Clinical trial NCT03643965
Conditions: Primary IgA Nephropathy
Keywords: IgA Nephropathy
Sponsor: Calliditas Therapeutics AB
Start date: 2018-09-05; Completion date: 2023-07-10
Enrollment: 365 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The overall aim of the study is to evaluate the efficacy, safety, and tolerability of Nefecon 16 mg per day in the treatment of patients with primary IgAN (Immunoglobulin A nephropathy) at risk of progressing to end-stage renal disease (ESRD), despite maximum tolerated treatment with renin-angiotensin system (RAS) blockade using angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II type I receptor blockers (ARBs).

Detailed description:
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy, safety, and tolerability of oral Nefecon compared to matching placebo in patients with primary IgAN on a background of optimized RAS inhibitor therapy. The study will consist of 2 parts, Part A and Part B. Part A will include a 9 month blinded Treatment Period, and a 3-month Follow up Period. Part B of the study will consist of a 12-month observational Follow up Period; no study drug will be administered during Part B. Part A and B will be blinded. Safety will be monitored by an independent Data Safety Monitoring Board.

Arms: arm 1: Nefecon 16 mg once daily by mouth for 9 months. arm 2: Placebo oral capsule once daily by mouth for 9 months.
Interventions: intervention 1: Nefecon intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: Nefecon 16 mg for daily administration by mouth for 9 months. intervention 2: Placebo capsules for daily administration by mouth for 9 months.

Protocol documents:
Prot_SAP_000.pdf: 
 
CLINICAL STUDY PROTOCOL  
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED 
STUDY TO EVALUATE EFFICACY AND SAFETY OF 
NEFECON IN PATIENTS WITH PRIMARY IGA 
NEPHROPATHY AT RISK OF PROGRESSING TO END-STAGE 
RENAL DISEASE (NefIgArd) 
 
Investigational Product: Nefecon (budesonide modified-release capsules) 
Protocol Number: Nef-301 
EudraCT Number: 2017-004902-16 
IND Number: 107950 
NCT Number: 03643965 
 
Sponsor: 
Calliditas Therapeutics AB 
Kungsbron 1 
SE-111 22 Stockholm, Sweden 
Telephone: +46 8 411 3005 
 
Version Number: 5.0  
(global amendment that includes Version 1.0, 16 January 2018; Version 1.1, 24 January 2018; 
Version 1.2, 16 March 2018; Version 1.3, 08 June 2018 [Czech Republic only]; 
Version 1.4, 08 November 2018; Version 2.0, 02 January 2019; Version 3.0, 19 December 2019; 
and Version 4.0, 28 April 2020 [US and Europe only]) 
 
Date: 14 January 2021 
 
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. 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
2
SIGNATURE PAGE  
STUDY TITLE: A Randomized, Double-Blind, Placebo Controlled Study to Evaluate 
Efficacy and Safety of Nefecon in Patients with Primary IgA Nephropathy at Risk of 
Progressing to End-Stage Renal Disease (NefIgArd) 
 
We, the undersigned, have read this protocol and agree that it contains all necessary information 
required to conduct the study. 
Signature 
 
 
 
 
 
 
 
Date 
 
Richard Philipson, MD 
Chief Medical Officer 
Calliditas Therapeutics AB 
 
Bernard Ilson, MD 
Vice President, Medical Department 
Medpace, Inc. 
 
Piotr Krzeski, MD, PhD 
Vice President, Medical Department 
Medpace, Inc. 
 
Ajay Srivastava, MD, FASN 
Senior Medical Director 
Medpace, Inc. 
 
Ruiqi (Rachel) Liu, PhD 
Biostatistician 
Medpace, Inc. 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
3
INTERNATIONAL COORDINATING INVESTIGATOR SIGNATURE 
PAGE  
STUDY TITLE: A Randomized, Double-Blind, Placebo Controlled Study to Evaluate 
Efficacy and Safety of Nefecon in Patients with Primary IgA Nephropathy at Risk of 
Progressing to End-Stage Renal Disease (NefIgArd) 
 
I, the undersigned, have read this protocol and agree that it contains all necessary information 
required to conduct the study. 
Signature 
 
 
 
 
 
 
 
Date 
 
Bengt Fellström, MD, PhD 
Senior Professor of Nephrology 
Uppsala University Hospital, Sweden 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
4
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 
 
 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
5
SYNOPSIS  
TITLE:  A Randomized, Double-Blind, Placebo Controlled Study to Evaluate Efficacy and 
Safety of Nefecon in Patients with Primary IgA Nephropathy at Risk of Progressing to End-Stage 
Renal Disease (NefIgArd) 
PROTOCOL NUMBER:  Nef-301 
EudraCT NUMBER:  2017-004902-16 
INVESTIGATIONAL PRODUCT:  Nefecon (budesonide modified-release capsules) 
PHASE:  3 
INDICATION:  Treatment of primary immunoglobulin A nephropathy (IgAN) 
OBJECTIVES: 
The overall aim of the study is to evaluate the efficacy, safety, and tolerability of Nefecon 16 mg 
per day in the treatment of patients with primary IgAN at risk of progressing to end-stage renal 
disease (ESRD), despite maximum tolerated treatment with renin-angiotensin system (RAS) 
blockade using angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type I receptor 
blockers (ARBs). 
Primary Objectives: 
Part A 
The primary objective of Part A is to assess the effect of Nefecon 16 mg treatment on urine protein 
to creatinine ratio (UPCR) over 9 months compared to placebo. 
Part B 
The primary objective of Part B is to assess the effect of the Nefecon 16 mg treatment given in 
Part A on clinical consequences of any proteinuria reduction as measured by estimated glomerular 
filtration rate (eGFR) recorded over 2 years compared to placebo. 
Secondary Objectives: 
Part A 
The secondary objectives of Part A are: 
 To assess the effect of Nefecon 16 mg treatment on eGFR at 9 and 12 months compared to 
placebo, and 
 To evaluate additional aspects of renal function, and safety and tolerability of Nefecon 16 mg 
treatment over 9 months compared to placebo. 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
6
Part B 
The secondary objectives of Part B are to assess the effects of the Nefecon 16 mg treatment given 
in Part A on different aspects of renal function and safety compared to placebo over 2 years. 
POPULATION: 
The population for this study is patients 18 years of age, diagnosed with IgAN with biopsy 
verification within the 10 years prior to screening, on a stable dose of RAS inhibitor therapy for 
the 3 months prior to randomization, eGFR 35 mL/min per 1.73 m2 and 90 mL/min per 1.73 m2
using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, and 
proteinuria based on 2 consecutive measurements separated by at least 2 weeks and calculated by 
the central laboratory showing either 1 g per day (1000 mg per day) in 2 consecutive 
measurements or UPCR 0.8 g/gram (90 mg/mmol) in 2 consecutive measurements. Patients 
will be excluded from the study if they have undergone a kidney transplant; have liver cirrhosis, 
as assessed by the Investigator; have poorly controlled type 1 or type 2 diabetes mellitus; have 
history of unstable angina, class III or IV congestive heart failure, and/or clinically significant 
arrhythmia, as judged by the Investigator; have unacceptable blood pressure control; have known 
osteoporosis in medium- or high-risk category; have known glaucoma, known cataract(s), and/or 
history of cataract surgery, unless the surgery was performed on both eyes; have been treated with 
systemic immunosuppressive medications, other than glucocorticoids (GCSs), within the 
12 months before randomization; have been treated with any systemic GCSs within the 3 months
before randomization; have been treated with any systemic GCSs within the 12 months before 
randomization 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; or are taking potent inhibitors of 
cytochrome P450 3A4. 
STUDY DESIGN AND DURATION: 
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter study to evaluate the 
efficacy, safety, and tolerability of oral Nefecon compared to matching placebo in patients with 
primary IgAN on a background of optimized RAS inhibitor therapy. Approximately 360 patients 
will be randomized at approximately 160 sites in Europe, North America, South America, Asia 
Pacific, and China. The study will consist of 2 parts, Part A and Part B. Part A will include a 
Screening Period (up to 35 days) followed by a 9-month blinded Treatment Period, and a 3-month 
Follow-up Period (including a 2-week Tapering Period). The total duration of Part A is up to 
13.5 months. 
Part B will consist of a 12-month (+14 to 35 days) observational Follow-up Period after Part A 
has ended. Each patient randomized will be followed for 25 months after the first dose (or, if the 
patient randomized does not receive any study drug, 25 months after the patient is randomized). 
The total duration of the study is up to 26.5 months (including the Screening Period and a final 
visit for replicate eGFR sampling at 2 years). Part A will be blinded, and the blinding will remain 
in place throughout Part B. No study drug will be administered during Part B. The primary analysis 
in Part B will occur 25 months after the 360th/last patient is dosed (or, if the 360th/last patient 
randomized does not receive any study drug, 25 months after the 360th/last patient is randomized). 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
7
Part A 
In order to be eligible for randomization, patients must be 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 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for at 
least 3 months prior to randomization. A stable dose is defined as doses within 25% of the dose at 
randomization. Patients should remain on their regimens of RAS inhibitors for the whole duration 
of the study (Part A and Part B). It is recommended that patients achieve a target systolic blood 
pressure <125 mmHg and target diastolic blood pressure <75 mmHg according to the 
2012 KDIGO guidelines. The use of additional antihypertensive therapy will be permitted as 
needed. Investigators should ensure that patients are informed at screening of potentially 
beneficial lifestyle choices including weight normalization, smoking cessation, physical activity, 
and diet (low salt and low protein). Patients must, after informed consent, have 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 (baseline will be the geometric mean of 
these 2 measurements).  
Both samples of the same parameter must show either of the following: 
 Proteinuria 1 g per day (1000 mg per day) in 2 consecutive measurements, or 
 UPCR 0.8 g/gram (90 mg/mmol) in 2 consecutive measurements. 
Additionally, all other eligibility criteria must be met in order to be eligible for randomization.  
After confirming all eligibility criteria, patients will be randomized in a 1:1 ratio to Nefecon 16 mg 
or placebo within 35 days of Study Visit 1 (screening). The study will be double-blinded, and 
randomization will be stratified according to baseline proteinuria, eGFR, and geographic region. 
Randomized patients will receive either Nefecon 16 mg (four 4 mg budesonide modified-release 
capsules once per day [QD]) or placebo (4 matching capsules QD) for a 9-month Treatment 
Period.  
Following completion of the Treatment Period, patients will enter the 3-month Part A 
Follow-up Period. The first 2 weeks of this Follow-up Period will consist of a 2-week Tapering 
Period to reduce the risk of insufficiency of the adrenal glands. During the 2-week Tapering 
Period, the study drug dose will be reduced from 4 capsules QD (Nefecon 16 mg or placebo) to 
2 capsules QD (Nefecon 8 mg or placebo). 
Patients will discontinue study drug at the end of the Tapering Period and then complete the 
remainder of the Part A Follow-up Period before entering Part B. 
Patients who prematurely discontinue study drug during the Treatment Period should complete 
the 2-week Tapering Period, if feasible, to prevent insufficiency of the adrenal glands. All patients 
who prematurely discontinue study drug should have eGFR, proteinuria, and creatinine measured 
at each scheduled visit; it is of particular importance for the 9- and 12-month study visits (Study 
Visits 11 and 13). All patients who prematurely discontinue study drug should also subsequently 
enter Part B of the study and continue to have eGFR, proteinuria, and creatinine measured unless 
they have withdrawn their consent to any kind of follow-up. In the case of patients who are 
randomized but do not receive any study drug, they should have eGFR, proteinuria, and creatinine 
measured at each scheduled visit; it is of particular importance for the 9- and 12-month study visits 
(Study Visits 11 and 13). They should also subsequently enter Part B of the study and continue to 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
8
have eGFR, proteinuria, and creatinine measured unless they have withdrawn their consent to any 
kind of follow-up. 
Part B 
Part B of the study will consist of a 12-month (+14 to 35 days) observational Follow-up Period; 
no study drug will be administered during Part B. Each patient randomized will be followed for 
25 months after the first dose (or, if the patient randomized does not receive any study drug, 
25 months after the patient is randomized). Following completion of Part A, patients will remain 
on their optimized RAS inhibitor/antihypertensive therapy and continue into Part B of the study. 
During Part B, the Investigator may consider that rescue medication (steroids and/or 
immunosuppressive treatment) may be needed. Such treatment can be initiated by the Investigator; 
however, patients should have a proteinuria level at least above 1 g per 24 hours, as suggested in 
the 2012 KDIGO guidelines, and the Medical Monitor should be consulted for advice. 
During Part B of the study, patients will complete onsite study visits at 18 and 24 months, 
including a final visit for replicate eGFR sampling at 14 to 35 days after the 24-month visit. 
Telephone contacts will be performed between the onsite study visits at 15 and 21 months. The 
measurements of eGFR, proteinuria, and creatinine will continue in Part B. Additional telephone 
contacts and/or unscheduled study visits can be made as needed.  
Part B will continue until 25 months after the 360th/last patient is dosed (or, if the 360th/last patient 
randomized does not receive any study drug, 25 months after the 360th/last patient is randomized).
Patients who receive rescue medication should continue in the study and complete all study 
procedures as indicated in the Schedule of Procedures table. Patients will be followed until 
initiation of dialysis, undergoing renal transplantation, death, or study completion (i.e., maximum 
of 25.5 months after the first dose [or, if the patient randomized does not receive any study drug, 
25.5 months after the patient is randomized]), whichever occurs first. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
Nefecon 16 mg (four 4 mg budesonide modified-release capsules QD) or placebo (4 matching 
capsules QD) will be administered orally for 9 months (or up to 10 months, when applicable, due 
to the Coronavirus Disease 2019 [Covid-19] pandemic) during the Treatment Period in Part A. 
Patients must take the first dose of study drug (Nefecon 16 mg or placebo) in the presence of site 
staff during Study Visit 4 within 10 days after their randomization. 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 
approximately 1 hour before breakfast. 
The daily dose of double-blinded study drug may be reduced from 4 capsules QD (Nefecon 16 mg 
or placebo) to 2 capsules QD (Nefecon 8 mg or placebo) if clinically relevant adverse events (AEs) 
develop 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 daily dose of study drug 
during the first 9 months (or up to 10 months, when applicable, due to the Covid-19 pandemic) of 
treatment (Treatment Period in Part A). If a dose reduction is made during this time, then the dose 
should not be increased back to 4 capsules QD (Nefecon 16 mg or placebo). 
After completing 9 months (or up to 10 months, when applicable, due to the Covid-19 pandemic) 
of study drug treatment, the daily dose of study drug will be reduced from 4 capsules QD 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
9
(Nefecon 16 mg or placebo) to 2 capsules QD (Nefecon 8 mg or placebo) for 2 weeks to prevent 
insufficiency of the adrenal glands (Tapering Period in Part A). Patients who have their daily dose 
of study drug reduced to 2 capsules QD (Nefecon 8 mg or placebo) due to safety and/or tolerability 
reasons during the first 9 months (or up to 10 months, when applicable, due to the Covid-19
pandemic) of treatment (Treatment Period in Part A), will remain on this dose of study drug for 
an additional 2 weeks after completing 9 months (or up to 10 months, when applicable, due to the 
Covid-19 pandemic) of study drug treatment (during the Tapering Period in Part A). Patients who 
prematurely discontinue study drug treatment while taking 4 capsules QD (Nefecon 16 mg or 
placebo), should have the daily dose of study drug reduced to 2 capsules QD (Nefecon 8 mg or 
placebo) for 2 weeks, if feasible, to prevent insufficiency of the adrenal glands. 
EFFICACY VARIABLES:  
Part A Analysis 
The data cut-off for the Part A analysis will occur once the first 201 patients randomized have had 
the opportunity to complete their 9-month visit. Therefore, it is expected the data cut-off will occur 
at the latest 9.5 months after the 201st patient randomized is dosed. 
The dataset extracted from the database, and cleaned for analysis, will include all safety data from 
all patients randomized at the data cut-off date and all efficacy data up to and including the 
12-month visit from all patients randomized at the data cut-off date. Therefore, any efficacy data 
recorded after 12 months will not be extracted from the database. 
Part A Analysis Primary Efficacy Endpoint 
The primary efficacy endpoint for the Part A analysis is defined as the ratio of UPCR (based on 
24-hour urine collections) at 9 months following the first dose of study drug compared to baseline. 
Part A Analysis Secondary Efficacy Endpoints 
The secondary efficacy endpoints for the Part A analysis are: 
 Ratio of eGFR at 9 and 12 months compared to baseline calculated using the CKD-EPI 
formula, and 
Note: A supportive analysis of 1-year eGFR slope will also be performed. 
 Ratio of urine albumin to creatinine ratio (UACR) at 9 months compared to baseline. 
Supportive analyses of the above endpoints will also be performed at all time points up to 
12 months to describe the time course of effect. 
Part B Analysis 
The Part B analysis will be performed when the 360th/last patient randomized has had the 
opportunity to complete Visit 17b, which can occur up to 35 days after Visit 17a (the 24-month 
visit). 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
10
Part B Analysis Primary Efficacy Endpoint 
The primary efficacy endpoint for the Part B analysis is an area under the curve (AUC)-based 
endpoint of eGFR calculated as a time-weighted average of eGFR recordings observed at each 
time point over 2 years. The eGFR (CKD-EPI) at 2 years (which must be repeated to provide a 
second value obtained within 14 to 35 days) will be the geometric mean of the 2 assessments. A 
supportive analysis of 2-year eGFR slope will also be performed. 
Part B Analysis Secondary Efficacy Endpoints 
The secondary efficacy endpoints for the Part B analysis are: 
 Time to 30% reduction from baseline in eGFR (CKD-EPI) confirmed by a second value, with 
4 weeks of separation between the 2 sampling time points; 
 Time from the first dose of study drug until receiving rescue medication; 
 Ratio of UPCR, UACR, and eGFR (CKD-EPI) compared to baseline averaged over time 
points between 12 and 24 months, inclusive, following the first dose of study drug; 
 Proportion of patients without microhematuria in at least 2 of the following time points: 12, 18, 
and 24 months following the first dose of study drug; 
 Proportion of patients receiving rescue treatment; and 
 Short Form 36 (SF-36) quality of life assessment at 9 and 24 months. 
Part B Analysis Exploratory Efficacy Endpoints 
Exploratory analyses may be performed on blood and urine to explore potential changes between 
the treatment groups that may add to the understanding of the disease mechanism and how the 
treatment influences these mechanisms. In addition, already existing kidney biopsy samples will 
be collected for exploratory analyses at a central reading unit. Participation and sample shipment 
for exploratory analyses will be optional. 
SAFETY VARIABLES: 
The safety variables will include the following: 
 Treatment-emergent AEs, defined as AEs that occur for the first time after dosing with study 
drug, or exist before but worsen in severity or relationship to study drug after dosing; 
 AEs of special interest (AESIs) (severe infections 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); and 
 Vital signs, body weight, clinical laboratory variables, and physical examination findings. 
STATISTICAL ANALYSES: 
The primary efficacy analyses will be based on the Full Analysis Set (FAS), which will include
all randomized patients, regardless of whether the patient received study drug. For Part A, the FAS 
will include the first 201 patients randomized. The data cut-off for the Part A analysis will occur 
once the first 201 patients randomized have had the opportunity to complete their 9-month visit.


