Conditions: Primary IgA Nephropathy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 119
Healthy volunteers: no

Brief summary:
This is a Phase 3b, multicenter, open-label extension (OLE) study to evaluate the efficacy and safety of Nefecon treatment in patients with IgAN who have completed the Phase 3 Study Nef-301 and continue to be treated with a stable dose of RAS inhibitor therapy (ACEIs and/or ARBs). Patients who previously received Nefecon in Study Nef-301 will receive retreatment, whereas patients who previously received placebo in Study Nef-301 will be treatment naïve to Nefecon.

Detailed description:
This is a Phase 3b, multicenter, open-label extension (OLE) study to evaluate the efficacy and safety of Nefecon treatment in patients with IgAN who have completed the Phase 3 Study Nef 301 and continue to be treated with a stable dose of RAS inhibitor therapy (ACEIs and/or ARBs). Patients who previously received Nefecon in Study Nef-301 will receive retreatment, whereas patients who previously received placebo in Study Nef-301 will be treatment naïve to Nefecon. During Study Nef-301 OLE, the patients and Investigators will remain blinded to treatment given in Study Nef-301.

During Study Nef-301 OLE, patients will receive Nefecon for a 9-month period. The dose may be reduced if clinically relevant adverse events (AEs) develop during the 9-month Treatment Period that the Investigator considers related to the study drug and that mandate dose reduction.

Patients will remain on a stable dose of RAS inhibitor therapy (ACEIs and/or ARBs) throughout the study. The patient will come for a follow-up visit at 12 months after first dose.

Arms:
arm 1: Nefecon 16 mg once daily by mouth for 9 months

Interventions: intervention 1: Nefecon 16mg daily
Intervention descriptions: intervention 1: All study patients received Nefecon 16 mg daily for 9 months.

Protocol document:
Prot_SAP_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
AN OPEN-LABEL EXTENSION (OLE) STUDY TO EVALUATE 
THE EFFICACY AND SAFETY OF NEFECON TREATMENT IN 
PATIENTS WITH IGA NEPHROPATHY WHO HAVE 
COMPLETED STUDY NEF-301 
 
Investigational Product: Nefecon™ (budesonide modified-release capsules) 
Protocol Number: Nef-301 OLE 
EudraCT Number: 2020-003308-14 
IND Number: 107950 
NCT Number: NCT04541043 
 
Sponsor: 
Calliditas Therapeutics AB 
Kungsbron 1, C8 
111 22 Stockholm 
Sweden 
Telephone: +46 8 411 3005 
 
Version Number: 1.0 
Date: 06 August 2020 
 
 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Calliditas Therapeutics AB except to the extent that disclosure would be required by 
law and for the purpose of evaluating and/or conducting a clinical study for Calliditas 
Therapeutics AB. You are allowed to disclose the contents of this document only to your 
Institutional Review Board or Independent Ethics Committee and study personnel directly 
involved with conducting this protocol. Persons to whom the information is disclosed must be 
informed that the information is confidential and proprietary to Calliditas Therapeutics AB and 
that it may not be further disclosed to third parties. 


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SIGNATURE PAGE 
STUDY TITLE: An Open-Label Extension (OLE) Study to Evaluate the Efficacy and 
Safety of Nefecon Treatment in Patients With IgA Nephropathy Who Have Completed 
Study Nef-301 
 
We, the undersigned, have read this protocol and agree that it contains all necessary information 
required to conduct the study. 
Signature 
 
 
 
 
 
 
 
Date 
 
 
Chief Medical Officer 
Calliditas Therapeutics AB 
 
 
Clinical Operations Director 
Calliditas Therapeutics AB 
 
 
Vice President, Medical Department 
Medpace, Inc. 
 
 
Vice President, Medical Department 
Medpace, Inc. 
 
 
Senior Medical Director, Medical Department 
Medpace, Inc. 


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INVESTIGATOR AGREEMENT 
By signing below, I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by Calliditas Therapeutics AB to study personnel under my supervision. I will discuss this material 
with them to ensure they are fully informed about the study product and study procedures. I will 
let them know that this information is confidential and proprietary to Calliditas Therapeutics AB 
and that it may not be further disclosed to third parties. I understand that the study may be 
terminated, or enrollment suspended at any time by Calliditas Therapeutics AB, with or without 
cause, or by me if it becomes necessary to protect the best interests of the study patients. 
I agree to conduct this study in full accordance with International Council for Harmonisation for 
Good Clinical Practice, the Declaration of Helsinki as amended, and all other applicable regulatory 
requirements. 
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 
 


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SYNOPSIS 
TITLE:  An Open-Label Extension (OLE) Study to Evaluate the Efficacy and Safety of Nefecon 
Treatment in Patients With IgA Nephropathy Who Have Completed Study Nef-301 
PROTOCOL NUMBER:  Nef-301 OLE 
EudraCT NUMBER:  2020-003308-14 
INVESTIGATIONAL PRODUCT:  Nefecon™ (budesonide modified-release capsules; 
Nefecon™ is a trademark of Calliditas Therapeutics AB [hereinafter Calliditas]) 
PHASE:  3b 
INDICATION:  Treatment of primary immunoglobulin A nephropathy (IgAN) 
OBJECTIVES: 
Primary Objectives: 
The primary objectives are the following: 
 To assess the effect of 9 months of retreatment with Nefecon on urine protein to creatinine 
ratio (UPCR) and estimated glomerular filtration rate (eGFR) in patients who completed 
Study Nef-301 with Nefecon treatment; and 
 To assess the effect of 9 months of treatment with Nefecon on UPCR and eGFR in patients 
who completed Study Nef-301 with placebo treatment. 
Secondary Objectives: 
The secondary objectives are the following: 
 To assess the safety and tolerability of 9 months of retreatment with Nefecon in patients who 
completed Study Nef-301 with Nefecon treatment; 
 To assess the safety and tolerability of 9 months of treatment with Nefecon in patients who 
completed Study Nef-301 with placebo treatment; 
 To assess the effect of 9 months of retreatment with Nefecon on additional aspects of renal 
function in patients who completed Study Nef-301 with Nefecon treatment; and 
 To assess the effect of 9 months of treatment with Nefecon on additional aspects of renal 
function in patients who completed Study Nef-301 with placebo treatment. 
POPULATION: 
Patients who have completed Study Nef-301 and meet all eligibility criteria will be able to enter 
Study Nef-301 OLE and start treatment. Patients must continue to be treated with a stable dose of 
renin-angiotensin system (RAS) inhibitor therapy (angiotensin-converting enzyme inhibitors 
[ACEIs] and/or angiotensin II type I receptor blockers [ARBs]). In addition to meeting all other 
eligibility criteria, patients must have proteinuria based on 2 consecutive measurements separated 


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by at least 2 weeks and calculated by the central laboratory showing either 1 g/day 
(1000 mg/day) or UPCR 0.8 g/gram (90 mg/mmol) in 2 consecutive measurements. Patients 
must also have eGFR 30 mL/min per 1.73 m2 using the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) formula. 
STUDY DESIGN AND DURATION: 
This is a Phase 3b, multicenter, open-label extension (OLE) study to evaluate the efficacy and 
safety of Nefecon treatment in patients with IgAN who have completed the Phase 3 Study Nef-301 
and continue to be treated with a stable dose of RAS inhibitor therapy (ACEIs and/or ARBs). 
Patients who previously received Nefecon in Study Nef-301 will receive retreatment, whereas 
patients who previously received placebo in Study Nef-301 will be treatment naïve to Nefecon. 
During Study Nef-301 OLE, the patients and Investigators will remain blinded to treatment given 
in Study Nef-301. 
Assuming that 75% of the patients who have completed Study Nef-301 will enter Study Nef-301 
OLE, the total number of patients to be included is estimated to be approximately 250 patients, 
but up to 360 patients may be enrolled. 
Preferably, Visit 17a in Study Nef-301 should be combined with Visit 1 in Study Nef-301 OLE, 
and Visit 17b in Study Nef-301 should be combined with Visit 2 in Study Nef-301 OLE. If the 
visits are not combined, Visit 3 in Study Nef-301 OLE must occur within 3 months after Visit 17b 
in Study Nef-301. 
Patients who do not meet all of the eligibility requirements may be rescreened in Study Nef-301 
OLE within 3 months after Visit 17b in Study Nef-301. Patients who do not meet all of the 
eligibility requirements within this 3-month period will be screen failures and will not be followed 
any further. 
In addition to meeting all other eligibility criteria, patients must have proteinuria based on 
2 consecutive measurements separated by at least 2 weeks and calculated by the central laboratory 
showing either 1 g/day (1000 mg/day) or UPCR 0.8 g/gram (90 mg/mmol) in 2 consecutive 
measurements. Patients must also have eGFR 30 mL/min per 1.73 m2 using the CKD-EPI 
formula. 
During Study Nef-301 OLE, patients will receive Nefecon 16 mg/day for a 9-month period. The 
16 mg/day dose may be reduced to 8 mg/day if clinically relevant adverse events (AEs) develop 
during the 9-month Treatment Period that the Investigator considers related to the study drug and 
that mandate dose reduction. 
From the first day of dosing, a telephone visit will occur at 1 month, and onsite visits will occur 
at 3, 6, and 9 months. After completing 9 months of study drug treatment, patients will enter the 
2-week Tapering Period with Nefecon 8 mg/day. To perform replicate laboratory sampling, an 
onsite visit will occur 14 to 35 days after the 9-month visit. An onsite follow-up visit will also 
occur at 12 months.  
Patients will remain on a stable dose of RAS inhibitor therapy (ACEIs and/or ARBs) throughout 
the study. If a patient receives rescue treatment (systemic steroids and/or immunosuppressive 
treatment), the patient will be withdrawn from Nefecon treatment and continue with study visits 
for a total of 12 months follow-up after first dose.  


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Patients who prematurely discontinue Nefecon at 16 mg/day should have the dose reduced to 
8 mg/day for 2 weeks, if feasible, to prevent adrenal insufficiency.  
Unless a patient withdraws his/her consent to participate in the study, all patients should complete 
the remaining study visits (especially at 9 and 12 months), regardless of whether they are still 
receiving study drug. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
Nefecon 16 mg (four 4 mg budesonide modified-release capsules once per day [QD]) will be 
administered orally for 9 months during the Treatment Period. 
Patients must take the first dose of study drug in the presence of site staff during Study Visit 4. As 
a result, the first dose of study drug may be administered at any time of day and without regard to 
the timing of meals. Patients may self-dose for all other doses of study drug and should take study 
drug in the morning at least 1 hour before breakfast. The capsules must be swallowed whole and 
may not be chewed or crushed. 
The 16 mg/day dose may be reduced to 8 mg/day if clinically relevant AEs develop during the 
9-month Treatment Period that the Investigator considers related to the study drug and that 
mandate dose reduction. The Medical Monitor should preferably be consulted prior to reducing 
the dose. If a dose reduction is made, then the dose should not be increased back to 4 capsules QD 
(Nefecon 16 mg). 
After completing 9 months of study drug treatment, the daily dose of study drug will be reduced 
from 4 capsules QD (Nefecon 16 mg) to 2 capsules QD (Nefecon 8 mg) for 2 weeks to prevent 
adrenal insufficiency (Tapering Period). Patients who have their daily dose of study drug reduced 
to 2 capsules QD (Nefecon 8 mg) due to safety and/or tolerability reasons during the 9-month 
Treatment Period will remain on this dose during the 2-week Tapering Period. Patients who 
prematurely discontinue study drug while taking 4 capsules QD (Nefecon 16 mg) should have the 
daily dose of study drug reduced to 2 capsules QD (Nefecon 8 mg) for 2 weeks, if feasible, to 
prevent adrenal insufficiency. 
EFFICACY VARIABLES:  
Primary Efficacy Endpoints: 
The primary efficacy endpoints will include the following: 
 Ratio of eGFR at 9 months compared to baseline, calculated using the CKD-EPI formula; and 
 Ratio of UPCR at 9 months compared to baseline. 
Secondary Efficacy Endpoints: 
The secondary efficacy endpoints will include the following: 
 Ratio of urine albumin to creatinine ratio (UACR) at 9 months compared to baseline; 
 Short Form 36 quality of life assessment at 12 months compared to baseline; 
 Proportion of patients with microhematuria at 9 months compared to baseline; 
 Proportion of patients receiving rescue treatment and time to receiving rescue treatment; 


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 Proportion of patients on dialysis, undergoing kidney transplantation, or with eGFR 
<15 mL/min per 1.73 m2; and 
 Cortisol suppression at 9 and 12 months, measured as urinary cortisol excretion over 24 hours 
compared to baseline. 
SAFETY VARIABLES: 
The safety variables will include the following: 
 Treatment-emergent AEs, defined as AEs that occur for the first time after dosing in 
Study Nef-301 OLE, or exist before dosing in Study Nef-301 OLE but worsen in severity after 
dosing in Study Nef-301 OLE; 
 AEs leading to study drug discontinuation; 
 AEs of special interest (AESIs) (severe infections requiring hospitalization, new onset of 
diabetes, confirmed fracture, new osteonecrosis, gastrointestinal bleeding that requires 
hospitalization, reported occurrence of cataract formation, and reported onset of glaucoma); 
and 
 Vital signs, body weight, clinical laboratory variables, and physical examination findings. 
STATISTICAL ANALYSES: 
No formal statistical analyses will be performed. eGFR, UPCR, and UACR are expected to be 
log-normally distributed; therefore, the ratio of 9 months to baseline for eGFR, UPCR, and UACR 
will be summarized using geometric mean and its associated 95% confidence interval. If outlying 
data are present for an endpoint, a supplementary description of the data will be performed using 
a robust regression approach. Separate summaries will be provided according to whether the 
patient received Nefecon or placebo in Study Nef-301. 
Each efficacy variable will be summarized in 2 different analysis sets, a Completers Analysis Set 
and a Full Analysis Set. The Completers Analysis Set will include all patients who receive 
Nefecon for 9 months. The Full Analysis Set will include all patients who receive at least 1 dose 
of Nefecon, with at least 1 efficacy measurement (UPCR or eGFR) collected after dosing. Any 
data recorded after rescue treatment will not be included in the analysis for either analysis 
population. 
Baseline eGFR, UPCR, and UACR will be defined as the geometric mean of the 2 consecutive 
measurements prior to dosing. The 9-month eGFR, UPCR, and UACR values will be defined as 
the geometric mean of the values recorded at Study Visits 8 and 9. 
For UPCR, the primary analysis will calculate the mean of the change from baseline in 
log(UPCR), with results back-transformed to provide a geometric mean ratio and 95% confidence 
interval. For eGFR, due to the possible presence of outlying data, the primary analysis will use the 
same approach but deriving the mean change and its confidence interval using a robust regression 
model. 
If a reasonable proportion of patients do not provide 9-month data, a sensitivity analysis will be 
performed by fitting a mixed model that incorporates any data recorded at 3, 6, and 12 months 
with different assumptions made about efficacy after discontinuation of treatment. 


