Open-Label Phase II Study to Evaluate the Efficacy and Safety of IdeS in Anti-GBM Disease (GOOD-IDES-01)

• ClinicalTrials.gov Identifier: NCT03157037
• Recruitment Status: Completed
• First Posted: May 17, 2017
• Results First Posted: April 7, 2022
• Last Update Posted: April 7, 2022
• Sponsor: Mårten Segelmark
• Collaborator: Hansa Biopharma AB
• Information provided by (Responsible Party): Mårten Segelmark, Linkoeping University

Tracking Information

• First Submitted Date: May 11, 2017
• First Posted Date: May 17, 2017
• Results First Submitted Date: December 20, 2021
• Results First Posted Date: April 7, 2022
• Last Update Posted Date: April 7, 2022
• Actual Study Start Date: June 16, 2017
• Actual Primary Completion Date: July 24, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 7, 2022)

Number of Patients With Independent Renal Function at 6 Months [ Time Frame: 6 months after dosing ]

Number of patients without need for dialysis at 6 months. A patient with independent renal function is defined as a patient without need for dialysis.

Original Primary Outcome Measures (submitted: May 15, 2017)

Proportion of patients with independent renal function at 6 months [ Time Frame: 6 months after dosing ]

Number of patients without need for dialysis

Current Secondary Outcome Measures (submitted: February 7, 2022)

• Number of Patients With Independent Renal Function at 3 Months [ Time Frame: 3 months after dosing ]
  Number of patients without need for dialysis at 3 months. A patient with independent renal function is defined as a patient without need for dialysis.
• Renal Function at 3 and 6 Months [ Time Frame: 3 and 6 months after imlifidase dosing ]
  Estimated glomerular filtration rate (eGFR) is a measure of kidney function. eGFR was calculated based on p-creatinine according to the modification of diet in renal disease (MDRD) equation. eGFR for a kidney with normal function is above 90 mL/min/1.73m^2. Reduced kidney function is characterised by a decreased eGFR value.
• Number of Patients With Renal Function Over Time Stratified by Ranges of eGFR [ Time Frame: Pre-imlifidase, 1, 3 and 6 months after imlifidase dosing ]
  eGFR is a measure of kidney function. eGFR has been calculated based on p-creatinine according to the modification of diet in renal disease (MDRD) equation. eGFR for a kidney with normal function is above 90 mL/min/1.73m^2. Reduced kidney function is characterised by a decreased eGFR value. Number of patients per 4 different eGFR categories (0-15, 15-30, 30-60, ≥60 mL/min/1.73m^2) are presented. A shift towards a higher category during the study indicates improved renal function over time.
• Number of Patients With Anti-GBM Antibodies Above a Toxic Level Stratified by Number of Study Visits [ Time Frame: Predose up to 6 months after dosing ]
  Anti-GBM antibodies above a toxic level defined as >20 U/mL. The level of anti-GBM antibodies was measured centrally using the Phadia ELiA(TM) anti-GBM kit. The enzyme-linked immunoassay (ELiA) is a fluorescence enzyme immunoassay.
• Number of Patients With Haematuria (Blood in Urine) [ Time Frame: At 6 months after dosing ]
  Haematuria was assessed using urine dipstick. The result was presented as: Negative/Trace/+1/+2/+3/+4. In the analysis results being +2 or above are considered as relevant. Haematuria was an inclusion criterion. All 15 patients had haematuria when included in the study.
• Change in Proteinuria During the Study [ Time Frame: Pre-imlifidase, 3 and 6 months after imlifidase dosing ]
  Change in proteinuria measured as u-albumin/creatinine (g/mol) in morning void during the study .
• Number of PLEXs Needed Over Time [ Time Frame: Pre-screening and up to Day 93 after imlifidase dosing ]
  Number of PLEXs needed before anti-GBM antibodies are below toxic levels. PLEX was initiated at the discretion of the investigator throughout the study.
• Pharmacokinetics of Imlifidase (Cmax) [ Time Frame: Pre-dose, 45min, 2h, 6h, 24h, Day3, Day 7, Day 10, and Day15 ]
  Maximum observed plasma concentration of IdeS following dosing (Cmax)
• Pharmacokinetics of Imlifidase (AUC) [ Time Frame: Pre-dose, 45min, 2h, 6h, 24h, Day3, Day 7, Day 10, and Day15 ]
  Area under the plasma concentration versus time curve (AUC)
• Pharmacokinetics of Imlifidase (t1/2) [ Time Frame: Pre-dose, 45min, 2h, 6h, 24h, Day3, Day 7, Day 10, and Day15 ]
  Half-life during distribution phase (Alpha-t1/2) Half-life during elimination phase (Beta-t1/2) The results refers to harmonic mean.
• Pharmacokinetics of Imlifidase (CL) [ Time Frame: Pre-dose, 45min, 2h, 6h, 24h, Day3, Day 7, Day 10, and Day15 ]
  Clearance (CL) is a measure of the ability of the body to clear imlifidase from plasma
• Pharmacokinetics of Imlifidase (Vz) [ Time Frame: Pre-dose, 45min, 2h, 6h, 24h, Day3, Day 7, Day 10, and Day15 ]
  Vz = Volume of distribution during the elimination phase
• Pharmacodynamics (IgG Degradation Measured as Remaining Concentration of Intact and Single Cleaved IgG) [ Time Frame: Pre-dose up to 6 months after imlifidase administration ]
  Imlifidase specifically cleaves all subclasses of human IgG rapidly and efficiently. The cleaving process involves two steps: (i) intact IgG to single cleaved IgG followed by (ii) single cleaved IgG to completely cleaved IgG (one F(ab')2- and one homodimeric Fc-fragment) The electroluminescence analysis method used measures the sum of intact and single cleaved IgG in serum. The efficacy of imlifidase is evaluated as remaining concentration of intact and single cleaved IgG in serum after treatment.
• Anti-imlifidase Antibodies (ADA) [ Time Frame: Up to 6 months after dosing ]
  Determination of anti-imlifidase antibody concentration
• Renal Histology [ Time Frame: Before administration of imlifidase (0-33 days) and after administration of imlifidase (3-6 days) ]
  Kidney biopsies were classified according to the histopathologic classification for antineutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis developed by Berden et al. 2010. This classification has previously been applied in a study of 123 anti-GBM disease patients (von Daalen et al 2018). Histopathologic class:

