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
Phase: PHASE2
Conditions: Anti-Glomerular Basement Membrane Antibody Disease
Sponsor: Mårten Segelmark

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Study protocol: GOOD-IDES-01, 13 February 2018 
 
An 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 
Short title: IdeS --GOOD-IDES  
 
 
Protocol Version: 3.3 AT 
EudraCT number: 2016-004082-39 
Sponsor protocol number: GOOD-IDES-01 
 
 
Hansa Medical AB, protocol number: 15-HMedIdeS-10 
Partial funding: Hansa Medical AB, P.O. Box 785 SE-220 07, Lund, SWEDEN 
 
 
 
__________________________________________________ 
 
 
Coordinating Principle Investigator (CPI) and Sponsor 
 
Division of Drug Research 
 
 
 
Department of Medical and Health Sciences  
 
Linköping University  
 
 
  
SE-581 83 Linköping  
 
 
 
SWEDEN 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 

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Title page  
Study Title: An 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 
Protocol Number: GOOD-IDES-01 
Investigational Product: HMED-IdeS 
Indication: Anti-GBM-disease (Goodpasture’s disease) 
Sponsor: Linköping University   
Development Phase: II 
EudraCT number 2016-004082-39 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Abbreviations 
 
AAV 
 
ANCA-associated vasculitis 
ACR  
 
Albumin/Creatinine Ratio 
ADA  
 
Anti-IdeS antibodies 
AE  
 
Adverse Event 
ANCA 
 
Anti-neutrophil cytoplasm antibody 
BW 
 
Body weight 
CPI 
 
Coordinating Principle Investigator 
CRF  
 
Case report form  
CYC  
 
Cyclophosphamide 
DD 
 
Deceased donor 
DSMB 
 
Data Safety Monitoring Board 
DSUR 
 
Developmental Summary Update Report 
EC 
 
Ethics Committee 
eGFR 
 
Estimated glomerular filtration rate 
ELISA 
 
Enzyme-Linked Immunosorbent Assay 
ESRD 
 
End-stage renal disease 
GBM 
 
Glomerular Basement Membrane 
GC 
 
Glucocorticoids 
GCP 
 
Good Clinical Practice  
GMP 
 
Good Manufacturing Practice 
GP 
 
Goodpasture’s disease 
HLA 
 
Human Leukocyte Antigen 
ICH 
 
The International Council for Harmonisation 
IMP 
 
Investigational Medicinal Product 
IgG 
 
Immunoglobulin G 

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IdeS 
IgG-degrading enzyme of Streptococcus pyogenes 
IMP 
Investigational medicinal product 
KDIGO  
Kidney Disease, Improving Global Outcomes 
LD 
Living donor 
MDRD 
 
The Modification of Diet in Renal Disease equation 
PLEX 
 
Plasma Exchange 
RA 
 
Regulatory Authority 
SAE 
 
Serious Adverse Event 
SUSAR 
 
Suspected unexpected Serious Adverse Reaction 
TB 
 
Tuberculosis 
TRALI 
 
Transfusion related Acute Lung Injury 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Contact information 
Investigators 
 
Site 
Sweden 
 
Department of Nephrology, University Hospital, SE-581 85 
Linköping
 
 
 
 
Department of Nephrology M99 Clinical Science, Intervention and 
Technology, Karolinska University Hospital, SE-141 86 
Stockholm,
 
 
 
 
 
Department of Nephrology, Faculty of Medicine, Lund University, 
University Hospital, SE-221 85 Lund, 
 
 
 
                                                                                       
Department of Nephrology, Uppsala University Hospital, entr 30, 
5th floor 75185, Uppsala,
                                  
  
Co-investigator 
, Department of 
Nephrology, University Hospital, SE-75185 Uppsala, 
 
 
 
 
       
Department of Nephrology, Sahlgrenska University Hospital, SE- 
413 45 Gothenburg, 
 
 
Co-investigator 
 Department of 
Nephrology, Sahlgrenska University Hospital, SE- 413 45 
Gothenburg
 
                                                                                                                                  
01 
 
 
 
 
02 
 
 
 
 
 
 
03 
 
 
 
 
04 
 
 
 
 
 
 
 
 
05 
Denmark 
 
Department of Department of Nephrology, Rigshospitalet, 
Blegdamsvej 9, 2100 Copenhagen, Denmark, 
 
 
 
 
 
Department of Renal Medicine, Aarhus University Hospital, Palle 
Juul-Jensen Boulevard 99, DK-8200 Aarhus N, Denmark, 
 
  
Co-investigator, 
Department of Renal Medicine, 
06 
 
 
 
 
 
07 
 

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Aarhus University Hospital, Palle Juul-Jensen Boulevard 99, DK-
8200 Aarhus N, Denmark. 
 
 
 
Austria 
  
Division of Nephrology, Department of Internal Medicine Medical 
University of Graz Auenbruggerplatz 15,  A-8036 Graz,
 
 
 
  
Medical University of Vienna Department of Internal Medicine III 
Division of Nephrology and Dialysis  Waehringer Guertel 18-20, 
A-1090 Vienna,
 
 
 
 
Universitätsklinik für Innere Medizin IV,  
 
 
Co.investigator 
                                                     
Department of Internal Medicine IV (Nephrology and 
Hypertension), Anichstraße 35, A-6020 Innsbruck, 
 
 
Co-investigator, 
, Innsbruck 
  
 
 
 
Innere Medizin III (Nephrologie und Dialyse) Akademisches 
Lehrkrankenhaus Feldkirch, Carinagasse 47, A-6800 Feldkirch  
 
 
 
08 
 
 
 
 
 
 
09 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
 
 
 
11 
 
Czech 
Republic 
 
Department of Department of nephrology, First Faculty of 
Medicine and General Teaching Hospital, U Nemocnice 2, 121 08 
PRAHA 2, CZECH REPUBLIC and Charles University in Prague, 
Prague, CZ, Czech Republic,
                          
 
Co-investigator, 
, Department of Nephrology 
Nephrology, Internal Medicine (General Medicine) Charles 
University in Prague , Prague (1. LF), 
  
 
 
UK 
  
Department of Medicine, Imperial College London, London, UK 
 

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Research staff 
Sweden: 
Project coordinator (Linköping): 
 
 
Study coordinator (Linköping):  
 
 
Study coordinator (Uppsala): 
 
 
                                                           
Back-up study coordinator (Uppsala): 
 
 
 
Study coordinator (Stockholm): 
 
 
 
Study coordinator (Lund):
 
Study coordinator (Göteborg):
 
 
 
Denmark: 
Study coordinator (Copenhagen): 
 
 
 
Study coordinator (Aarhus): 
 
     
Austria:  
Study coordinator (Graz) 
 
Study coordinator (Wien): 
 
 
 
 
Study coordinator (Innsbruck): 
 
 
 
Study coordinator (Feldkirch): 
 
UK: 
Study Coordinator (London): 
 
 

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Study Coordinator, 
                                              
 
Czech Republic: 
France: 
 
Study monitoring: 
Copenhagen, Aarhus: 
 
 
Sweden: 
 
 
Graz, Wien: 
 
 
Innsbruck, Feldkirch:
  
 
 
 
 
Laboratory contact: 
Division of Drug Research Department of Medical and Health Sciences Linköping 
University SE-581 83 Linköping, SWEDEN  
Hansa Medical AB, P.O. Box 785 SE-220 07, Lund, SWEDEN 
 
 
Hansa Medical: 
 
Clinical Research Manager 
Hansa Medical AB 
Scheelevägen 22, P.O Box 785 
SE-220 07 Lund, Sweden 
 
 
Web: www.hansamedical.com 
 
 
Director Clinical Operations 
Hansa Medical 
 
 

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Visiting address: 
Scheelevägen 22 
223 63 Lund, Sweden 
Postal address: 
P.O. Box 785 
220 07 Lund, Sweden 
 
 
 
 
 
 
AE/SAE reporting: 
Contact Information: 
CRO: 
 
 
 
e-mail: 
  
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
An 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 .......................... 1 
Title page ................................................................................................................................... 2 
Abbreviations ............................................................................................................................. 3 
1. Study synopsis ..................................................................................................................... 14 
2. Background and Rationale ................................................................................................... 20 
2.1 Description of IdeS and summary of findings from earlier studies ............................... 20 
2.2 Potential risks and befits to human subjects .................................................................. 24 
2.3 Route of administration and dosage of IdeS .................................................................. 26 
2.4 Trial statement ............................................................................................................... 26 
2.5 Target population ........................................................................................................... 26 
3. Objectives and Purpose ........................................................................................................ 26 
3.1 Primary Objectives......................................................................................................... 26 
3.2 Secondary Objectives..................................................................................................... 27 
4. Trial design .......................................................................................................................... 27 
4.2 Number of Centres ......................................................................................................... 27 
4.3 Number of Participants .................................................................................................. 27 
4.4 Study Duration ............................................................................................................... 27 
4.5 Trial Endpoints............................................................................................................... 28 
4.5.1 Primary Endpoint .................................................................................................... 28 
4.5.2 Secondary Endpoints .............................................................................................. 28 
4.6 Trial treatments .............................................................................................................. 28 
4.8 Data to be recorded ........................................................................................................ 29 
4.9 Benefit risk assessment .................................................................................................. 29 
5. Selection of Patients and Criteria for Discontinuation ........................................................ 30 
5.1 Subject inclusion criteria................................................................................................ 31 
5.2 Subject exclusion criteria ............................................................................................... 31 
5.3 Subject withdrawal criteria ............................................................................................ 32 
5.3.1 Criteria for discontinuation from the study ............................................................. 32 
5.3.2 Procedures for discontinuation of a patient from the study .................................... 32 
5.3.3 Procedures after completion of the trial ...................................................................... 32 
6. Treatment of Patients ........................................................................................................... 33 
6.1 Investigational Medicinal Product ................................................................................. 33 
6.1.1 Storage and handling............................................................................................... 33 
6.2 Packaging and labelling ............................................................................................. 33 