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AEs will be coded using the Medical Dictionary for Regulatory Activities and will include all 
safety data from patients who have received at least 1 dose of study drug at the time of the analysis. 
The incidence of treatment-emergent AEs will be summarized by system organ class. In addition, 
the time to first occurrence of the most common event will be summarized using cumulative 
incidence plots. Safety data will be summarized or listed separately for the period between 
screening and the first dose of study drug. In addition, the safety data will be summarized for the 
entire period following the first dose of study drug and separately for periods during and after 
dosing. 
Summary statistics will be presented for changes in vital signs and laboratory tests throughout the 
study. Physical examinations will be listed. 
SAMPLE SIZE DETERMINATION: 
All patients who have completed Study Nef-301 and meet all eligibility criteria will be able to 
participate in Study Nef-301 OLE. Assuming that 75% of the patients who have completed 
Study Nef-301 will enter Study Nef-301 OLE, the total number of patients to be included is 
estimated to be approximately 250 patients, but up to 360 patients may be enrolled. 
In Study Nef-202, a completed, randomized, double-blind study of Nefecon in comparison to 
placebo, the standard deviation for the change from baseline in log(UPCR) and log(eGFR) was 
0.59 and 0.18, respectively. If 125 patients are recruited within each efficacy group (prior Nefecon 
or prior placebo) and a 25% reduction (ratio of 0.75) in UPCR is observed in this study, the upper 
95% confidence limit for the baseline ratio will extend to 0.83. Likewise, if there is no change in 
eGFR observed in this study (ratio of 1), the lower 95% confidence limit for the baseline ratio will 
extend to 0.97. Therefore, this study will provide a sufficiently precise estimate of the efficacy of 
Nefecon according to whether the patient previously received Nefecon or placebo. 
SITES: 
It is anticipated that there will be approximately 140 sites globally. 


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TABLE OF CONTENTS 
Signature Page ................................................................................................................................ 2 
Investigator Agreement ................................................................................................................... 3 
Synopsis .......................................................................................................................................... 4 
Table of Contents ............................................................................................................................ 9 
List of Tables ................................................................................................................................ 13 
List of Abbreviations and Definition of Terms............................................................................. 14 
1  Introduction and Background Information ............................................................................. 16 
1.1 
Rationale ........................................................................................................................ 16 
1.2 
Benefit/Risk ................................................................................................................... 17 
2  Study Objectives ..................................................................................................................... 19 
2.1 
Primary Objectives ........................................................................................................ 19 
2.2 
Secondary Objectives .................................................................................................... 19 
3  Study Description.................................................................................................................... 20 
3.1 
Summary of Study Design ............................................................................................ 20 
4  Selection and Withdrawal of Patients ..................................................................................... 22 
4.1 
Inclusion Criteria ........................................................................................................... 22 
4.2 
Exclusion Criteria .......................................................................................................... 22 
4.3 
Withdrawal Criteria ....................................................................................................... 24 
4.3.1  Withdrawal From the Study .............................................................................. 24 
4.3.2  Premature Discontinuation of Study Drug ........................................................ 25 
4.3.3  Lost to Follow-Up ............................................................................................. 25 
4.4 
Patient Rescreening Procedures .................................................................................... 26 
5  Study Treatments .................................................................................................................... 27 
5.1 
Treatment Groups .......................................................................................................... 27 
5.2 
Rationale for Dosing ..................................................................................................... 27 
5.3 
Randomization and Blinding ......................................................................................... 27 
5.4 
Breaking the Blind ........................................................................................................ 27 
5.5 
Drug Supplies ................................................................................................................ 27 
5.5.1  Formulation and Packaging ............................................................................... 27 
5.5.2  Study Drug Preparation and Dispensing ........................................................... 28 


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5.5.3  Study Drug Administration ............................................................................... 28 
5.5.4  Treatment Compliance ...................................................................................... 28 
5.5.5  Storage and Accountability ............................................................................... 29 
5.6 
Prior and Concomitant Medications and/or Procedures ................................................ 29 
5.6.1  Excluded Medications and/or Procedures ......................................................... 29 
5.6.2  Restricted Medications and/or Procedures ........................................................ 29 
5.6.3  Documentation of Prior and Concomitant Medication Use .............................. 29 
5.6.4  Dietary and Lifestyle Recommendations .......................................................... 30 
6  Study Procedures .................................................................................................................... 31 
6.1 
Informed Consent .......................................................................................................... 31 
6.2 
Screening Period (Study Visits 1 to 3) .......................................................................... 31 
6.2.1  Study Visit 1 ...................................................................................................... 31 
6.2.2  Study Visit 2 ...................................................................................................... 32 
6.2.3  Study Visit 3 (2 to 4 Weeks After Study Visit 2) .............................................. 32 
6.3 
Treatment Period (Study Visits 4 to 9 – Study Day 1 to Study Month 9) .................... 33 
6.3.1  Study Visit 4 (Study Day 1) .............................................................................. 33 
6.3.2  Telephone Study Visit 5 (Study Month 1) ........................................................ 33 
6.3.3  Study Visits 6 (Study Month 3), 7 (Study Month 6), and 8 (Study Month 9) .. 33 
6.3.4  Study Visit 9 (14 to 35 Days After Study Visit 8) (For Replicate Laboratory 
Sampling) .......................................................................................................... 34 
6.4 
Follow-up Period (Study Visit 10 – Study Month 12) .................................................. 34 
6.4.1  Study Visit 10 (Study Month 12) ...................................................................... 34 
7  Efficacy Assessments .............................................................................................................. 36 
7.1 
Primary Efficacy Endpoints .......................................................................................... 36 
7.2 
Secondary Efficacy Endpoints ...................................................................................... 36 
8  Safety Assessments ................................................................................................................. 37 
8.1 
Adverse Events .............................................................................................................. 37 
8.1.1  Adverse (Drug) Reaction .................................................................................. 37 
8.1.2  Unexpected Adverse Drug Reaction ................................................................. 38 
8.1.3  Assessment of Adverse Events by the Investigator .......................................... 38 
8.2 
Adverse Events of Special Interest ................................................................................ 39 
8.3 
Serious Adverse Events ................................................................................................. 40 
8.4 
Serious Adverse Event Reporting − Procedures for Investigators ................................ 40 


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8.5 
Pregnancy Reporting ..................................................................................................... 41 
8.6 
Expedited Reporting ...................................................................................................... 41 
8.7 
Safety Assessments ....................................................................................................... 42 
8.8 
Clinical Laboratory Evaluations .................................................................................... 42 
8.9 
Vital Signs ..................................................................................................................... 42 
8.10  Physical Examinations .................................................................................................. 42 
8.11  Body Weight and Height ............................................................................................... 42 
9  Statistics .................................................................................................................................. 43 
9.1 
Analysis Populations ..................................................................................................... 43 
9.2 
Statistical Methods ........................................................................................................ 43 
9.2.1  Analysis of Efficacy .......................................................................................... 43 
9.2.2  Analysis of Safety ............................................................................................. 43 
9.2.3  Sample Size Determination ............................................................................... 44 
10  Data Management and Record Keeping ................................................................................. 45 
10.1  Data Management ......................................................................................................... 45 
10.1.1  Data Handling ................................................................................................... 45 
10.1.2  Computer Systems ............................................................................................. 45 
10.1.3  Data Entry ......................................................................................................... 45 
10.1.4  Medical Information Coding ............................................................................. 45 
10.1.5  Data Validation ................................................................................................. 45 
10.2  Record Keeping ............................................................................................................. 45 
11  Sponsor/Investigator Requirements and Quality Control ....................................................... 47 
11.1  Ethical Conduct of the Study ........................................................................................ 47 
11.2  Institutional Review Board/Independent Ethics Committee ......................................... 47 
11.3  Informed Consent .......................................................................................................... 47 
11.4  Study Monitoring Requirements ................................................................................... 48 
11.5  Disclosure of Data ......................................................................................................... 48 
11.6  Retention of Records ..................................................................................................... 48 
11.7  Publication Policy ......................................................................................................... 49 
11.8  Financial Disclosure ...................................................................................................... 49 
11.9  Insurance and Indemnity ............................................................................................... 49 
11.10 Legal Aspects ................................................................................................................ 49 


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12  Study Administrative Information .......................................................................................... 50 
12.1  Protocol Amendments ................................................................................................... 50 
13  References ............................................................................................................................... 51 
Appendix A:  Schedule of Procedures .......................................................................................... 53 
Appendix B:  Clinical Laboratory Analytes ................................................................................. 56 
Appendix C:  Renin-Angiotensin System Inhibitor and Other Antihypertensive Therapy 
Recommendations According to the 2012 Kidney Disease: Improving Global Outcomes 
Guidelines ............................................................................................................................... 58 
Appendix D:  Recommendations for Defining Medium- or High-Risk Osteoporosis ................. 59 
Appendix E:  Immunosuppressive Drugs Other Than Glucocorticoids ....................................... 60 


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LIST OF TABLES 
Table 1. 
Schedule of Procedures ............................................................................................... 53 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
ACEI 
Angiotensin-converting enzyme inhibitor 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ARB 
Angiotensin II type I receptor blocker 
CEC 
Central Ethics Committee 
CFR 
Code of Federal Regulations 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CRA 
Clinical research associate 
CTA 
Clinical trial authorization 
CYP3A4 
Cytochrome P450 3A4 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
ESRD 
End-stage renal disease 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GCS 
Glucocorticoid 
Gd-IgA1 
Galactose-deficient polymeric immunoglobulin A1 
GFR 
Glomerular filtration rate 
HbA1c 
Hemoglobin A1c 
HIV 
Human immunodeficiency virus 
HRT 
Hormone replacement therapy 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IgA 
Immunoglobulin A 
IgAN 
Immunoglobulin A nephropathy 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
KDIGO 
Kidney Disease: Improving Global Outcomes 
MedDRA 
Medical Dictionary for Regulatory Activities 
OLE 
Open-label extension 
OSTA 
Osteoporosis Self-Assessment Tool for Asians 
QD 
Once per day 
RAS 
Renin-angiotensin system 
RSI 
Reference Safety Information 
SAE 
Serious adverse event 


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Abbreviation 
Definition 
SF-36 
Short Form 36 
SUSAR 
Suspected unexpected serious adverse reaction 
TB 
Tuberculosis 
UACR 
Urine albumin to creatinine ratio 
UPCR 
Urine protein to creatinine ratio 
WOCBP 
Women of childbearing potential 


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1 
INTRODUCTION AND BACKGROUND INFORMATION  
Immunoglobulin A (IgA) nephropathy (IgAN), also known as Berger’s disease, is the most 
common cause of glomerulonephritis worldwide, with prevalence estimates varying from 5% to 
more than 40% of patients with glomerular disease.1 It is characterized by the deposition of 
IgA-containing immune complexes in the glomerular mesangium, leading to inflammation. 
Primary IgAN may present in different forms. One form is characterized by recurrent episodes of 
hematuria, often associated with viral infections, but no or minimal proteinuria and long-term 
stable renal function. Another form is characterized by persistent proteinuria and frequently 
hypertension and/or reduced glomerular filtration rate (GFR). Patients with this more severe form 
are at risk of progressing to end-stage renal disease (ESRD) and require treatment. 
Primary IgAN can occur at any age, but the clinical onset is common during the second or third 
decades of life.2 IgAN progresses to ESRD in 15% to 20% of patients within 10 years and in 30% 
to 40% within 20 years from disease onset.3,4,5 It is the main cause of ESRD in patients with 
primary glomerular disease who require renal-replacement therapy.6 It is estimated that IgAN 
accounts for 10% of renal transplants among patients with primary glomerulonephritis in the 
United States, and between 7% to 20% of patients in Europe and Australia in long-term dialysis 
and renal transplantation programs.6,7 
Risk factors for disease progression include persistent proteinuria, elevated serum creatinine, 
microhematuria, and specific histological lesions.8,9,10 Other risk factors for progressive renal 
failure include hypertension, reduced GFR, and to a lesser extent, hyperlipidemia.11,12,13 
Clinical and nonclinical evidence suggests a pivotal role for the mucosal immune system in the 
pathogenesis of IgAN.14,15,16,17 In IgAN patients, mucosal B-cells located in Peyer’s patches are 
primed to produce aberrantly glycosylated, galactose-deficient polymeric immunoglobulin A1 
(Gd-IgA1), which in circulation can form large immune complexes with anti-glycan 
immunoglobulin G antibodies.14,18,19,20 These complexes bind to glomerular mesangial cells and 
stimulate cell proliferation, release of inflammatory mediators that promote proteinuria, and 
fibrotic remodeling, ultimately leading to loss of renal function.14,18 This pathogenesis suggests 
that local immunosuppression of mucosal B-cell activation and proliferation in Peyer’s patches, 
which reside in high density in the distal part of the small intestine, could attenuate Gd-IgA1 
production and leakage to the systemic circulation, thereby reducing subsequent 
pathophysiological changes in the kidneys. 
1.1 
Rationale 
There is currently no optimal management strategy for IgAN. Treatment recommendations have 
been provided in the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines.21 
Rigorous blood pressure control with angiotensin-converting enzyme inhibitors (ACEIs) and/or 
angiotensin II type I receptor blockers (ARBs) to achieve blood pressure targets of <130/80 mmHg 
is the cornerstone of therapy. For patients with proteinuria despite rigorous blood pressure control 
by renin-angiotensin system (RAS) inhibition, immunosuppressive agents such as corticosteroids 
or cyclophosphamide may be added. Corticosteroids may lower the risk of kidney disease 
progression and the need for dialysis and transplantation, but the use is limited by well-known 
adverse effects.4 
Budesonide is a potent glucocorticoid (GCS) with weak mineralocorticoid activities. 
Immunosuppressive and anti-inflammatory properties have led to the approval of budesonide 