  • Focal (≤50% normal glomeruli)
  • Crescentic (≥50% glomeruli with cellular crescents)
  • Mixed (<50% normal, <50%crescentic, <50% globally sclerotic glomeruli)
  • Sclerotic (≥50% globally sclerotic glomeruli) In addition information on the histological activity and kidney outcome was provided.

  Focal class is associated with favourable kidney outcome, whereas sclerotic carries a poor outcome. Crescentic/mixed class could have an intermediate outcome between focal and sclerotic. Immunofluorescence performed at the local hospitals was also used to assess linear IgG deposits which is a hallmark of anti-GBM antibody disease.

Original Secondary Outcome Measures (submitted: May 15, 2017)

• The proportion of subjects with independent renal function, defined as no need for dialysis at 3 months, as compared to historical controls. [ Time Frame: 3 months after dosing ]
  Number of patients without need for dialysis
• Renal function at 3 and 6 months [ Time Frame: 3 and 6 months after dosing ]
  eGFR and change in GFR from baseline;
• Number of days with anti-GBM antibodies above a toxic level [ Time Frame: 6 months after dosing ]
  Days with anti-GBM antibodies >30 ELISA units
• Disappearance of haematuria [ Time Frame: 6 months after dosing ]
  Number of days until disappearance of haematuria, measured in days from start of treatment
• Change in proteinuria during the study [ Time Frame: 6 months after dosing ]
  Change in proteinuria during the study measured as u-albumin/creatinine ratio in morning void
• Number of PLEXs needed [ Time Frame: 6 months after dosing ]
  Number of PLEXs needed before anti-GBM antibodies are below toxic levels
• Renal histology [ Time Frame: 6 months after dosing ]
  Renal histology measurements and changes in renal histology if a second renal biopsy is performed
• Anti-IdeS antibodies (ADA) [ Time Frame: 6 months after dosing ]
  Determination of anti-IdeS antibody concentration
• Pharmacodynamics (IgG degradation) [ Time Frame: Day 0 to day 28 after dosing ]
  Determination of IgG and determination of IgG fragments
• Pharmacokenetics [ Time Frame: Day 0 to day 14 after dosing ]
  Area under the plasma concentration versus time curve (AUC)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Open-Label Phase II Study to Evaluate the Efficacy and Safety of IdeS in Anti-GBM Disease
• Official Title: Open-Label Phase II Study in Anti-GBM Disease (Goodpasture's Disease) With Adverse Renal Prognosis to Evaluate the Efficacy and Safety of IdeS - GOOD-IDES
• Brief Summary: This study will evaluate the safety and tolerability of IdeS in patients with severe anti-glomerular basement membrane (anti-GBM) disease receiving standard of care consisting of pulse-methylprednisolone, oral prednisolone and intravenous cyclophosphamide combined with plasma exchange (PLEX).
• Detailed Description: This is an Open-Label Phase 2 Study to Evaluate the Efficacy and Safety of IdeS in anti-GBM disease (Goodpasture's disease, i.e. GP) with Adverse Renal Prognosis. The primary efficacy objective is to evaluate the efficacy of an IdeS based regimen to salvage independent renal function measured as no need for dialysis at 6 months after IdeS treatment. The primary safety objective of this study is to evaluate the safety and tolerability of IdeS in patients with severe anti-GBM disease on background of standard care consisting of pulse-methylprednisolone, oral prednisolone and intravenous cyclophosphamide (CYC) combined with plasma exchange (PLEX). The patients will be followed during 6 months according to the study visit plan.
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