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
11
Therefore, it is expected the data cut-off will occur at the latest 9.5 months after the 201st patient 
randomized is dosed. Two patients are excluded from the Part A FAS due to errors in 
randomization; this decision was pre-defined in the Statistical Analysis Plan prior to unblinding.
Baseline proteinuria, eGFR, UPCR, and UACR will be the geometric mean of the 2 consecutive 
measurements prior to randomization. 
The protocol requires that all randomized patients continue to have assessments performed at each 
scheduled visit regardless of whether they prematurely discontinue study drug or even if they are
randomized but do not receive any study drug. However, any data recorded after a patient receives 
rescue medication will be excluded from the primary efficacy analyses in Parts A and B so that 
the underlying effect of Nefecon can be estimated free from the confounding effects of rescue 
medication. 
The primary efficacy endpoint for the Part B analysis is an AUC-based endpoint calculated as a 
time-weighted average of eGFR (CKD-EPI) measurements recorded over 2 years, where each 
time point is given a weight in proportion to the time elapsing from the previous recording. 
Therefore, recordings made at 18 and 24 months receive twice as much weight as those made at 
3, 6, 9, and 12 months. The weights will sum to one so that the treatment effect can be interpreted 
as the average effect of Nefecon over 2 years. 
The eGFR data will be log-transformed prior to analysis. Data included at baseline and 24 months 
will be the log of the geometric mean of the 2 replicate values recorded at each time point, 
respectively. Previous eGFR data from Nefecon trials suggest it is possible there will be a small 
sub-population of patients with extreme outlying data resulting from very rapid progression of 
disease. Therefore, the primary analysis will be based on a Robust Regression of each patient’s 
AUC having multiply imputed missing data. 
The primary efficacy endpoint for the Part A analysis, the ratio of UPCR at 9 months to baseline,
will be log-transformed prior to analysis, as will data from the other time points used in the 
analysis model. The primary analysis of the log-transformed baseline ratios in UPCR will be 
analyzed using a Mixed Model Repeated Measures analysis based on the FAS and incorporating 
UPCR data from baseline, 3 months, 6 months, 9 months, and 12 months.   
A multiplicity strategy will be used to control type I error amongst the primary and key secondary 
efficacy endpoints across both Part A and Part B.  
The Safety Analysis Set will include all patients who receive at least 1 dose of study drug. For 
both Part A and Part B, 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 and AESIs will be summarized 
by body system and organ class. 
SAMPLE SIZE DETERMINATION: 
Part A Analysis 
The Nefecon Phase 2b study (Nef-202) gave an estimated standard deviation of 0.59 for the change 
in the log of UPCR from baseline after 9 months of treatment. Based on this assumption, 
200 patients in Part A will provide >90% power to demonstrate statistical significance at a 1-sided 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
12
alpha level of 0.025 given a true 25% relative reduction in UPCR with Nefecon treatment 
compared to placebo. 
Part B Analysis 
A 28% reduction in UPCR, relative to placebo, was observed with the 16 mg dose of Nefecon in 
the Phase 2b study. Based on an analysis of the relationship between treatment effects on 
proteinuria at 1 year and the 2-year eGFR slope using aggregate data for trials in IgAN presented 
at the March 2018 NKF/FDA/EMA workshop Change in Albuminuria and GFR as End Points for 
Clinical Trials in Early Stages of Chronic Kidney Disease, a 28% reduction in UPCR is predicted 
to translate into a treatment effect of 1.12 mL/min/1.73 m2/year on 2-year eGFR slope, and hence, 
a 2.24 mL/min/1.73 m2 treatment effect for the difference in mean eGFR at 2 years. If 360 patients 
are recruited and followed for 2 years, and replicate values of eGFR are recorded both at baseline 
and at 2 years, Part B will have 90% power to detect a statistically significant difference in eGFR 
at 2 years, using a 2-sided alpha of 5%, if the true effect of Nefecon is 2.24 mL/min/1.73 m2.  
The power for the primary efficacy endpoint for Part B, 2-year eGFR AUC, is >90% for the 
expected mean eGFR profiles for Nefecon and placebo over 2 years, if the treatment effect 
increases linearly over the first year to a maximum of at least 3 mL/min/1.73 m2 and decreases 
linearly thereafter to a minimum of at least 2.24 mL/min/1.73 m2. 
A total of 360 randomized patients are planned to be evaluable for the final primary efficacy 
analysis for the study. 
It is estimated that approximately 900 patients will be screened. 
SITES:   
It is anticipated that there will be approximately 160 sites in Europe, North America,
South America, Asia Pacific, and China. 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
13
TABLE OF CONTENTS 
Signature Page ................................................................................................................................ 2 
International Coordinating Investigator Signature Page ................................................................. 3 
Investigator Agreement ................................................................................................................... 4 
Synopsis .......................................................................................................................................... 5 
Table of Contents .......................................................................................................................... 13 
List of Tables ................................................................................................................................ 18 
List of Figures ............................................................................................................................... 19 
List of Abbreviations and Definition of Terms............................................................................. 20 
1 Introduction and Background Information ............................................................................. 22 
1.1 
Rationale ........................................................................................................................ 23 
1.2 
Benefit/Risk ................................................................................................................... 23 
2 Study Objectives ..................................................................................................................... 25 
2.1 
Primary Objectives ........................................................................................................ 25 
2.1.1 Part A Primary Objective .................................................................................. 25 
2.1.2 Part B Primary Objective .................................................................................. 25 
2.2 
Secondary Objectives .................................................................................................... 25 
2.2.1 Part A Secondary Objectives ............................................................................. 25 
2.2.2 Part B Secondary Objectives ............................................................................. 25 
3 Study Description.................................................................................................................... 26 
3.1 
Summary of Study Design ............................................................................................ 26 
3.1.1 Part A ................................................................................................................. 27 
3.1.2 Part B ................................................................................................................. 28 
4 Selection and Withdrawal of Patients ..................................................................................... 30 
4.1 
Inclusion Criteria ........................................................................................................... 30 
4.2 
Exclusion Criteria .......................................................................................................... 30 
4.3 
Withdrawal Criteria ....................................................................................................... 32 
4.3.1 Withdrawal From the Study .............................................................................. 32 
4.3.2 Premature Discontinuation of Study Drug ........................................................ 33 
4.3.3 Lost to Follow-Up ............................................................................................. 33 
4.4 
Patient Re-Screening Procedures .................................................................................. 34 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
14
5 Study Treatments .................................................................................................................... 35 
5.1 
Treatment Groups .......................................................................................................... 35 
5.2 
Rationale for Dosing ..................................................................................................... 35 
5.3 
Randomization and Blinding ......................................................................................... 35 
5.4 
Breaking the Blind ........................................................................................................ 36 
5.5 
Drug Supplies ................................................................................................................ 36 
5.5.1 Formulation and Packaging ............................................................................... 36 
5.5.2 Study Drug Preparation and Dispensing ........................................................... 36 
5.5.2.1 Direct to patient shipment ................................................................... 37 
5.5.3 Study Drug Administration ............................................................................... 37 
5.5.4 Treatment Compliance ...................................................................................... 38 
5.5.5 Storage and Accountability ............................................................................... 38 
5.6 
Prior and Concomitant Medications and/or Procedures ................................................ 38 
5.6.1 Excluded Medications and/or Procedures ......................................................... 38 
5.6.2 Restricted Medications and/or Procedures ........................................................ 39 
5.6.2.1 Part A restricted medications and/or procedures ................................ 39 
5.6.2.2 Part B restricted medications and/or procedures ................................ 39 
5.6.3 Documentation of Prior and Concomitant Medication Use .............................. 39 
5.6.4 Dietary and Lifestyle Recommendations .......................................................... 40 
6 Study Procedures .................................................................................................................... 41 
6.1 
Informed Consent .......................................................................................................... 41 
6.2 
Part A – Screening Period (Study Visits 1 to 3) ............................................................ 41 
6.2.1 Study Visit 1 (Within 35 Days Prior to Randomization, Inclusive) .................. 41 
6.2.2 Study Visit 2 ...................................................................................................... 42 
6.2.3 Study Visit 3 (At Least 2 Weeks After Study Visit 2) ...................................... 42 
6.3 
Randomization (Within 35 Days After Study Visit 1, Inclusive) ................................. 43 
6.4 
Part A – Treatment Period (Study Visits 4 to 11 – Study Day 1 to Study Month 9 [or 
Month 10, When Applicable, due to the Covid-19 Pandemic]) .................................... 43 
6.4.1 Study Visit 4 (Study Day 1) .............................................................................. 43 
6.4.2 Telephone Study Visits 5 (Study Week 3 [7 Days]), 6 (Study Week 6 
[7 Days]), 8 (Study Month 4.5 [7 Days]), and 10 (Study Month 7.5 
[7 Days]).......................................................................................................... 44 
6.4.3 Study Visits 7 (Study Month 3 [7 Days]) and 9 (Study Month 6 [7 Days]) . 44 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
15
6.4.4 Study Visit 11 (Study Month 9 [or Month 10, When Applicable, due to the 
Covid-19 Pandemic] [-7 to +28 Days])/Early Termination Visit ..................... 45 
6.5 
Part A Follow-up Period (Study Visits 12 and 13 – Study Months 9 to 12) ................. 46 
6.5.1 Telephone Study Visit 12 (Study Month 10.5 [7 Days]) ................................ 46 
6.5.2 Study Visit 13 (Study Month 12 [7 Days]) ..................................................... 46 
6.6 
Part B – Follow-up Period (Study Visits 14 to 17b – Study Years 1 and 2) ................. 47 
6.6.1 Telephone Study Visits 14 (Study Year 1 and 3 Months [7 Days]) and 16 
(Study Year 1 and 9 Months [7 Days]) ........................................................... 47 
6.6.2 Study Visits 15 (Study Year 1 and 6 Months [30 Days]) and 17a (Study 
Year 2 [30 Days]) ............................................................................................ 47 
6.6.3 Study Visit 17b (14 to 35 Days After Study Visit 17a) (For Replicate eGFR 
Sample) .............................................................................................................. 48 
6.7 
Early Termination Visit, End of Study Visit, and Withdrawal Procedures .................. 48 
6.7.1 Early Termination Visit ..................................................................................... 49 
6.7.2 End of Study Visit ............................................................................................. 49 
7 Efficacy Assessments.............................................................................................................. 50 
7.1 
Part A Analysis .............................................................................................................. 50 
7.1.1 Part A Analysis Primary Efficacy Endpoint ..................................................... 50 
7.1.2 Part A Analysis Secondary Efficacy Endpoints ................................................ 50 
7.2 
Part B Analysis .............................................................................................................. 50 
7.2.1 Part B Analysis Primary Efficacy Endpoint ...................................................... 50 
7.2.2 Part B Analysis Secondary Efficacy Endpoints ................................................ 51 
7.2.3 Part B Analysis Exploratory Efficacy Endpoints .............................................. 51 
7.3 
Quality of Life Assessment ........................................................................................... 51 
7.4 
Exploratory Biomarker Analyses and Genetic Analyses .............................................. 51 
8 Safety Assessments ................................................................................................................. 52 
8.1 
Adverse Events .............................................................................................................. 52 
8.1.1 Adverse (Drug) Reaction .................................................................................. 53 
8.1.2 Unexpected Adverse Drug Reaction ................................................................. 53 
8.1.3 Assessment of Adverse Events by the Investigator .......................................... 53 
8.2 
Adverse Events of Special Interest ................................................................................ 54 
8.3 
Serious Adverse Events ................................................................................................. 55 
8.4 
Serious Adverse Event Reporting − Procedures for Investigators ................................ 56 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
16
8.5 
Pregnancy Reporting ..................................................................................................... 56 
8.6 
Expedited Reporting ...................................................................................................... 57 
8.7 
Safety Assessments ....................................................................................................... 57 
8.8 
Clinical Laboratory Evaluations .................................................................................... 57 
8.9 
Vital Signs ..................................................................................................................... 57 
8.10 Physical Examinations .................................................................................................. 58 
8.11 Body Weight and Height ............................................................................................... 58 
9 Statistics .................................................................................................................................. 59 
9.1 
Analysis Populations ..................................................................................................... 59 
9.2 
Statistical Methods ........................................................................................................ 59 
9.2.1 Analysis of Efficacy .......................................................................................... 60 
9.2.1.1 Analysis of Part B primary efficacy endpoint ..................................... 60 
9.2.1.2 Analysis of eGFR slope ...................................................................... 61 
9.2.1.3 Analysis of time to 30% reduction in eGFR (Part B) ......................... 61 
9.2.1.4 Analysis of other secondary efficacy endpoints in Part B .................. 62 
9.2.1.5 Hypothesis testing strategy ................................................................. 62 
9.2.1.6 Analysis by subgroup .......................................................................... 63 
9.2.2 Analysis of Safety ............................................................................................. 64 
9.2.3 Part A Analysis .................................................................................................. 64 
9.2.4 Data and Safety Monitoring Board ................................................................... 66 
9.2.5 Sample Size Determination ............................................................................... 66 
9.2.5.1 Part A analysis .................................................................................... 66 
9.2.5.2 Part B analysis..................................................................................... 66 
10 Data Management and Record Keeping ................................................................................. 68 
10.1 Data Management ......................................................................................................... 68 
10.1.1 Data Handling ................................................................................................... 68 
10.1.2 Computer Systems ............................................................................................. 68 
10.1.3 Data Entry ......................................................................................................... 68 
10.1.4 Medical Information Coding ............................................................................. 68 
10.1.5 Data Validation ................................................................................................. 68 
10.2 Record Keeping ............................................................................................................. 68 
11 Sponsor/Investigator Requirements and Quality Control ....................................................... 70 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
17
11.1 Ethical Conduct of the Study ........................................................................................ 70 
11.2 Institutional Review Board/Independent Ethics Committee ......................................... 70 
11.3 Delegation of Investigator Duties.................................................................................. 70 
11.4 Informed Consent .......................................................................................................... 70 
11.5 Study Monitoring Requirements ................................................................................... 71 
11.6 Disclosure of Data ......................................................................................................... 71 
11.7 Retention of Records ..................................................................................................... 72 
11.8 Publication Policy ......................................................................................................... 72 
11.9 Financial Disclosure ...................................................................................................... 72 
11.10 Insurance and Indemnity ............................................................................................... 72 
11.11 Legal Aspects ................................................................................................................ 72 
12 Study Administrative Information .......................................................................................... 73 
12.1 Protocol Amendments ................................................................................................... 73 
12.2 Address List ................................................................................................................... 73 
12.2.1 Sponsor .............................................................................................................. 73 
12.2.2 Contract Research Organization ........................................................................ 73 
12.2.3 Serious Adverse Event Reporting ..................................................................... 73 
12.2.4 Biological Specimens ........................................................................................ 73 
13 References ............................................................................................................................... 74 
Appendix A:  Schedule of Procedures .......................................................................................... 76 
Appendix B:  Clinical Laboratory Analytes ................................................................................. 81 
Appendix C:  Summary of Part A and Part B ............................................................................... 83 
Appendix D:  Renin-Angiotensin System Inhibitor and Other Antihypertensive Therapy 
Recommendations According to the 2012 Kidney Disease: Improving Global Outcomes 
Guidelines ............................................................................................................................... 85 
Appendix E:  Recommendations for Defining Medium- or High-Risk Osteoporosis .................. 86 
Appendix F:  Immunosuppressive Drugs Other Than Glucocorticoids........................................ 87 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
18
LIST OF TABLES 
Table 1. 
Time Windows Applied to Efficacy Assessments ...................................................... 60 
Table 2. 
Weight Applied to Each Time Point in the Calculation of the 2-Year eGFR AUC ... 60 
Table 3. 
Schedule of Procedures – Part A ................................................................................ 76 
Table 4. 
Schedule of Procedures – Part B ................................................................................. 79 
 