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formulations for use in respiratory indications since 1981 and for inflammatory bowel diseases 
including Crohn’s disease and ulcerative colitis.22,23 Budesonide has a high first-pass metabolism 
with formation of metabolites with very low GCS activity, reducing the degree of systemic effects. 
Nefecon is an oral, modified-release capsule formulation of budesonide that combines a delayed 
capsule disintegration with a sustained/prolonged release of the active ingredient in the distal part 
of the small intestine. By directing release of budesonide to the distal part of the small intestine 
where the target immune tissues, Peyer’s patches, reside in high density, a local pharmacological 
effect is achieved. Budesonide may suppress local B-cell activation and proliferation in these 
patches and inhibit subsequent production and leakage of Gd-IgA1 into the systemic circulation. 
Glomerular mesangial deposition of Gd-IgA1 resulting in nephritis and loss of renal function can 
thereby be prevented. 
Nefecon is under investigation for the treatment of patients with primary IgAN at risk of 
developing ESRD. From the results in Phase 1 and 2 studies in healthy volunteers and in patients 
with primary IgAN, Nefecon is suggested to be a safe and well-tolerated steroid formulation for 
adjunctive therapy to ACEI and/or ARB treatment in IgAN patients at risk of progressing to ESRD. 
Further details regarding the nonclinical studies of Nefecon and the clinical development program 
can be found in the Investigator’s Brochure.24 
The current study is a Phase 3b, multicenter, open-label extension (OLE) study to evaluate the 
efficacy and safety of Nefecon treatment in patients with IgAN who have completed the Phase 3 
Study Nef-301 and continue to be treated with a stable dose of RAS inhibitor therapy (ACEIs 
and/or ARBs). 
1.2 
Benefit/Risk 
The active ingredient in Nefecon is budesonide, a potent steroid with a high first pass liver 
metabolism, which makes it well suited for local treatment, where feasible. The advantage of local 
application of budesonide has been demonstrated in several marketed products, such as for the 
treatment of asthma, where the inhaled budesonide products can provide a high concentration of 
steroid to the airway tissue with only limited systemic exposure due to the low bioavailability. In 
this way, high exposure of the steroid can be achieved to the target tissue with only limited 
systemic exposure and risk for steroid-related adverse effects.  
Budesonide is a well-characterized glucocorticosteroid that, apart from treatment of asthma, also 
has been developed for local treatment of inflammatory conditions such as Crohn’s disease and 
ulcerative colitis. These products have been on the market for up to 25 years. Budesonide has been 
studied extensively in nonclinical and clinical development programs that have supported the 
approval of several medicinal products (e.g., Pulmicort Respules®, Pulmicort Flexhaler®, 
Entocort®, Uceris®).22,23,25,26 A vast amount of safety information from previous human experience 
with budesonide, both from inhaled and oral administered products, is available. 
Nefecon can, by directing the release of budesonide to the distal part of the small intestine, achieve 
a local pharmacological effect. When the budesonide is absorbed it will undergo a high first pass 
metabolism in the liver, resulting in only limited systemic exposure. The Nefecon formulation of 
budesonide has been tested in patients with IgAN at a daily dose of 8 mg or 16 mg for up to 
9 months. Nefecon was found to be safe and well tolerated, and the treatment-provided evidence 
that local exposure of budesonide to a restricted area of the gut, where the Peyer’s patches are 


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located, results in significant reduction in proteinuria and improvement in renal function 
parameters. 
There are currently no treatments approved for patients with IgAN at risk of progressing to ESRD. 
However, the current standard of care includes rigorous blood pressure control using ACEIs and/or 
ARBs to target <130/80 mmHg to reduce hemodynamic stress and proteinuria.12,13,27 For those 
patients with proteinuria despite rigorous blood pressure control by RAS inhibition, a 6-month 
treatment course of high-dose systemic corticosteroids can be considered; however, there is not 
consensus for this treatment regimen, mainly due to the increased level of severe side effects.21,28 
Based on experience from the treatment of patients suffering from IgAN with Nefecon and the 
already documented safety profile of budesonide, it is judged that the benefit/risk of Nefecon 
treatment for patients with IgAN at risk of progressing to ESRD, who have persistent proteinuria 
despite rigorous blood pressure control with ACEIs and/or ARBs, will be favorable. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
The primary objectives are the following: 
 To assess the effect of 9 months of retreatment with Nefecon on urine protein to creatinine 
ratio (UPCR) and estimated glomerular filtration rate (eGFR) in patients who completed 
Study Nef-301 with Nefecon treatment; and 
 To assess the effect of 9 months of treatment with Nefecon on UPCR and eGFR in patients 
who completed Study Nef-301 with placebo treatment. 
2.2 
Secondary Objectives 
The secondary objectives are the following: 
 To assess the safety and tolerability of 9 months of retreatment with Nefecon in patients who 
completed Study Nef-301 with Nefecon treatment; 
 To assess the safety and tolerability of 9 months of treatment with Nefecon in patients who 
completed Study Nef-301 with placebo treatment; 
 To assess the effect of 9 months of retreatment with Nefecon on additional aspects of renal 
function in patients who completed Study Nef-301 with Nefecon treatment; and 
 To assess the effect of 9 months of treatment with Nefecon on additional aspects of renal 
function in patients who completed Study Nef-301 with placebo treatment. 


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3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
This is a Phase 3b, multicenter, OLE study to evaluate the efficacy and safety of Nefecon treatment 
in patients with IgAN who have completed the Phase 3 Study Nef-301 and continue to be treated 
with a stable dose of RAS inhibitor therapy (ACEIs and/or ARBs). Patients who previously 
received Nefecon in Study Nef-301 will receive retreatment, whereas patients who previously 
received placebo in Study Nef-301 will be treatment naïve to Nefecon. During Study Nef-301 
OLE, the patients and Investigators will remain blinded to treatment given in Study Nef-301. 
Assuming that 75% of the patients who have completed Study Nef-301 will enter Study Nef-301 
OLE, the total number of patients to be included is estimated to be approximately 250 patients, but 
up to 360 patients may be enrolled. 
Preferably, Visit 17a in Study Nef-301 should be combined with Visit 1 in Study Nef-301 OLE, 
and Visit 17b in Study Nef-301 should be combined with Visit 2 in Study Nef-301 OLE. If the 
visits are not combined, Visit 3 in Study Nef-301 OLE must occur within 3 months after Visit 17b 
in Study Nef-301. 
Patients who do not meet all of the eligibility requirements may be rescreened in Study Nef-301 
OLE within 3 months after Visit 17b in Study Nef-301. Patients who do not meet all of the 
eligibility requirements within this 3-month period will be screen failures and will not be followed 
any further. 
In addition to meeting all other eligibility criteria, patients must have proteinuria based on 
2 consecutive measurements separated by at least 2 weeks and calculated by the central laboratory 
showing either 1 g/day (1000 mg/day) or UPCR 0.8 g/gram (90 mg/mmol) in 2 consecutive 
measurements. Patients must also have eGFR 30 mL/min per 1.73 m2 using the CKD-EPI 
formula. 
During Study Nef-301 OLE, patients will receive Nefecon 16 mg/day for a 9-month period. The 
16 mg/day dose may be reduced to 8 mg/day if clinically relevant adverse events (AEs) develop 
during the 9-month Treatment Period that the Investigator considers related to the study drug and 
that mandate dose reduction. 
From the first day of dosing, a telephone visit will occur at 1 month, and onsite visits will occur at 
3, 6, and 9 months. After completing 9 months of study drug treatment, patients will enter the 
2-week Tapering Period with Nefecon 8 mg/day. To perform replicate laboratory sampling, an 
onsite visit will occur 14 to 35 days after the 9-month visit. An onsite follow-up visit will also 
occur at 12 months. 
Patients will remain on a stable dose of RAS inhibitor therapy (ACEIs and/or ARBs) throughout 
the study. If a patient receives rescue treatment (systemic steroids and/or immunosuppressive 
treatment), the patient will be withdrawn from Nefecon treatment and continue with study visits 
for a total of 12 months follow-up after first dose.  
Patients who prematurely discontinue Nefecon at 16 mg/day should have the dose reduced to 
8 mg/day for 2 weeks, if feasible, to prevent adrenal insufficiency.  


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Unless a patient withdraws his/her consent to participate in the study, all patients should complete 
the remaining study visits (especially at 9 and 12 months), regardless of whether they are still 
receiving study drug. 


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4 
SELECTION AND WITHDRAWAL OF PATIENTS  
4.1 
Inclusion Criteria 
Patients must meet all of the following inclusion criteria at screening to be eligible for admission 
into the study:  
1. Completed Study Nef-301, defined as Part A (9-month study drug treatment [Nefecon 
16 mg/day or placebo] and 3-month follow-up) and Part B (12-month follow-up); 
2. Completed Visit 17b in Study Nef-301 within 3 months before Study Visit 3; 
3. On a stable dose of RAS inhibitor therapy (ACEIs and/or ARBs) at the maximum allowed dose 
or maximum tolerated dose according to the 2012 KDIGO guidelines21 (see Appendix C). 
A stable dose is defined as a dose within 25% of the dose at Visit 17a or 17b in Study Nef-301; 
and 
4. Willing and able to provide written informed consent at screening (at the latest). 
In addition, patients must meet all of the following inclusion criteria prior to the start of study drug 
treatment: 
5. Proteinuria based on 2 consecutive measurements (24-hour urine sampling) after informed 
consent, separated by at least 2 weeks and calculated by the central laboratory. Both samples 
of the same parameter must show either of the following: 
o Proteinuria 1 g/day (1000 mg/day) in 2 consecutive measurements; or 
o UPCR 0.8 g/gram (90 mg/mmol) in 2 consecutive measurements; and 
6. eGFR 30 mL/min per 1.73 m2 using the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) formula confirmed by the central laboratory at Study Visit 1 or Study Visit 3. 
4.2 
Exclusion Criteria 
Patients who meet any of the following exclusion criteria at screening will not be eligible for 
admission into the study: 
1. Had a dose reduction to Nefecon 8 mg/day in Study Nef-301; 
2. Systemic diseases that may cause mesangial IgA deposition including, but not limited to, 
Henoch Schönlein purpura, systemic lupus erythematosus, dermatitis herpetiformis, and 
ankylosing spondylitis;  
3. Patients who have undergone a kidney transplant; 
4. Patients with presence of other glomerulopathies (e.g., C3 glomerulopathy and/or diabetes 
nephropathy); 
5. Patients with nephrotic syndrome (i.e., proteinuria >3.5 g/day and with serum albumin 
<3.0 g/dL, with or without edema); 
6. Patients with acute, chronic, or latent infectious disease including hepatitis, tuberculosis (TB), 
human immunodeficiency virus (HIV), and chronic urinary tract infections; 
7. Patients with liver cirrhosis, as assessed by the Investigator; 


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8. Patients with a diagnosis of type 1 or type 2 diabetes mellitus which is poorly controlled 
(defined as hemoglobin A1c [HbA1c] 8% [64 mmol/mol]); 
9. Patients with history of unstable angina, class III or IV congestive heart failure, and/or 
clinically significant arrhythmia, as judged by the Investigator; 
10. Patients with unacceptable blood pressure control defined as a blood pressure consistently 
above national guidelines for proteinuric renal disease, as assessed by the Investigator. Patients 
with 140 mmHg systolic blood pressure or 90 mmHg diastolic blood pressure are not 
eligible. At least 1 blood pressure measurement at either Study Visit 1 or Study Visit 3 should 
be within these limits (based on up to 3 measurements, measured 1 minute apart, after resting 
in the supine position for at least 5 minutes); 
11. Patients with diagnosed malignancy within the past 5 years, except for treated basal cell 
carcinoma of the skin, curatively resected squamous cell carcinoma of the skin, colon polyps, 
or cervical carcinoma in situ; 
12. Patients with known osteoporosis in the medium- or high-risk category according to the 
2010 American College of Rheumatology recommendations (see Appendix D). For patients in 
China, the medium- or high-risk category is defined according to the Osteoporosis 
Self-Assessment Tool for Asians (OSTA) index (see Appendix D);  
13. Patients with known glaucoma, known cataract(s), and/or history of cataract surgery, unless 
the surgery was performed on both eyes;  
14. Gastrointestinal disorders (e.g., peptic ulcer disease, inflammatory bowel disease, and chronic 
diarrhea) that may interfere with the effects or release of the study drug; 
15. Patients with hypersensitivity to budesonide or any component of the study drug formulation; 
16. Patients with previous severe adverse reactions to steroids, including psychotic symptoms, 
mood disorders, or suicidal ideation, as assessed by the Investigator; 
17. Patients who have received rescue therapy with systemic immunosuppressants, including 
GCSs, during Study Nef-301; 
18. Patients who have been treated with any systemic GCSs within the 3 months before screening;  
19. Patients who have been treated with any systemic GCSs within the 12 months before screening 
except for a maximum of 3 periods of 2 weeks with the equivalent of 0.5 mg/kg/day 
prednisolone or less for non-IgAN indications; 
20. Patients taking potent inhibitors of cytochrome P450 3A4 (CYP3A4); 
21. Current or prior (within the past 2 years) alcohol or drug abuse; 
22. Patients unwilling or unable to meet the requirements of the protocol; 
23. Other medical or social reasons for exclusion at the discretion of the Investigator; 
24. Life expectancy <5 years; 
25. Females who are pregnant, breastfeeding, or unwilling to use highly-effective contraception 
during the study (contraception only required for women of childbearing potential [WOCBP]);  
o Highly-effective methods of contraception are defined as those that achieve a low failure 
rate (<1% per year) when used consistently and correctly. Such methods include the use of 