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6.3 Drug accountability and compliance check ............................................................... 33 
6.4 Administration of IMP ............................................................................................... 34 
6.5 Concomitant Administration of other drugs .............................................................. 34 
6.5.1 Plasma exchange (PLEX) ....................................................................................... 34 
6.5.2 Glucocorticoids (GC) .............................................................................................. 35 
6.5.3 Cyclophosphamide (CYC) ...................................................................................... 35 
6.5.4 Concomitant medication ............................................................................................. 36 
6.5.5 Premedication ......................................................................................................... 36 
6.5.6 Prophylactic antibiotic ............................................................................................ 36 
6.5.7 Laboratory Markers ................................................................................................ 36 
7. Assessment of efficacy ........................................................................................................ 37 
7.1 Efficiency parameters .................................................................................................... 37 
7.2 Method for timing, assessing, recording, and analysis of efficiency parameters .......... 37 
8. Assessment of Safety ........................................................................................................... 37 
8.1 Safety parameters ........................................................................................................... 37 
8.2 Method for timing, assessing, recording, and analysis of safety parameters ................. 37 
8.3 Definitions...................................................................................................................... 38 
8.3.1 Adverse event (AE) ................................................................................................. 38 
8.3.2 Serious adverse event (SAE) or serious adverse reaction ....................................... 38 
8.4 Expected adverse reactions ............................................................................................ 38 
8.4.1 Plasma exchange ..................................................................................................... 38 
8.4.2 Prednisone and prednisolone .................................................................................. 39 
8.4.3 Cyclophosphamide .................................................................................................. 39 
8.5 Reporting of AE and SAE.............................................................................................. 39 
8.6 Recording and evaluation of SAEs ................................................................................ 40 
8.6.1 Assessment of severity ............................................................................................ 40 
8.6.2 Assessment of causality .......................................................................................... 40 
8.7 Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) ................ 41 
8.7.1 Who should report and whom to report to? ............................................................ 41 
8.8 Reporting adverse events and breaches ......................................................................... 41 
8.8.1 Reporting adverse events ............................................................................................ 41 
8.8.2 Reporting on breaches ................................................................................................. 41 
8.9 Follow-up of adverse events .......................................................................................... 41 
8.10 Developmental Safety Update Report (DSUR) ........................................................... 41 
8.11 Study Risk Assessment ................................................................................................ 42 
9. Statistical Considerations ..................................................................................................... 42 
9.1 Sample Size Estimation ................................................................................................. 42 

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9.2 Outcome calculations ..................................................................................................... 43 
10. Study Monitoring ............................................................................................................... 43 
11. Procedures for Recruitment and for obtaining informed consent ...................................... 43 
12. Ethical Considerations ....................................................................................................... 44 
12.1 Regulation statement .................................................................................................... 44 
12.2 Protection against risks ................................................................................................ 44 
12.3 Trial Ethical Approval ................................................................................................. 44 
13. Handling and Archiving of Data ........................................................................................ 45 
13.1 End of study report....................................................................................................... 45 
13.2 Archiving data .............................................................................................................. 45 
14. Insurance ............................................................................................................................ 45 
15. Funding .............................................................................................................................. 45 
16. Reporting and Publishing ................................................................................................... 45 
17. References .......................................................................................................................... 46 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. Study synopsis 
Name of Sponsor 
  Linköping 
university  
Name of Active Ingredient 
HMedIdeS 
Study number:  
2016-004082-39 
Title 
An Open-Label Phase II Study to Evaluate the Efficacy and Safety of IdeS in anti-GBM 
disease (Goodpasture’s disease) with Adverse Renal Prognosis --GOOD-IDES 
Investigators 
 
 
 
Study centers 
Multi-center (up to15 sites), in 4-6 countries (Sweden, Denmark, UK, Czech Republic, 
France, Austria)  
Study period 
24 months 
Phase of development 
Phase II 
Aim 
The aim of this study is to evaluate the treatment with IdeS in anti-GBM disease  
Objectives 
The primary objective of this study is to evaluate the safety and tolerability of IdeS in 
patients with severe anti-GBM (Glomerular Basement Membrane) disease on background 
of standard care consisting of pulse-methylprednisolone, oral prednisolone and 
intravenous cyclophosphamide combined with plasma exchange (PLEX). 
The primary efficacy objective is to evaluate the efficacy of an IdeS based regimen to 
salvage independent renal function defined as no need for dialysis at 6 months and after 
IdeS treatment. 
The secondary objectives of this study include assessment of: 
1. Renal function 3 months  
2. Change in eGFR during the study period; 
3. Number of days with anti-GBM antibodies above a toxic level (i.e. >30 ELISA units)  
4. Disappearance of hematuria, days from start of treatment; 
5. Change in proteinuria during the study measured as u-albumin/creatinine ratio in 
morning void; 
6. Number of PLEX needed; 
7. Changes in renal histology (optional)  
8. Anti-IdeS antibodies (ADA) 
9. Pharmacokinetics, Pharmacodynamics (IgG degradation) 

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Rationale 
Patients with anti-GBM disease presenting with advanced renal injury (p-creatinine above 
500 mol/L) have a very poor renal prognosis. Less than 10% survive with independent 
renal function. The pathogenic process is driven by IgG autoantibodies directed against 
the glomerular basement membrane. The antibodies attract neutrophils to the site of 
injury and to complement activation mediated by the Fc-portion of the molecule. IdeS 
specifically cleave human IgG of all four subclasses, while all other plasma proteins are left 
undigested. A single injection clears circulating levels of IgG completely and levels of 
newly synthesized IgG cannot be detectable until two weeks after dosing. PLEX is known 
to alter the course of anti-GBM disease but each session clears less than a third of total 
body IgG. Consequently it takes several days of PLEX to reach non-toxic levels of 
circulating autoantibodies, and PLEX has no effect on membrane bound autoantibodies. In 
animal experiments IdeS can also cleave IgG that has bound to the basement membrane 
preventing subsequent glomerular injury as well as complement activation and neutrophil 
influx. It is probable that fast cleavage of all toxic antibodies including those already 
bound, would halt the inflammatory process and lead to a better prognosis. 
Methodology 
This is a pilot study to test the safety, tolerability, and efficacy of IdeS in severe anti-GBM 
disease. 
All patients with anti-GBM disease confirmed by the combination of hematuria and 
circulating anti-GBM antibodies are eligible for inclusion provided they have an eGFR < 15 
ml/min/1.73 m2 and that they are not anuric (i.e. having voided >200 ml urine during the 
last 48 hours). Standard treatment including PLEX may have been started but patients will 
be excluded if anti-GBM is below a level considered as toxic by the treating physician. 
Screening procedures will include demographics, medical history, medication history, 
physical examination and vital signs, serum pregnancy test for women of childbearing 
potential, serum chemistry, hematology, urinalysis, viral screening (HCV, HBV, HIV), chest 
x-ray and estimated glomerular filtration rate (eGFR) assessment.  
A renal biopsy is not necessary to be included in the study. But if not done before 
inclusion, a biopsy should be performed as soon as possible after anti-GBM antibodies 
have reached a non-toxic level. An optional renal biopsy could be performed to assess the 
effect of IdeS treatment on kidney histology.  
On Day 1 of the study patients will be given a single intravenous infusion of IdeS (0.25 mg 
IdeS/kg BWt). Anti-GBM antibodies will be measured with decreasing frequency through 
the study. PLEX will be performed when necessary to keep the anti-GBM levels below a 
level considered as a toxic level at each participating center. PLEX should not be issued the 
first 36 hours following the infusion of IdeS. 
Glucocorticoids (GC) therapy starts with intravenous methylprednisolone given as 3 daily 
pulse doses. Each pulse dose may be between 0.5 g and 1 g.  Any dose given prior to 
inclusion in the study should be subtracted from the total dose. Oral prednisolone therapy 
shall commence after stopping methylprednisolone. Dosing will be given according to 
local practice, a preferential range is listed in Table 2. Prophylaxis against peptic ulcers 
and osteoporosis will be given based on the investigators decision in each individual case. 
Cyclophosphamide (CYC) either intravenous pulses or daily oral will be prescribed for at 
least 13 weeks in patients with independent renal function, but may be withdrawn earlier 

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in patients considered to have reached end-stage renal disease (ESRD). A starting dose of 
10 mg/kg/pulse will be used for pulse CYC (maximum 1.0 g/dose) or 1.5 mg/kg/day for 
oral CYC (maximum 150 mg/day) with reductions made for age. Pulse CYC will be 
administered intravenous at a frequency of every two weeks for the first 3 doses then 
every 3 weeks thereafter. Modifications to dose and frequency will be made in the case of 
leucopenia. Full blood counts will be performed regularly. Concomitant use of mesna is 
optional and left to the discretion of the investigator and local practice.  
Number of Patients 
Up to approximately 15 male or female patients with anti-GBM disease will be enrolled in 
this study.  
Questionnaire about the feasibility at each site and the availability of patients with anti-
GBM disease with Adverse Renal Prognosis for the last 5 years will be evaluated before 
sites will be included. 
Main Criteria for Inclusion 
1. 
Anti-GBM antibodies detected by Enzyme-Linked Immunosorbent Assay (ELISA) 
above a level that is considered toxic by the investigator. Patients double-positive for 
anti-GBM and ANCA may be entered in the trial, but only if their level of anti-GBM 
antibodies fulfil the criteria above.  
2. 
eGFR < 15 ml/min/1.73 m2 (by MDRD equation) or if the patient is non-responsive 
to standard treatment, and has lost  >15 ml/min/1.73 m2  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. 
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.  
Main Criteria for Exclusion 
1. Anuria for more than 48 hours (less than 200 ml) 
2. Dialysis dependency for more than 5  days (maximum 3 sessions before signing 
informed consent) 
3. Moderate to severe pulmonary haemorrhage as defined in the protocol 
4. Pregnant 
5. Symptomatic congestive heart failure (NYHA class 2-4) 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 

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Hepatitis B, C or HIV; 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. 
Test Product 
HMED-IdeS, administered intravenously once per subject. 
Duration of Treatment and Observation  
HMED-IdeS will be given as a single infusion over 30 minutes. Within 36 hours after the 
HMED-IdeS infusion no PLEX should be given. After that patients will be treated according 
to standard of care and followed according to the protocol for 6 months. 
Safety Assessments 
Safety assessments include adverse events, evaluation for lung haemorrhage, physical 
examination abnormalities, vital signs, and clinical laboratory tests (including blood 
chemistry, complement analysis, haematology, and urinalysis). Safety assessment will also 
include occurrence of infections. 
Physical examination including vital signs will be performed at screening, day 1, day 7, day 
29, day 93 and end of study at day 180. Visits to the research nurse/site coordinator will 
be made at other times, in accordance with the study visit plan Appendix 1. 
The patients will be closely monitored for all adverse events. The principal investigator 
must make sure that sufficient facilities and procedures are available to handle emergency 
situations during the study. The hospitals should have adequate procedures in place to 
handle unexpected adverse reactions. 
Efficacy Assessments 
Efficacy assessments include: 
1. Independent renal function measured as no need for chronic renal replacement 
therapy 
2. eGFR by Modification of Diet in Renal Disease (MDRD) formula based on serum 
creatinine; 
3. Albuminuria measured as first morning urinary Albumin/Creatinine Ratio (ACR); 
4. Haematuria based on urine sticks 
5. Histological changes in a second biopsy (optional).                                                                         
Laboratory Markers 
Plasma samples will be collected for analysis both at local (at site) and at central 
laboratory on Days 1, 3, 7, 10, 15, 22, 29, 50, 93, 135 and 180 (end of study) for laboratory 
marker measurements for example anti-GBM, CRP and inflammatory cytokine and 
chemokine levels. Urine samples will also be collected on Days 1, 7, 15, 50, 93 and 180 
(end of study) for biomarker assessments including for example complement fragments, 
inflammatory chemokine and cytokine levels. Blood and urine samples will be sent on the 
same day for analysis at local laboratories for safety surveillance. Samples for central 

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laboratory will be frozen at site and sent during the study period (for more detailed 
information see section 6.5.7 and study visits, Appendix 1). 
Statistical Methods 
Historical data indicate that when using standard therapy only 7% of patients fulfilling the 
inclusion criteria of this study survive with independent renal function. If the 
experimental therapy raises this figure to 50 %, 15 patients are needed (power 0.98). The 
corresponding figures for a response rate of 40 % or 30 % and would then have a power 
of 0.92 and 0.77 respectively. Chi square (χ2) calculations (alt. Fisher's exact test), at 
significance level p=0.05, will be used to compare changes proportions dialysis 
independent patients. For the other endpoints (2-6) descriptive statistics will be used. 
To compare patients treated for anti-GBM disease under similar conditions, matched 
historical controls will be used in each site that includes patients to the study. The 
variables to be matched will be age and gender. 
 