 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
19
LIST OF FIGURES 
Figure 1. Summary of Study Design .......................................................................................... 27 
Figure 2. Summary of the Hypothesis Testing Strategy ............................................................ 63 
Figure 3. Summary of Part A* ................................................................................................... 83 
Figure 4. Summary of Part B...................................................................................................... 84 
 
 
 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
20
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 
AUC 
Area under the curve 
CEC 
Central Ethics Committee 
CI 
Confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Covid-19 
Coronavirus Disease 2019 
CRA 
Clinical research associate 
CTA 
Clinical trial authorization 
CYP3A4 
Cytochrome P450 3A4 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
ESRD 
End-stage renal disease 
FAS 
Full Analysis Set 
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 
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 
MMRM 
Mixed Model Repeated Measures 
MTD 
Maximum tolerated dose 
OSTA 
Osteoporosis Self-Assessment Tool for Asians 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
21
Abbreviation 
Definition 
QD 
Once per day 
RAS 
Renin-angiotensin system 
RSI 
Reference Safety Information 
SAE 
Serious adverse event 
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 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
22
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 commonly during the second or third 
decades of life.2 Immunoglobulin A nephropathy 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 ileum, could attenuate Gd-IgA1 production and leakage 
to the systemic circulation, thereby reducing subsequent pathophysiological changes in the 
kidneys. 
In March 2020, the Coronavirus Disease 2019 (Covid-19), caused by infection with the newly 
discovered coronavirus, was characterized as a pandemic by the World Health Organization. The 
Covid-19 pandemic impacted clinical studies worldwide due to quarantines, site closures, travel 
limitations, diversion of resources, and/or general interruptions in study-related procedures. Due 
to the Covid-19 pandemic, contingency procedures were implemented during this study in the US 
and Europe to manage possible disruptions due to the Covid-19-risk-of-infection-associated 
control measures. The contingency procedures will be applicable only for patients impacted by the 
Covid-19 control measures and will no longer be necessary once the Covid-19 pandemic resolves. 
Contingency procedures described herein are to prevent treatment disruption for patients who are 
not able to visit the sites for the scheduled end of treatment Visit 11 when the study primary 
endpoint is to be evaluated and, therefore, maintain the study integrity. It is also to ensure the study 
drug tapering bottle is dispensed in a timely manner, which otherwise may raise an important 
safety concern. 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
23
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 glucocorticoid (GCS) with potent GCS and weak mineralocorticoid activities. 
Immunosuppressive and anti-inflammatory properties have led to the approval of budesonide 
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 is designed to deliver 
its active ingredient to the ileum where the target immune tissues, Peyer’s patches, reside in high 
density and for a sufficient length of time to provide the local therapeutic effect. By targeting local 
administration of budesonide to this area, Nefecon treatment may suppress local B-cell activation 
and proliferation, and the subsequent production of Gd-IgA1 and leakage to the systemic 
circulation, thereby decreasing glomerular mesangial deposition and consequential nephritis and 
loss of renal function. 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 indicated to be a safe and well-tolerated steroid 
formulation for adjunctive therapy to ACEIs 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 3 study to evaluate the efficacy, safety, and tolerability of Nefecon 
16 mg per day in the treatment of patients with primary IgAN at risk of progressing to ESRD, 
despite maximum tolerated treatment with RAS blockade using ACEIs 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 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
24
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 is a unique optimized formulation which combines a delayed capsule disintegration with 
a concentrated short, but sustained release of the active substance budesonide, ensuring delivery 
of budesonide to the ileum, and a release profile providing exposure through the passage of the 
distal part of the small bowel where the Payer’s patches are located. 
Thereby a high local concentration of budesonide can be delivered to the mucosa in a restricted 
part of the gut. 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 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 
ARB 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 ACEI and/or ARB, will be favorable. 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
25
2 
STUDY OBJECTIVES 
The overall aim of the study is to evaluate the efficacy, safety, and tolerability of Nefecon 16 mg 
per day in the treatment of patients with primary IgAN at risk of progressing to ESRD, despite 
maximum tolerated treatment with RAS blockade using ACEIs or ARBs. 
2.1 
Primary Objectives 
2.1.1 
Part A Primary Objective 
The primary objective of Part A is to assess the effect of Nefecon 16 mg treatment on urine protein 
to creatinine ratio (UPCR) over 9 months compared to placebo. 
2.1.2 
Part B Primary Objective 
The primary objective of Part B is to assess the effect of the Nefecon 16 mg treatment given in 
Part A on clinical consequences of any proteinuria reduction as measured by estimated glomerular 
filtration rate (eGFR) recorded over 2 years compared to placebo. 
2.2 
Secondary Objectives 
2.2.1 
Part A Secondary Objectives 
The secondary objectives of Part A are: 
 To assess the effect of Nefecon 16 mg treatment on eGFR at 9 and 12 months compared to 
placebo, and 
 To evaluate additional aspects of renal function, and safety and tolerability of Nefecon 16 mg 
treatment over 9 months compared to placebo. 
2.2.2 
Part B Secondary Objectives 
The secondary objectives of Part B are to assess the effects of the Nefecon 16 mg treatment given 
in Part A on different aspects of renal function and safety compared to placebo over 2 years. 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
26
3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter study to evaluate the 
efficacy, safety, and tolerability of oral Nefecon compared to matching placebo in patients with 
primary IgAN on a background of optimized RAS inhibitor therapy. Approximately 360 patients 
will be randomized at approximately 160 sites in Europe, North America, South America, Asia 
Pacific, and China. The study will consist of 2 parts, Part A and Part B. Part A will include a 
Screening Period (up to 35 days) followed by a 9-month blinded Treatment Period, and a 3-month 
Follow-up Period (including a 2-week Tapering Period). The total duration of Part A is up to 
13.5 months. 
Part B will consist of a 12-month (+14 to 35 days) observational Follow-up Period after Part A has 
ended. Each patient randomized will be followed for 25 months after the first dose (or, if the patient 
randomized does not receive any study drug, 25 months after the patient is randomized). The total 
duration of the study is up to 26.5 months (including the Screening Period and a final visit for 
replicate eGFR sampling at 2 years). Part A will be blinded, and the blinding will remain in place 
throughout Part B. No study drug will be administered during Part B. The primary analysis in 
Part B will occur 25 months after the 360th/last patient is dosed (or, if the 360th/last patient 
randomized does not receive any study drug, 25 months after the 360th/last patient is randomized).  
Figure 1 provides a summary of the study design. 
 
 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
27
Figure 1. Summary of Study Design 
 
AUC = area under the curve; eGFR = estimated glomerular filtration rate; R = randomization; RAS = renin-angiotensin system; 
SOC = standard of care; tx = treatment. 
3.1.1 
Part A 
In order to be eligible for randomization, patients must be on a stable dose of RAS inhibitor therapy 
(ACEIs and/or ARBs) at the maximum allowed dose or maximum tolerated dose (MTD) according 
to the 2012 KDIGO guidelines for at least 3 months prior to randomization. A stable dose is defined 
as doses within 25% of the dose at randomization. Patients should remain on their regimens of 
RAS inhibitors for the whole duration of the study (Part A and Part B). It is recommended that 
patients achieve a target systolic blood pressure <125 mmHg and target diastolic blood pressure 
<75 mmHg according to the 2012 KDIGO guidelines. The use of additional antihypertensive 
therapy will be permitted as needed. Investigators should ensure that patients are informed at 
screening of potentially beneficial lifestyle choices including weight normalization, smoking 
cessation, physical activity, and diet (low salt and low protein). Patients must, after informed 
consent, have 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 (baseline 
will be the geometric mean of these 2 measurements).  
 
R 
NEFECON  
16 mg/day
PLACEBO
Treatment
9 Months of
Double-blind 
Treatment 
Screening
No treatment follow-up Period
PART A
PART B
Optimized RAS Inhibition
Study Visits Every 6 Months and 
Telephone Contacts 3 Months After 
Each Study Visit 
No Study Drug Administered 
Blinding Will Remain in Place 
If Required, Rescue tx = SOC 
Immunosuppressants 
1-year follow-up from Part A based on 
statistical significance in eGFR AUC 
endpoint 
15 to 
35 Days 
Follow-up Period
2 Week 
Tapering of 
Double-
blind 
Treatment 
10 Week 
Follow-up 
NEFECON 
8 mg/day
PLACEBO
No Study Drug 
Administered 
Blinding Will 
Remain in 
Place 
Proteinuria Endpoint
eGFR AUC-based Endpoint


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
28
Both samples of the same parameter must show either of the following: 
 Proteinuria 1 g per day (1000 mg per day) in 2 consecutive measurements, or 
 UPCR 0.8 g/gram (90 mg/mmol) in 2 consecutive measurements. 
Additionally, all other eligibility criteria must be met in order to be eligible for randomization.  
After confirming all eligibility criteria, patients will be randomized in a 1:1 ratio to Nefecon 16 mg 
or placebo within 35 days of Study Visit 1 (screening). The study will be double-blinded, and 
randomization will be stratified according to baseline proteinuria, eGFR, and geographic region. 
Randomized patients will receive either Nefecon 16 mg (four 4 mg budesonide modified-release 
capsules once per day [QD]) or placebo (4 matching capsules QD) for a 9-month Treatment Period. 
Following completion of the Treatment Period, patients will enter the 3-month Part A 
Follow-up Period. The first 2 weeks of this Follow-up Period will consist of a 2-week Tapering 
Period to reduce the risk of insufficiency of the adrenal glands. During the 2-week Tapering Period, 
the study drug dose will be reduced from 4 capsules QD (Nefecon 16 mg or placebo) to 
2 capsules QD (Nefecon 8 mg or placebo). 
Patients will discontinue study drug at the end of the Tapering Period and then complete the 
remainder of the Part A Follow-up Period before entering Part B. 
Patients who prematurely discontinue study drug during the Treatment Period should complete the 
2-week Tapering Period, if feasible, to prevent insufficiency of the adrenal glands. All patients 
who prematurely discontinue study drug should have eGFR, proteinuria, and creatinine measured 
at each scheduled visit; it is of particular importance for the 9- and 12-month study visits (Study 
Visits 11 and 13). All patients who prematurely discontinue study drug should also subsequently 
enter Part B of the study and continue to have eGFR, proteinuria, and creatinine measured unless 
they have withdrawn their consent to any kind of follow-up. In the case of patients who are 
randomized but do not receive any study drug, they should have eGFR, proteinuria, and creatinine 
measured at each scheduled visit; it is of particular importance for the 9- and 12-month study visits 
(Study Visits 11 and 13). They should also subsequently enter Part B of the study and continue to 
have eGFR, proteinuria, and creatinine measured unless they have withdrawn their consent to any 
kind of follow-up. 
Figure 3 (Appendix C) provides a schematic summary of Part A. 
3.1.2 
Part B 
Part B of the study will consist of a 12-month (+14 to 35 days) observational Follow-up Period; 
no study drug will be administered during Part B. Each patient randomized will be followed for 
25 months after the first dose (or, if the patient randomized does not receive any study drug, 
25 months after the patient is randomized). Following completion of Part A, patients will remain 
on their optimized RAS inhibitor/antihypertensive therapy and continue into Part B of the study. 
During Part B, the Investigator may consider that rescue medication (steroids and/or 
immunosuppressive treatment) may be needed. Such treatment can be initiated by the Investigator; 
however, patients should have a proteinuria level at least above 1 g per 24 hours, as suggested in 
the 2012 KDIGO guidelines, and the Medical Monitor should be consulted for advice (see 
Section 5.6.2.2). 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
29
During Part B of the study, patients will complete onsite study visits at 18 and 24 months, including 
a final visit for replicate eGFR sampling at 14 to 35 days after the 24-month visit. Telephone 
contacts will be performed between the onsite study visits at 15 and 21 months. The measurements 
of eGFR, proteinuria, and creatinine will continue in Part B. Additional telephone contacts and/or 
unscheduled study visits can be made as needed.  
Part B will continue until 25 months after the 360th/last patient is dosed (or, if the 360th/last patient 
randomized does not receive any study drug, 25 months after the 360th/last patient is randomized). 
Patients who receive rescue medication should continue in the study and complete all study 
procedures as indicated in the Schedule of Procedures table (see Appendix A). Patients will be 
followed until initiation of dialysis, undergoing renal transplantation, death, or study completion 
(i.e., maximum of 25.5 months after the first dose [or, if the patient randomized does not receive 
any study drug, 25.5 months after the patient is randomized]), whichever occurs first. 
Figure 4 (Appendix C) provides a schematic summary of Part B. 
 