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combined (estrogen and progesterone) hormonal contraceptives (oral, intravaginal, or 
transdermal), progesterone-only hormonal contraceptives (oral, injectable, or implantable), 
intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, 
vasectomized partner, or sexual abstinence;  
o WOCBP are defined as women who are not surgically or chemically sterilized, including 
hysterectomy or bilateral oophorectomy (tubal ligation is not acceptable), and who are 
between menarche and 1 year post-menopause; and 
o Postmenopausal is defined as amenorrhoeic for at least 1 year AND, if aged under 60 years, 
have a serum follicle-stimulating hormone (FSH) level of at least 30 IU/L. Women who 
are taking hormone replacement therapy (HRT) do not have to have FSH assessments, but 
the amenorrhea (before starting HRT) must have been naturally (spontaneously) occurring 
and have been accompanied by an appropriate clinical profile (e.g., age appropriate, history 
of vasomotor symptoms); or 
26. Staff involved in the conduct of the study. 
4.3 
Withdrawal Criteria 
A distinction must be made between patients who prematurely discontinue study drug treatment 
and those who withdraw consent to any follow-up in the study.  
In all cases of impending study drug discontinuation or patient requests for withdrawal from study 
visits, Investigators should discuss with the patient his/her options for continuing in the study. At 
a minimum, Investigators should encourage patients to continue follow-up with Investigators (or 
his/her designee) in order to collect the patient’s eGFR, proteinuria, and creatinine at 9 months. 
The Investigator should ensure he/she understands the reasons for a patient’s desire to prematurely 
discontinue study drug or withdraw from the study prior to completion and document these reasons 
in the electronic case report form (eCRF). 
Unless a patient withdraws his/her consent to participate in the study, all patients should complete 
the remaining study visits (especially at 9 and 12 months), regardless of whether they are still 
receiving study drug. 
4.3.1 
Withdrawal From the Study 
Participation of a patient may be permanently discontinued for any of the following reasons: 
 The patient requests discontinuation and withdraws consent from the study for any follow-up; 
or 
 The study is terminated by the Sponsor or the regulatory authority. 
For patients who are withdrawn from the study, the End of Study Visit procedures will be 
completed, if possible, at the time the decision is made to withdraw the patient. The End of Study 
Visit will consist of all of the Study Visit 10 procedures (see Section 6.4.1 and Appendix A). 
Withdrawn patients will not be replaced. 


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4.3.2 
Premature Discontinuation of Study Drug 
Patients who prematurely discontinue study drug treatment should complete the remaining study 
visits (especially at 9 and 12 months) despite discontinuation of study drug. 
Patients who prematurely discontinue Nefecon at 16 mg/day should have the dose reduced to 
8 mg/day for 2 weeks, if feasible, to prevent adrenal insufficiency (see Section 5.5.3). 
The following do not fulfil the criteria for withdrawal from the study, but do require 
discontinuation of study drug:  
 Use of rescue treatment (systemic steroids and/or immunosuppressive treatment); 
 Occurrence of any medical condition or circumstance that exposes the patient to substantial 
risk and/or does not allow the patient to adhere to the requirements of the protocol; 
 Any serious adverse event (SAE), clinically significant AE, severe laboratory abnormality, 
intercurrent illness, or other medical condition which indicates to the Investigator that 
continued participation is not in the best interest of the patient; 
 Pregnancy; 
 Requirement of prohibited concomitant medication; or 
 Patient failure to comply with protocol requirements or study-related procedures. 
If one of the above criteria are met, every effort should be made to keep the patient in the study 
and continue follow-up after study drug discontinuation. 
4.3.3 
Lost to Follow-Up 
The Investigator will make reasonable effort to contact patients who fail to return for scheduled 
study visits. These actions might include, but are not limited to, the following: 
 Contact all telephone numbers for the patient and his/her listed contacts (to be collected in the 
source documents at the patient’s entry into the study), as applicable. This includes making 
telephone calls after normal business hours or on holidays or weekends; 
 Contact the patient’s primary care physician, referring specialist, pharmacist, or other 
healthcare professional, as applicable; 
 Send e-mails, text messages, and postal mail with certified letters to all of the patient’s 
addresses and contacts, as applicable, and document all attempted contacts; 
 Review available medical records/notes for details of hospitalizations, clinic visits, or other 
procedures that may indicate the status of the patient, as applicable; 
 Utilize the internet to search for additional contact information, as applicable; and 
 Check local, regional, and national public records to locate the patient or search for mortality 
status as allowed by law, as applicable. 
Once all of these actions have been exhausted and documented, then Calliditas Therapeutics AB 
(hereinafter Calliditas) or their designee should be contacted for additional guidance. 


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4.4 
Patient Rescreening Procedures 
Patients who do not meet all of the eligibility requirements defined in Sections 4.1 and 4.2 may be 
rescreened in Study Nef-301 OLE within 3 months after Visit 17b in Study Nef-301. Patients who 
do not meet all of the eligibility requirements within this 3-month period will be screen failures 
and will not be followed any further.  
If the patient will be rescreened more than once, this must be discussed and agreed upon with the 
Medical Monitor. All rescreened patients must be reconsented and sign a new Informed Consent 
Form (ICF) prior to completion of any rescreening study procedures. Rescreened patients will be 
assigned a new patient number at the time of rescreening and all screening assessments must be 
repeated except hepatitis B and C, HIV, and TB screenings if done as part of the study within the 
last 12 months. The rescreened patient’s new eCRF casebook will contain a reference to the 
patient’s previous identification number(s). 
 


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5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
Patients will receive Nefecon 16 mg/day for a 9-month period. The 16 mg/day dose may be 
reduced to 8 mg/day if clinically relevant AEs develop during the 9-month Treatment Period that 
the Investigator considers related to the study drug and that mandate dose reduction. 
After completing 9 months of study drug treatment, patients will enter the 2-week Tapering Period 
with Nefecon 8 mg/day to prevent adrenal insufficiency. See Section 5.5.3. Patients will then enter 
the 3-month Follow-up Period. 
5.2 
Rationale for Dosing 
Budesonide, which is the active drug substance in Nefecon, is a well-documented compound with 
extensive experience from clinical use in the treatment of asthma and inflammatory bowel disease. 
Nefecon is a modified-release oral formulation, designed specifically to release budesonide in the 
distal part of the small intestine where Peyer’s patches reside at high density, thus providing a 
potent immunosuppressive effect to reduce local B-cell activation and proliferation and the 
subsequent production of Gd-IgA1. Based on safety and efficacy data from the Phase 2b study, 
where doses of placebo and Nefecon 8 mg and 16 mg were given daily for 9 months, the Nefecon 
16 mg/day dose was selected for Phase 3. Nefecon treatment at doses of up to 16 mg/day for 
9 months in IgAN patients at risk of developing ESRD despite optimized RAS blockade, has 
demonstrated promising efficacy results on proteinuria reduction and eGFR stabilization, with no 
safety concerns.24  
5.3 
Randomization and Blinding 
This is an open-label study. All patients will receive Nefecon treatment for 9 months. 
During Study Nef-301 OLE, the patients and Investigators will remain blinded to treatment given 
in Study Nef-301. 
5.4 
Breaking the Blind 
Procedures for breaking the blind are not applicable for the current study (Nef-301 OLE). 
5.5 
Drug Supplies 
5.5.1 
Formulation and Packaging 
Nefecon is a modified-release capsule containing 4 mg of the active substance budesonide. The 
capsule is white to off-white, of size 1, with black printing “CAL10 4MG,” and is coated with an 
enteric coating layer that delivers the capsule intact until it reaches the distal part of the small 
intestine. The capsule contains triple coated beads with a sugar sphere as the core. The inner 
coating layer contains the active substance, and the outer coating layer is a prolonged-release 
polymer coating that controls the rate of release of the active substance once the capsule has 
dissolved.  
Nefecon capsules will be packaged in high-density polyethylene bottles and should be stored 
between 15°C to 25°C in their original container with the cap tightly sealed. Nefecon will be 
packaged and labeled according to the requirements of local law and legislation, as well as current 


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Good Manufacturing Practices and Good Clinical Practice (GCP) guidelines. Proof labels, 
detailing actual label text, will be available in the study files. 
5.5.2 
Study Drug Preparation and Dispensing 
Interactive Response Technology (IRT) will trigger the first shipment of study drug to the site for 
the patient. The Investigator (or his/her designee) will dispense the study drug to the patient. 
Patients must take the first dose of study drug in the presence of site staff during Study Visit 4.  
Following initial shipment, there will be an automatic resupply of study drug to the site for 
dispensing to the patient at Study Visits 6 and 7. 
The Investigator (or his/her designee) must record the patient number, the identification number 
of the study drug dispensed, the date dispensed, and the amount dispensed in the source documents. 
The disposition of study drug delivered to an Investigator will be recorded on a per-patient basis. 
Dispensation logs will be completed for all patients at each site documenting dispensed and 
returned study drug throughout the course of the study. Patients will be reminded at each scheduled 
study visit to return all empty bottles and unused study drug. The dispensation logs will be 
monitored by Medpace on an ongoing basis. 
5.5.3 
Study Drug Administration 
Nefecon 16 mg (four 4 mg budesonide modified-release capsules QD) will be administered orally 
for 9 months during the Treatment Period.  
Patients must take the first dose of study drug in the presence of site staff during Study Visit 4. As 
a result, the first dose of study drug may be administered at any time of day and without regard to 
the timing of meals. Patients may self-dose for all other doses of study drug and should take study 
drug in the morning at least 1 hour before breakfast. The capsules must be swallowed whole and 
may not be chewed or crushed. 
The 16 mg/day dose may be reduced to 8 mg/day if clinically relevant AEs develop during the 
9-month Treatment Period that the Investigator considers related to the study drug and that 
mandate dose reduction. The Medical Monitor should preferably be consulted prior to reducing 
the dose. If a dose reduction is made, then the dose should not be increased back to 4 capsules QD 
(Nefecon 16 mg). 
After completing 9 months of study drug treatment, the daily dose of study drug will be reduced 
from 4 capsules QD (Nefecon 16 mg) to 2 capsules QD (Nefecon 8 mg) for 2 weeks to prevent 
adrenal insufficiency (Tapering Period). Patients who have their daily dose of study drug reduced 
to 2 capsules QD (Nefecon 8 mg) due to safety and/or tolerability reasons during the 9-month 
Treatment Period will remain on this dose during the 2-week Tapering Period. Patients who 
prematurely discontinue study drug while taking 4 capsules QD (Nefecon 16 mg) should have the 
daily dose of study drug reduced to 2 capsules QD (Nefecon 8 mg) for 2 weeks, if feasible, to 
prevent adrenal insufficiency. 
5.5.4 
Treatment Compliance 
Patients will be instructed to return all empty bottles and unused study drug to the site at the next 
study visit. Accountability of the used and unused study drug will be recorded. Compliance with 
the study drug regimen will be evaluated by counting unused capsules. During the Treatment 


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Period, if compliance is not between 80% and 120%, inclusive, the patient will be counseled about 
the importance of compliance with the study drug regimen. 
5.5.5 
Storage and Accountability 
Study drug must be stored in a pharmacy or a locked and secure storage facility, accessible only 
to those individuals authorized by the Investigator to dispense the drug, between 15°C to 25°C in 
the original container with the cap tightly sealed. The Investigator or his/her designee will maintain 
accurate records of all study drug received, dispensed, or returned/disposed, as well as a 
temperature log to document temperature conditions during storage. 
Temperature excursions up to 30°C will be allowed. Details regarding allowed excursions will be 
available in the pharmacy manual. 
Return and destruction of study drug will be described in the pharmacy manual. The Investigator 
agrees to only distribute study drug to patients participating in the study. 
5.6 
Prior and Concomitant Medications and/or Procedures 
5.6.1 
Excluded Medications and/or Procedures 
Patients must not receive other investigational drugs during the study. 
Systemic immunosuppressive drugs (including GCSs) are prohibited during the study. Herbs for 
medicinal use, including Eastern herbs and Eastern traditional medicines, with a known effect on 
the immune system (e.g., Tripterygium wilfordii or ginseng) or with a known effect on proteinuria 
or creatinine, are not allowed during the study. Patients should be encouraged to not use herbs for 
medicinal use, including Eastern herbs and Eastern traditional medicines, during the study; 
however, if used, they should be recorded as concomitant medications. See Appendix E for 
additional information on immunosuppressive drugs. 
Potent inhibitors of CYP3A4 (e.g., ketoconazole) are prohibited during treatment with study drug. 
See the US Food and Drug Administration website for additional examples.29 During this time, 
patients should also be instructed to avoid grapefruit and grapefruit juice. 
If a patient receives rescue treatment (systemic steroids and/or immunosuppressive treatment), the 
patient will be withdrawn from Nefecon treatment and continue with study visits for a total of 
12 months follow-up after first dose. 
5.6.2 
Restricted Medications and/or Procedures 
Patients should avoid starting new medications and making changes to existing medications. 
However, if needed, the introduction of new medications or changes to existing medications are 
permitted at the discretion of the Investigator. 
5.6.3 
Documentation of Prior and Concomitant Medication Use 
Medications taken within 3 months prior to Study Visit 1 and concomitant medications and 
therapies will be recorded in the eCRFs. All concomitant medications and changes in concomitant 
medications will be recorded throughout the course of the study in the eCRFs. 
Herbs for medicinal use, including Eastern herbs and Eastern traditional medicines, should be 
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Patients are required to continue on a stable dose of RAS inhibitor therapy (ACEIs and/or ARBs) 
at the maximum allowed dose or maximum tolerated dose according to the 2012 KDIGO 
guidelines during the study.21 A stable dose is defined as a dose within 25% of the dose at Visit 17a 
or 17b in Study Nef-301. Therefore, RAS inhibitor therapies (ACEIs and/or ARBs) must be 
recorded. 
5.6.4 
Dietary and Lifestyle Recommendations 
The following lifestyle choices should be recommended to the patient at Study Visit 1: 
 Weight normalization; 
 Smoking cessation; 
 Physical activity; and 
 Diet (low salt and low protein). 
Patients should be encouraged to maintain stable lifestyle choices while participating in the study. 
 


