6 months after randomisation | 
| Time to non-toxic level of anti-GBM antibodies |  | 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. | From randomisation up to Day 22 and to Day 29 respectively | 
| Renal function as evaluated by eGFR at 3 months |  | At 3 months after randomisation | 
| Proportion of patients with functioning kidney at 3 months, |  | At 3 months after randomisation | 
| Proportion of patients experiencing end stage renal disease (ESRD) within 6 months |  | During the study from randomisation up to 6 months | 
| Proportion of patients experiencing death due to anti-GBM disease within 6 months |  | During the study from randomisation up to 6 months | 
| Change in urine creatinine clearance (CrCl) from randomisation to 3 and 6 months |  | At randomisation and at 3 and 6 months | 
| U-albumin/creatinine ratio at 3 and 6 months (24h collection) |  | At screening and at 3 and 6 months | 
| U-albumin/creatinine ratio at screening and during study (morning urine void) |  | During the study from screening up to 6 months | 
| Renal function as evaluated by eGFR at screening and during study |  | During the study from screening up to 6 months | 
| Number of PLEX sessions within 3 months from randomisation |  | During the study from randomisation up to 3 months | 
| Number of days on dialysis within 3 and 6 months from randomisation |  | 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 |  | 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 |  | 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 |  | 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. | 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. | 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. | 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. | 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. | 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. | During the study from before administration of imlifidase up to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-GBM