 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
30
4 
SELECTION AND WITHDRAWAL OF PATIENTS  
All inclusion and exclusion criteria must be assessed at screening and must be reassessed before 
randomization to confirm that the patient is still eligible. The confirmation of patient eligibility at 
screening and prior to randomization will be documented in the source documents and the 
electronic case report forms (eCRFs). 
4.1 
Inclusion Criteria 
Patients must meet all of the following inclusion criteria at screening to be eligible for admission 
into the study:  
1. Female or male patients 18 years of age; 
2. Diagnosed IgAN with biopsy verification within the past 10 years; 
3. On a stable dose of RAS inhibitor therapy (ACEIs and/or ARBs) at the maximum allowed dose 
or MTD according to the 2012 KDIGO guidelines for the 3 months prior to randomization (see 
Appendix D). In this instance, a stable dose is defined as doses within 25% of the dose at 
randomization. Patients on a stable dose of RAS inhibitor therapy (ACEIs and/or ARBs) below 
the maximum allowed dose or MTD according to the 2012 KDIGO guidelines will be 
permitted into the study if an attempt to reach the maximum allowed dose or MTD has been 
performed21 or if such attempt is deemed unsafe for the patient by the Investigator; and 
Note: It is recommended that patients achieve a target systolic blood pressure <125 mmHg and 
target diastolic blood pressure <75 mmHg according to the 2012 KDIGO guidelines. 
4. Willing and able to provide written informed consent at screening. 
In addition, patients must meet the following inclusion criteria before randomization into the study: 
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 per day (1000 mg per day) in 2 consecutive measurements, or  
o UPCR 0.8 g/gram (90 mg/mmol) in 2 consecutive measurements; and 
6. eGFR 35 mL/min per 1.73 m2 and 90 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. Systemic diseases that may cause mesangial IgA deposition including, but not limited to, 
Henoch Schönlein purpura, systemic lupus erythematosus, dermatitis herpetiformis, and 
ankylosing spondylitis;  
2. Patients who have undergone a kidney transplant; 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
31
3. Patients with presence of other glomerulopathies (e.g., C3 glomerulopathy and/or diabetes 
nephropathy) and with nephrotic syndrome (i.e., proteinuria >3.5 g per day and with serum 
albumin <3.0 g/dL, with or without edema); 
4. Patients with acute, chronic, or latent infectious disease including hepatitis, tuberculosis (TB), 
human immunodeficiency virus (HIV), and chronic urinary tract infections; 
5. Patients with liver cirrhosis, as assessed by the Investigator; 
6. 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]); 
7. Patients with history of unstable angina, class III or IV congestive heart failure, and/or 
clinically significant arrhythmia, as judged by the Investigator; 
8. 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 one 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); 
9. 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; 
10. Patients with known osteoporosis in medium- or high-risk category according to the 
2010 American College of Rheumatology recommendations (see Appendix E). 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 E);  
11. Patients with known glaucoma, known cataract(s), and/or history of cataract surgery, unless 
the surgery was performed on both eyes;  
12. 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; 
13. Patients with hypersensitivity to budesonide or any component of the study drug formulation; 
14. Patients with previous severe adverse reactions to steroids, at the discretion of the Investigator, 
including psychotic symptoms; 
15. Patients who have been treated with systemic immunosuppressive medications, other than 
GCSs, within the 12 months before randomization. See Appendix F for more information on 
immunosuppressive medications; 
16. Patients who have been treated with any systemic GCSs within the 3 months before 
randomization;  
17. Patients who have been treated with any systemic GCSs within the 12 months before 
randomization 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; 
18. Patients taking potent inhibitors of cytochrome P450 3A4 (CYP3A4); 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
32
19. Current or prior (within the past 2 years) alcohol or drug abuse; 
20. Intake of an investigational drug within 30 days and at least 5 half-lives before randomization; 
21. Patients unwilling or unable to meet the requirements of the protocol; 
22. Other medical or social reasons for exclusion at the discretion of the Investigator; 
23. Life expectancy <5 years; 
24. Females who are pregnant, breastfeeding, or unwilling to use highly-effective contraception 
during the Treatment Period and the 3-month Follow-up Period in Part A of 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 
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 
25. 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. If a patient is withdrawn from study 
drug treatment, they are still to continue their participation in the study. The reason for premature 
discontinuation of study drug or patient withdrawal for any follow-up in the study must be 
documented in the eCRF. 
See Section 6.7 for additional information on the Early Termination Visit, End of Study Visit, and 
withdrawal procedures. 
4.3.1 
Withdrawal From the Study 
Participation of a patient may be permanently discontinued if the patient requests discontinuation 
and withdraws consent from the study for any follow-up. 
If a patient withdraws prematurely from the study due to the below criteria or any other reason, 
study staff should make every effort to complete an Early Termination Visit (see Section 6.7) if 
the patient discontinues prior to completion of Study Visit 11, or an End of Study Visit (see 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
33
Section 6.7) if the patient discontinues after completion of Study Visit 11 but prior to completion 
of Part B. 
Withdrawn patients will not be replaced. 
4.3.2 
Premature Discontinuation of Study Drug 
Patients who prematurely discontinue study drug treatment should complete the remaining study 
visits (especially those required for key efficacy assessments, i.e., 9 and 12 months and 2 years 
[Study Visits 11, 13, and 17a/b]) despite discontinuation of study drug and should have the daily 
dose of study drug reduced to 2 capsules QD (Nefecon 8 mg or placebo) for 2 weeks, if feasible, 
to prevent insufficiency of the adrenal glands (see Section 5.5.3). 
The following do not fulfil the criteria for withdrawal from the study, but do require 
discontinuation of study drug:  
 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 adverse event (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. 
If a patient requires treatment with other interventional therapies this does not require early 
withdrawal from the study unless the patient withdraws consent to any follow-up; however, this 
will require discontinuation from study drug treatment with continued patient follow-up 
(i.e., continuation in the study). 
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 
phone 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; 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
34
 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. 
4.4 
Patient Re-Screening Procedures 
Patients who do not meet all of the eligibility requirements defined in Sections 4.1 and 4.2 may be 
re-screened for the study. If the patient will be re-screened more than once, this must be discussed 
and agreed upon with the Medical Monitor. All re-screened patients must be re-consented and sign 
a new Informed Consent Form (ICF) prior to completion of any re-screening study procedures. 
Re-screened patients will be assigned a new patient number at the time of re-screening 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 re-screened patient’s new eCRF casebook will 
contain a reference to the patient’s previous identification number(s). 
If a re-screened patient agrees to participate in the exploratory kidney biopsy and/or biomarker 
analyses and signed the specific ICF for the previous screening, then this patient must be 
re-consented and the biomarker samples must be repeated (except for the already existing kidney 
biopsy samples). 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
35
5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
During Part A, patients will be randomized to receive either Nefecon 16 mg (four 4 mg budesonide 
modified-release capsules QD) or placebo (4 matching capsules QD) orally for 9 months 
(Treatment Period). After completing 9 months (or up to 10 months, when applicable, due to the 
Covid-19 pandemic) of study drug treatment, the daily dose of study drug will be reduced from 
4 capsules QD (Nefecon 16 mg or placebo) to 2 capsules QD (Nefecon 8 mg or placebo) for 
2 weeks to prevent insufficiency of the adrenal glands (Tapering Period). 
Part B of the study will consist of a 12-month (+14 to 35 days) observational Follow-up Period; 
no study drug will be administered during Part B. 
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 
ileum 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, 
8 mg and 16 mg Nefecon doses, given daily for 9 months, were studied, the Nefecon 16 mg dose 
was selected for Phase 3. Nefecon treatment at doses of up to 16 mg daily 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 
After confirming all eligibility criteria, patients will be randomized in a 1:1 ratio to Nefecon 16 mg 
or placebo using an Interactive Response Technology (IRT) system. Randomization will be 
stratified according to baseline proteinuria, eGFR, and geographic region. 
Part A will be blinded, and the blinding will remain in place throughout Part B. The patients, 
Investigators, and site staff conducting study procedures, evaluating patients, entering study data, 
and/or evaluating study data will be blinded to treatment assignment. The only exception would 
be if an emergency situation involving a patient requires unblinding of the treatment assignment. 
The Part A analysis is specified in Section 9.2.3. An unblinded team will be assembled, including 
an unblinded independent biostatistician, a medical monitor, and other individuals from Calliditas 
or their designee. This unblinded team will be independent from the study team and will not be 
involved with study conduction other than submission preparation. Calliditas will be unblinded to 
the results on a group level. In addition, a limited number of named Sponsor personnel will be 
unblinded on an individual patient level. Further details are provided in the Blinding Plan and 
Blinding Charter. 
A Data and Safety Monitoring Board (DSMB) will be established to review and discuss the 
available study data as patients are randomized and followed throughout the study. The DSMB 
will meet periodically throughout the course of the study to review unblinded safety data.  