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6 
STUDY PROCEDURES 
The Schedule of Procedures is provided in Table 1 in Appendix A. A detailed list of procedures to 
be conducted at each study visit is also described below. 
6.1 
Informed Consent 
Prior to conducting any study-related activities, the current, approved ICF must be signed and 
dated by the patient. See Section 11.3 for more information. 
6.2 
Screening Period (Study Visits 1 to 3) 
6.2.1 
Study Visit 1 
Preferably, Visit 17a in Study Nef-301 should be combined with Visit 1 in Study Nef-301 OLE. 
If the visits are combined, procedures do not need to be duplicated.  
If the visits are not combined, Visit 3 in Study Nef-301 OLE must occur within 3 months after 
Visit 17b in Study Nef-301. 
The following procedures will be performed at Study Visit 1: 
 Obtain written informed consent, if not obtained prior to Study Visit 1; 
 Update demographic information and medical/surgical history; 
 Conduct eligibility assessment based on inclusion and exclusion criteria; 
 Conduct laboratory eligibility assessment based on laboratory values from Visit 17a and/or 
17b in Study Nef-301; 
 Obtain vital sign measurements (systolic and diastolic blood pressure and heart rate [up to 
3 measurements, measured 1 minute apart, after resting in the supine position for at least 
5 minutes]); 
 Obtain height and body weight (see Section 8.11); 
 Perform a complete physical examination (see Section 8.10); 
 Collect blood samples for the following assessments: 
o Hematology (including HbA1c) and serum chemistry (including eGFR [CKD-EPI]); 
o FSH (postmenopausal women only); 
o Serum pregnancy test (WOCBP only); and 
o Hepatitis B and C, HIV, and TB screening; 
 Collect fresh urine sample for the following assessments: 
o Urinalysis; and 
o Urine drug and alcohol screen; 
 Complete the Short Form 36 (SF-36) quality of life assessment; 


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 Provide the following dietary and lifestyle recommendations: weight normalization, smoking 
cessation, physical activity, and diet (low salt and low protein). Patients should be encouraged 
to maintain stable lifestyle choices while participating in the study; 
 Supply the patient with the container(s) for 24-hour urine collection; and 
 Assess AEs, including adverse events of special interest (AESIs) and SAEs, and concomitant 
medications and procedures. 
6.2.2 
Study Visit 2 
Preferably, Visit 17b in Study Nef-301 should be combined with Visit 2 in Study Nef-301 OLE. 
If the visits are not combined, Study Visit 2 must occur within 2 weeks after Study Visit 1. 
The following procedures will be performed at Study Visit 2: 
 Obtain the 24-hour urine sample, including cortisol (sample collected by the patient during the 
24-hour period prior to the scheduled study visit); and 
 Supply the patient with new container(s) for the next 24-hour urine collection. 
6.2.3 
Study Visit 3 (2 to 4 Weeks After Study Visit 2) 
Study Visit 3 must occur 2 to 4 weeks, inclusive, after Study Visit 2 in order to collect the 
second proteinuria measurement to determine eligibility. 
Patients will be required to fast for at least 10 hours prior to Study Visit 3. 
The following procedures will be performed onsite at Study Visit 3: 
 Update demographic information and medical/surgical history; 
 Conduct eligibility assessment based on inclusion and exclusion criteria; 
 Obtain vital sign measurements (systolic and diastolic blood pressure and heart rate [up to 
3 measurements, measured 1 minute apart, after resting in the supine position for at least 
5 minutes]); 
 Obtain the 24-hour urine sample, including cortisol (sample collected by the patient during the 
24-hour period prior to the scheduled study visit); 
 Collect fresh urine sample for the following assessments: 
o Urinalysis; and 
o Pregnancy test via a local urine assessment (WOCBP only); 
 Collect blood samples for the following assessments: 
o Hematology (including HbA1c), serum chemistry (including eGFR [CKD-EPI] and fasting 
blood glucose), and fasting lipid panel; and 
 Assess AEs, including AESIs and SAEs, and concomitant medications and procedures. 


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6.3 
Treatment Period (Study Visits 4 to 9 – Study Day 1 to Study Month 9) 
After confirming all eligibility criteria (laboratory values from Study Visits 1, 2, 3, etc.) (eGFR 
values from Study Visits 1 or 3 must be 30 mL/min per 1.73 m2 for the patient to be eligible 
[see Section 4.1]), IRT will trigger the first shipment of study drug to the site for the patient. 
Following initial shipment, there will be an automatic resupply of study drug to the site for 
dispensing to the patient at Study Visits 6 and 7. 
Patients must take the first dose of study drug in the presence of site staff during Study Visit 4. 
6.3.1 
Study Visit 4 (Study Day 1) 
Study Visit 4 must occur within 4 weeks after Study Visit 3. 
The following procedures will be performed at Study Visit 4 (Study Day 1): 
 Update demographic information and medical/surgical history; 
 Obtain vital sign measurements (systolic and diastolic blood pressure and heart rate [measured 
after resting in the supine position for at least 5 minutes]); 
 Obtain body weight; 
 Collect fresh urine sample for the pregnancy test via a local urine assessment (WOCBP only); 
 Dispense study drug and instruct patient on study drug administration; 
 Administer the first dose of study drug;  
 Capture the occurrence of dialysis or kidney transplantation;  
 Supply the patient with the container(s) for 24-hour urine collection; and 
 Assess AEs (occurring after administration of the first dose of study drug), including AESIs 
and SAEs, and concomitant medications and procedures. 
6.3.2 
Telephone Study Visit 5 (Study Month 1) 
The following procedures will be performed at Study Visit 5 (Study Month 1), which will be 
conducted with the patient by telephone: 
 Capture the occurrence of dialysis or kidney transplantation; and 
 Assess AEs, including AESIs and SAEs; concomitant medications and procedures; and 
treatment compliance. 
6.3.3 
Study Visits 6 (Study Month 3), 7 (Study Month 6), and 8 (Study Month 9) 
The following procedures will be performed onsite at Study Visits 6 (Study Month 3), 7 (Study 
Month 6) and 8 (Study Month 9): 
 Dispense study drug and instruct patient on study drug administration (Study Visits 6 and 7 
only); 
 Collect study drug from previous visit, assess for treatment compliance, and perform drug 
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 Obtain vital sign measurements (systolic and diastolic blood pressure and heart rate [measured 
after resting in the supine position for at least 5 minutes]); 
 Obtain the 24-hour urine sample, including cortisol (sample collected by the patient during the 
24-hour period prior to the scheduled study visit); 
 Supply the patient with new container(s) for the next 24-hour urine collection; 
 Collect fresh urine sample for the following assessments: 
o Urinalysis; and 
o Pregnancy test via a local urine assessment (WOCBP only); 
 Collect blood samples for the following assessments: 
o Hematology (including HbA1c) and serum chemistry (including eGFR [CKD-EPI]); 
 Capture the occurrence of dialysis or kidney transplantation; and 
 Assess AEs, including AESIs and SAEs, and concomitant medications and procedures. 
After completing 9 months of study drug treatment, patients will enter the 2-week Tapering Period 
to prevent adrenal insufficiency. During the 2-week Tapering Period, the daily dose of study drug 
will be reduced from 4 capsules QD (Nefecon 16 mg) to 2 capsules QD (Nefecon 8 mg). Patients 
who have their daily dose of study drug reduced to 2 capsules QD (Nefecon 8 mg) due to safety 
and/or tolerability reasons during the 9-month Treatment Period will remain on this dose during 
the 2-week Tapering Period. 
6.3.4 
Study Visit 9 (14 to 35 Days After Study Visit 8) (For Replicate Laboratory 
Sampling) 
The following procedures will be performed onsite at Study Visit 9 (14 to 35 days after Study 
Visit 8) (for replicate laboratory sampling): 
 Collect blood samples for the following assessments: 
o Hematology (including HbA1c) and serum chemistry (including eGFR [CKD-EPI]);  
 Obtain the 24-hour urine sample, including cortisol (sample collected by the patient during the 
24-hour period prior to the scheduled study visit); 
 Supply the patient with new container(s) for the next 24-hour urine collection; and 
 Assess AEs, including AESIs and SAEs, and concomitant medications and procedures. 
6.4 
Follow-up Period (Study Visit 10 – Study Month 12) 
Following completion of the Treatment Period, patients will enter the 3-month Follow-up Period.  
6.4.1 
Study Visit 10 (Study Month 12)  
The following procedures will be performed onsite at Study Visit 10 (Study Month 12) (End of 
Study Visit): 
 Collect study drug from previous visit, assess for treatment compliance, and perform drug 
accountability; 


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 Obtain body weight; 
 Perform a complete physical examination; 
 Obtain the 24-hour urine sample, including cortisol (sample collected by the patient during the 
24-hour period prior to the scheduled study visit); 
 Collect fresh urine sample for the following assessments: 
o Urinalysis; and 
o Pregnancy test via a local urine assessment (WOCBP only); 
 Collect blood samples for the following assessments: 
o Hematology (including HbA1c) and serum chemistry (including eGFR [CKD-EPI]); 
 Complete the SF-36 quality of life assessment; 
 Capture the occurrence of dialysis or kidney transplantation; and 
 Assess AEs, including AESIs and SAEs, and concomitant medications and procedures. 
For patients who are withdrawn from the study, the End of Study Visit procedures will be 
completed, if possible, at the time the decision is made to withdraw the patient. The End of Study 
Visit will consist of all of the Study Visit 10 procedures. See Section 4.3. 
 


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7 
EFFICACY ASSESSMENTS 
7.1 
Primary Efficacy Endpoints 
The primary efficacy endpoints will include the following: 
 Ratio of eGFR at 9 months compared to baseline, calculated using the CKD-EPI formula; and 
 Ratio of UPCR at 9 months compared to baseline. 
7.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints will include the following: 
 Ratio of urine albumin to creatinine ratio (UACR) at 9 months compared to baseline; 
 SF-36 quality of life assessment at 12 months compared to baseline; 
 Proportion of patients with microhematuria at 9 months compared to baseline; 
 Proportion of patients receiving rescue treatment and time to receiving rescue treatment; 
 Proportion of patients on dialysis, undergoing kidney transplantation, or with eGFR 
<15 mL/min per 1.73 m2; and 
 Cortisol suppression at 9 and 12 months, measured as urinary cortisol excretion over 24 hours 
compared to baseline. 
 


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8 
SAFETY ASSESSMENTS 
8.1 
Adverse Events 
Ongoing AEs from the patient’s involvement in Study Nef-301 will continue to be followed in 
Study Nef-301 OLE and captured as ongoing AEs. New AEs will be collected from Study Visit 1 
through 12 months after the first dose of study drug in Study Nef-301 OLE. New 
treatment-emergent AEs will be those starting with Study Nef-301 OLE dosing (Study Visit 4). 
An AE is defined as any untoward medical occurrence in a clinical investigation patient 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and/or unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational medicinal product, whether or not related to the investigational medicinal product. 
The Investigator will collect AEs with a non-leading question such as “have you experienced any 
new health problems or worsening of existing conditions” as well as collecting events directly 
observed or spontaneously volunteered by patients or caregivers. All AEs, including observed or 
volunteered problems, complaints, or symptoms, are to be recorded on the appropriate eCRF. 
AEs, including AESIs and SAEs, will be monitored and documented by the Investigator (or his/her 
designee) from Study Visit 1 until 12 months after the first dose of study drug, inclusive, regardless 
of whether the patient discontinues the study prematurely. Patients should be instructed to report 
any AE that they experience to the Investigator (or his/her designee).  
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate AE on the eCRF. Additionally, 
the condition that led to a medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, 
or transfusion) should be recorded as an AE, not the procedure.  
Any medical condition already present at Study Visit 1 should not be reported as an AE unless the 
medical condition or signs or symptoms present at baseline worsens in severity or seriousness at 
any time during the study. In this case, it should be reported as an AE. 
Clinically significant abnormal laboratory or other examination (e.g., physical examination) 
findings that are detected during the study or are present at Study Visit 1 and significantly worsen 
during the study should be reported as AEs. The Investigator will exercise his or her medical and 
scientific judgment in deciding whether an abnormal laboratory finding or other abnormal 
assessment is clinically significant. Clinically significant abnormal laboratory values occurring 
during the clinical study will be followed until repeat tests return to normal, stabilize, or are no 
longer clinically significant. Any abnormal test that is determined to be an error does not require 
reporting as an AE. 
Any medical condition or abnormal finding that worsens in severity or seriousness and that fulfils 
the criteria for an SAE will be reported as such, from signature of informed consent. 
8.1.1 
Adverse (Drug) Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. “Responses” to a medicinal product means that a causal 


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relationship between a medicinal product and an AE is at least a reasonable possibility, i.e., the 
relationship cannot be ruled out. 
8.1.2 
Unexpected Adverse Drug Reaction 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable Reference Safety Information (RSI). For Nefecon the 
RSI is included in the Investigator’s Brochure currently in force.24 The RSI will be reviewed yearly 
and the periodicity of the review will be harmonized with the reporting period of the Development 
Safety Update Report. 
8.1.3 
Assessment of Adverse Events by the Investigator 
The Investigator will assess the severity (intensity) of each AE as mild, moderate, or severe, and 
will also categorize each AE as to its potential relationship to study drug using the categories of 
yes or no. 
Assessment of Severity: 
 Mild – An event that is easily tolerated and generally not interfering with normal daily 
activities. 
 Moderate – An event that is sufficiently discomforting to interfere with normal daily activities. 
 Severe – An event that is incapacitating with inability to work or perform normal daily 
activities. 
Causality Assessment: 
The relationship of an AE to the administration of the study drug is to be assessed according to the 
following definitions: 
No (not related, unlikely to be related) – The time course between the administration of study drug 
and the occurrence or worsening of the AE rules out a causal relationship and another cause 
(concomitant drugs, therapies, complications, etc.) is suspected. 
Yes (related) – The time course between the administration of study drug and the occurrence or 
worsening of the AE is consistent with a causal relationship and no other cause (concomitant drugs, 
therapies, complications, etc.) can be identified. 
The definition implies a reasonable possibility of a causal relationship between the event and the 
study drug. This means that there are facts (evidence) or arguments to suggest a causal relationship. 
The following factors should also be considered: 
 The temporal sequence from study drug administration- 
o The event should occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event. 
 Underlying, concomitant, intercurrent diseases- 
o Each report should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the patient may have. 