Demographics and Baseline Characteristics 
All subject baseline characteristics and demographic data (age, sex, weight, height, 
smoking status, viral test results, eGFR, proteinuria (ACR), physical examination 
abnormalities, medical history, previous (within 6 months of screening) and concomitant 
medications at study entry will be listed by study center and subject number, and will also 
be summarized.  
 
Safety Analysis 
The primary safety endpoint is incidence of adverse events or disease progression in the 
lungs. 
Other safety endpoints include: 
• Change from screening in all safety laboratory parameters; 
• Change from screening in vital signs; 
All clinical safety and tolerability data will be listed by subject and will be summarized. 
Treatment-emergent adverse events will be listed and summarized by System Organ 
Class, by relatedness and by maximum severity. Serious adverse events and adverse 
events leading to withdrawal will be listed and summarized. Individual vital signs and 
change from baseline in vital signs will be listed by subject, and study visit, and 
summarized descriptively. Laboratory data (actual values and change from baseline) will 
be listed by subject and study visit. Abnormal laboratory values will be flagged. 
 
Efficacy Analysis 
The primary efficacy endpoint is proportion of patients with independent renal function at 
6 months.  
Other efficacy endpoints include: 
1. The proportion of subjects with independent renal function, defined as no need for dialysis 
at 3 months, as compared to historical controls.  

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2. Renal function at 3 and 6 months expressed as eGFR and as change in GFR from baseline; 
3. Number of days with anti-GBM antibodies above a toxic level (i.e. >30 ELISA units) 
measured at a central laboratory using the Wieslab anti-GBM kit; 
4. Disappearance of haematuria, measured in days from start of treatment; 
5. Change in proteinuria during the study measured as u-albumin/creatinine ratio in morning 
void; 
6. Number of PLEXs needed; 
7. Renal histology measurements and changes in renal histology if a second renal biopsy is 
performed; 
8. Anti-IdeS antibodies (ADA) 
9. Pharmacokinetics, Pharmacodynamics (IgG degradation)  
 
 
 
 
 
 

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Study 13-HMedIdeS-02 (EudraCT no. 2013-005417-13) was a single centre, single arm, 
dose finding, Phase II study in sensitized CKD patients assessing safety, tolerability, 
pharmacokinetics (PK) and efficacy of HMED-IdeS without intent to transplantation. 
However, patients were not removed from the transplant waitlist during the study. 
Included patients had a panel reactive antibody [PRA] >70% (n=7). All patients received 
the infusions: 0.25mg/kg once (n=2), 0.12mg/kg twice (n=3), or 0.25mg/kg twice (n=2) 
HMED-IdeS. Five serious adverse events (SAEs) were reported of which 4 were 
classified as probably or possibly related to the study drug. Those were 3 infections and 
1 myalgia.  
For all patients, >99% of plasma IgG was degraded within 48 hours after treatment with 
<1% plasma IgG detectable for up to 7 days. The HLA antibodies started to recover from 
day 7/8 and were back to pre-dose levels between day 14/15 and day 28. Efficacy of 
HMED-IdeS was also demonstrated on PRA crossmatch test in which PRA was reduced 
from 69% (range 11% to 100%) pre-treatment to 3% (range 0% to 21%) after 
treatment. The PRA decreased in all patients within one hour of treatment and 
remained low for approximately one week (Hansa Doc 2015-30). 
The primary objective of the study was to find an HMED-IdeS dosing scheme which 
resulted in HLA-antibody levels acceptable for transplantation in the majority of 
patients. The acceptance criteria for transplantation was defined as a mean fluorescence 
intensity (MFI) of <1100, within 24 hours from HMED-IdeS dosing and the primary 
objective of the study was reached (Hansa doc. 2015-029). Two days after HMED-IdeS 
treatment, one patient was offered a cadaveric kidney that was crossmatch test positive 
prior to HMED-IdeS treatment and turned to negative after treatment. Transplantation 
was successful and the patient is doing well with very good kidney function >16 months 
after transplantation. 
In the 2 completed studies, there was a total of 2 non-serious infusion related reactions 
with no reports of serious infusion related reactions reported in ongoing studies.  Signs 
and symptoms associated with infusion related reactions included but were not limited 
to the following: dyspnoea, pharyngeal oedema, sinus tachycardia, chest discomfort and 
flushing. To date there have been no reports of anaphylactic or anaphylactoid reactions. 
All adverse events were mild or moderate. 

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Study 13-HMedIdeS-03 (EudraCT no. 2014-000712-34) was a single arm, Phase II study 
to assess safety and efficacy of HMED-IdeS given immediately prior to kidney 
transplantation in order to reduce DSAs in sensitized CKD patients awaiting deceased 
donor (DD) or living donor (LD) transplantation. The cut of level for inclusion was the 
same as in 13-HMedIdeS-02 3000 MFI with patients eligible for transplantation if 
crossmatch test was negative after IdeS treatment with acceptable antibody levels. 10 
patients (2 LD, 8 DD) have been treated with single doses of 0.25 or 0.5 mg/kg HMED-
IdeS along with standard immunosuppressive treatment, but no additional 
desensitizing agents. There have been no deaths and no study discontinuations due to 
adverse events (AEs). There were 26 SAEs reported by 8 patients. Five SAEs in 4 
patients were considered treatment-related (abdominal infection, device related 
infection, pneumonia, sepsis, parvo virus). All patients experienced complete absence of 
complement binding antibodies within 1 hour of treatment, cleavage of all IgG within 6 
hours of treatment and negative crossmatch test post-treatment, with initial recovery of 
IgG levels after 7-14 days. At the end-of-study the kidney function (creatinine and eGFR) 
was good in all patients and 9 out of the 10 patients the biopsy was normal. One patient 
showed signs of chronic ABMR at evaluation of the kidney biopsy on day 180. This study 
is completed with the last patient last visit performed in October 2016. 
Study 14-HMedIdeS-04 (IND no. 124301) is an ongoing investigator initiated Phase I/II, 
single arm, exploratory study to assess safety, tolerability, and efficacy of HMED-IdeS 
given immediately prior to kidney transplantation to reduce DSAs in highly sensitized 
(PRA range 82-100%, all DSA+) CKD patients awaiting DD renal transplantation. Study 
14-HMedIdeS-04 has enrolled 15 patients to date and all data presented are 
preliminary. All included patients were treated with a single dose of 0.24 mg/kg HMED-
IdeS. There have been 15 SAEs reported in 10 patients to date. None of them were 
considered related to IdeS. There were no signs of increased incidence of infections. All 
patients showed efficient inactivation of IgGs and eradication of HLA antibodies as 
measured by Luminex at 6-24 hours post-HMED-IdeS infusion and all included patients 
were transplanted. Target inclusion is 20 patients. 
Study 15-HMedIdeS-06 (IND no. 128074, EudraCT no. 2016-002064-13) is an ongoing 
Phase II study to evaluate the efficacy of HMED-IdeS to desensitize transplant patients 
with a positive crossmatch test. The study will enroll 15-20 patients (7-13 with LD and 
7-13 with a DD) who exhibit DSAs and have a positive crossmatch test to their available 
live or deceased donor organs. The study will primarily examine the efficacy of IdeS in 
creating a negative crossmatch in these patients. Included patients will be treated with 
HMED-IdeS on day 0. If it is considered safe and the desired effect is not achieved 
(negative crossmatch) a second dose can be given within 2 days of the first infusion. In 
addition to HMED-IdeS, patients will be given high dose IVIg (2 g/kg BW, maximum of 
140 g) on day 7 and B-cell depleting agent anti-CD20 (Rituximab) on day 9. DSA levels 
will be monitored 2, 6, 24 and 48 hours and 7, 14, 21, 28, 64, 90, 120 and 180 days after 
the last HMED-IdeS dosing. Safety, including kidney function will be monitored at 
multiple time points up to 180 days after treatment. Pharmacokinetics, 
pharmacodynamics (PD) and anti-drug antibodies will be measured. To date 4 patients 
have been included, dosed and transplanted. So far there have been five SAEs in three 
patients, none related to IdeS.  
Study 15-HMedIdeS-08 (EudraCT no. 2016-000249-30) is an ongoing Phase II study in 
patients diagnosed with asymptomatic antibody-mediated TTP with low ADAMTS13 

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activity. The primary objective is to monitor safety and tolerability after receiving single 
intravenous doses of IdeS. The secondary objective is to investigate IdeS efficacy in 
significantly increasing ADAMTS13 activity and decreasing ADAMTS13 antibody levels 
in patients with asymptomatic antibody-mediated TTP. In the current study this will be 
investigated in asymptomatic patients with reduced levels of ADAMTS13 activity and 
measurable levels of circulating ADAMTS13 antibodies. 
Eligible patients must have ADAMTS13 activity levels less than 10% of normal levels. 
Each patient will receive one dose of 0.25 mg/kg BW IdeS. Following an evaluation of 
safety and efficacy in 3 patients dosed at 0.25 mg/kg, there will be a possibility to 
increase the dose to 0.5 mg/kg for the next 3 patients. The dose will be given as a single 
intravenous infusion over 30 minutes. So far, two patients have been dosed with 0.25 
mg/kg. Both patients have experienced symptoms of serum sickness six days after IdeS 
administration. Follow up of the patients is currently ongoing. An overview of the 
ongoing and completed clinical studies is presented in Table 1. 
  
Table 1.  
Clinical Studies 
Study No./ 
Status 
Phase/ 
Subjects 
Doses/ 
Follow up 
time 
Main objectives 
Comments 
11-
HMedIdeS-
01/ 
Completed 
 
 
 
 
 
 
 
 
 
 
 
 
        
 
13-
HMedIdeS-
02/ 
Completed 
II/    
CKD 
Patients 
N=8 
0.12 and 0.25 
mg/kg BW 
given once or 
twice within 
48 h 
Efficacy in CKD patients 
defined as an HMED-IdeS 
dosing scheme resulting in 
HLA antibody levels 
acceptable for 
transplantation, within 24 
hours from dosing.       
Safety in the 
transplantation setting. 
Single arm with ascending 
doses. Primary efficacy 
endpoint reached.              
Safe and well tolerated. 
 