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
36
Both Nefecon and placebo will be provided in modified-release capsules. The capsules and their 
ingredients will be carefully matched in appearance, smell, and taste to ensure maintenance of 
treatment masking. 
5.4 
Breaking the Blind 
In an emergency, when knowledge of the patient’s treatment assignment is essential for the clinical 
management or welfare of the patient, the Investigator (or his/her designee) can unblind the study 
treatment. If useful and when times allows, the investigator is recommended to discuss the 
rationale for breaking the blind with the Medical Monitor, although the decision lies solely with 
the Investigator. 
The Investigator (or his/her designee) must then contact IRT to unblind an individual patient’s 
treatment assignment. If the blind is broken for any reason, the Investigator must record the date 
and reason for breaking the blind on the appropriate eCRF and source documents, and the patient 
should remain in the study. 
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, 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 that have a sugar sphere as the core. The inner coating layer contains the active 
substance, and the outer polymer coating layer is a prolonged-release coating that controls the rate 
of release of the active substance once the capsule has dissolved. A seal layer is also included 
between the budesonide and the polymer coating layer.  
The placebo formulation consists of the same enteric coated capsule as for the active capsules, but 
is only filled with sugar spheres, without any coating layers. 
Nefecon and placebo 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 
and placebo will be packaged and labeled according to the requirements of local law and 
legislation, as well as current 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 
According to the IRT system, the Investigator (or his/her designee) will dispense the assigned 
study drug to the patient. The IRT randomization will trigger the first shipment of study drug to 
the site for the patient (on-demand shipment). 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 7, 9, and 11 (for the Tapering Period). If the patient will 
be treated for up to 10 months (due to the Covid-19 pandemic), then the replacement resupply 
bottle will be provided to the patient for the extended treatment period.  
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. 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
37
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. 
5.5.2.1 
Direct to patient shipment 
Direct to patient shipments of study drug will originate from the site and are considered as only a 
Covid-19 pandemic-related measure to ensure uninterrupted patient treatment when no other 
option is available. Direct to patient shipments must be approved by the Sponsor or representative. 
The Investigator or designee will request Sponsor approval of a direct to patient shipment. The 
Investigator or designee must ensure that informed consent is obtained for direct to patient 
shipment. In emergency situations, at minimum, this should be obtained verbally with proper 
documentation in the medical records. At the earliest time point, written confirmation will be 
required. The Investigator or designee must ensure study drug accountability and reconciliation as 
well as documentation is maintained in site files.  
The Sponsor or representative will assist direct to patient shipments for sites that do not have this 
process pre-established as part of their internal policy or standard operating procedures.  
5.5.3 
Study Drug Administration 
Nefecon 16 mg (four 4 mg budesonide modified-release capsules QD) or placebo (4 matching 
capsules QD) will be administered orally for 9 months (or up to 10 months, when applicable, due 
to the Covid-19 pandemic) during the Treatment Period in Part A.  
Patients must take the first dose of study drug (Nefecon 16 mg or placebo) in the presence of site 
staff during Study Visit 4 within 10 days after their randomization. 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 
approximately 1 hour before breakfast. 
The daily dose of double-blinded study drug may be reduced from 4 capsules QD (Nefecon 16 mg 
or placebo) to 2 capsules QD (Nefecon 8 mg or placebo) if clinically relevant AEs develop 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 daily dose of study drug during the 
first 9 months (or up to 10 months, when applicable, due to the Covid-19 pandemic) of treatment 
(Treatment Period in Part A). If a dose reduction is made during this time, then the dose should 
not be increased back to 4 capsules QD (Nefecon 16 mg or placebo). 
After completing 9 months (or up to 10 months, when applicable, due to the Covid-19 pandemic) 
of study drug treatment, the daily dose of study drug will be reduced from 4 capsules QD (Nefecon 
16 mg or placebo) to 2 capsules QD (Nefecon 8 mg or placebo) for 2 weeks to prevent insufficiency 
of the adrenal glands (Tapering Period in Part A). Patients who have their daily dose of study drug 
reduced to 2 capsules QD (Nefecon 8 mg or placebo) due to safety and/or tolerability reasons 
during the first 9 months (or up to 10 months, when applicable, due to the Covid-19 pandemic) of 
treatment (Treatment Period in Part A), will remain on this dose of study drug for an additional 
2 weeks after completing 9 months (or up to 10 months, when applicable, due to the Covid-19 
pandemic) of study drug treatment (during the Tapering Period in Part A). Patients who 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
38
prematurely discontinue study drug treatment while taking 4 capsules QD (Nefecon 16 mg or 
placebo), should have the daily dose of study drug reduced to 2 capsules QD (Nefecon 8 mg or 
placebo) for 2 weeks, if feasible, to prevent insufficiency of the adrenal glands. 
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 
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), except when used as rescue medications, 
are prohibited during the study. However, over the entirety of the study (Parts A and B), patients 
will be allowed up to 3 courses of treatment with GCSs in any 2-year period for non-IgAN 
indications, provided no treatment course is greater than 2 weeks and the GCS dose does not 
exceed the equivalent of 0.5 mg/kg/day prednisolone. Such short-term treatment will not require 
change or stop of study drug treatment in Part A. For both Part A and Part B, study visits that 
include collection of 24-hour urine samples for efficacy assessments (see Appendix A) must not 
be performed within 4 weeks of such short-term GCS treatment. A 24-hour urine collection can 
be repeated if the Investigator suspects that the sampling is insufficient. Study visits are to be 
postponed as needed. Herbs for medicinal use, including Chinese herbs and Chinese traditional 
medicines, with a known effect on the immune system (e.g., Tripterygium wilfordii) or with a 
known effect on decreasing proteinuria and creatinine, are not allowed during the study. Patients 
should be encouraged to not use herbs for medicinal use, including Chinese herbs and Chinese 
traditional medicines, during the study; however, if used, they should be recorded as concomitant 
medications. Topical or inhalation products containing GCS or immunosuppressants are allowed. 
See Appendix F for additional information on immunosuppressive drugs. 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
39
Potent inhibitors of CYP3A4 (e.g., ketoconazole) are prohibited during treatment with study drug 
in Part A. During this time, patients should also be instructed to avoid grapefruit and grapefruit 
juice. 
All randomized patients will be followed for the entire duration of the study regardless of initiation 
of other interventional therapies for IgAN. 
5.6.2 
Restricted Medications and/or Procedures 
5.6.2.1 
Part A 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. 
If a patient requires treatment with other interventional therapies, including immunosuppressants, 
this does not require early withdrawal from the study unless the patient withdraws consent to any 
follow-up; however, this will require discontinuation from study drug treatment (see Section 6.7 
for study drug withdrawal procedures) with continued patient follow-up (i.e., continuation in the 
study). See Appendix F for additional information on immunosuppressive drugs. 
5.6.2.2 
Part B restricted medications and/or procedures 
The Investigator may consider that rescue medication (steroids and/or immunosuppressive 
treatment) may be needed. Such treatment can be initiated by the Investigator; however, patients 
should have a proteinuria level at least above 1 g per 24 hours, as suggested in the 2012 KDIGO 
guidelines, in order for rescue medication to be relevant.21 Although the Investigator is responsible 
for the decision to implement new treatment, the Medical Monitor should be consulted for advice. 
If the Investigator determines that rescue medication is necessary, the Investigator can initiate 
standard of care treatment according to local treatment policies, preferably in accordance with the 
2012 KDIGO guidelines.21 In regions where Nefecon is made commercially available prior to the 
end of Part B, the Investigator may initiate treatment with Nefecon according to the given label. 
See Appendix F for additional information on immunosuppressive drugs. 
All randomized patients will be followed for the entire duration of the study regardless of initiation 
of other interventional therapies for IgAN. 
5.6.3 
Documentation of Prior and Concomitant Medication Use 
Medications taken within 3 months prior to Study Visit 1 (screening) 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 Chinese herbs and Chinese traditional medicines, should be 
recorded as concomitant medications. 
Patients are required to be on a stable dose of RAS inhibitor therapies (ACEIs and/or ARBs) at the 
maximum allowed dose or MTD according to the 2012 KDIGO guidelines for the 3 months prior 
to randomization.21 Therefore, all RAS inhibitor therapies (ACEIs and/or ARBs) taken within the 
3 months prior to Study Visit 1 must be recorded. If the patient is on a stable dose of RAS inhibitor 
therapy that is below the maximum allowed dose or MTD of RAS inhibitor therapy, then the site 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
40
must have documentation that an attempt to reach the maximum allowed dose or MTD has been 
performed or if such attempt is deemed unsafe for the patient by the Investigator. 
5.6.4 
Dietary and Lifestyle Recommendations 
The following lifestyle choices should be recommended to the patient at the Study Visit 1 
(screening): 
 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. 
 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
41
6 
STUDY PROCEDURES 
Study visit schedules in tabular format are provided in Table 3 and Table 4 for Part A and Part B, 
respectively, 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, written informed consent must be signed and dated 
by the patient. See Section 11.4 for more information. 
The ICF will include Part A and Part B of the study. The estimated duration of individual patient 
participation in Part A will be approximately 1 year and the estimated median duration of 
individual patient participation in Part B will be approximately 1 year (maximum of 26.5 months 
of individual patient participation in the study). As part of the informed consent process, only 
patients who fully understand and agree to full participation and follow-up should be consented to 
participate. All re-screened patients must be re-consented and sign a new ICF prior to completion 
of any re-screening study procedures.  
At Study Visit 1 (screening), patients will be given the option to participate in the exploratory 
kidney biopsy and biomarker analyses and to provide a genetic sample for exploratory, limited 
candidate gene analyses; participation will require signing of separate ICFs, one for the biomarker 
analyses, one for the kidney biopsy analyses, and one for the genetic analyses. The kidney biopsy 
samples will be already existing biopsies collected from local hospital pathology units, where 
allowed and agreed to by the patient, pathology unit, and biobanks, as applicable. 
Patients who are not allowed to visit the site for the scheduled Visit 11 (9-month Visit) due to the 
Covid-19 pandemic, and who will be treated for up to 10 months, will be asked to give consent by 
phone, which will be documented in their medical records. Patients will sign the Covid-19 
pandemic-related ICF addendum when they are able to visit the site.  
6.2 
Part A – Screening Period (Study Visits 1 to 3) 
Patients will undergo a Screening Period lasting up to 35 days (prior to randomization). 
Study Visit 3 must occur at least 2 weeks after Study Visit 2 in order to collect 2 proteinuria 
measurements separated by at least 2 weeks to determine eligibility. 
6.2.1 
Study Visit 1 (Within 35 Days Prior to Randomization, Inclusive) 
Written informed consent is to be obtained prior to screening procedures. If informed consent has 
been obtained, SAEs have been assessed, and the patient has been supplied with container(s) for 
the next 24-hour urine collection, the remaining Study Visit 1 procedures may, at the discretion of 
the Investigator, be performed at Study Visit 2 (indicated with *). 
The following procedures will be performed at Study Visit 1: 
 Record demographic information and medical/surgical history*; 
 Record prior and concomitant medications and procedures (including all medications taken 
within the past 3 months)*; 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
42
 Confirm that the kidney biopsy report(s) verifies IgAN diagnosis and that the kidney biopsy 
slide(s), or equivalent, can be obtained for central reading*; 
 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 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); 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; 
 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 the next 24-hour urine collection; and 
 Assess SAEs. 
* = may be performed at Study Visit 2.  
6.2.2 
Study Visit 2 
The Study Visit 1 procedures indicated with * may be performed at Study Visit 2. 
The following procedures will be performed at Study Visit 2: 
 Obtain the 24-hour urine sample (sample collected by the patient during the 24-hour period 
prior to the scheduled study visit); and 
 Supply the patient with the container(s) for the next 24-hour urine collection (if not supplied 
at Study Visit 1). 
6.2.3 
Study Visit 3 (At Least 2 Weeks After Study Visit 2) 
Study Visit 3 must occur at least 2 weeks after Study Visit 2 in order to collect 2 proteinuria 
measurements separated by at least 2 weeks 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 at Study Visit 3: 
 Update medical/surgical history; 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
43
 Assess concomitant medications and procedures; 
 Conduct eligibility reassessment based on inclusion and exclusion criteria. For patients with 
proteinuria in the nephrotic range, it is recommended to discuss the case with the Medical 
Monitor prior to inclusion in the study; 
 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]); 
 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; 
o Serum pregnancy test (WOCBP only); and 
o Exploratory biomarker analyses (optional); 
 Collect fresh urine sample for the following: 
o Urinalysis; and 
o Exploratory biomarker analyses (optional); 
 Complete the Short Form 36 (SF-36) quality of life assessment; 
 Obtain the 24-hour urine sample (sample collected by the patient during the 24-hour period 
prior to the scheduled study visit); and 
 Assess SAEs. 
6.3 
Randomization (Within 35 Days After Study Visit 1, Inclusive)  
After confirming all eligibility criteria (laboratory values from Study Visits 1, 2, 3, etc.) (eGFR 
values from Study Visits 1 or 3 must be within the limits defined by the inclusion criteria for the 
patient to be eligible [see Section 4.1]), randomization will be performed through IRT, which 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 7, 
9, and 11 (for the Tapering Period). Patients will be randomized in a 1:1 ratio to Nefecon 16 mg 
or placebo. 
Patients must take the first dose of study drug in the presence of site staff during Study Visit 4. 
6.4 
Part A – Treatment Period (Study Visits 4 to 11 – Study Day 1 to Study Month 9 
[or Month 10, When Applicable, due to the Covid-19 Pandemic]) 
6.4.1 
Study Visit 4 (Study Day 1) 
Study Visit 4 should occur within 10 days after randomization. 
The following procedures will be performed at Study Visit 4: 
 Update medical/surgical history; 
 Assess concomitant medications and procedures; 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
44
 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; 
 Perform a pregnancy test via a local urine assessment (WOCBP only); 
 Supply the patient with the container for the next 24-hour urine collection; 
 Dispense study drug and instruct patient on study drug administration; 
 Administer the first dose of study drug; 
 Assess AEs (occurring after administration of the first dose of study drug), including adverse 
events of special interest (AESIs) and SAEs; and 
 Assess the occurrence of one of the following study endpoints: 
o Initiation of maintenance dialysis for at least 1 month; 
o Kidney transplantation; or 
o Any death. 
6.4.2 
Telephone Study Visits 5 (Study Week 3 [7 Days]), 6 (Study Week 6 [7 Days]), 
8 (Study Month 4.5 [7 Days]), and 10 (Study Month 7.5 [7 Days]) 
The following procedures will be performed at Study Visits 5, 6, 8, and 10, which will be 
conducted with the patient by telephone: 
 Assess AEs, including AESIs and SAEs; concomitant medications and procedures; and 
treatment compliance; and 
 Assess the occurrence of one of the following study endpoints: 
o Initiation of maintenance dialysis for at least 1 month; 
o Kidney transplantation; or 
o Any death. 
6.4.3 
Study Visits 7 (Study Month 3 [7 Days]) and 9 (Study Month 6 [7 Days]) 
The following procedures will be performed at Study Visits 7 and 9: 
 Assess AEs, including AESIs and SAEs, and concomitant medications and procedures; 
 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 blood samples for the following assessments: 
o Hematology (including HbA1c) and serum chemistry (including eGFR [CKD-EPI]); 
o Exploratory biomarker analyses (optional); and 
o Genetic sample (Study Visit 7 only) (optional); 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
45
 Collect fresh urine sample for the following assessments: 
o Urinalysis; 
o Exploratory biomarker analyses (optional); and 
o Pregnancy test via a local urine assessment (WOCBP only); 
 Obtain the 24-hour urine sample (sample collected by the patient during the 24-hour period 
prior to the scheduled study visit); 
 Supply the patient with the container for the next 24-hour urine collection; 
 Collect study drug from previous visit, assess for treatment compliance, and perform drug 
accountability; 
 Dispense study drug and instruct patient on study drug administration; and 
 Assess the occurrence of one of the following study endpoints: 
o Initiation of maintenance dialysis for at least 1 month; 
o Kidney transplantation; or 
o Any death. 
6.4.4 
Study Visit 11 (Study Month 9 [or Month 10, When Applicable, due to the Covid-19 
Pandemic] [-7 to +28 Days])/Early Termination Visit 
The following procedures will be performed at Study Visit 11/Early Termination Visit: 
 Assess AEs, including AESIs and SAEs, and concomitant medications and procedures; 
 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; 
 Perform a complete physical examination; 
 Collect blood samples for the following assessments: 
o Hematology (including HbA1c) and serum chemistry (including eGFR [CKD-EPI]); and 
o Exploratory biomarker analyses (optional); 
 Collect fresh urine sample for the following assessments: 
o Urinalysis; 
o Exploratory biomarker analyses (optional); and 
o Pregnancy test via a local urine assessment (WOCBP only); 
 Complete the SF-36 quality of life assessment; 
 Obtain the 24-hour urine sample (sample collected by the patient during the 24-hour period 
prior to the scheduled study visit); 
 Supply the patient with the container for the next 24-hour urine collection; 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
46
 Collect study drug from previous visit, assess for treatment compliance, and perform drug 
accountability; 
 Dispense study drug and instruct patient on study drug administration. Study drug dispensed 
at Study Visit 11 will be for the Tapering Period; and 
 Assess the occurrence of one of the following study endpoints: 
o Initiation of maintenance dialysis for at least 1 month; 
o Kidney transplantation; or 
o Any death. 
6.5 
Part A Follow-up Period (Study Visits 12 and 13 – Study Months 9 to 12) 
Following completion of the Treatment Period, patients will enter the 3-month Part A Follow-up 
Period. The first 2 weeks of this Follow-up Period will consist of a 2-week Tapering Period to 
reduce the risk of insufficiency of the adrenal glands. Study drug will be dispensed for the Tapering 
Period at Study Visit 11 and patients will return unused study drug at the next onsite study visit 
(Study Visit 13) (see Sections 6.4.4 and 6.5.2).  
6.5.1 
Telephone Study Visit 12 (Study Month 10.5 [7 Days]) 
The following procedures will be performed at Study Visit 12, which will be conducted with the 
patient by telephone: 
 Assess AEs, including AESIs and SAEs; concomitant medications and procedures; and 
treatment compliance; and 
 Assess the occurrence of one of the following study endpoints: 
o Initiation of maintenance dialysis for at least 1 month; 
o Kidney transplantation; or 
o Any death. 
6.5.2 
Study Visit 13 (Study Month 12 [7 Days]) 
The following procedures will be performed at Study Visit 13: 
 Assess AEs, including AESIs and SAEs, and concomitant medications and procedures; 
 Assess the occurrence of one of the following study endpoints: 
o Initiation of maintenance dialysis for at least 1 month; 
o Kidney transplantation; or 
o Any death; 
 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; 
 Perform a complete physical examination; 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
47
 Collect blood samples for the following assessments: 
o Hematology (including HbA1c) and serum chemistry (including eGFR [CKD-EPI]); and 
o Exploratory biomarker analyses (optional); 
 Collect fresh urine sample for the following assessments: 
o Urinalysis; 
o Exploratory biomarker analyses (optional); and 
o Pregnancy test via a local urine assessment (WOCBP only); 
 Obtain the 24-hour urine sample (sample collected by the patient during the 24-hour period 
prior to the scheduled study visit);  
 Supply the patient with the container for the next 24-hour urine collection; and 
 Collect study drug from previous visit, assess for treatment compliance, and perform drug 
accountability. 
6.6 
Part B – Follow-up Period (Study Visits 14 to 17b – Study Years 1 and 2) 
Part B will consist of a 12-month (+14 to 35 days) observational Follow-up Period after Part A has 
ended. Each patient randomized will be followed for 25 months after the first dose (or, if the patient 
randomized does not receive any study drug, 25 months after the patient is randomized) or until 
initiation of dialysis, undergoing renal transplantation, or death, whichever comes first. 
6.6.1 
Telephone Study Visits 14 (Study Year 1 and 3 Months [7 Days]) and 16 
(Study Year 1 and 9 Months [7 Days])  
The following procedures will be performed at Study Visits 14 and 16, which will be conducted 
with the patient by telephone and will occur between onsite study visits: 
 Assess AEs, including AESIs and SAEs; 
 Assess concomitant medications and procedures; and 
 Assess the occurrence of one of the following study endpoints: 
o Initiation of maintenance dialysis for at least 1 month; 
o Kidney transplantation; or 
o Any death. 
6.6.2 
Study Visits 15 (Study Year 1 and 6 Months [30 Days]) and 17a (Study Year 2 
[30 Days]) 
The following procedures will be performed at Study Visits 15 and 17a (End of Study Visit): 
 Assess AEs, including AESIs and SAEs; 
 Assess concomitant medications and procedures; 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
48
 Assess the occurrence of one of the following study endpoints: 
o Initiation of maintenance dialysis for at least 1 month; 
o Kidney transplantation; or 
o Any death; 
 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; 
 Perform a complete physical examination (Study Visit 17a only); 
 Collect blood samples for the following assessments: 
o Hematology (including HbA1c) and serum chemistry (including eGFR [CKD-EPI]); and 
o Exploratory biomarker analyses (optional) (Study Visit 15 only); 
 Collect fresh urine sample for the following assessments: 
o Urinalysis; and 
o Exploratory biomarker analyses (optional) (Study Visit 15 only); 
 Obtain the 24-hour urine sample (sample collected by the patient during the 24-hour period 
prior to the scheduled study visit);  
 Supply the patient with the container for the next 24-hour urine collection (Study Visit 15 
only); and 
 Complete the SF-36 quality of life assessment (Study Visit 17a only). 
6.6.3 
Study Visit 17b (14 to 35 Days After Study Visit 17a) (For Replicate eGFR Sample) 
The following procedures will be performed at Study Visit 17b (14 to 35 days after Study 
Visit 17a) (for replicate eGFR sample) (End of Study Visit): 
 Assess AEs, including AESIs and SAEs; 
 Assess concomitant medications and procedures; and 
 Collect blood samples for serum creatinine (eGFR [CKD-EPI]) assessments. 
6.7 
Early Termination Visit, End of Study Visit, and Withdrawal Procedures 
It is of the utmost importance to encourage patients to remain in the study until completion. If a 
patient requires treatment with other interventional therapies, this does not require early 
withdrawal from the study unless the patient withdraws consent to any follow-up; however, this 
will require discontinuation from study drug treatment with continued patient follow-up 
(i.e., continuation in the study). Patients who prematurely discontinue study drug treatment should 
complete the remaining study visits (especially those required for key efficacy assessments, i.e., 
9 and 12 months and 2 years [Study Visits 11, 13, and 17a/b]) (see Section 4.3.2). 
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 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
49
a minimum, Investigators should encourage patients to continue follow-up with Investigators (or 
his/her designee) in order to collect the patient’s eGFR at 2 years (eGFR assessed twice separated 
by 14 to 35 days) and vital status until study completion. 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 eCRF. 
6.7.1 
Early Termination Visit 
For patients who are withdrawn from the study prior to completion of Study Visit 11, the Early 
Termination Visit procedures will be completed, if possible, at the time the decision is made to 
withdraw the patient. The Early Termination Visit will consist of all of the Study Visit 11 
procedures (see Section 6.4.4 and Appendix A); however, study drug will only be dispensed at this 
visit if tapering is applicable, and if so, the daily dose of study drug will be reduced to 
2 capsules QD (Nefecon 8 mg or placebo) for 2 weeks to prevent insufficiency of the adrenal 
glands (see Section 5.5.3). The patient is to continue in the study (unless the patient has withdrawn 
consent for any follow-up), and eGFR, proteinuria, and creatinine are to be measured at the 9- and 
12-month study visits (Study Visits 11 and 13) and the patient is to continue the follow-up in 
Part B. 
6.7.2 
End of Study Visit 
The study will continue until 25 months after the 360th/last patient is dosed (or, if the 360th/last 
patient randomized does not receive any study drug, 25 months after the 360th/last patient is 
randomized). 
For patients who are withdrawn from the study after completion of Study Visit 11 but prior to 
completion of Part B, 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 17a and 17b procedures (see Sections 6.6.2 and 6.6.3 and Appendix A). 
The patient will complete the End of Study Visit (Study Visits 17a and 17b) per protocol and 
subsequently end participation in the study if any of the following occur after completion of Study 
Visit 11 but prior to completion of Part B: 
 The patient experiences one of the following study endpoints: 
o Initiation of maintenance dialysis for at least 1 month; or 
o Kidney transplantation; 
 Termination of the study by Calliditas or the regulatory authority; or 
 The patient withdraws consent or requests discontinuation from the study for any reason. 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
50
7 
EFFICACY ASSESSMENTS 
For a detailed description of the statistical methods including the efficacy analyses, see Section 9.2.  
7.1 
Part A Analysis 
The data cut-off for the Part A analysis will occur once the first 201 patients randomized have had 
the opportunity to complete their 9-month visit. Therefore, it is expected the data cut-off will occur 
at the latest 9.5 months after the 201st patient randomized is dosed. The details of the Part A 
analysis are described in Section 9.2.3. 
The dataset extracted from the database, and cleaned for analysis, will include all safety data from 
all patients randomized at the data cut-off date and all efficacy data up to and including the 
12-month visit from all patients randomized at the data cut-off date. Therefore, any efficacy data 
recorded after 12 months will not be extracted from the database. 
7.1.1 
Part A Analysis Primary Efficacy Endpoint 
The primary efficacy endpoint for the Part A analysis is defined as the ratio of UPCR (based on 
24-hour urine collections) at 9 months following the first dose of study drug compared to baseline.  
7.1.2 
Part A Analysis Secondary Efficacy Endpoints 
The secondary efficacy endpoints for the Part A analysis are: 
 Ratio of eGFR at 9 and 12 months compared to baseline calculated using the CKD-EPI 
formula, and 
Note: A supportive analysis of 1-year eGFR slope will also be performed. 
 Ratio of urine albumin to creatinine ratio (UACR) at 9 months compared to baseline.  
Supportive analyses of the above endpoints will also be performed at all time points up to 
12 months to describe the time course of effect. 
7.2 
Part B Analysis 
The Part B analysis will be performed when the 360th/last patient randomized has had the 
opportunity to complete Visit 17b, which can occur up to 35 days after Visit 17a (the 24-month 
visit). 
7.2.1 
Part B Analysis Primary Efficacy Endpoint 
The primary efficacy endpoint for the Part B analysis is an area under the curve (AUC)-based 
endpoint of eGFR calculated as a time-weighted average of eGFR recordings observed at each 
time point over 2 years. The eGFR (CKD-EPI) at 2 years (which must be repeated to provide a 
second value obtained within 14 to 35 days) will be the geometric mean of the 2 assessments. A 
supportive analysis of 2-year eGFR slope will also be performed. 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
51
7.2.2 
Part B Analysis Secondary Efficacy Endpoints 
The secondary efficacy endpoints for the Part B analysis are: 
 Time to 30% reduction from baseline in eGFR (CKD-EPI) confirmed by a second value, with 
4 weeks of separation between the 2 sampling time points; 
 Time from the first dose of study drug until receiving rescue medication; 
 Ratio of UPCR, UACR, and eGFR (CKD-EPI) compared to baseline averaged over time points 
between 12 and 24 months, inclusive, following the first dose of study drug; 
 Proportion of patients without microhematuria in at least 2 of the following time points: 12, 18, 
and 24 months following the first dose of study drug; 
 Proportion of patients receiving rescue treatment; and 
 SF-36 quality of life assessment at 9 and 24 months (see Section 7.3). 
7.2.3 
Part B Analysis Exploratory Efficacy Endpoints 
Exploratory analyses may be performed on blood and urine to explore potential changes between 
the treatment groups that may add to the understanding of the disease mechanism and how the 
treatment influences these mechanisms (see Section 7.4). In addition, already existing kidney 
biopsy samples will be collected for exploratory analyses at a central reading unit. Participation 
and sample shipment for exploratory analyses will be optional. 
7.3 
Quality of Life Assessment 
The SF-36 quality of life assessment will be completed at the time points indicated in Appendix A. 
7.4 
Exploratory Biomarker Analyses and Genetic Analyses 
Where allowed per local regulations and Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) approval and patient consent (and assent, where applicable), optional exploratory 
blood (48 mL blood sample) and urine (20 mL urine sample) samples will be collected at the time 
points indicated in Appendix A. An optional exploratory genetic analysis blood (6 mL) sample 
will be collected at the time points indicated in Appendix A. Where local regulations allow, the 
samples will be stored at a central facility for up to 10 years and will be analyzed after the study 
is completed. The samples will be used to identify novel biomarkers predictive of disease 
progression or a response to Nefecon and to elucidate the biochemical pathways affected by 
treatment with Nefecon. Exploratory analyses of both blood and urine may include, but will not 
be limited to, IgA1, IgA2, monomer-polymer ratios, and immune complex levels. Exploratory, 
limited candidate gene analyses will be performed and may include, but will not be limited to, IgA 
allotypes, C1GALT1, and TAP1/PSMB genes as polymorphisms that are associated with response 
or adverse effects. These samples will only be collected and analyzed in countries where this is 
permitted. Details regarding the collection, processing, storage, and shipping of samples can be 
found in the laboratory manual. In addition, already existing kidney biopsy samples will be 
collected for exploratory analyses at a central reading unit. The kidney biopsies will be collected 
from local hospital pathology units, where allowed and agreed to by the patient, pathology unit, 
and biobanks, as applicable. All biopsy samples will be returned as required. 
 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
52
8 
SAFETY ASSESSMENTS 
8.1 
Adverse Events 
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. 
Adverse events, which include clinical laboratory test variables, will be monitored and 
documented by the Investigator (or his/her designee) from administration of the first dose of study 
drug (Study Visit 4) until 2 years (+14 to 35 days) after the first dose of study drug (Study 
Visit 17b), inclusive, regardless of whether the patient discontinues the study prematurely. If the 
patient does not receive study drug at Study Visit 4, AEs should still be monitored and documented 
from Study Visit 4. Patients should be instructed to report any AE that they experience to the 
Investigator (or his/her designee).  
Serious adverse events will be monitored and reported from signature of informed consent. 
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 when the first dose of study drug is administered 
(Study Visit 4) 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 when the first dose of study drug is 
administered (Study Visit 4) 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. 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
53
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 
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. 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
54
 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. 
 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)? 
Adverse events of special interest may or may not constitute an SAE. However, all types of AESIs 
must be reported 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 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
55
SAEs will be recorded from administration of first dose of study drug (Study Visit 4) until 2 years 
(+14 to 35 days) after the first dose of study drug (Study Visit 17b), inclusive, regardless of 
whether the patient discontinues the study prematurely. If the patient does not receive study drug 
at Study Visit 4, AESIs should still be monitored and documented from Study Visit 4. 
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. 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
56
8.4 
Serious Adverse Event Reporting − Procedures for Investigators 
Initial Reports 
All SAEs, irrespective of relatedness, occurring from signature of informed consent until 2 years 
(+14 to 35 days) after the first dose of study drug (Study Visit 17b) 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 (phone 
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. 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
57
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 
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 with study 
drug, or exist before but worsen in severity or relationship to study drug after dosing; 
 AESIs (severe infections 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); 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. 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
58
Blood pressure and heart rate will be measured after resting in the supine position for at least 
5 minutes. At the applicable study visits in the Screening Period, 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. 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
59
9 
STATISTICS 
9.1 
Analysis Populations 
The primary efficacy analyses will be based on the Full Analysis Set (FAS), which will include all 
randomized patients, regardless of whether the patient received study drug. For Part A, the FAS 
will include the first 201 patients randomized. The data cut-off for the Part A analysis will occur 
once the first 201 patients randomized have had the opportunity to complete their 9-month visit. 
Therefore, it is expected the data cut-off will occur at the latest 9.5 months after the 201st patient 
randomized is dosed. Two patients are excluded from the Part A FAS due to errors in 
randomization; this decision was pre-defined in the Statistical Analysis Plan prior to unblinding. 
It is a regulatory requirement in China that an appropriate number of patients (approximately 60) 
are recruited from this region in order to perform a consistency evaluation between China results 
and global results. If there are less than 60 patients from China when the global target of 
360 patients randomized has been reached, recruitment is closed in the global part of the study but 
continues in China. For Part B, the primary FAS will include all patients randomized at the 
completion of recruitment to the global part of the study, including any patients already recruited 
in China, with a data cut-off 25 months after the 360th/last patient is randomized. Any patient 
recruited in China after recruitment to the global part of the study will not be included in the Part B 
primary FAS. In addition, the Part A analysis will be repeated using all patients randomized when 
the Part B analysis is performed. 
The Safety Analysis Set will include all patients who receive at least 1 dose of study drug. All 
patients who have received at least 1 dose of study drug by the time of the data cut-off for Part A 
will be included in the safety analysis for Part A. Likewise, for Part B, the Safety Analysis Set will 
include all patients who have received at least 1 dose of study drug by the time recruitment is 
closed in the global part of the study. 
The China Cohort will include all patients randomized from China at any time with the 
corresponding FAS and Safety Analysis Set defined in the same manner as the global part of the 
study. 
The Per Protocol Set will include all patients in the FAS for whom no major protocol deviations 
(which may interfere with efficacy evaluation) occurred in Part A and Part B. Full details of 
inclusions and exclusions from the Per Protocol Set – Part A and Per Protocol Set – Part B will be 
in the classifications specifications and finalized before unblinding. The Per Protocol Set will be 
used to assess robustness of the primary analysis results. 
9.2 
Statistical Methods 
Patients will be randomized in a 1:1 ratio to Nefecon 16 mg or placebo. Randomization will be 
stratified according to baseline proteinuria, eGFR, and geographic region. 
A multiplicity strategy will be used to control type I error amongst the primary and key secondary 
efficacy endpoints across both Part A and Part B. See Section 9.2.1.5 for further details. 
Baseline proteinuria, eGFR, UPCR, and UACR will be the geometric mean of the 2 consecutive 
measurements prior to randomization. 
The protocol requires that all randomized patients continue to have assessments performed at each 
scheduled visit regardless of whether they prematurely discontinue study drug or even if they are 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
60
randomized but do not receive any study drug. However, any data recorded after a patient receives 
rescue medication will be excluded from the primary efficacy analyses in Parts A and B so that 
the underlying effect of Nefecon can be estimated free from the confounding effects of rescue 
medication. Rescue is defined as any immunosuppressive medication that would be expected to 
materially impact efficacy, regardless of whether the medication is used for IgAN. A blinded 
medical review of concomitant therapy will be performed prior to unblinding to decide and 
document which patients are to be defined as having rescue and over what time period. 
All efficacy assessments, including those from unscheduled visits and regardless of visit label, will 
be allocated to analysis visits based on Table 1. 
Table 1. 
Time Windows Applied to Efficacy Assessments 
Study Period 
Scheduled Visit 
Time Interval (days after first 
dose of study drug) 
Part A Treatment 
Visit 7 (3 months, Day 91)
2 to 137
Visit 9 (6 months, Day 183)
138 to 228
Visit 11 (9 months, Day 274)
229 to 319
Part A Follow-up
Visit 13 (12 months, Day 365)
320 to 456
Part B Follow-up 
Visit 15 (18 months, Day 548)
457 to 639
Visit 17 (24 months, Day 730)
640 to 821
If more than one measurement is recorded within a visit window, the geometric mean of all measurements within the window 
will be used in the analysis.
9.2.1 
Analysis of Efficacy 
9.2.1.1 
Analysis of Part B primary efficacy endpoint 
The primary efficacy endpoint for the Part B analysis is an AUC-based endpoint calculated as a 
time-weighted average of eGFR (CKD-EPI) measurements recorded over 2 years, where each time 
point is given a weight in proportion to the time elapsing from the previous recording. Therefore, 
recordings made at 18 and 24 months receive twice as much weight as those made at 3, 6, 9, and 
12 months. The weights will sum to one so that the treatment effect can be interpreted as the 
average effect of Nefecon over 2 years. Table 2 displays the weight given to each time point. 
Table 2. 
Weight Applied to Each Time Point in the Calculation of the 2-Year eGFR AUC 
Time Point 
Weight Applied to Each Time Point 
3 months
0.125
6 months
0.125
9 months
0.125
12 months
0.125
18 months
0.25
24 months
0.25
AUC = area under the curve; CKD-EPI = Chronic Kidney Disease Epidemiology 
Collaboration; eGFR = estimated glomerular filtration rate (CKD-EPI).
The eGFR data will be log-transformed prior to analysis. Data included at baseline and 24 months 
will be the log of the geometric mean of the 2 replicate values recorded at each time point, 
respectively. Previous eGFR data from Nefecon trials suggest it is possible there will be a small 
sub-population of patients with extreme outlying data resulting from very rapid progression of 
disease. Therefore, the primary analysis will be based on a Robust Regression approach.29 In order 
to handle missing data, the analysis will be performed over 3 phases: an imputation, analysis, and 
pooling phase, as described below. Further details are provided in the Statistical Analysis Plan.  