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 Concomitant drug- 
o The other drugs the patient is taking or the treatment the patient receives should be 
examined to determine whether any of them might be recognized to cause the event in 
question. 
 Known response pattern for this class of study drug- 
o Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect. 
 Exposure to physical and/or mental stresses- 
o The exposure to stress might induce adverse changes in the recipient and provide a logical 
and better explanation for the event. 
 The pharmacology and pharmacokinetics of the study drug- 
o The known pharmacologic properties (absorption, distribution, metabolism, and excretion) 
of the study drug should be considered. 
8.2 
Adverse Events of Special Interest 
The following, which are established potentially clinically significant consequences of steroid 
treatment, will be considered AESIs:  
 Severe infection requiring hospitalization; 
 New onset of diabetes mellitus; 
 Confirmed fracture; 
 New osteonecrosis; 
 Gastrointestinal bleeding that requires hospitalization; 
 Reported occurrence of cataract formation; and 
 Reported onset of glaucoma. 
If not already determined from the general questions used to capture AE, the patient must be 
explicitly asked if the following have occurred since the last study visit:  
 Have you been hospitalized due to any infection and/or gastrointestinal bleeding? 
 Have you had any X-ray confirmed fractures? 
 Have you been diagnosed with diabetes mellitus? 
 Have you visited an ophthalmologist and been diagnosed with glaucoma or cataract(s)? 
AESIs may or may not constitute an SAE. However, all types of AESIs must be reported to 
Medpace Clinical Safety and processed as SAEs, regardless of their formal classification of 
seriousness, in accordance with the instructions in Section 8.4. The AESIs that do not fall into the 
category of SAEs will be recorded from Study Visit 1 until 12 months after the first dose of study 
drug, inclusive, regardless of whether the patient discontinues the study prematurely. 


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8.3 
Serious Adverse Events 
An AE or adverse reaction is considered serious if, in the view of either the Investigator or 
Calliditas, it results in any of the following outcomes: 
 Death; 
 A life-threatening AE; 
o NOTE: An AE or adverse reaction is considered “life-threatening” if, in view of either the 
Investigator or Calliditas, its occurrence places the patient at immediate risk of death. It 
does not include an event that, had it occurred in a more severe form, might have caused 
death. 
 Requires hospitalization or prolongation of existing hospitalizations; 
o NOTE: Any hospital admission with at least 1 overnight stay will be considered an 
inpatient hospitalization. An emergency room visit without hospital admission for more 
than 24 hours will not be recorded as a SAE under this criterion, nor will elective 
hospitalization/surgery or hospitalization for treatment of pre-existing (prior to signing of 
the ICF) conditions that did not worsen from baseline. However, unexpected complications 
and/or prolongation of hospitalization that occur during elective surgery should be recorded 
as AEs and assessed for seriousness. Admission to the hospital for social or situational 
reasons (i.e., no place to stay, live too far away to come for hospital visits) will not be 
considered inpatient hospitalizations.  
 A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions; 
 A congenital anomaly/birth defect; or 
 An important medical event. 
o NOTE: Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention 
to prevent one of the outcomes listed above. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalizations, or the 
development of drug dependency. 
8.4 
Serious Adverse Event Reporting − Procedures for Investigators 
Initial Reports 
All SAEs, irrespective of relatedness, occurring from Study Visit 1 until 12 months after the first 
dose of study drug must be reported to Medpace Clinical Safety within 24 hours of the knowledge 
of the occurrence (this refers to any AE that meets any of the aforementioned serious criteria). 
To report the SAE, complete the SAE form electronically in the electronic data capture (EDC) 
system for the study. When the form is completed, Medpace Safety personnel will be notified 
electronically and will retrieve the form. If the event meets serious criteria and it is not possible to 
access 
the 
EDC 
system, 
send 
an 
e-mail 
to 
Medpace 
Safety 
at 
Medpace-safetynotification@medpace.com or call the Medpace SAE reporting line (telephone 


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number listed below). The site should then complete the paper SAE form and send via e-mail or 
fax to Medpace (e-mail and fax number are listed below) within 24 hours of awareness. When the 
EDC system becomes available, the SAE information must be entered within 24 hours of the 
system becoming available.  
Safety Contact Information: Medpace Clinical Safety 
Medpace SAE reporting line – USA/Canada/Australia/Asia Pacific: 
Telephone: +1-800-730-5779, dial 3 or +1-513-579-9911, dial 3 
Fax: +1-866-336-5320 or +1-513-579-0444 
e-mail: medpace-safetynotification@medpace.com 
 
Medpace SAE reporting line – Europe/All other countries: 
Telephone: +49 89 89 55 718 44 
Fax: +49 89 89 55 718 104 
e-mail: medpace-safetynotification@medpace.com 
Follow-Up Reports 
The Investigator must continue to follow the patient until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the patient 
dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(e.g., patient discharge summary or autopsy reports) to Medpace Clinical Safety via fax or e-mail. 
If it is not possible to access the EDC system, refer to the procedures outlined above for initial 
reporting of SAEs.  
8.5 
Pregnancy Reporting 
If the patient participating in the study becomes pregnant during the study or within 30 days of the 
last dose of study drug, the Investigator should report the pregnancy to Medpace Clinical Safety 
via telephone or e-mail within 24 hours of being notified. Medpace Clinical Safety will then 
forward the Exposure In Utero form to the Investigator for completion.  
A patient becoming pregnant while on study drug will immediately discontinue study drug 
treatment but will not be withdrawn from the study. 
The patient should be followed by the Investigator until completion of the pregnancy. If the 
pregnancy ends for any reason before the anticipated date, the Investigator should notify Medpace 
Clinical Safety. At the completion of the pregnancy, the Investigator will document the outcome 
of the pregnancy. If the outcome of the pregnancy meets the criteria for immediate classification 
as an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly), the Investigator should follow the procedures for reporting an SAE. 
8.6 
Expedited Reporting 
Calliditas (or their designee) will report all relevant information about suspected unexpected 
serious adverse reactions (SUSARs) that are fatal or life-threatening as soon as possible to all 
regulatory authorities in the concerned countries and Central Ethics Committees (CECs) as 
applicable in each participating country, and in any case no later than 7 days after knowledge by 


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Calliditas (or their designee) of such a case. Relevant follow-up information will subsequently be 
communicated within an additional 8 days.  
All other SUSARs will be reported to all regulatory authorities in the concerned countries and to 
the CECs as soon as possible but within a maximum of 15 days of first knowledge by Calliditas.  
Calliditas (or their designee) will also inform all Investigators as required.  
8.7 
Safety Assessments 
The safety variables will include the following: 
 Treatment-emergent AEs, defined as AEs that occur for the first time after dosing in 
Study Nef-301 OLE, or exist before dosing in Study Nef-301 OLE but worsen in severity after 
dosing in Study Nef-301 OLE; 
 AEs leading to study drug discontinuation; 
 AESIs (severe infections requiring hospitalization, new onset of diabetes, confirmed fracture, 
new osteonecrosis, gastrointestinal bleeding that requires hospitalization, reported occurrence 
of cataract formation, and reported onset of glaucoma); and 
 Vital signs, body weight, clinical laboratory variables, and physical examination findings. 
8.8 
Clinical Laboratory Evaluations 
Clinical safety laboratory assessments will include hematology, serum chemistry, and urinalysis 
parameters from collection of blood and urine samples as indicated in Appendix A. See 
Appendix B for a complete list of laboratory analytes. 
All laboratory analyses will be performed or managed by a central laboratory. The TB test must 
be the specific QuantiFERON®-TB Gold test and can be done locally if needed. However, the 
report must be available to confirm a negative TB result. Details regarding the collection, 
processing, storage, and shipping of samples can be found in the laboratory manual. 
8.9 
Vital Signs 
Vital sign measurements will include systolic and diastolic blood pressure and heart rate as 
indicated in Appendix A. Blood pressure and heart rate will be measured after resting in the supine 
position for at least 5 minutes. At Study Visits 1 and 3, blood pressure and heart rate will be 
measured up to 3 times with each measurement separated by 1 minute (the lowest value will be 
recorded on the eCRF). 
8.10 
Physical Examinations 
A complete physical examination will be performed as indicated in Appendix A and will consist 
of examination of the head, eyes, ears, nose, throat, lymph nodes, chest, abdomen, and extremities, 
as well as the respiratory, musculoskeletal, cardiovascular, dermatologic, and nervous systems 
(including sensory, motor, and deep tendon reflexes).  
8.11 
Body Weight and Height 
Measurement of body weight should be performed with the patient dressed in indoor clothing, with 
shoes removed, and bladder empty. Height will only be collected at Study Visit 1. 


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9 
STATISTICS 
9.1 
Analysis Populations 
The Completers Analysis Set will include all patients who receive Nefecon for 9 months. 
The Full Analysis Set will include all patients who receive at least 1 dose of Nefecon, with at least 
1 efficacy measurement (UPCR or eGFR) collected after dosing. 
The Safety Analysis Set will include all patients who have received at least 1 dose of study drug 
at the time of the analysis. 
9.2 
Statistical Methods 
9.2.1 
Analysis of Efficacy 
No formal statistical analyses will be performed. eGFR, UPCR, and UACR are expected to be 
log-normally distributed; therefore, the ratio of 9 months to baseline for eGFR, UPCR, and UACR 
will be summarized using geometric mean and its associated 95% confidence interval. If outlying 
data are present for an endpoint, a supplementary description of the data will be performed using 
a robust regression approach. Separate summaries will be provided according to whether the 
patient received Nefecon or placebo in Study Nef-301. 
Each efficacy variable will be summarized in 2 different analysis sets, the Completers Analysis 
Set and the Full Analysis Set. Any data recorded after rescue treatment will not be included in the 
analysis for either analysis population. 
Baseline eGFR, UPCR, and UACR will be defined as the geometric mean of the 2 consecutive 
measurements prior to dosing. The 9-month eGFR, UPCR, and UACR values will be defined as 
the geometric mean of the values recorded at Study Visits 8 and 9. 
For UPCR, the primary analysis will calculate the mean of the change from baseline in log(UPCR), 
with results back-transformed to provide a geometric mean ratio and 95% confidence interval. For 
eGFR, due to the possible presence of outlying data, the primary analysis will use the same 
approach but deriving the mean change and its confidence interval using a robust regression model. 
If a reasonable proportion of patients do not provide 9-month data, a sensitivity analysis will be 
performed by fitting a mixed model that incorporates any data recorded at 3, 6, and 12 months 
with different assumptions made about efficacy after discontinuation of treatment. 
9.2.2 
Analysis of Safety 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and will 
include all safety data from patients who have received at least 1 dose of study drug at the time of 
the analysis. The incidence of treatment-emergent AEs will be summarized by system organ class. 
In addition, the time to first occurrence of the most common event will be summarized using 
cumulative incidence plots. Safety data will be summarized or listed separately for the period 
between screening and the first dose of study drug. In addition, the safety data will be summarized 
for the entire period following the first dose of study drug and separately for periods during and 
after dosing. 
Summary statistics will be presented for changes in vital signs and laboratory tests throughout the 
study. Physical examinations will be listed.  


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9.2.3 
Sample Size Determination 
All patients who have completed Study Nef-301 and meet all eligibility criteria will be able to 
participate in Study Nef-301 OLE. Assuming that 75% of the patients who have completed 
Study Nef-301 will enter Study Nef-301 OLE, the total number of patients to be included is 
estimated to be approximately 250 patients, but up to 360 patients may be enrolled. 
In Study Nef-202, a completed, randomized, double-blind study of Nefecon in comparison to 
placebo, the standard deviation for the change from baseline in log(UPCR) and log(eGFR) was 
0.59 and 0.18, respectively. If 125 patients are recruited within each efficacy group (prior Nefecon 
or prior placebo) and a 25% reduction (ratio of 0.75) in UPCR is observed in this study, the upper 
95% confidence limit for the baseline ratio will extend to 0.83. Likewise, if there is no change in 
eGFR observed in this study (ratio of 1), the lower 95% confidence limit for the baseline ratio will 
extend to 0.97. Therefore, this study will provide a sufficiently precise estimate of the efficacy of 
Nefecon according to whether the patient previously received Nefecon or placebo. 