13-
HMedIdeS-
03/ 
Completed 
 
II/ 
Patients 
N=10 
0.25 and 0.5 
mg/kg        
180 d 
Safety in the 
transplantation setting. 
Efficacy defined as HLA 
antibody levels acceptable 
for transplantation. 
Similar design as 13-
HMedIdeS-02 but 
transplantation part of 
protocol.                      
Deceased and living donors. 
14-
HMedIdeS-
04/ Ongoing 
(Investigator 
initiated 
study) 
II/ 
Patients 
N=10-20 
0.25 and 0.5 
mg/kg        
180 d 
Safety in combination with 
Cedars Sinai’s “standard 
protocol” for 
desensitization of highly 
sensitized patients. Efficacy 
in preventing AMR. 
Investigator sponsored IND 
(IND 124301). HMED-IdeS 
combined with rituximab 
and IVIg.                     
Deceased donors. 

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15-
HMedIdeS-
06/ Ongoing 
II/ 
Patients 
N=20 
0.25 and 0.5 
mg/kg 
Primary 
endpoint: 24h 
Safety: 180 d 
Efficacy in creating a 
negative crossmatch test.  
Safety in the 
transplantation setting. 
Deceased and living donors. 
Target population cannot be 
transplanted with current 
available methods for 
desensitization. 
15-
HMedIdeS-
08/Ongoing 
II/ 
Patients 
N=6 
0.25 and 
possibly 0.5 
mg/kg    
Safety and 
efficacy: 64 d 
Safety and tolerability in 
patients with asymptomatic 
antibody-mediated TTP 
with low ADAMTS13 
activity.                          
Change from baseline in 
ADAMTS13 activity and 
antibody (IgG and F(ab’)2) 
Pilot study to investigate 
IdeS safety, tolerability and 
efficacy in patients 
diagnosed with 
asymptomatic antibody-
mediated TTP with low 
ADAMTS13 activity 
BW=body weight, h=hours, d=days, TTP Thrombotic Thrombocytopenic Purpura 
 
2.2 Potential risks and befits to human subjects 
The Data and Safety Monitoring Board (DSMB) will follow the progress and outcome of 
the study including patient safety. 
A single dose of 0.25 mg/kg BW has been selected for this study. The primary efficacy 
objective of the study is to evaluate the efficacy of an IdeS based regimen to salvage 
independent renal function defined as no need for dialysis at 3 and 6 months after IdeS 
treatment. A single of dose of 0.24 or 0.25 mg/kg is the dose that has been administered 
to the majority of renal transplant patients and has been shown to be highly effective in 
degrading donor specific antibodies with a favorable risk benefit profile.  
The phase I study in healthy subjects did not identify any dose limiting factors even at 
the highest tested dose (0.24 mg/kg BW) and CKD patients in a completed phase II 
study (13-HMedIdeS-02) in Sweden were exposed to a total dose of 0.5 mg/kg BW with 
acceptable safety profile. In another recently completed study in Sweden (13-
HMedIdeS-03) to evaluate the safety, tolerability, efficacy and pharmacokinetics of 
intravenous ascending doses of IdeS in kidney transplantation the first 5 patients in the 
study received a dose of 0.25 mg/kg BW and next 5 patients received a dose of 0.5 
mg/kg BW, respectively. Both dose levels were well tolerated.  More information on the 
design of the study is found in the Investigators Brochure and in section 2.1 above.  
 
an evaluation of the female and male reproductive organ in rabbit and dog 
were performed as part of the pivotal toxicological studies. In conclusion, there were no 
observations considered related to IdeS treatment on the female and male reproduction 
organs neither in rabbit nor dog. In order to avoid pregnancies the requirement for 
highly effective contraception is part of the inclusion criteria for this study. In addition, 
a pregnancy test will be performed prior to dosing and approximately at monthly 
intervals throughout the study, see appendix 1, Study visit plan. 
A pilot toxicology study in beagle dogs, showed that repeated IV administration of 
2 mg/kg BW or 20 mg/kg BW IdeS to Beagle dogs can result in clinical signs resembling 
an immune-mediated anaphylactic shock that correlates with high levels of anti-IdeS 

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antibodies. However, injection of IdeS did not increase the serum levels of total IgE. In 
completed and ongoing clinical studies two non-serious infusion related reactions, 
which included the following signs and symptoms: dyspnoea, pharyngeal oedema, sinus 
tachycardia, chest discomfort and flushing, were reported. Non clinical toxicology 
studies identified a no observed adverse effect level (NOAEL) of 2.0 mg/kg BW.  
In an ongoing study in asymptomatic patients with Thrombotic thrombocytopenic 
purpura (TTP), two subjects developed signs and symptoms of serum sickness about 6 
days after receiving a single dose of 0.25 mg/kg BW. In one of the patients there was 
laboratory evidence of consumption of complement.  Both subjects responded well to 
treatment with corticosteroids. Neither of the patients was receiving 
immunosuppressive therapy at the time of presentation.  All renal transplant patients 
who have been treated with IdeS received immunosuppressive therapy post infusion 
and no signs of serum sickness have been observed in any of these patients. This 
indicates that the risk of serum sickness is low in patients receiving 
immunosuppression following IdeS therapy. Patients in the current study will be 
treated with prednisolone and cyclophosphamide which should mitigate the risk of 
serum sickness.  
Some patients may have pre-existing antibodies to IdeS subsequent to streptococcal 
infections. As a precaution patients included in the study will receive premedication 
with hydrocortisone and antihistamine (chlorphenamine maleate) before IdeS infusion 
in order to mitigate the risk of infusion-related reactions. Patients and healthy subjects 
who have been previously treated have formed antibodies to IdeS that persist for some 
months and then decline. The relevance of this finding with respect to administering a 
second dose of IdeS is currently unknown. There is no experience giving a second dose 
of IdeS with a longer interval than approximately 30 hours. In this study only a single 
dose of IdeS will be administered.  In addition, mild and reversible proteinuria has been 
detected in healthy subjects treated with IdeS. 
In the IdeS studies in renal transplantation the IgG fragments resulting from IdeS 
cleavage of IgG do not appear to impair kidney function. The potential increased risk for 
patients with anti-GBM disease due to IgG fragments is unknown and renal function in 
patients will be closely monitored. Since IdeS effectively removes the IgG pool, there 
may be an increased risk of infection. In order to minimise the risk for bacterial 
infections all patients treated with IdeS will receive a two-week regimen of prophylactic 
antibiotics following IdeS dosing. Patients positive for viruses (Hepatitis B, C and human 
immunodeficiency virus [HIV]), tuberculosis and other active bacterial infections 
requiring antibiotics will be excluded from the study. Patients will be instructed to 
contact the principal investigator immediately if they have any sign of infection. In case 
of infection in a patient with low IgG plasma levels, intravenous immunoglobulin may be 
indicated if a patient with low levels of plasma IgG develops an infection.  
It has been demonstrated in laboratory studies that IdeS cleaves biologics based on 
human IgG including; IVIg, basiliximab, rituximab, adalimumab, denosumab, belatacept 
and etanercept. IdeS also cleaves rabbit anti-thymocyte globulin (rATG) but not equine 
anti-thymocyte globulin (ATGAM). The optimal interval between HMedIdeS 
administration and these biologics have not been defined [8]. The concomitant use of 
these other biologics and IdeS will continue to be closely monitored in order to mitigate 
any changes in the efficacy of these biologics. 

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To date, there have been 3 reports of myalgia in completed studies, 1 was serious and 
unexpected and occurred in a patient with a previous history of myalgia after 
atorvastatin treatment and who was on chronic glucocorticoid treatment. An extensive 
workup including muscle biopsy, electromyograms and other muscle related 
biomarkers showed no abnormalities or explanation for the myalgia. The remaining 2 
myalgias were non-serious. The non-serious cases resolved and the serious case was 
improving upon steroid tapering. Myalgias have been reported with treatment with 
other biologics such as IVIg and rituximab [13].   
No local adverse reactions have been observed at the site of IdeS infusion. 
The patients will be closely monitored for all adverse events. The principal investigators 
must make sure that sufficient facilities and procedures are available to handle 
emergency situations during the study. The included sites have experience in early 
phase studies and there are adequate procedures in place to handle unexpected adverse 
reactions. Measures for risk minimization are listed and discussed under section 4.9 
2.3 Route of administration and dosage of IdeS 
The present test product IdeS will be given as a single intravenous infusion of 0.25 
mg/kg BW, during 30 minutes, as soon as the diagnosis has been set and inclusion 
criteria have been fulfilled and no exclusion criteria are met, in order to reduce the risk 
of IgG attack of the GBM.  
2.4 Trial statement 
The study will be conducted in accordance by this Protocol with the ethical principles 
that have their origin in the Declaration of Helsinki (2013), Good Clinical Practice, ICH-
GCP, and all applicable regulatory requirements. 
2.5 Target population 
The current standard treatment of anti-GBM disease consisting of combining extensive 
PLEX and immunosuppressive therapy has poor outcome in patients presenting with a 
low GFR. Different studies have defined the adverse prognosis group in various ways. In 
this study adverse prognosis is defined as either an eGFR <15 ml/min/1.73 m2 or poor 
response to standard therapy indicated by a fall in eGFR >15 ml/min/1.73 m2 after start 
of standard therapy. 
3. Objectives and Purpose  
3.1 Primary Objectives 
The primary objective of this study is to evaluate the safety and tolerability of IdeS in 
patients with severe anti-GBM (Glomerular Basement Membrane) disease on 
background of standard care consisting of pulse-methylprednisolone, oral prednisolone 
and intravenous cyclophosphamide combined with plasma exchange (PLEX). 
The primary efficacy objective is to evaluate the efficacy of an IdeS based regimen to 
salvage independent renal function defined as no need for dialysis at 6 months and after 
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3.2 Secondary Objectives  
1. Renal function 3 months  
2. Change in eGFR during the study period; 
3. Number of days with anti-GBM antibodies above a toxic level (i.e. >30 ELISA units)  
4. Disappearance of hematuria, days from start of treatment; 
5. Change in proteinuria during the study measured as u-albumin/creatinine ratio in 
morning void; 
6. Number of PLEX needed; 
7. Changes in renal histology (optional)  
8. Anti-IdeS antibodies (ADA) 
9. Pharmacokinetics, Pharmacodynamics (IgG degradation) 
4. Trial design 
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 --GOOD-
IdeS. 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, Appendix 1. 
4.1 Overview 
This trial will include patients with anti-GBM disease that meets the inclusion criteria 
consecutively. Since the incidence of anti-GBM disease is approximately one per million 
enrolments in the study is anticipated to be slow. For this reason multiple centres in 
several countries are planned.  
4.2 Number of Centres 
The study will be conducted in multiple centres in Europe. It is anticipated that 
enrolment will start in Sweden followed by Denmark, UK, Czech Republic, France and 
Austria, however this may change based on the availability of anti-GBM disease patients. 
If the inclusion of patients proceeds slowly more countries might be added. 
4.3 Number of Participants 
This study will aim to recruit 15 patients with anti-GBM disease over a period of 18 
months from the start of the first country, Sweden. The enrolment rate of patients is 
expected to be slow and if at least 12 patients have been enrolled at 18 months, this will 
considered an acceptable number of participants to meet the objectives of this study.    
4.4 Study Duration 
Each patient will be followed for 6 months (180 days) after the intravenously given 
single study dose of IdeS at Day 1. During this 6 month period, a total of 10 follow-up 