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
61
Imputation phase 
The first step of the imputation phase will create data with a monotone data structure having 
imputed 20 datasets separately within each treatment arm. For example, in this step, patients with 
missing data at Month 18 would only have data imputed if they had data recorded at Month 24. 
The number of burn-in iterations will be set to 200, and observations will be sampled every 
100 iterations within the same chain for each imputed dataset. In the second step of the imputation 
phase, data will be multiply imputed using a regression method sequentially imputing data across 
successive visits separately by treatment arm from each dataset imputed in the first step. 
Analysis phase 
In the analysis phase, the AUC will be calculated for each patient within each imputed dataset and 
analyzed using Robust Regression with independent variables of treatment and log-transformed 
baseline eGFR. M-estimation will be used with Huber weights and a cut-off value of 2 with the 
median method used to estimate the scale parameter. 
Pooling phase  
In the pooling phase, estimated treatment effects and associated standard errors from each 
imputation will be combined using Rubin’s rules to provide an overall treatment effect, associated 
95% confidence interval (CI), and 2-sided p-value. 
9.2.1.2 
Analysis of eGFR slope 
A supportive analysis of 2-year eGFR slope will be performed using a random coefficients 
model.30 This model is a mixed, repeated measures model which enables the analysis to be 
performed in a single step, allowing for the eGFR slope to vary between patients. Note, unlike the 
primary approach, data will not be log-transformed prior to analysis. The actual time 
measurements taken, in years after randomization, will be included in the model as a continuous 
variable. Any unscheduled values will be included in the model at the actual time they were 
recorded.   
A sensitivity analysis will be planned in case the normality of the between-patient distribution of 
slopes is questionable (e.g., if there are outlying data). In this sensitivity analysis, each patient’s 
slope will be estimated from a separate linear regression fitted to each patient, with the resultant 
slope data compared between arms using Robust Regression.   
9.2.1.3 
Analysis of time to 30% reduction in eGFR (Part B) 
The time to a 30% reduction in eGFR (CKD-EPI) will be measured from the time of the first dose 
of study drug and will include all data prior to the use of rescue medication even if the clinical 
event occurs in Part A. 
To count as a clinical event and to reduce the presence of false-positive reductions, the 30% 
reduction should be confirmed at a later time point. When a clinical event is confirmed, the time 
to the first reduction will be used in the analysis. The first eGFR reduction that is greater than 30% 
will count as a clinical event in the following situations: 
 If a later reduction is observed, but after at most 1 intervening occurrence where the eGFR has 
not reduced by 30%, and the geometric mean reduction of these 3 values is reduced by greater 
than 30%;  