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10 
DATA MANAGEMENT AND RECORD KEEPING 
10.1 
Data Management 
10.1.1 
Data Handling 
Patient numbers will be assigned in IRT at Study Visit 1 and will be automatically downloaded 
into the EDC system. Data will be recorded at the site in the eCRFs and reviewed by the clinical 
research associate (CRA) during monitoring visits. The CRAs will verify data recorded in the EDC 
system against source documents. All corrections or changes made to any study data will be 
appropriately tracked in an audit trail in the EDC system. An eCRF will be considered complete 
when all missing, incorrect, and/or inconsistent data have been accounted for. 
10.1.2 
Computer Systems 
Data will be processed using ClinTrak EDC, which is a validated computer system that conforms 
to regulatory requirements. 
10.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. Site personnel are 
expected to enter data into EDC within 5 business days of each study visit, as well as respond to 
data queries in EDC and enter/update any applicable data within 5 business days of the queries 
being issued in EDC. All site personnel must log into the system using their secure user name and 
password in order to enter, review, or correct study data. These procedures must comply with 
Title 21 of the Code of Federal Regulations (CFR) Part 11 and other appropriate international 
regulations. All passwords will be strictly confidential. 
10.1.4 
Medical Information Coding 
For medical information, the current and updated versions of the following thesauri will be used: 
 The MedDRA for medical history and AEs, and 
 The World Health Organization Drug Dictionary for prior and concomitant medications. 
10.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the investigative site for resolution through data queries. 
The data on the eCRFs must be reviewed and the eCRFs must be electronically signed by the 
Investigator. 
10.2 
Record Keeping 
Records of patients, source documents, monitoring visit logs, eCRFs, inventory of study product, 
regulatory documents, and other Calliditas correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data is defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 


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clinical study necessary for the evaluation and reconstruction of the clinical study. Additionally, 
the definition of source data will be specified in the Site Source Documentation Process Form. 
Source data are contained in source documents (original records or certified copies). These records 
will be retained in a secure file for the period as set forth in the Clinical Study Agreement. Prior 
to transfer or destruction of these records, Calliditas must be notified in writing and be given the 
opportunity to further store such records.  


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11 
SPONSOR/INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL  
11.1 
Ethical Conduct of the Study 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve human patients. Compliance with this 
standard provides public assurance that the rights, safety, and well-being of study patients are 
protected, consistent with the principles that have their origin in the Declaration of Helsinki, and 
that the clinical study data are credible. The study will be conducted in compliance with the 
protocol, regulatory requirements, International Council for Harmonisation (ICH) for GCP and the 
ethical principles of the latest version of the Declaration of Helsinki as adopted by the World 
Medical Association. 
11.2 
Institutional Review Board/Independent Ethics Committee 
The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will review all 
appropriate study documentation in order to safeguard the rights, safety, and well-being of patients. 
The study will only be conducted at sites where IRB/IEC approval has been obtained. The protocol, 
Investigator’s Brochure, ICFs, advertisements (if applicable), written information given to the 
patients, safety updates, annual progress reports, and any revisions to these documents will be 
provided to the IRB/IEC by the Investigator. 
Federal regulations and ICH Guidelines require that approval be obtained from an IRB/IEC prior 
to participation of patients in research studies. Prior to study onset, the protocol, any protocol 
amendments, ICFs, advertisements to be used for patient recruitment, and any other written 
information regarding this study to be provided to a patient or patient’s legal guardian must be 
approved by the IRB/IEC. 
No drug will be released to the site for dosing until written IRB/IEC authorization has been 
received by Calliditas or their designee (i.e., Medpace). 
It is the responsibility of Calliditas or their designee (i.e., Medpace) to obtain the approval of the 
responsible IRB/IEC according to the national regulations. 
11.3 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by 
Calliditas or their designee and the IRB/IEC prior to its use and must be in compliance with all 
ICH GCP, local regulatory requirements, and legal requirements. 
The Investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
patient has been informed of his/her rights to privacy. The Investigator will obtain written informed 
consent from each patient before any study-specific activity is performed and should document in 
the source documentation that consent was obtained prior to enrollment in the study. The original 
signed ICF must be maintained by the Investigator and is subject to inspection by a representative 
of Calliditas, their representatives, auditors, the IRB/IEC and/or regulatory agencies. A copy of 
the signed ICF will be given to the patient. 
All rescreened patients must be reconsented and sign a new ICF prior to completion of any 
rescreening study procedures. 


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11.4 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, ICH GCP, Directive 2001/20/EC (EU sites only), applicable regulatory requirements, 
and the Declaration of Helsinki and that valid data are entered into the eCRFs. 
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same time, 
Calliditas in the maintenance of complete, legible, well organized and easily retrievable data. 
Before the enrollment of any patient in this study, Calliditas or their designee will review with the 
Investigator and site personnel the following documents: protocol, Investigator’s Brochure, eCRFs 
and procedures for their completion, informed consent process, and the procedure for reporting 
SAEs. 
The Investigator will permit Calliditas or their designee to monitor the study, which will require 
direct access to source data, as frequently as deemed necessary to determine that data recording 
and protocol adherence are satisfactory. During the monitoring visits, information recorded on the 
eCRFs will be verified against source documents and requests for clarification or correction may 
be made. After the eCRF data is entered by the site, the CRA will review the data for safety 
information, completeness, accuracy, and logical consistency. Computer programs that identify 
data inconsistencies may be used to help monitor the clinical study. If necessary, requests for 
clarification or correction will be sent to Investigators. The Investigator and his/her staff will be 
expected to cooperate with the monitor and provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring log. 
11.5 
Disclosure of Data 
All relevant patient source data and eCRF data must be available for inspection by regulatory 
health authorities, Calliditas or their designee, and the IRB/IEC as appropriate. Patients or their 
legal representatives may request their medical information be given to their personal physician or 
other appropriate medical personnel responsible for their welfare. 
Patient source data is confidential and disclosure to third parties other than those noted above is 
prohibited. 
11.6 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or Calliditas, the Investigator will 
keep records, including the identity of all participating patients (sufficient information to link 
records, e.g., eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE 
forms, source documents, and detailed records of treatment disposition. The records should be 
retained by the Investigator according to specifications in the ICH guidelines, local regulations, or 
as specified in the Clinical Study Agreement, whichever is longer. The Investigator must obtain 
written permission from Calliditas before disposing of any records, even if retention requirements 
have been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, Calliditas should 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another Investigator, another institution, or to Calliditas. 


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11.7 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with Calliditas before any study 
data are submitted for publication. Calliditas reserves the right to deny publication rights until 
mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication are achieved. 
11.8 
Financial Disclosure 
Investigators are required to provide financial disclosure information to Calliditas to permit 
Calliditas to fulfil its obligations under 21 CFR Part 54. In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a period 
of 1 year after the completion of the study. 
11.9 
Insurance and Indemnity 
In accordance with the relevant national regulations, Calliditas has taken out patient liability 
insurance for all patients who have given their consent to the clinical study. This cover is designed 
for the event that a fatality, physical injury, or damage to health occurs during the clinical study’s 
execution. 
11.10 
Legal Aspects 
The clinical study is submitted to the relevant national competent authorities in all participating 
countries to achieve a clinical trial authorization (CTA). 
The study will commence (i.e., initiation of study centers) when the CTA and favorable Ethics 
opinion have been received.  


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12 
STUDY ADMINISTRATIVE INFORMATION 
12.1 
Protocol Amendments 
Any amendments to the study protocol will be communicated to the Investigators by Medpace or 
Calliditas. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
IRB/IEC, unless immediate implementation of the change is necessary for patient safety. In this 
case, the situation must be documented and reported to the IRB/IEC within 5 working days. 
 
 


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13 
REFERENCES
 
1. 
Schena FP and Pesce F. Epidemiology and ancestral difference. In: Kar Neng Lai 
editor(s). Recent advances in IgA nephropathy. Singapore: World Scientific, 2009:9-19. 
2. 
Donadio JV, Bergstralh EJ, Grande JP, Rademcher DM. Proteinuria patterns and their 
association with subsequent end-stage renal disease in IgA nephropathy. Nephrol Dial 
Transplant. 2002;17(7):1197-1203. 
3. 
Moriyama T, Tanaka K, Iwasaki C, et al. Prognosis in IgA nephropathy: 30-year analysis 
of 1,012 patients at a single center in Japan. PLoS One. 2014;9(3):e91756. 
4. 
Vecchio M, Bonerba B, Palmer SC, et al. Immunosuppressive agents for treating IgA 
nephropathy. Cochrane Database Syst Rev. 2015;(8):CD003965. 
5. 
Lai KN, Leung JC, Tang SC. Recent advances in the understanding and management of 
IgA nephropathy. F1000Res. 2016;5:161. 
6. 
Donadio JV, Grande JP. IgA nephropathy. N Engl J Med. 2002;347(10):738-748. 
7. 
Alamartine E, Sabatier JC, Guerin C, Berliet JM, Berthoux F. Prognostic factors in 
mesangial IgA glomerulonephritis: an extensive study with univariate and multivariate 
analyses. Am J Kidney Dis. 1991;18(1):12-19. 
8. 
Gallo GR, Katafuchi R, Neelakantappa K, Baldwin DS. Prognostic pathologic markers in 
IgA nephropathy. Am J Kidney Dis. 1988;12(5):362-365. 
9. 
Manno C, Strippoli GF, D’Altri C, Torres D, Rossini M, Schena FP. A novel simpler 
histological classification for renal survival in IgA nephropathy: a retrospective study. 
Am J Kidney Dis. 2007;49(6):763-775. 
10. 
Neelakantappa K, Gallo GR, Baldwin DS. Proteinuria in IgA nephropathy. Kidney Int. 
1988;33(3):716-721. 
11. 
Galla JH. IgA nephropathy. Kidney Int. 1995;47(2):377-387. 
12. 
Aucella F, Netti GS, Piemontese M, Cincione IR, Infante B, Gesualdo L. Proteinuria in 
the prognosis of IgA nephropathy. Minerva Urol Nefrol. 2009;61(3):235-248. 
13. 
Floege J and Eitner F. Current therapy for IgA nephropathy. J Am Soc Nephrol. 
2011;22(10):1785-1794. 
14. 
Wyatt RJ and Julian BA. IgA nephropathy. N Engl J Med. 2013;368(25):2402-2414. 
15. 
Kiryluk K, Li Y, Scolari F, et al. Discovery of new risk loci for IgA nephropathy 
implicates genes involved in immunity against intestinal pathogens. Nat Genet. 
2014;46(11):1187-1196.  
16. 
McCarthy DD, Kujawa J, Wilson C, et al. Mice overexpressing BAFF develop a 
commensal flora-dependent, IgA-associated nephropathy. J Clin Invest. 
2011;121(10):3991-4002. 
17. 
Lai KN. Pathogenesis of IgA nephropathy. Nat Rev Nephrol. 2012;8(5):275-283. 
18. 
Suzuki H, Kiryluk K, Novak J, et al. The pathophysiology of IgA nephropathy. J Am Soc 
Nephrol. 2011;22(10):1795-1803.  
19. 
Tomana M, Novak J, Julian BA, Matousovic K, Konecny K, Mestecky J. Circulating 
immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge 
region and antiglycan antibodies. J Clin Invest. 1999;104 (1):73-81.  
20. 
Smith AC, Molyneux K, Feehally J, Barratt J. O-glycosylation of serum IgA1 antibodies 
against mucosal and systemic antigens in IgA nephropathy. J Am Soc Nephrol. 
2006;17(12):3520-3528. 
 


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21. 
Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work 
Group. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Int Suppl. 
2012;2:139-274. 
22 . 
UCERIS® (budesonide) [package insert]. Bridgewater, NJ. Salix Pharmaceuticals. 
November 2016. 
23. 
ENTOCORT® EC (budesonide) [package insert]. Wilmington, DE. AstraZeneca 
Pharmaceuticals LP. December 2011. 
24. 
Nefecon® budesonide modified-release capsules Investigator’s Brochure. 
25. 
PULMICORT RESPULES® (budesonide) [package insert]. Wilmington, DE. 
AstraZeneca Pharmaceuticals LP. October 2016. 
26. 
PULMICORT FLEXHALER® (budesonide) [package insert]. Wilmington, DE. 
AstraZeneca Pharmaceuticals LP. October 2016. 
27. 
Locatelli F, Pozzi C, Andrulli S. IgA nephritis: ACE inhibitors, steroids, both or neither? 
Nephrol Dial Transplant. 2006;21(12):3357-3361. 
28. 
Lv J, Zhang H, Wong MG, et al. Effect of oral methylprednisolone on clinical outcomes 
in patients with IgA nephropathy: the TESTING randomized clinical trial. JAMA. 
2017;318(5):432-442. 
29. 
US Food and Drug Administration. Drug development and drug interactions: table of 
substrates, inhibitors and inducers. https://www.fda.gov/drugs/drug-interactions-
labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-
inducers#table3-2. Accessed 10 June 2020. 
 