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visits/blood tests with increasing intervals between visits will be conducted (see 
Appendix 1).  
4.5 Trial Endpoints 
4.5.1 Primary Endpoint 
The primary efficacy endpoint is proportion of patients with independent renal function 
at 6 months.  
4.5.2 Secondary Endpoints 
The secondary endpoints of this study include assessment of: 
1. The proportion of subjects with independent renal function, defined as no need for 
dialysis at 3 months, as compared to historical controls.  
2. Renal function at 3 and 6 months expressed as eGFR and as change in GFR from 
baseline; 
3. Number of days with anti-GBM antibodies above a toxic level (i.e. >30 ELISA units) 
measured at a central laboratory using the Wieslab anti-GBM kit; 
4. Disappearance of haematuria, measured in days from start of treatment; 
5. Change in proteinuria during the study measured as u-albumin/creatinine ratio in 
morning void; 
6. Number of PLEXs needed; 
7. Renal histology measurements and changes in renal histology if a second renal 
biopsy is performed; 
8. Anti-IdeS antibodies (ADA) 
9. Pharmacokinetics, Pharmacodynamics (IgG degradation)  
4.6 Trial treatments 
All patients will receive treatment with a single dose of HMED-IdeS at Day 1 (more 
details in 6.1.1 Storage and handling).  
4.6.1 Plasma Exchange for Treatment of anti-GBM disease  
PLEX was introduced for anti-GBM disease in the 1970-ties. Concurrently the prognosis 
of the disease improved considerably compared to historic control. There is, however, 
only one randomized study [15]. In this study, the PLEX group showed a better 
outcome, but the study was not well balanced with respect to severity. There are several 
studies showing that anti-GBM levels fall much faster with PLEX which together with 
studies showing that levels of circulating antibodies correlate with prognosis provide 
additional rationale for the use of PLEX in the treatment of anti-GBM disease.  
4.6.2 The treatment of anti-GBM disease with Cyclophosphamide (CYC) 
Cyclophosphamide (CYC) was introduced simultaneously with PLEX. [16] No clinical 
trials specifically addressing the use of CYC or dosing of CYC have been published. 
Experience from the field of ANCA associated vasculitis a disease with similar clinical 
features has been used to support the use of CYC in the treatment of anti-GBM disease. 
In animal models of anti-GBM disease the use of CYC has been shown to reduce 
autoantibody production [17].  
4.6.3 The treatment of anti-GBM disease with Glucocorticoids  
Glucocorticoids were introduced for the treatment of various inflammatory conditions 
in the 1950s. Their efficacy in anti-GBM disease has never been formally tested in 

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clinical trials, but there use is by expert opinion considered to be as indispensable. 
Steroid in the combination with CYC and PLEX is recommended treatment for anti-GBM 
disease according to the Kidney Disease, Improving Global Outcomes 2012 (KDIGO) 
guidelines [18]. 
4.7 Trial discontinuation  
The study drug will only be given once therefor discontinuation of treatment after the 
first dose is not applicable in this study. However discontinuation of the infusion before 
completion is feasible for any safety reason. After the single infusion of IdeS is 
administered the regular treatment regimen for anti-GBM disease will follow. If patients 
at this stage wish to withdraw their consent, the planned extra visits and blood 
sampling included in the study will be stopped. Any collected samples can be destroyed 
upon the patient’s request. 
4.8 Data to be recorded  
Since this study only will include a maximum number of 15 participants, a paper CRF 
will be used. Data will be recorded directly on the CRF and will be considered as source 
data. After the CRF is completed it will be scanned in and sent by email to the study 
coordinator in Linköping for entry into a database. Appropriate information about the 
study and information considered important for patients’ treatment will also be entered 
in the patients’ medical record. 
4.9 Benefit risk assessment  
Participants in this study may have a direct benefit from participation, if chronic dialysis 
for these patients could be avoided. The patients may also have a decreased risk for 
developing severe lung haemorrhage, which in this disease can start also after onset of 
severe renal disease. Furthermore, knowledge from this study can lead to opportunities 
to apply IdeS to other IgG-related autoimmune diseases. These potential benefits should 
be weighed against the potential risks.  
Infections: As IdeS degrades all IgG in the body there is most probably an increased 
risk of infections during the period when IgG is low. The patients are still protected by 
their IgM and IgA, which is not cleaved by IdeS. An increased number of infections has 
not been seen in the phase I and II studies performed so far, but the risk must still be 
appreciated. To minimize risks patients with ongoing infections requiring antibiotics, 
chronic virus infections and active tuberculosis will not be allowed in the study. A 
Quatiferon® test or similar test for latent tuberculosis should be performed at 
screening, if a positive result is returned after start of treatment specialists in the 
treatment of tuberculosis should be contacted and appropriate actions taken. To 
mitigate the risk of infections it is recommended that all patients will be given prophylactic 
antibiotics until IgG levels return to acceptable values as judged by the investigator. The 
preferred drug is penicillin V (erythromycin if the patient is allergic to penicillin). 
Infusion reactions: Mild to moderate infusion reactions have been noted in some 
patients and heathy subjects in the phase I and II studies.  To reduce this risk  
premedication with Solu-Medrol 100 mg i.v. and 10 mg loratadine p.o. will be given 
before the IdeS infusion.  
Unexpected reactions: Cases of serum sickness like reaction has been noted in another 
phase IIs study. The high doses of corticosteroid used in this study probably reduce this 

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risk. Analysis of complement components will be done as part of safety monitoring. 
There is a theoretical a risk that IdeS treatment can lead to a rebound of autoantibody 
production which can potentiate the disease. Anti-GBM levels will be closely monitored 
and PLEX should be instituted when (if) rebound occurs. Patients with severe lung 
haemorrhage that would be most vulnerable for such rebound are not allowed in the 
study. It is also possible that PLEX has other beneficial mechanisms than autoantibody 
removal, that IdeS treated patients will not benefit from.  
 
an evaluation of the female and male reproductive organ in rabbit and dog 
were performed as part of the pivotal toxicological studies. In conclusion, there were no 
observations considered related to IdeS treatment on the female and male reproduction 
organs neither in rabbit nor dog. In order to avoid pregnancies the requirement for 
highly effective contraception is part of the inclusion criteria for this study. The patients 
must be willing to accept birth control methods which are considered as highly effective 
birth control methods according to CTFG (clinical trial facilitation group) guidance 2014: 
Recommendations related to contraception and pregnancy testing in clinical trials. [18] 
Such methods include [19]:  
1) combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: 
- 
oral 
- 
intravaginal 
- 
transdermal 
2) progestogen-only hormonal contraception associated with inhibition of 
ovulation: 
- 
oral 
- 
injectable 
- 
implantable  
3) intrauterine device (IUD)  
4) intrauterine hormone-releasing system (IUS)  
5) bilateral tubal occlusion  
6) vasectomised partner  
7) sexual abstinence  
In addition, a pregnancy test will be performed prior to dosing and approximately at 
monthly intervals throughout the study, see appendix 1, Study visit plan. 
For risks associated with background medication, PLEX, Glucocorticoids and CYC, see 
section 8.5. 
Overall the risks associated with the current protocol are considered smaller than the 
potential benefits for the participants.   
5. Selection of Patients and Criteria for Discontinuation 
The patients have the right to withdraw their consent of participating in the study at 
any time without giving any reason why and without affecting future care and 
treatment. 

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The Sponsor and the investigators reserve the right to discontinue the study at any time 
for safety reasons or other reasons jeopardizing the justification of the study. Such a 
termination will be implemented in a time frame that is compatible with the patient’s 
wellbeing. If the study is prematurely terminated or suspended, the investigator will 
promptly inform the patients and assure appropriate therapy and follow-up. The 
Sponsor will notify the Regulatory Authorities and the Ethics Committee of any plans to 
terminate the study. 
 
5.1 Subject 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 ANCA 
may be entered in the trial, but only if their level of anti-GBM antibodies fulfil the 
criteria listed above. 
2. eGFR < 15 ml/min/1.73 m2 (by MDRD equation) or if the patient is non-responsive 
to standard treatment, and has lost  >15 ml/min/1.73 m2  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 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. 
5.2 Subject 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  

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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.  
5.3 Subject withdrawal criteria 
5.3.1 Criteria for discontinuation from the study 
Patients may be discontinued from study treatment and assessments at any time. 
Specific reasons for discontinuation can be: 
1. Voluntary discontinuation by the patient who is at any time free to discontinue 
his/her participation in the study, without prejudice to further treatment; 
2. Risk to patients as judged by the investigator and/or sponsor; 
3. Severe non-compliance to protocol as judged by the investigator and/or sponsor; 
4. Incorrectly enrolled patients; 
5. Patient lost to follow-up; 
6. Adverse events; 
7. Withdrawal of informed consent for the use of biological samples collected in the 
study.  
Patients who are withdrawn from the study by the investigator due to AE will not be 
replaced. Patients who withdraw for reasons other than AE may be replaced. A 
replacement patient must be an eligible patient according to the protocol’s 
inclusion/exclusion criteria and will follow the procedures described in this protocol. 
5.3.2 Procedures for discontinuation of a patient from the study 
A patient who discontinues after study drug administration will always be asked about 
the reason(s) for discontinuation and the presence of any AE. If possible, they will be 
seen and assessed by an investigator(s). AEs will be followed until they resolve, stabilize 
or the clinical outcome of the patient is ascertained. If possible, patients who 
discontinue from the study before completion should undergo the assessments and 
procedures scheduled for the end of study follow up visit. Patients who, for a medical 
reason, cannot comply with the protocol procedures will contacted, e.g., telephone call, 
to retrieve safety and efficacy data. 
5.3.3 Procedures after completion of the trial 
Patients who have completed the trial are recommended to be monitored according to the 
KDIGO-guidelines [17] and according to local practice. Patients with anti-GBM disease 
require long term follow up and in selected patients maintenance therapy to avoid relapses is 
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6. Treatment of Patients  
6.1 Investigational Medicinal Product 
IdeS is a clear colourless liquid. It is formulated at 10 g/L in phosphate buffered saline 
and intended for intravenous infusion after dilution.
 