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
62
 The first reduction occurs at 24 months or the visit for the replicate eGFR sample, and there 
are no later recordings of eGFR; and/or 
 The patient receives dialysis, undergoes renal transplantation, or dies after the first reduction, 
but before a confirmation can be made. 
To prevent informative censoring, if a patient dies from a renal-related event, as determined by a 
blinded medical review, or has dialysis for at least 1 month, kidney transplantation, or kidney 
failure defined as a sustained eGFR <15 mL/min/1.73 m2 prior to a 30% reduction, they will be 
included in the analysis as having had a clinical event occur at that time. Patients will be defined 
as having a renal-related death if the Investigator provides “Death due to kidney failure” as being 
the reason for early termination from the study and is confirmed on blinded medical review.  
Dialysis and kidney transplantation will be identified from the concomitant procedures eCRF.  
Otherwise, patients will be censored at the time of their last eGFR recording prior to the use of 
rescue medication. 
The time to a 30% reduction in eGFR (CKD-EPI) will be analyzed using an Inverse Probability of 
Censoring Weights model. This approach estimates the effect of Nefecon in the absence of the use 
of rescue medication and censors patients who take rescue medication and matches them with 
those that did not based on their clinical status at the time, such as their change in UPCR or eGFR 
from baseline and whether they have had an initial 30% reduction from baseline in eGFR, and 
reweighting based on the outcome of matched patients. Full details are provided in the Statistical 
Analysis Plan.  
9.2.1.4 
Analysis of other secondary efficacy endpoints in Part B 
To estimate the average of parameters UPCR and UACR between 12 and 24 months, values will 
be log-transformed prior to analysis and will be analyzed using a Mixed Model Repeated Measures 
(MMRM) model with separate visit terms for 3, 6, 9, 12, 18, and 24 months together with terms 
for treatment-by-visit, baseline, and baseline-by-visit, and back-transformed to estimate the 
geometric mean of the treatment effects over 12, 18, and 24 months. The corresponding analysis 
of average eGFR (CKD-EPI) over 12 to 24 months will use the same methodology that is applied 
to the Part B primary efficacy endpoint, except that the visits at 12, 18, and 24 months will be 
given equal weight.  
Any binary endpoints that compare the proportion of patients with an outcome will be analyzed 
using a logistic regression model and will include terms for randomized treatment, log-baseline 
UPCR, log-baseline eGFR, and geographic region. The odds ratio will be estimated together with 
the associated 95% CI and p-value, with the CI estimated using a profile-likelihood approach and 
the p-values from a likelihood-ratio test. 
9.2.1.5 
Hypothesis testing strategy 
In order to provide strong control of the type I error rate of 2.5% 1-sided across both Part A 
and Part B of the study, the endpoints of UPCR at 9 months from Part A and 2-year eGFR AUC 
from Part B will be tested in an endpoint hierarchy as described in Figure 2. If an endpoint is 
statistically significant at the specified alpha level, its alpha will be recycled to the next endpoint 
in the hierarchy. 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
63
Figure 2. Summary of the Hypothesis Testing Strategy 
 
Alpha is 1-sided. 
2-year slope = 2-year eGFR slope; AUC = area under the curve; CKD-EPI = Chronic Kidney Disease Epidemiology 
Collaboration; eGFR = estimated glomerular filtration rate (CKD-EPI); m = months; UPCR = urine protein to creatinine ratio. 
This approach means the primary endpoint in Part A, UPCR at 9 months, will be statistically 
significant if the 1-sided p-value is 0.02, in which case the Part B primary endpoint, 2-year eGFR 
AUC, will be tested at a 1-sided significance level of 0.025. If the 1-sided p-value for UPCR is 
>0.02, the Part B primary endpoint will be tested at a 1-sided significance level of 0.005. If the 
Part B primary endpoint is statistically significant, 2-year eGFR slope will be tested at the same 
significance level as applied to the Part B primary endpoint. 
9.2.1.6 
Analysis by subgroup 
The primary endpoint will be summarized according to important subgroups. The subgroup 
analyses performed will include the following: 
 Baseline proteinuria, 
 Baseline eGFR, 
 Dose of RAS inhibitor therapy (ACEIs and/or ARBs) (taking the maximum acceptable dose 
or MTD versus not taking the maximum acceptable dose or MTD), 
 Region, 
 Age, 
 Gender, 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
64
 Ethnicity, and 
 Race. 
A global interaction test amongst all subgroups will be performed for UPCR at 9 months and 
2-year eGFR AUC to assess whether any heterogeneity in the treatment effect between subgroups 
is consistent with a constant treatment effect across all subgroups. This analysis will be performed 
by comparing the fit of a model that contains treatment, the main effects for all subgroups, and all 
treatment-by-subgroup interactions to one without the interaction terms. 
9.2.2 
Analysis of Safety 
For both Part A and Part B, 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 and 
AESIs, as described in Section 8.2, will be summarized by body system and organ class. In 
addition, the time to first occurrence of the most common event will be summarized using 
cumulative incidence plots by each period of the study. Safety data will be summarized or listed 
separately for the period between screening and the first dose of medication. 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. 
The primary objective of the analyses is to describe the safety and tolerability of Nefecon, for the 
intended 9-month regimen, while patients are still receiving therapy. The on-treatment period, used 
to determine whether the patient is still receiving therapy, is defined from the first dose of therapy 
until 14 days after completion of the Tapering Period. Secondary analyses will be performed to 
describe the safety recorded during follow-up, after discontinuation of study treatment. 
Summary statistics will be presented for changes in vital signs and laboratory tests throughout the 
study. Physical examinations will be listed.  
9.2.3 
Part A Analysis 
The data cut-off for the Part A analysis will occur once the first 201 patients randomized have had 
the opportunity to complete their 9-month visit. Therefore, it is expected the data cut-off will occur 
at the latest 9.5 months after the 201st patient randomized is dosed. 
The dataset extracted from the database, and cleaned for analysis, will include all safety data from 
all patients randomized at the data cut-off date and all efficacy data up to and including the 
12-month visit from all patients randomized at the data cut-off date. Therefore, any efficacy data 
recorded after 12 months will not be extracted from the database. 
The primary efficacy endpoint for the Part A analysis, the ratio of UPCR at 9 months to baseline, 
will be log-transformed prior to analysis, as will data from the other time points used in the analysis 
model. The treatment effect will be expressed as a percent reduction in UPCR for Nefecon 
compared to placebo and will be derived from the geometric least squares mean ratios estimated 
at 9 months for each treatment arm. The primary analysis of the log-transformed baseline ratios in 
UPCR will be analyzed using an MMRM analysis based on the FAS and incorporating UPCR data 
from baseline, 3 months, 6 months, 9 months, and 12 months. Baseline UPCR will be included as 
a covariate and will be calculated as the geometric mean of the 2 pre-randomization UPCR 
measurements. The model will also include terms for treatment group, visit, baseline by visit, and 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
65
visit by treatment group interaction. Patient will be included as a random effect. An unstructured 
covariance matrix will be used to model the within-patient correlation of data. The 
Kenward-Roger’s degrees-of-freedom adjustment will be used. Restricted maximum likelihood 
will be used to obtain parameter estimates. The least-squares means will be estimated by visit 
along with the associated 95% CI and p-values with the primary analysis taken from the estimate 
at 9 months. Model assumptions of the MMRM will be assessed using residual plots (such as q-q 
plots, histograms, box plots, and scatter plots). 
The following sensitivity analyses will be performed on the primary efficacy endpoint for Part A: 
1. Sensitivity to missing data at 9 months: While it is intended that complete data will be recorded 
at 9 months, if there is a reasonable amount of missing data, the robustness of the primary 
analysis will be assessed. The objective of the primary analysis is to estimate the net effect of 
Nefecon despite any early patient withdrawal. If missing data are observed following 
discontinuation, the MMRM will estimate what would have happened had patients not 
discontinued and the treatment effect may be biased. To assess the robustness, a multiple 
imputation approach will be performed where the relationship between 9-month data and 
discontinuation will be modelled separately within each treatment group, and using that 
relationship, data missing post-discontinuation will be multiply imputed based on data 
observed post-discontinuation in other patients. The exact specification of the model used will 
be defined in the Statistical Analysis Plan. In the unlikely event a patient dies before 9 months, 
they will have the worst observed outcome across treatment arms imputed; 
2. Sensitivity to assumption of normality: If examination of residual plots indicates clear 
non-normality, then UPCR data at 9 months will additionally be analyzed using a Robust 
Regression approach after first multiply imputing any missing data in the same manner as 
described for the analysis of 2-year eGFR AUC (Section 9.2.1.1);  
3. Sensitivity to handling of rescue medication: In this analysis, the primary analysis will be 
repeated, except any data observed after rescue treatment will be included;   
4. Tipping point analysis: A 2-dimensional tipping point analysis will be performed, whose 
purpose is to assess how much worse the outcomes on Nefecon patients, and how much better 
the outcomes on placebo patients, with missing data would need to be before the statistical 
significance of the primary endpoint is lost. Further details are provided in the Statistical 
Analysis Plan; and 
5. Supplementary analysis including all patients randomized: When the primary efficacy analysis 
is performed, there will be additional patients who have been randomized but have yet to be 
followed for 9 months. A supplementary analysis will be performed where the MMRM is 
repeated but includes all patients randomized and hence will increase the amount of data 
included at 3 and 6 months. This analysis would be expected to produce a very similar 
treatment effect and CI at 9 months, unless the treatment effect at 3 and 6 months amongst 
patients recruited after the 201st patient is different than those included in the primary analysis. 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
66
9.2.4 
Data and Safety Monitoring Board 
A DSMB will be established to review and discuss the available study data as patients are 
randomized and followed throughout the study. The DSMB may also act as an expert, independent 
advisory to study conduct. The DSMB will meet periodically throughout the course of the study 
to review unblinded safety data. Details of the composition, roles, and responsibilities of the 
DSMB will be documented in the DSMB Charter. 
9.2.5 
Sample Size Determination 
9.2.5.1 
Part A analysis 
The Nefecon Phase 2b study (Nef-202) gave an estimated standard deviation of 0.59 for the change 
in the log of UPCR from baseline after 9 months of treatment. Based on this assumption, 
200 patients in Part A will provide >90% power to demonstrate statistical significance at a 1-sided 
alpha level of 0.025 given a true 25% relative reduction in UPCR with Nefecon treatment 
compared to placebo. 
9.2.5.2 
Part B analysis 
A 28% reduction in UPCR, relative to placebo, was observed with the 16 mg dose of Nefecon in 
the Phase 2b study. Based on an analysis of the relationship between treatment effects on 
proteinuria at 1 year and the 2-year eGFR slope31 using aggregate data for trials in IgAN presented 
at the March 2018 NKF/FDA/EMA workshop Change in Albuminuria and GFR as End Points for 
Clinical Trials in Early Stages of Chronic Kidney Disease, a 28% reduction in UPCR is predicted 
to translate into a treatment effect of 1.12 mL/min/1.73 m2/year on 2-year eGFR slope, and hence, 
a 2.24 mL/min/1.73 m2 treatment effect for the difference in mean eGFR at 2 years. If 360 patients 
are recruited and followed for 2 years, and replicate values of eGFR are recorded both at baseline 
and at 2 years, Part B will have 90% power to detect a statistically significant difference in eGFR 
at 2 years, using a 2-sided alpha of 5%, if the true effect of Nefecon is 2.24 mL/min/1.73 m2. This 
calculation is based on the following set of assumptions: 
 The mean eGFR at 2 years in the placebo group is 60 mL/min/1.73 m2 so that the treatment 
effect corresponds to a difference of 0.03665 on the log-scale; 
 The between-patient standard deviation of eGFR at baseline and 2 years is 0.32 and 0.35, 
respectively, on the log-scale as observed at baseline and 1 year in the Phase 2b study; 
 The correlation between repeat log-transformed values at baseline and 2 years is 0.946 and 
0.939, respectively, and the correlation between baseline and 2-year eGFR values is 0.935. 
These values were based on data observed in the Phase 2b study; 
 Combining the between-patient variability and correlation coefficients leads to an expected 
standard deviation for a log-transformed analysis of covariance of the mean of replicate eGFR 
values of 0.093; 
 A 1-sided significance level of 2.5%; and 
 A worst-case assumption for dropout rate by 2 years of 25%. 
The power for the primary efficacy endpoint for Part B, 2-year eGFR AUC, is >90% for the 
expected mean eGFR profiles for Nefecon and placebo over 2 years. A worst-case analysis of 
eGFR data from Nef-202 demonstrated a 3.7 mL/min/1.73 m2 improvement in eGFR at 12 months. 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
67
In this case, the power for 2-year eGFR AUC is >99%, assuming efficacy reduces linearly after 
12 months to a mean difference of 2.24 mL/min/1.73 m2 at 2 years. Supportive simulations 
demonstrated that Part B remains fully powered for 2-year eGFR AUC, using the primary analysis 
method of Robust Regression with imputation, even if the rate of outlying data more than doubles 
compared to Nef-202. 
A total of 360 randomized patients are planned to be evaluable for the final primary efficacy 
analysis for the study. 
It is estimated that approximately 900 patients will be screened. 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
68
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 (21 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 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
69
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.  


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
70
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 IRB/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 
Delegation of Investigator Duties 
The Investigator should ensure that all persons assisting with this study are adequately qualified 
and informed about their study-related duties and functions, including the study treatment.  
The International Coordinating Investigator selected by Calliditas will be a representative of all 
Investigators for this study. The International Coordinating Investigator will be the signatory on 
the clinical study report. Each Investigator will maintain a list of Sub-Investigators and other 
appropriately qualified persons to whom they delegate significant study-related duties.  
Should the Investigator delegate the supervision of the administration of study treatment, the 
designee should have the appropriate medical qualifications to effectively conduct or supervise 
any potential resuscitation procedures. 
11.4 
Informed Consent 
The ICF will include Part A and Part B of the study. 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 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
71
legal requirements. The Covid-19 pandemic-related ICF addendum will be implemented at the 
time of IRB submission of the current protocol amendment (Version 5.0).  
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. 
Patients will also be given the option to participate in the exploratory kidney biopsy and biomarker 
analyses and to provide a genetic sample for exploratory, limited candidate gene analyses; 
participation will require completion of a separate ICF and separate consents each for the 
biomarker analyses, kidney biopsy analyses, and genetic analyses. 
11.5 
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. 
11.6 
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. 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
72
Patient source data is confidential and disclosure to third parties other than those noted above is 
prohibited. 
11.7 
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. 
11.8 
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. 
11.9 
Financial Disclosure 
Investigators are required to provide financial disclosure information to Calliditas to permit 
Calliditas to fulfill 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. 
11.10 
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. 
11.11 
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.  