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APPENDIX A:  SCHEDULE OF PROCEDURES 
Table 1. 
Schedule of Procedures 
Study Period 
Screening 
Treatment 
Follow-
Up 
Study Visit 
(17a) 
1 
(17b) 
2 
31 
NA 
42 
5 
6 
7 
8 
9 
10/EOS3 
Study Day or Month 
See footnote4 
 
1d 
1m 
3m 
6m 
9m 
9m 
12m 
Visit Window (Days) 
Procedure 
 
 
 
 
 
7 
7 
7 
7 
14-35 days 
after Visit 8 
7 
Visit conducted by telephone 
 
 
 
 
 
X 
 
 
 
 
 
Informed consent (if not yet obtained) 
X 
 
 
 
 
 
 
 
 
 
 
Update demographics and medical/surgical 
history 
X 
 
X 
 
X 
 
 
 
 
 
 
Eligibility criteria assessment 
X 
 
X 
X 
 
 
 
 
 
 
 
Contact IRT to trigger study drug shipment5 
 
 
 
X 
 
 
 
 
 
 
 
Concomitant medications and procedures 
X6 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
AE assessment (incl. AESIs, SAEs) 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
X 
Vital signs7 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
Body weight and height8 
X 
 
 
 
X 
 
 
 
 
 
X 
Hematology (incl. HbA1c)9 
X 
 
X 
 
 
 
X 
X 
X 
X 
X 
Serum chemistry 
(incl. eGFR [CKD-EPI])9,10 
X 
 
X 
 
 
 
X 
X 
X 
X 
X 
HIV, TB, HBV, and HCV11 
X 
 
 
 
 
 
 
 
 
 
 
Drug and alcohol screen (urine) 
X 
 
 
 
 
 
 
 
 
 
 
Fasting lipid profile 
 
 
X 
 
 
 
 
 
 
 
 
Urinalysis12 
X 
 
X 
 
 
 
X 
X 
X 
 
X 
24-hour urine collection (incl. cortisol) 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
Supply 24-hour urine container(s) 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
Pregnancy test13 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
FSH14 
X 
 
 
 
 
 
 
 
 
 
 
Dispense study drug and instruct patient on 
study drug administration 
 
 
 
 
X 
 
X 
X 
 
 
 
Start of study drug15 
 
 
 
 
X 
 
 
 
 
 
 
See footnotes at the end of the Schedule of Procedures table 
 


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Table 1. 
Schedule of Procedures (Continued) 
Study Period 
Screening 
Treatment 
Follow-
Up 
Study Visit 
(17a) 
1 
(17b) 
2 
31 
NA 
42 
5 
6 
7 
8 
9 
10/EOS3 
Study Day or Month 
See footnote4 
 
1d 
1m 
3m 
6m 
9m 
9m 
12m 
Visit Window (Days) 
Procedure 
 
 
 
 
 
7 
7 
7 
7 
14-35 days 
after Visit 8 
7 
Begin 2-week Tapering Period16 
 
 
 
 
 
 
 
 
X 
 
 
Collect study drug from previous visit 
 
 
 
 
 
 
X 
X 
X 
 
X 
Study drug accountability and compliance 
assessment17 
 
 
 
 
 
X 
X 
X 
X 
 
X 
SF-36 QoL assessment 
X 
 
 
 
 
 
 
 
 
 
X 
Capture dialysis or kidney transplant 
 
 
 
 
X 
X 
X 
X 
X 
 
X 
Dietary and lifestyle recommendations18 
X 
 
 
 
 
 
 
 
 
 
 
Note: Prior to conducting any study-related activities, the current, approved Informed Consent Form must be signed and dated by the patient. 
1. 
Patients will be required to fast for at least 10 hours prior to Study Visit 3. 
2. 
Study Visit 4 must occur within 4 weeks after Study Visit 3. 
3. 
See Section 4.3 for additional details related to withdrawal criteria. For patients who are withdrawn from the study, the End of Study Visit procedures will be completed, if 
possible, at the time the decision is made to withdraw the patient. The End of Study Visit will consist of all of the Study Visit 10 procedures. 
4. 
Preferably, Visit 17a in Study Nef-301 should be combined with Visit 1 in Study Nef-301 OLE. If the visits are combined, procedures do not need to be duplicated. If the 
visits are not combined, Visit 3 in Study Nef-301 OLE must occur within 3 months after Visit 17b in Study Nef-301. Preferably, Visit 17b in Study Nef-301 should be 
combined with Visit 2 in Study Nef-301 OLE. If the visits are not combined, Study Visit 2 must occur within 2 weeks after Study Visit 1. Study Visit 3 must occur 2 to 
4 weeks, inclusive, after Study Visit 2 in order to collect the second proteinuria measurement to determine eligibility. 
5. 
After confirming all eligibility criteria (laboratory values from Study Visits 1, 2, 3, etc.) (eGFR values from Study Visits 1 or 3 must be 30 mL/min per 1.73 m2 for the 
patient to be eligible), IRT will trigger the first shipment of study drug to the site for the patient. Following initial shipment, there will be an automatic resupply of study drug 
to the site for dispensing to the patient at Study Visits 6 and 7. 
6. 
Medications taken within 3 months prior to Study Visit 1 and concomitant medications and therapies will be recorded in the eCRFs. 
7. 
Vital sign measurements will include systolic and diastolic blood pressure and heart rate. Blood pressure and heart rate will be measured after resting in the supine position for 
at least 5 minutes. At Study Visits 1 and 3, blood pressure and heart rate will be measured up to 3 times with each measurement separated by 1 minute (the lowest value will 
be recorded on the eCRF). 
8. 
Height will only be collected at Study Visit 1. 
9. 
See Appendix B for the complete list of analytes. 
10. The central laboratory will calculate the eGFR using the CKD-EPI formula. 
11. If the patient is rescreened, HBV, HCV, HIV, and TB screenings should not be repeated if done as part of the study within the last 12 months. 
12. A fresh urine sample will be collected for the urinalysis, and in addition urine will be assessed by dipstick. See Appendix B for the complete list of analytes. 
13. For women of childbearing potential only. A serum pregnancy test will only be performed at Study Visit 1. A pregnancy test via a local urine assessment will be performed at 
all other applicable study visits. 
14. Postmenopausal women will have a confirmatory FSH test performed at Study Visit 1. 
15. Patients must take the first dose of study drug in the presence of site staff during Study Visit 4. As a result, the first dose of study drug may be administered at any time of day 
and without regard to the timing of meals. Patients may self-dose for all other doses of study drug and should take study drug in the morning at least 1 hour before breakfast. 


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16. During the 2-week Tapering Period, the daily dose of study drug will be reduced from 4 capsules QD (Nefecon 16 mg) to 2 capsules QD (Nefecon 8 mg). Patients who have 
their daily dose of study drug reduced to 2 capsules QD (Nefecon 8 mg) due to safety and/or tolerability reasons during the 9-month Treatment Period will remain on this dose 
during the 2-week Tapering Period. 
17. Only treatment compliance will be assessed during study visits conducted by telephone. 
18. The following lifestyle choices should be recommended to the patient: weight normalization, smoking cessation, physical activity, and diet (low salt and low protein). Patients 
should be encouraged to maintain stable lifestyle choices while participating in the study. 
AE = adverse event; AESI = adverse event of special interest; CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; d = day(s); eCRF = electronic case report form; 
eGFR = estimated glomerular filtration rate; EOS = End of Study; FSH = follicle-stimulating hormone; HbA1c = hemoglobin A1c; HBV = hepatitis B virus; 
HCV = hepatitis C virus; HIV = human immunodeficiency virus; incl. = including; IRT = Interactive Response Technology; m = month(s); NA = not applicable; OLE = open-label 
extension; QD = once per day; QoL = quality of life; SAE = serious adverse event; SF-36 = Short Form 36; TB = tuberculosis. 
 


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APPENDIX B:  CLINICAL LABORATORY ANALYTES 
Standard Safety Chemistry Panel [1] 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase 
Amylase 
Aspartate aminotransferase (AST) 
Blood urea nitrogen (BUN) 
Calcium 
Creatine kinase 
Creatinine 
Estimated glomerular filtration rate (eGFR) [2] 
Gamma-glutamyl transferase (GGT) 
Glucose (fasting), only at Study Visit 3 
Inorganic phosphorus 
Lactate dehydrogenase 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Uric acid 
 
1. The chemistry panel will be assessed under fasting conditions at Study Visit 3 and 
non-fasting conditions for all other applicable study visits. 
2. Calculated by the central laboratory using the following:  
a. Chronic Kidney Disease Epidemiology Collaboration formula (eGFR = 141  
min(SCr/K, 1)α  max(SCr/K, 1)-1.209  0.993Age  1.018[if female]  1.159[if 
black] where SCr is standardized serum creatinine in mg/dL, K is 0.7 for females 
and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the 
minimum of SCr/K or 1, and max indicates the maximum of SCr/K or 1).1 
 
Fasting Lipid Panel 
High-density lipoprotein (HDL) 
cholesterol 
Low-density lipoprotein (LDL) 
cholesterol [1] 
Total cholesterol 
Total triglyceride 
1. Assessed as follows by the Friedewald calculation: 
a. Conventional units (mg/dL) LDL cholesterol = Total cholesterol – HDL 
cholesterol - triglycerides/5, or 
b. International System of Units (mmol/L) LDL cholesterol = Total 
cholesterol – HDL cholesterol – triglycerides/2.2.2 
 
Endocrinology 
Follicle-stimulating hormone (FSH) [1] 
 
1. Postmenopausal is defined as amenorrhoeic for at least 1 year AND, if aged under 
60 years, have a serum follicle-stimulating hormone level of at least 30 IU/L. 
 
Additional Serology 
Tuberculosis (TB) 
Human immunodeficiency virus (HIV) 
Hepatitis B virus (HBV) 
Hepatitis C virus (HCV) 
 
 
 
 


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Hematology 
Hematocrit 
Hemoglobin 
Platelets 
Red blood cell count 
White blood cell count and differential [1] 
 
1. Manual microscopic review is performed only if white blood cell count 
and/or differential values are out of reference range. 
 
Additional Hematology 
Glycosylated hemoglobin (HbA1c) 
 
 
Urinalysis (Freshly Voided Urine) 
Assessed by Dipstick 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
Assessed by Chemical Assay 
Albumin 
Creatinine 
Protein 
Sodium 
 
Urine Screen (Freshly Voided Urine) 
Alcohol 
Amphetamines 
Cannabinoids 
Cocaine 
Ecstasy 
Methamphetamine 
Opiates 
Oxycodone 
 
24-Hour Urine Analysis 
Creatinine clearance 
Total albumin 
Total cortisol 
Total creatinine 
Total protein 
Urine albumin to creatinine ratio (UACR) 
Urine protein to creatinine ratio (UPCR) 
 
 
Sources: 
1. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern 
Med. 2009;150(9):604-612. 
2. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein 
cholesterol in plasma, without use of the preparative centrifuge. Clin Chem. 1972;18(6): 499-502. 


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APPENDIX C:  RENIN-ANGIOTENSIN SYSTEM INHIBITOR AND 
OTHER ANTIHYPERTENSIVE THERAPY RECOMMENDATIONS 
ACCORDING TO THE 2012 KIDNEY DISEASE: IMPROVING GLOBAL 
OUTCOMES GUIDELINES 
Patients must continue on a stable dose of renin-angiotensin system (RAS) inhibitor therapy 
(angiotensin-converting enzyme inhibitors [ACEIs] and/or angiotensin II type I receptor blockers 
[ARBs]) at the maximum allowed dose or maximum tolerated dose according to the 2012 Kidney 
Disease: Improving Global Outcomes (KDIGO) guidelines.1 A stable dose is defined as a dose 
within 25% of the dose at Visit 17a or 17b in Study Nef-301.  
The following are recommendations for optimization and maintenance of RAS/antihypertensive 
therapy that are in line with the 2012 KDIGO guidelines1 and should be followed throughout the 
study: 
 Antihypertensive therapy is recommended to achieve a target systolic blood pressure 
<125 mmHg and target diastolic blood pressure <75 mmHg. Antiproteinuric therapy should 
be used to try to achieve a target proteinuria level <1 g/day. Antihypertensive therapy in these 
patients will follow current clinical guidelines; 
 ACEIs are recommended as a first-line therapy and increased to the maximum tolerated daily 
dose (not to exceed the maximum recommended daily dose) depending on the degree of arterial 
hypertension and proteinuria. Patients can be converted to an ARB when ACEIs are not 
tolerated. Combination ACEI and ARB therapy is discouraged, but may be used at the 
discretion of the Investigator. If combination therapy is used, the stable dose should be based 
on the maximum tolerated dose rather than the maximum allowed dose; 
 In patients who do not tolerate ACEIs or ARBs, other antihypertensive treatments may be used 
according to local treatment guidelines to achieve the target blood pressure. Study centers are 
not limited to the use of specific compounds; 
 Antihypertensive therapy with other agents including diuretics, aldosterone agonists, calcium 
channel blockers, and β-blockers may be maintained or added according to the 2012 KDIGO 
guidelines and the clinical guideline of the individual study center in order to achieve the target 
blood pressure;1  
 In the case of hypotension, withdrawal of other antihypertensive (non-ACEI/non-ARB) 
medications should be considered as the first alternative; and  
 In the case of hypertension, addition or dose increase of other antihypertensive 
(non-ACEI/non-ARB) medications, as recommended by the 2012 KDIGO guidelines, should 
be considered.1  
Source: 
1. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO Clinical 
Practice Guideline for Glomerulonephritis. Kidney Int Suppl. 2012;2:139-274. 


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APPENDIX D:  RECOMMENDATIONS FOR DEFINING MEDIUM- OR 
HIGH-RISK OSTEOPOROSIS 
 
Source: Grossman JM, Gordon R., Ranganath VK, et al. American College of Rheumatology 2010 recommendations for the 
prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Car Res (Hoboken). 2010;62(11):1515-1526. 
 
For patients in China, the medium- or high-risk category is defined according to the Osteoporosis 
Self-Assessment Tool for Asians (OSTA) index: 
 OSTA index = (Weight [kg] – Age [year]) × 0.2 
 High-risk subgroup = index < -4 
 Intermediate-risk subgroup = index -1 to -4 
 Low-risk subgroup = index > -1 
Source: Koh LK, Sedrine WB, Torralba TP, et al. A simple tool to identify asian women at increased risk of osteoporosis. 
Osteoporos Int. 2001;12(8):699-705. 
 


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APPENDIX E:  IMMUNOSUPPRESSIVE DRUGS OTHER THAN 
GLUCOCORTICOIDS 
Systemic immunosuppressive drugs (including glucocorticoids) are prohibited during the 
study. Systemic immunosuppressive drugs will include, but will not be limited to the 
following: 
Azathioprine 
Calcineurin inhibitors (e.g., cyclosporin, tacrolimus) 
Cyclophosphamide 
Mycophenolate mofetil 
Rituximab 
Herbs for medicinal use, including Eastern herbs 
and Eastern traditional medicines, with a known 
effect on the immune system (e.g., Tripterygium 
wilfordii or ginseng) 
 
Hydroxychloroquine