 
 
  
 
 
 
  
 
  
 
 
  
 
  
  
 
 
  
 
 
  
 
 
6.1.1 Storage and handling 
All patients will receive treatment with HMED-IdeS. HMED-IdeS will be supplied to site 
 in 7 mL vials packed into cartons containing 10 vials each. Vials should be 
kept in the dark at - 20°C. HMED-IdeS infusion solution will be prepared by the 
pharmacy or site staff at the study unit. Administration will be performed using an 
infusion syringe or infusion bag with a filter containing infusion set and an infusion 
pump. Details on preparation, labelling and administration of HMED-IdeS are described 
in the pharmacy manual (provided by Hansa Medical). 
6.2 Packaging and labelling 
Packaging and labelling of the investigational medicinal product (IMP) will be 
performed in accordance with Good Manufacturing Practice (GMP) and national 
regulatory requirements. The IMP will be labelled according to Annex 13, EudraLex 
Volume 4 and national regulatory requirements. 
6.3 Drug accountability and compliance check 
The administration of all medication (including IMP) must be recorded in the 
appropriate sections of the case report form (CRF). Treatment compliance will be 
assured by supervised administration of the investigational product by the investigator 
or delegate. The dose, date and time of administration of the investigational product will 
be checked by the monitor at monitoring visits. 
It is the principal investigators/institution’s responsibility to establish a system for 
handling study treatments, including investigational medicinal products, to ensure that: 
1. 
Deliveries are correctly received by a responsible person (e.g. pharmacist or 
designated study personnel); 
2. 
Deliveries are recorded; 
3. 
Study treatments are handled and stored safely and properly; 

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4. 
The study drug provided for this study will be used only as directed in the study 
protocol; 
5. 
The study personnel will account for all drugs dispensed and returned. Any 
discrepancies must be documented, investigated and appropriately resolved; 
6. 
At the end of the study, the study personnel will account for all unused drugs and 
for appropriate destruction/return of all unused drugs to the sponsor for 
destruction. Certificates of delivery, destruction and return must be signed by a 
study team member. 
6.4 Administration of IMP 
An intravenous dose of IdeS will be administered over 30 minutes. Each patient will 
receive a single dose of 0.25 mg IdeS/kg BW. Detailed instructions on preparation and 
administration are provided in the pharmacy manual. The infusion may be slowed down 
or stopped and restarted if required. This will be recorded in the CRF. 
6.5 Concomitant Administration of other drugs 
A single infusion with the IdeS will be given on top of the standard of care in the 
treatment of patients with anti-GBM disease. The treatment included in standard of care 
is Plasma exchange (PLEX), Glucocorticoids (GC) and Cyclophosphamide (CYC). 
6.5.1 Plasma exchange (PLEX) 
PLEX will be issued according to local practice, and will be given at a dose considered 
necessary to keep anti-GBM below a toxic level. Observe that the 36 hours after the IdeS 
infusion there should be no PLEX issued. Also after 36 hours there might be harmless 
IgG breakdown products circulating that gives false positive results on anti-GBM ELISA. 
This has to be taken into account when starting PLEX after IdeS treatment. A standard 
session usually consists of 60 ml/kg (based on actual body weight) using albumin (3% 
to 5% depending on local availability, with or without crystalloid) as a replacement 
solution.  
The following parameters may be determined according to local practice: 1) PLEX may 
be performed by centrifugation or filter separation technique 2) Anticoagulation may be 
provided by citrate or by heparin but it is suggested that in patients with active bleeding 
regional citrate anticoagulation be utilized, 3) PLEX may be performed via a central 
venous catheter if patient is deemed unsuitable for peripheral venous access, the latter 
is strongly recommended, and 4) monitoring of coagulation parameters 5) PLEX dose 
may be reduced for PLEX related complications according to local best medical practice 
and indication and dose alteration noted for future analysis. 
Local practice should be followed for patients with active bleeding including patients 
with known pulmonary haemorrhage or a bleeding episode from any source within the 
24 hours prior to PLEX treatment. This may include fresh frozen plasma at the end of 
the exchange. This information will be recorded in the case report form. 
NOTE: No PLEX should be done up to 36 hours after the IdeS infusion is administered.  

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6.5.2 Glucocorticoids (GC) 
GC therapy shall commence with intravenous methylprednisolone. Intravenous 
methylprednisolone shall be given as 3 daily pulse doses. Each pulse dose may be 
between 0.5 g and 1 g at the local investigators discretion.  Any dose given prior to 
inclusion in the study should be subtracted from the total dose. Additional pulses of 
methyl prednisolone can be given to curb resistant pulmonary haemorrhage 
Oral GC therapy shall commence after stopping methylprednisolone. Oral GC therapy 
will consist of prednisolone. Dosing will be given according to local practice, 
preferentially within the range listed in Table 3, which indicates the local guidelines in 
Linköping for ANCA vasculitis (lower values) and the KDIGO guidelines for anti-GBM 
disease (higher values). All oral GC will be given as a single daily dose. Patients 
intolerant of oral medications or for who oral medications are contraindicated may be 
given an equivalent daily intravenous dose. Prophylaxis against peptic ulcers and 
osteoporosis will be given based on the investigators decision in each individual case. 
Table 3. Recommended range of prednisone dosing 
Week 
<50 kg 
50-75 kg 
>75 kg 
1 
40-50 
50-75 
60-80 
2 
40-50 
50-75 
60-80 
3 
25-30 
30-45 
40-60 
4 
20-30 
25-45 
30-60 
5-6 
17.5-20 
20-30 
25-40 
7-8 
15-20 
17.5-30 
20-40 
9-10 
12,5-20 
15-30 
17,5-30 
11-12 
10-20 
12.5-20 
15-20 
13-14 
7.5-15 
10-15 
12.5-15 
15-16 
7.5-10 
7.5-10 
10 
17-18 
5-7.5 
7.5 
7.5-10 
19-26 
5-7.5 
5-7.5 
7.5-10 
6.5.3 Cyclophosphamide (CYC)  
Induction therapy with CYC will be prescribed for at least 13 weeks in patients with 
independent renal function, but may be withdrawn earlier in patients considered to 
have reached end-stage renal disease. As the experience of using either oral or intra-
venous routes of administration varies between centres and there is no apparent 
difference in efficacy or safety, the study protocol will allow the use of either oral or 
intravenous CYC.  
A starting dose of 10 mg/kg/pulse will be used for pulse CYC (maximum 1.0 g/dose) or 
1.5 mg/kg/day for oral CYC (maximum 150 mg/day) with reductions made for age. In 
patients responding well to therapy increases should be considered when eGFR is >30 
ml/min/1.73m2. Oral CYC will be administered daily with the recommendation for 
morning administration of full dose, if tolerated. Pulse CYC will be administered 
intravenous at a frequency of every two weeks for the first 3 doses then every 3 weeks 
thereafter. Modifications to dose and frequency will be made in the case of leucopenia. 

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For patients undergoing PLEX, PLEX will not occur for at least 15 hours following an IV 
dose of CYC. 
For patients receiving PLEX and daily CYC (oral or IV), on days when PLEX is performed, 
CYC will be given following PLEX. PLEX will not be performed for at least 12 hours 
following a dose of oral CYC. 
Full (complete) blood counts will be performed according to local protocol but the 
following minimum is recommended: patients receiving oral CYC should have their 
blood count monitored weekly for the first four weeks and weekly for four weeks after 
any dose adjustment and every other week thereafter. Patients receiving pulse CYC 
should have their blood count monitored 10 to 14 days after each dose and within 1 day 
prior to each dose. 
Concomitant use of mesna is optional and left to the discretion of the investigator and 
local practice.  
6.5.4 Concomitant medication 
Therapeutic IgG based drugs such as Rituximab will be cleaved by IdeS during 7 days 
following dosing therefore Rituximab treatment within 7 days prior to IdeS dosing is 
not allowed. Other concomitant medication may be administered at the discretion of the 
Investigator. All concomitant medication, including premedication and prophylactic 
antibiotics will be recorded in the CRF, together with the main reason for its 
prescription. 
6.5.5 Premedication 
Patients will receive premedication with Solu-Medrol 100 mg i.v. and 10 mg loratadine 
p.o. (or equivalent) before the IdeS infusion. 
6.5.6 Prophylactic antibiotic 
To mitigate the risk of infections it is recommended that all patients will be given 
prophylactic antibiotics until IgG levels return to acceptable values as judged by the 
investigator. The preferred drug is penicillin V (erythromycin if the patient is allergic to 
penicillin). Prophylactic medication against Pneumocystis jiroveci pneumonia (PCP) is 
strongly recommended, to be begun at day 15, in all patients who are not allergic to 
sulfamethoxazole or trimethoprim, pentacarinat inhalation can be an alternative. The 
prophylaxis should be continued for a minimum of 3 months and until prednisone doses 
are below 12.5 mg/day. Quantiferon® test or similar test for latent tuberculosis should 
be performed at screening, in case of positive tests results after start of treatment 
specialist in management of tuberculosis should be consulted and appropriate 
measures taken.  
6.5.7 Laboratory Markers 
Plasma samples will be collected for analysis both at local (at site) and at central 
laboratory in Linköping University Hospital, Sweden, at Hansa Medical AB in Lund, 
Sweden and 
 At screening and Day 1, 3, 
7, 10, 15, 22, 29, 50, 93, 135 and 180 (end of study) anti-GBM (for clinical evaluation), 
Creatinine, Haematology, CRP and urinalysis will be measured. ANCA will be measured 
Day 1 and 29 and Total IgG and cystatin C will be assessed Day 1, 15, 29 and 180, IdeS 
concentration (PK) will be taken Day 1, 3,7,10 and 15. PD (IgG) will be assessed Day 1, 3, 

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7, 10, 15, 22, 29, 50 and 180, ImmunoCAP IgG (ADA) will be measured Day 1, 7, 15, 22, 
29, 50, 93 and 180. Complement fragments will be taken at Day 1 and 180, and RNA and 
Anti-GBM (not for clinical evaluation) will only be taken on Day 1. In addition will serum 
and plasma samples for research be taken at Visit 2-11, to investigate various cytokines 
and chemokines and substances related to leukocyte activation and tissue damage, see 
Study Visit Plan Appendix 1. Anti-GBM samples will be sent both to local and central 
laboratory, in case of local for clinical evaluation of PLEX and in case of central as study 
variable. On Day 1 all laboratory samples should be taken before the infusion of IdeS. In 
addition; anti-GBM, serum, PK and PD (central lab.) should be taken at 2, 6 and 24 hours 
after start of the infusion of IdeS and anti-GBM (local lab.) should be taken at 6 hours 
after start of the infusion. Urine samples will also be collected on Days 1, 7, 15, 50, 93 
and 180 (end of study) for biomarker assessments including for example complement 
fragments, inflammatory chemokine and cytokine levels. Blood and urine samples will 
be sent on the same day for analysis at local laboratories for safety surveillance. 
Samples for central laboratory will be frozen at site and sent during the study period. 
7. Assessment of efficacy 
7.1 Efficiency parameters 
1. Independent renal function measured as no need for chronic renal replacement 
therapy. 
2. eGFR absolute values and change in ml/min from start of therapy. 
3. Change in proteinuria during the study measured as ACR in morning void. 
4. Haematuria based on urine sticks, time to remission defined as a value <1+ (in 
arbitrary units, local laboratory). 
5. Histological changes in a second biopsy (optional). 
7.2 Method for timing, assessing, recording, and analysis of efficiency 
parameters 
Assessing paragraph 1 (in 7.1) will be a Yes or No if patient is dependent on 
replacement therapy (haemodialysis or peritoneal dialysis) at the time of assessment 
(at 6 months primary and at 3 months secondary, after infusion with the IdeS). 
Assessing paragraph 2-5 will be performed by standard laboratory methods.  To obtain 
reliable values, all blood samples should be taken before PLEX treatment at all sampling 
time points.   
8. Assessment of Safety 
8.1 Safety parameters 
 