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
73
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. 
12.2 
Address List 
12.2.1 
Sponsor 
Calliditas Therapeutics AB 
Kungsbron 1 
SE-111 22 Stockholm, Sweden 
Telephone: +46 8 411 3005 
12.2.2 
Contract Research Organization 
Medpace, Inc. 
5375 Medpace Way 
Cincinnati, OH 45227 
United States 
Telephone: +1-513-579-9911 
Fax: +1-513-579-0444 
12.2.3 
Serious Adverse Event Reporting 
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 
12.2.4 
Biological Specimens 
Medpace Reference Laboratories (US, Belgium and/or Singapore locations)* 
Corporate address: 
5365 Medpace Way  
Cincinnati, OH 45227 
United States 
Telephone: +1-513-366-3270 
Fax: +1-513-366-3273 
*For specific shipping information refer to the laboratory manual. 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
74
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. 
 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
75
 
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 Version 8, dated 
28 February 2019. 
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. 
Maronna RA, Martin RD, Yohai VJ, et al. Robust statistics: theory and methods. 2nd ed. 
West Sussex, UK: John Wiley & Sons Ltd; 2019. 
30. 
Brown H, Prescott R. Applied mixed models in medicine. 3rd ed. John Wiley & Sons, 
Ltd; 2015. 
31. 
Stone AM, Cattran DC, Floege J, et al. Relationship between treatment effects for 
proteinuria and eGFR slope over 2 years in patients with IgA nephropathy. Abstract 
TH-OR108. American Society of Nephrology. 07 November 2019. 
 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
76
APPENDIX A:  SCHEDULE OF PROCEDURES 
Table 3. 
Schedule of Procedures – Part A 
Study Period
Screening 
Treatment 
Follow-Up1 
Study Visit
1 
2 
32 
NA 
43 
5 
6 
7 
8 
9 
10 
11/ET4 
12 
13 
Study Day, Week, or Month
See footnote5 
 
1d 
3w 
6w 
3m 
4.5m 
6m 
7.5m 
9m6 
10.5m 
12m 
Visit Window (Days)
Procedure 
 
 
 
 
 
7 
7 
7 
7 
7 
7 
-7 to 
+28 
7 
7 
Visit conducted by telephone 
X
X
X
X
X
Informed consent7
X
Demographics and 
medical/surgical history
X
 
 
 
 
 
 
 
 
Update medical/surgical history
X
X
Eligibility criteria assessment
X
X
X
Contact IRT to trigger study drug 
shipment and randomization8
X9
 
 
 
Concomitant medications and 
procedures10
X11
X
X
X
X
X
X
X
X
X
X
X
AE assessment12,13
 X13
 X13
 X12
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
Vital signs14
X
X
X
X
X
X
X
Body weight and height15
X
X
X
X
X
X
Confirm biopsy slide and report 
availability16
X
 
 
 
Hematology17
X
X
X
X
X
X
Serum chemistry18
X
X
X
X
X
X
HIV, tuberculosis, HBV, and 
HCV19
X
 
 
 
Drug and alcohol screen (urine)
X
Fasting lipid profile
X
eGFR (CKD-EPI)20
X
X
X
X
X
X
Urinalysis21
X
X
X
X
X
X
24-hour urine collection10
X
X
X
X
X
X
Supply 24-hour urine container
X
X
X
X
X
X
X
Exploratory sampling (optional)7,22
X
X
X
X
X
See footnotes at the end of the Schedule of Procedures – Part A table 
 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
77
Table 3. 
Schedule of Procedures – Part A (Continued) 
Study Period
Screening 
 
Treatment 
Follow-Up1 
Study Visit
1 
2 
32 
NA 
43 
5 
6 
7 
8 
9 
10 
11/ET4 
12 
13 
Study Day, Week, or Month
See footnote5 
 
1d 
3w 
6w 
3m 
4.5m 
6m 
7.5m 
9m6 
10.5m 
12m 
Visit Window (Days)
Procedure 
 
 
 
 
 
7 
7 
7 
7 
7 
7 
-7 to 
+28 
7 
7 
Genetic sample (optional)7,23
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Pregnancy test24
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
FSH25
X
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispensing of study drug8
 
 
 
 
X
 
 
X
 
X
 
 X26
 
 
Start of study drug9
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Begin 2-week Tapering Period
 
 
 
 
 
 
 
 
 
 
X
 
Return of unused study drug
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 X26 
Study drug accountability and 
compliance assessment27
X
X
X
X
X
X
X
X
X
SF-36 QoL assessment
X
X
Capture dialysis, transplant, or 
death28
X
X
X
X
X
X
X
X
X
X
Dietary and lifestyle 
recommendations29
X
Note: Prior to conducting any study-related activities, written informed consent must be signed and dated by the patient. 
1. 
Following completion of the Treatment Period, patients will enter the 3-month Part A Follow-up Period. The first 2 weeks of this Follow-up Period will consist of a 2-week 
Tapering Period to reduce the risk of insufficiency of the adrenal glands. During the 2-week Tapering Period, the study drug dose will be reduced from 4 capsules QD 
(Nefecon 16 mg or placebo) to 2 capsules QD (Nefecon 8 mg or placebo). For patients who are withdrawn from the study after completion of Study Visit 11 but prior to 
completion of Part B, the End of Study Visit procedures (see Table 4) will be completed, if possible, at the time the decision is made to withdraw the patient. 
2. 
Patients will be required to fast for at least 10 hours prior to Study Visit 3. 
3. 
Study Visit 4 should occur within 10 days after randomization. 
4. 
See Section 4.3 for additional details related to withdrawal criteria. For patients who are withdrawn from the study prior to completion of Study Visit 11, the ET Visit 
procedures will be completed, if possible, at the time the decision is made to withdraw the patient. The ET Visit will consist of all of the Study Visit 11 procedures; however, 
study drug will only be dispensed at this visit if tapering is applicable, and if so, the daily dose of study drug will be reduced to 2 capsules QD (Nefecon 8 mg or placebo) for 
2 weeks to prevent insufficiency of the adrenal glands. 
5. 
Patients will have a Screening Period lasting up to 35 days (prior to randomization). If informed consent has been obtained, SAEs have been assessed, and the patient has been 
supplied with container(s) for the next 24-hour urine collection, the remaining Study Visit 1 procedures may, at the discretion of the Investigator, be performed at Study 
Visit 2. Study Visit 3 must occur at least 2 weeks after Study Visit 2 in order to collect 2 proteinuria measurements separated by at least 2 weeks to determine eligibility.  
6. 
Study Visit 11 may occur at 10 months, when applicable, due to the Covid-19 pandemic. 
7. 
The ICF will include Part A and Part B of the study. The estimated duration of individual patient participation in Part A will be approximately 1 year and the estimated 
median duration of individual patient participation in Part B will be approximately 1 year (maximum of 26.5 months of individual patient participation in the study). As part 
of the informed consent process, only patients who fully understand and agree to full participation and follow-up should be consented to participate. At Study Visit 1 
(screening), patients will be given the option to participate in the exploratory kidney biopsy and biomarker analyses and to provide a genetic sample for exploratory, limited 
candidate gene analyses; participation will require signing of separate ICFs, one for the biomarker analyses, one for the kidney biopsy analyses, and one for the genetic 
analyses. If a re-screened patient agrees to participate in the exploratory kidney biopsy and/or biomarker analyses and signed the specific ICF for the previous screening, then 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
78
this patient must be re-consented and the biomarker samples must be repeated (except for the already existing kidney biopsy samples). A separate Covid-19 pandemic-related 
ICF addendum will be signed by patients to be treated for up to 10 months. 
8. 
After confirming all eligibility criteria (laboratory values from Study Visits 1, 2, 3, etc.) (eGFR values from Study Visits 1 or 3 must be within the limits defined by the 
inclusion criteria for the patient to be eligible), randomization will be performed through IRT which 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 7, 9, and 11 (for the Tapering Period). 
When study drug is dispensed, the patient will also be instructed on study drug administration. 
9. 
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 approximately 1 hour before 
breakfast. 
10. Systemic immunosuppressive drugs (including GCSs), except when used as rescue medications, are prohibited during the study. However, over the entirety of the study 
(Parts A and B), patients will be allowed up to 3 courses of treatment with GCSs in any 2-year period for non-IgAN indications, provided no treatment course is greater than 
2 weeks and the GCS dose does not exceed the equivalent of 0.5 mg/kg/day prednisolone. Such short-term treatment will not require change or stop of study drug treatment in 
Part A. For both Part A and Part B, study visits that include collection of 24-hour urine samples for efficacy assessments must not be performed within 4 weeks of such 
short-term GCS treatment. A 24-hour urine collection can be repeated if the Investigator suspects that the sampling is insufficient. Study visits are to be postponed as needed. 
11. Medications taken within 3 months prior to Study Visit 1 (screening) and concomitant medications and therapies will be recorded in the eCRFs. 
12. Beginning at Study Visit 4, AEs and AESIs will be assessed after administration of the first dose of study drug until 2 years (+14 to 35 days) after the first dose of study drug 
(Study Visit 17b), inclusive, regardless of whether the patient discontinues the study prematurely. If the patient does not receive study drug at Study Visit 4, AEs should still 
be monitored and documented from Study Visit 4. 
13. Serious adverse events will be monitored and reported from signature of informed consent. 
14. 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 the applicable study visits in the Screening Period, 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). 
15. Height will only be collected at Study Visit 1. 
16. Confirm that the kidney biopsy report(s) verifies IgAN diagnosis and that the kidney biopsy slide(s), or equivalent, can be obtained for central reading. 
17. Hematology, including HbA1c. See Appendix B for the complete list of analytes. 
18. Serum chemistry. See Appendix B for the complete list of analytes. 
19. If the patient is re-screened, HBV, HCV, HIV, and tuberculosis screenings should not be repeated if done as part of the study within the last 12 months. 
20. The central laboratory will calculate the eGFR using the CKD-EPI formula. The eGFR values from Study Visits 1 or 3 must be within the limits defined by the inclusion 
criteria for the patient to be eligible. 
21. 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. 
22. Blood (48 mL) and urine (20 mL) samples will be collected for exploratory biomarker analyses (optional). 
23. A blood (6 mL) sample will be collected for exploratory genetic analysis (optional). 
24. For women of childbearing potential only. A serum pregnancy test will only be performed at Study Visit 3. A pregnancy test via a local urine assessment will be performed at 
all other applicable study visits. 
25. Postmenopausal women will have a confirmatory FSH test performed at Study Visit 1. 
26. Study drug will be dispensed for the Tapering Period at Study Visit 11 and patients will return unused study drug at the next onsite study visit (Study Visit 13). 
27. Only treatment compliance will be assessed during study visits conducted by telephone. 
28. Assess the occurrence of one of the following study endpoints: initiation of maintenance dialysis for at least 1 month, kidney transplantation, or any death. 
29. 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; Covid-19 = Coronavirus Disease 2019; 
d = day(s); eCRF = electronic case report form; eGFR = estimated glomerular filtration rate; ET = Early Termination; FSH = follicle-stimulating hormone; GCS = glucocorticoid; 
HbA1c = hemoglobin A1c; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; ICF = Informed Consent Form; IgAN = immunoglobulin A 
nephropathy; IRT = Interactive Response Technology; m = month(s); NA = not applicable; QD = once per day; QoL = quality of life; SF-36 = Short Form 36; w = week(s).


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
79
Table 4. 
Schedule of Procedures – Part B 
Study Period
Part B Follow-Up1
Study Visit
14 
15 
16 
17a/EOS2 
17b/EOS2 
Study Year/Month
1y 
3m 
1y 
6m 
1y 
9m 
2 years 
2 years 
Visit Window (Days)
Procedures 
7 
30 
7 
30 
14 to 35 days 
after Visit 17a 
Visit conducted by telephone
X
X
Concomitant medications and procedures3
X
X
X
X
X
AE assessment (including AESIs and SAEs)
X
X
X
X
X
Physical examination
X
Vital signs4
X
X
Body weight
X
X
Hematology5
X
X
Serum chemistry6
X
X
X
eGFR (CKD-EPI)7 
X
X
X
Urinalysis8
X
X
24-hour urine collection3
X
X
Supply 24-hour urine container
X
Exploratory sampling (optional)9
X
SF-36 QoL assessment
X
Capture dialysis, transplant, or death10
X
X
X
X
1. 
Part B will continue until 25 months after the 360th/last patient is dosed (or, if the 360th/last patient randomized does not receive any study drug, 25 months after the 360th/last 
patient is randomized). 
2. 
See Section 4.3 for additional details related to withdrawal criteria. For patients who are withdrawn from the study after completion of Study Visit 11 but prior to completion 
of Part B, the EOS Visit procedures will be completed, if possible, at the time the decision is made to withdraw the patient. The EOS Visit will consist of all of the 
Study Visit 17a and 17b procedures. The patient will complete the EOS Visit (Study Visits 17a and 17b) per protocol and subsequently end participation in the study if any of 
the following occur: the patient experiences initiation of maintenance dialysis for at least 1 month or kidney transplantation; the 360th/last patient randomized has been 
followed for 25 months; termination of the study by Calliditas Therapeutics AB or the regulatory authority; or the patient withdraws consent or requests discontinuation from 
the study for any reason. 
3. 
Systemic immunosuppressive drugs (including GCSs), except when used as rescue medications, are prohibited during the study. However, over the entirety of the study 
(Parts A and B), patients will be allowed up to 3 courses of treatment with GCSs in any 2-year period for non-IgAN indications, provided no treatment course is greater than 
2 weeks and the GCS dose does not exceed the equivalent of 0.5 mg/kg/day prednisolone. Such short-term treatment will not require change or stop of study drug treatment in 
Part A. For both Part A and Part B, study visits that include collection of 24-hour urine samples for efficacy assessments must not be performed within 4 weeks of such 
short-term GCS treatment. A 24-hour urine collection can be repeated if the Investigator suspects that the sampling is insufficient. Study visits are to be postponed as needed. 
4. 
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. 
5. 
Hematology, including HbA1c. See Appendix B for the complete list of analytes. 
6. 
Serum chemistry. See Appendix B for the complete list of analytes. At Study Visit 17b, only serum creatinine will be assessed. 
7. 
The central laboratory will calculate the eGFR using the CKD-EPI formula. 
8. 
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. 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
80
9. 
Blood (48 mL) and urine (20 mL) samples will be collected for exploratory biomarker analyses (optional). 
10. Assess the occurrence of one of the following study endpoints: initiation of maintenance dialysis for at least 1 month, kidney transplantation, or any death. 
AE = adverse event; AESI = adverse event of special interest; CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; eGFR = estimated glomerular filtration rate; 
EOS = End of Study; GCS = glucocorticoid; HbA1c = hemoglobin A1c; IgAN = immunoglobulin A nephropathy; m = month(s); QoL = quality of life; SAE = serious adverse 
event; SF-36 = Short Form 36; y = year(s). 
 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
81
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 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)
 
 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
82
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
Cortisol
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.


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
83
APPENDIX C:  SUMMARY OF PART A AND PART B 
Figure 3. Summary of Part A*  
1. 
Assessments for AEs, including AESIs, and the occurrence of one of the study endpoints (initiation of maintenance dialysis for at least 1 month, kidney transplantation, or any 
death) will begin at Study Visit 4. 
*Patients may be treated for up to 10 months, when applicable, due to the Covid-19 pandemic. 
AE = adverse event; AESI = adverse event of special interest; Covid-19 = Coronavirus Disease 2019; d = day(s); h = hour; ICF = Informed Consent Form; m = months; 
labs = laboratory assessments; SAE = serious adverse event; V = Study visit; w = weeks. 
 
 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
84
Figure 4. Summary of Part B 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Assessments for the occurrence of one of the study endpoints (initiation of maintenance dialysis for at least 1 month, kidney transplantation, or any death) will continue until 
the end of the study. 
AE = adverse event; conmeds = concomitant medications; d = days; eGFR = estimated glomerular filtration rate; h = hour; labs = laboratory assessments; m = months; 
SCr = serum creatinine; V = Study visit; y = year. 
24h Urine, Labs, etc. 
24h Urine, Labs, etc.
Phone
          V17b 
14 to 35d after V17a 
Phone
V14 
1y3m 
V15 
1y6m 
V17a 
2yrs 
V16 
1y9m 
Labs (SCr), eGFR, AEs, & ConMeds
End of Study 
Part B Follow-up 
Beginning of Part B 
1y 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
85
APPENDIX D:  RENIN-ANGIOTENSIN SYSTEM INHIBITOR AND 
OTHER ANTIHYPERTENSIVE THERAPY RECOMMENDATIONS 
ACCORDING TO THE 2012 KIDNEY DISEASE: IMPROVING GLOBAL 
OUTCOMES GUIDELINES 
Patients must be 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 for the 3 months prior to 
randomization. In this instance, a stable dose is defined as doses within 25% of the dose at 
randomization.1 For all patients, two 24-hour urine samplings separated by at least 2 weeks must 
be performed prior to randomization for measurement of proteinuria.  
The following are recommendations for optimization and maintenance of RAS/antihypertensive 
therapy that are in line with the 2012 KDIGO guidelines and should be in place for at least 
3 months prior to randomization.1 These recommendations are also to be followed after 
randomization: 
 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 per 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. 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
86
APPENDIX E:  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. 
 


Calliditas Therapeutics AB 
Clinical Study Protocol Nef-301 
Confidential & Proprietary 
 
Version 5.0, 14 January 2021 
87
APPENDIX F:  IMMUNOSUPPRESSIVE DRUGS OTHER THAN 
GLUCOCORTICOIDS 
Systemic immunosuppressive drugs, except when used as rescue medications, 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 Chinese herbs 
and Chinese traditional medicines, with a known 
effect on the immune system (e.g., Tripterygium 
wilfordii)
Hydroxychloroquine
Note: Topical or inhalation products containing immunosuppressants are allowed.