Open-Label, Single Arm study

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Anti-Glomerular Basement Membrane Antibody Disease

Intervention

Biological: Imlifidase

One dose of 0.25 mg/kg body weight imlifidase on study day 1

Other Names:

• Immunoglobulin G-degrading enzyme of Streptococcus pyogenes
• HMed-IdeS
• IdeS

Study Arms

Experimental: Imlifidase

Imlifidase 0.25 mg/kg body weight intravenous infusion

Intervention: Biological: Imlifidase

Publications *

• Berden AE, Ferrario F, Hagen EC, Jayne DR, Jennette JC, Joh K, Neumann I, Noel LH, Pusey CD, Waldherr R, Bruijn JA, Bajema IM. Histopathologic classification of ANCA-associated glomerulonephritis. J Am Soc Nephrol. 2010 Oct;21(10):1628-36. doi: 10.1681/ASN.2010050477. Epub 2010 Jul 8.
• van Daalen EE, Jennette JC, McAdoo SP, Pusey CD, Alba MA, Poulton CJ, Wolterbeek R, Nguyen TQ, Goldschmeding R, Alchi B, Griffiths M, de Zoysa JR, Vincent B, Bruijn JA, Bajema IM. Predicting Outcome in Patients with Anti-GBM Glomerulonephritis. Clin J Am Soc Nephrol. 2018 Jan 6;13(1):63-72. doi: 10.2215/CJN.04290417. Epub 2017 Nov 21.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 15, 2017): 15
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: July 24, 2020
• Actual Primary Completion Date: July 24, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Anti-GBM antibodies detected by ELISA above a level that is considered toxic by the investigator using local laboratory. Patients double-positive for anti-GBM and anti-neutrophil cytoplasmic antibodies (ANCAs) may be entered in the trial, but only if their level of anti-GBM antibodies fulfil the criteria listed above.
2. Estimated glomerular filtration rate (eGFR) <15 ml/min/1.73 m^2 (by modification of diet in renal disease (MDRD) equation) or if the patient is non-responsive to standard treatment, and has lost >15 ml/min/1.73 m^2 after start of treatment
3. Haematuria on dipstick and/or urinary sediment
4. Male or female patients aged at least 18 years; Female patients of childbearing potential may participate if highly effective contraception is used during the study, according to Clinical Trials Facilitation and Coordination Group (CTFG) guidance [18], see also section 4.9 (pregnancy test should be performed before inclusion).
5. Willing and able to give written Informed Consent and to comply with the requirements of the study protocol; and
6. Judged to be otherwise healthy by the Investigator, based on medical history, physical examination, and clinical laboratory assessments. Patients with clinical laboratory values that are outside of normal limits (other than those specified in the Exclusion Criteria) and/or with other abnormal clinical findings that are judged by the Investigator not to be of clinical significance, may be entered into the study.

Exclusion Criteria:

1. Anuria for more than 2 days (less than 200 ml during last 48 hours);
2. Dialysis dependency for more than 5 days (maximum 3 sessions before signing informed consent);
3. Ongoing moderate to severe pulmonary haemorrhage (or having ceased within the last two weeks), defined as requiring assisted ventilation, oxygen or blood transfusions.
4. Pregnancy.
5. Symptomatic congestive heart failure (NYHA class 2-4) and requiring prescription medication or clinically evident peripheral edema of cardiac origin;
6. Myocardial infarction, unstable angina or stroke within 3 months prior to screening;
7. Ongoing bacterial infection requiring antibiotic therapy or viral infection with Hepatitis B, C or HIV (up to 3 months old negative test results are accepted); or active tuberculosis as indicated by chest x-ray.
8. Patients should not have received investigational drugs within 30 days prior to screening or within 4 half-lives (whichever is longer); and
9. History or presence of any medical condition or disease which, in the opinion of the Investigator, may place the subject at unacceptable risk for study participation.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Czechia, Denmark, France, Sweden

Administrative Information

• NCT Number: NCT03157037
• Other Study ID Numbers: GOOD-IDES-01
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Mårten Segelmark, Linkoeping University
• Original Responsible Party: Same as current
• Current Study Sponsor: Mårten Segelmark
• Original Study Sponsor: Same as current
• Collaborators: Hansa Biopharma AB

Investigators

• Principal Investigator: Mårten Segelmark, MD PhD Prof; Linkoeping University

• PRS Account: Linkoeping University
• Verification Date: February 2022