 
 
                
The primary safety endpoint is the incidence of AEs or disease progression in other 
organ systems than the kidneys such as the lungs (7.1.5). Other safety endpoints 
include: change from baseline in all safety laboratory parameters and/or change from 
baseline in vital signs. 
8.2 Method for timing, assessing, recording, and analysis of safety 
parameters  
 
 
 
 
        
Assessing safety parameters will be performed at visits; baseline and visit 1-4, 8 and 11 
by recording the vital signs and assessing values in blood and urine comparing with 

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baseline and previous visits. The scheduled visits 5, 7, 9 and 10 can be replaced with 
telephone contact if the patient is feeling well and no AE occurred. In addition all visits 
considered necessary for routine clinical follow-up as decided by the investigator. 
8.3 Definitions 
8.3.1 Adverse event (AE)  
Any untoward medical occurrence in a patient or clinical trial subject administered a 
medicinal product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use 
of an investigational medicinal product, whether or not considered related to the 
investigational medicinal product 
8.3.2 Serious adverse event (SAE) or serious adverse reaction  
Any untoward medical occurrence or effect that: 
- results in death, 
- is life-threatening 
- requires hospitalization or prolongation of existing inpatients hospitalization, 
- results in persistent or significant disability or incapacity, 
- is a congenital anomaly or birth defect. 
- important medical event 
Life-threatening in the definition of a SAE or serious adverse reaction refers to an event 
in which the subject was at risk of death at the time of event; it does not refer to an 
event which hypothetically might have caused death if it were more severe. 
8.4 Expected adverse reactions 
8.4.1 Plasma exchange    
Plasma exchange is associated with the following adverse reactions, in 5-10% of 
procedures [6, 20]: 
- Respiratory: dyspnea 
- Cardiac: arrhythmias, hypotension 
- Metabolic: hypocalcemia, metabolic alkalosis 
- Hematologic: coagulation abnormalities, bleeding 
- Infection: bacterial infections, catheter related blood stream infections, transmission of 
viral infections via blood products 
- Dermatologic: urticaria 
- Neurologic: paresthesia 
Plasma exchange is also associated with the following severe adverse reactions, in 0.5% of 
procedures: 
- Respiratory: acute respiratory distress syndrome, non-cardiogenic pulmonary edema 
transfusion-related acute lung injury (TRALI), pneumothorax, haemothorax 
- Cardiac: arrhythmias, hypotension, arterial dissection, air embolism 
- Haematological: bleeding, bleeding diathesis, venous thrombosis 
- Infection: blood stream infections, sepsis 
 
NOTE: A patient may for practical reasons have to stay in hospital during PLEX 
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hospitalisation or prolongation of hospitalization should not be reported as an SAE in 
this study.  
8.4.2 Prednisone and prednisolone  
Prednisone and prednisolone are associated with the following adverse drug reactions [21, 
22]: 
- >10%: Central nervous system: Insomnia, nervousness Gastrointestinal: Increased 
appetite, indigestion 
- 1% to 10%: Central nervous system: Dizziness or lightheadedness, headache 
Dermatologic: Hirsutism, hypopigmentation Endocrine & metabolic: Diabetes mellitus, 
glucose intolerance, hyperglycaemia Neuromuscular & skeletal: Arthralgia Ocular: 
Cataracts, glaucoma Respiratory: Epistaxis Miscellaneous: Diaphoresis 
- <1% (Limited to important): Cushing's syndrome, edema, fractures, hallucinations, 
hypertension, muscle-wasting, osteoporosis, pancreatitis, pituitary-adrenal axis 
suppression, seizures 
Prednisone and Prednisolone are also associated with the following severe adverse 
reactions: 
- Musculoskeletal: insufficiency fractures, avascular osteonecrosis 
- Cardiovascular: premature atherosclerosis, myocardial infarction 
- Gastrointestinal: ulceration and bleeding 
- Central nervous system: psychosis 
- Endocrine: hyperosmolar non-ketotic state, Addisonian crisis 
- Miscellaneous: Bacterial infections, fungal infections, viral infections, ocular herpes 
zoster 
8.4.3 Cyclophosphamide 
Cyclophosphamide is associated with the following severe adverse reactions [23, 24]: 
- Leucopenia and neutropenia 
- Thrombocytopenia 
- Anaemia 
- Bacterial, viral and fungal infections 
- Haemorrhagic cystitis 
- Malignancies, especially bladder cancer and haematological malignancies 
8.5 Reporting of AE and SAE 
All AE and SAE have to be reported, whether or not considered causally related to the 
investigational product, or to the study procedure(s). All AEs and SAEs will be recorded 
in the CRF. SAEs will be recorded from the time of informed consent.  
All SAEs must be reported, whether or not considered related to the study drug, on a 
separate SAE Report Form. An assigned CRO 
 will be responsible 
for reporting all SAEs to regulatory authorities and ethics committees in accordance 
with ICH Good Clinical Practice and local regulations. As soon as the Investigator is 
aware of a potential SAE he/she should contact 
 by fax or e-mail 
and in any case no later than 24 hours after the knowledge of such a case. At the time of 
initial reporting the investigator must provide as a minimum requirement, patient 
number, birth date, description of the SAE and a preliminary assessment of causality. 
 

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Contact Information: 
CRO: 
 
 
 
e-mail: 
  
 
For fatal or life-threatening adverse events where important or relevant information is 
missing, active follow-up is undertaken immediately. Investigators or other site 
personnel should inform the sponsor and monitor of any follow-up information on a 
previously reported SAE immediately but no later than within 24 hours of when he or 
she becomes aware of it. The monitor or sponsor will advise the investigator/study site 
personnel how to proceed. 
The SAE reporting procedures are detailed in the study specific Safety Management 
Plan. This plan is an agreement between the sponsor, and 
 
8.6 Recording and evaluation of SAEs 
Individual SAEs need to be recorded and to include expectedness assessment by the 
investigator and reported to the CPI, central study coordinator for evaluation 
immediately, and within 24 hours of the investigator becoming aware of the event. This 
includes the evaluation of its seriousness and the causality between the investigational 
medicinal product(s) and/or concomitant therapy and the adverse event. The CPI has to 
keep detailed records of all SAEs reported to him by the investigators. 
8.6.1 Assessment of severity 
Mild: The subject is aware of the event or symptom, but the event or symptom is easily 
tolerated 
Moderate: The subject experiences sufficient discomfort to interfere with or reduce his 
or her usual level of activity 
Severe: Significant impairment of functioning; the subject is unable to carry out usual 
activities and / or the subject’s life is at risk from the event. 
8.6.2 Assessment of causality 
Probable: A causal relationship is clinically / biologically highly plausible and there is a 
plausible time sequence between onset of the AE and administration of the 
investigational medicinal product and there is a reasonable response on withdrawal. 
Possible: A causal relationship is clinically / biologically plausible and there is a 
plausible time sequence between onset of the AE and administration of the 
investigational medicinal product. 
Unlikely: A causal relation is improbable and another documented cause of the AE is 
most plausible. 
Unrelated: A causal relationship can be definitely excluded and another documented 
cause of the AE is most plausible.  

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8.7 Reporting of Suspected Unexpected Serious Adverse Reactions 
(SUSARs) 
All suspected adverse reactions related to an investigational medicinal product which 
occur in the concerned trial, and that are both unexpected and serious (SUSARs) are 
subject to expedited reporting as per each approving Regulatory Authority and Ethics 
Committee as applicable. 
8.7.1 Who should report and whom to report to? 
A suspected serious adverse reaction is any serious adverse event for which there is a 
reasonable possibility that the investigational product caused the adverse event. A 
serious adverse reaction is considered "unexpected" if it is not listed in the Reference 
Safety Information (RSI) in the investigator brochure or is not listed in the RSI at the 
specificity or severity that has been observed.  
SUSARs with an outcome of death or are life threatening must be reported to the 
relevant Regulatory Authorities within 7 calendar days, all other SUSARs must be 
submitted within 15 calendar days. The SUSAR reporting procedures are detailed in the 
study Safety Management Plan. This plan is based on agreement with 
 
  
It is the responsibility of the site Investigator to promptly notify the Ethics Committee 
and other appropriate institutional regulatory bodies of all SUSARs received involving 
risk to human subjects as per their applicable requirements. 
8.8 Reporting adverse events and breaches 
8.8.1 Reporting adverse events 
The CPI, i.e. sponsor, is responsible for the prompt notification to all concerned 
investigator(s), the Research Ethics Committee and competent authority (Regulatory 
Authority) of each concerned Member State of findings that could adversely affect the 
health of subjects, impact on the conduct of the trial or alter the competent authority’s 
authorization to continue the trial in accordance with current regulations. An annual 
report will be written to the Competent Authority and the Research Ethics Committee. 
8.8.2 Reporting on breaches 
The sponsor shall notify the competent authority and Ethics Committee about a serious 
breach of this protocol without undue delay but no later than seven days of becoming aware 
of that breach. A ‘serious breach’ means a breach likely to affect to a significant degree the 
safety and rights of a subject or the reliability and robustness of the data generated in the 
clinical trial. 
8.9 Follow-up of adverse events  
All AEs will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported until the end of the study. 
8.10 Developmental Safety Update Report (DSUR)  
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year 
throughout the clinical trial, a safety report to the accredited competent authorities (i. e. 

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läkemedelsverket in Sweden) and ethics committee in accordance with existing EU 
regulations. This safety report consists of a list all suspected (unexpected or expected) 
serious adverse reactions, along with an aggregated summary table of all reported 
serious adverse reactions, ordered by organ system. The report will also consist about 
the safety of the patients, consisting of a complete safety analysis and an evaluation of 
the balance between the efficacy and the harmfulness of the medicine under 
investigation, i.e., benefit-risk profile of the investigational drug.  
8.11 Study Risk Assessment 
A PI from each country will constitute an internal Data and Safety Monitoring Board 
(DSMB) for this trial. The DSMB will have teleconferences at regular intervals and will 
discuss if dose reductions, protocol amendments or early termination of the study 
should be necessary. A specific document is prepared for DSMB Procedures which also 
includes safety laboratory variables to be evaluated (Internal Data Safety Monitoring 
Board Procedures, vers.no 1).  Data from this trial will be handled by the CPI and the 
study coordinator in Sweden with significant experience in conduct clinical trials. The 
CPI recognizes the responsibilities of data management with respect to the ethical 
practice of research and the adequate protection of human subjects. All study 
investigators are trained and certified in GCP standards. Additionally, all staff and 
investigators in this study who contact patients or their data or have the potential to 
handle patient data are required to be instructed in whom to provide documentation of 
GCP. 
9. Statistical Considerations 
All subject baseline characteristics and demographic data (age, sex, weight, height, 
smoking status, viral test results, eGFR, proteinuria, ACR, physical examination 
abnormalities, medical history, previous (within 6 months of screening) and 
concomitant medications at study entry will be listed by study center and subject 
number, and will also be summarized.  
9.1 Sample Size Estimation 
Since 1990, there are 11 case series published on anti-GBM disease with a total of 461 
patients, the combined renal survival (patient alive and free from dialysis) among these 
historical controls at 6-12 months for patients with creatinine > 500 µmol/L was 7%. In 
a more recent not yet published study the renal survival was 20 % (11/53). In the 
present study we will also include patients that are refractory to standard therapy, 
justifying the 7 % figure to be used for the sample size estimation.  If IdeS treatment 
would result in a survival rate similar to AAV (i.e. 50%) the study would have a power 
of 0.98 to detect a difference with a sample size of 15. If the survival rate instead would 
be 40 % or 30 % the power will be 0.92 and 0.77.  If only 10 patients are recruited to 
corresponding figures would be 0.94 (50 %), 0.83 (40 %) and 0.65 (30 % survival).   
The incidence of anti-GBM disease is estimated to 1 per million inhabitants per year. Of 
these, we estimate that about 65% will comply with the inclusion and exclusion criteria 
of the study protocol. We have an approximate catchment area of 35 million inhabitants. 
If half of those eligible for the study actually are included the study will be able to enroll 
about 15 participants over an 18 month period. See also under section 4.3 Number of 
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9.2 Outcome calculations 
Chi square (χ2) calculations (alt. Fisher's exact test), at significance level p=0.05, will be 
used to compare the proportion patients without need for dialysis. The authors of the 
published series will be contacted in order to better define the comparison group. 
Patients with adverse renal prognosis in these studies will be defined as patients who 
are either oliguric, having started dialysis, having a creatinine of above 500 at diagnosis 
or progressing in spite of therapy. Only patients receiving standard therapy will be 
included in the final analysis.  
In the secondary analysis (efficacy endpoint 2) changes in eGFR will be assessed using 
matched controls from two recent studies (Alchi and McAdoo). Patients will be matched 
for eGFR, sex, histology (percentage of crescents categorized), ANCA positivity and age 
(also in categories). Dialysis and death will be considered as eGFR of 0, as creatinine 
measurements do reflect dialysis efficacy rather than GFR in dialysis patients. Analysis 
will be performed using paired t-test at 3 and 6 months. Multiplicity will be corrected by 
post-hoc test (e.g. Bonferroni).  
For the other endpoints (3-6) descriptive statistics will be used; these data are 
important mainly for the design and power calculations in future studies. Anti-GBM 
antibodies will be measured at a central laboratory. A toxic level is predefined as 30 
ELISA units when using the Wieslab anti-GBM ELISA kit. Each plasma sample for visit 2-
10 (day 93) will be defined as above or below this level. All days in between two 
samples will classified as above the toxic level if both samples are above the cut-off, and 
half of the days if one only of the samples is above cut off. The number of days with toxic 
levels will be expressed in median, interquartile range, box plots and as histograms.  
The number of PLEX sessions will add up for each patient and expressed as median and 
interquartile range, box plots and as histograms. Disappearance of haemturia will be 
based on local laboratory dipsticks and the first study visit with a negative test (or trace 
amount) will be entered. Results will again be expressed as median and interquartile 
range, box plots and as histograms. Albumin/creatinine ratio will be analysed in the 
central laboratory at visit 4, 6, 9, 10 and 12. At each time point the value of that day will 
compared with the pre-treatment value for day 1, the result will expressed as the 
percentage which in turn will expressed as median and IQR for each day and presented 
graphically.    
10. Study Monitoring 
Monitoring of sites in Sweden and Denmark will be performed by 
 
Linköping will be monitored by 
. Sites outside Scandinavia will be 
monitored by independent staff contracted locally. 
11. Procedures for Recruitment and for obtaining informed 
consent 
Patients with suspected anti-GBM disease will usually be referred to a nephrology 
department. As soon as the diagnosis of anti-GBM disease is confirmed and the inclusion 
and exclusion criteria are met, the nephrologist who is responsible for the treatment of 
this patient will inform and ask the patient if he/she is interested in participating in the 
study. The study will be explained and written information will be provided. Patients 

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will be given one to three hours (or more if advise from relatives are needed) to 
consider their decision to participate after they have indicated that they agree to 
consider participation. The short time frame to consider participation is because it is 
important to start treatment as soon as possible with either study medication, i.e., IdeS, 
if the patient signs the informed consent or if not, PLEX. Patients who consent to 
participate will be asked to fill out the consent form. The treating nephrologist will also 
sign the consent form. The infusion of IdeS should be given within 48 hours after the 
signing of the informed consent.  
Anti-GBM disease patients are usually hospitalized for several weeks with intensive 
treatment and initial daily PLEXs.  
If an anti-GBM disease patient is not treated at any of the participating centres, the 
patient can be referred to such a centre if the patient wants to participate in the study.  
12. Ethical Considerations 
12.1 Regulation statement  
The study will be conducted according to the principles of the Declaration of Helsinki 
(2013) and in accordance with the Medical Research Involving Human Subjects Act 
(WMO).  
12.2 Protection against risks  
Recruitment will occur through the investigators’ clinical practices and from referring 
physicians. The Independent Ethics Committees of each participating country/center 
will provide ethical review and approval for this protocol as well as the consent forms 
to be used prior to study start or enrolment. Details of the goals of the research and the 
risk and benefits of the protocol will be reviewed with each potential study subject. 
Recruitment will occur by physicians, study nurses, and research coordinators.  
Patients who decline to participate in any or all parts of the study will still have 
available the opportunity of evaluation by a nephrologist if they or their physician feels 
this is appropriate.  
Strict patient confidentiality will be observed throughout all aspects of the study. While 
medical records will be reviewed by members of the research team, no individually 
identifiable patient data will be distributed to non-research or care-giving team 
members.  
In the event of adverse effects from the study, the full resources of the hospital will be 
available to intervene as medically necessary. Licensed physicians expert in the care of 
patients with vasculitis are available at all times at each study site.  
To avoid possible worsening of ongoing infections, patients who have active antibiotic 
treatment because of ongoing infections will be excluded. To prevent new infections all 
included patients will receive antibiotic prophylaxis (see 6.5.6). 
12.3 Trial Ethical Approval  
Each national coordinator or local coordinator will apply for national or regional ethics 
approval. Site agreements will be contingent upon the provision of evidence that study 
personnel have completed GCP training. 

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13. Handling and Archiving of Data 
The Sponsor is obligated to ensure that monitoring persons, ethics committees and 
competent authority have the right to have access to the source data.  The Sponsor also 
ensures that patients agree that the above parties have access to their patient records. 
Source data is patient records and the study CRF, a source data list will be used. A 
subject identification code list will be created in order to trace data to the individual 
subject. The code will not be based on participants’ initials or birth-date. The CPI and/or 
study coordinator will safeguard the key to the code to ensure patient confidentiality. 
13.1 End of study report 
 
 
 
              
The sponsor will notify the accredited drug authorities and ethics committee at the end 
of the study within a period of 90 days and a final report within 12 months. The end of 
the study is defined as the last patient’s last visit. 
In case the study is ended prematurely, the sponsor will notify the accredited drug 
authorities and ethics committee within 15 days, including the reasons for the 
premature termination. Within one year after the end of the study, the sponsor will 
submit a final study report with the results of the study, including any 
publications/abstracts of the study.  
13.2 Archiving data     
 
 
 
            
After completion of the study will all study data be archived for 15 years in a special 
storage area for this purpose. 
14. Insurance 
Products liability insurance will be held by Hansa Medical AB.  
15. Funding  
This trial is partly funded by the Hansa Medical AB, Lund, Sweden. The study is also 
funded by a grant from the Ingrid Asp Foundation in Linköping.  
16. Reporting and Publishing 
Results will be reported in scientific publications, as presentations at scientific 
conferences and also to the general population as popular science reports. As obligated, 
both the protocol and results will be publicly available.  
Authors of these reports will preferably be active study investigators and researchers, 
from both academia and the funding company, Hansa Medical AB.  
 
 

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[2] Hudson BG, Tryggvason K, Sundaramoorthy M. Alport's syndrome, Goodpasture's 
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[3] Salama AD, Levy JB, Lightstone L. Goodpasture's disease. Lancet 2001; 358: 917–920 
 
[4] Segelmark M, Hellmark T, Wieslander J. The prognostic significance in Goodpasture's 
disease of specificity, titre and affinity of anti-glomerular-basement-membrane 
antibodies. Nephron Clin Pract 2003; 94: c59–c68 
 
[5] Yang R, Hellmark T, Zhao J. Levels of epitope-specific autoantibodies correlate with 
renal damage in anti-GBM disease. Nephrol Dial Transplant 2009; 24: 1838–1844 
 
[6] Jayne DR, Gaskin G, Rasmussen N. Randomized trial of plasma exchange or high-
dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc 
Nephrol 2007; 18: 2180–2188 
 
[7] Hellmark, Segelmark. Anti-GBM disease; in Oxford Textbook of Medicine 6th edition, 
in press 
 
[8] HMed doc. No. 2012-003 
 
[9] von Pawel-Rammingen U, Johansson BP, Björck L. IdeS, a novel streptococcal 
cysteine proteinase with unique specificity for immunoglobulin G. EMBO J. 2002 ;21: 
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[10] Wenig K, Chatwell L, von Pawel-Rammingen U, Björck L, Huber R, Sondermann P. 
Structure of the streptococcal endopeptidase IdeS, a cysteine proteinase with strict 
specificity for IgG. Proc Natl Acad Sci U S A. 2004;101:17371-17376.  
 
[11] Vincents B, von Pawel-Rammingen U, Björck L, Abrahamson M. Enzymatic 
characterization of the streptococcal endopeptidase, IdeS, reveals that it is a cysteine 
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[13] Orbach et al., 2005, Rituximab Summary of Product Characteristics 
 
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[18] Anti-glomerular basement membrane antibody glomerulonephritis. Kidney 
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[22] Saag KG, Koehnke R, Caldwell JR, Brasington R, Burmeister LF, Zimmerman B, 
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[23] Walsh M, Faurschou M, Berden A, Flossmann O, Bajema I, Hoglund P, Smith R, 
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