A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled Study to Assess the Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Profile of BI 764198 Administered Orally Once Daily for 12 Weeks in Patients With Focal Segmental Glomerulosclerosis
Phase: PHASE2
Conditions: Kidney Disease, Chronic
Sponsor: Boehringer Ingelheim

 
 
001-MCS-40-106_RD-03 (18.0) / Saved on: 10 Jul 2019 
Clinical Trial Protocol 
TITLE PAGE  
Document Number: 
c30500151-06 
EudraCT No. 
  Universal Trial No. 
2020-000384-23 
 
U1111-1292-1333 
BI Trial No. 
1434-0004 
BI Investigational 
Medicinal Product(s) 
 
BI 764198 
Title 
A multicenter, randomized, double-blind, parallel group, 
placebo-controlled study to assess the efficacy, safety, tolerability, 
pharmacokinetics  and pharmacodynamics profile of BI 764198 
administered orally once daily for 12 weeks in patients with focal 
segmental glomerulosclerosis. 
Lay Title 
A study to test BI 764198 in people with a type of kidney disease called 
focal segmental glomerulosclerosis. 
Clinical Phase 
Phase 2a 
Clinical Trial Leader 
Phone: 
 
 
Coordinating 
Investigator 
Phone: 
 
 
Current Version and 
Date 
Version 5.0 
Date: 08 Jan 2024 
Original Protocol Date 
26 May 2021 
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© 2025 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. 
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 

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CLINICAL TRIAL PROTOCOL SYNOPSIS  
Company name 
Boehringer Ingelheim 
Original Protocol date 26 May 2021 
Revision date 
08 Jan 2024 
BI trial number 
1434-0004 
Title of trial 
A multicenter, randomized, double-blind, parallel group, 
placebo-controlled study to assess the efficacy, safety, tolerability, 
pharmacokinetics  and pharmacodynamics profile of BI 764198 
administered orally once daily for 12 weeks in patients with focal 
segmental glomerulosclerosis. 
Coordinating 
Investigator 
Phone: 
 
 
Trial sites 
Multicenter, multinational trial 
Clinical phase 
Phase 2a 
Trial rationale 
Due to the mechanism of action of BI 764198 and the likely biological link 
between focal segmental glomerulosclerosis (FSGS) and gain of function 
mutations of Transient Receptor Potential Cation subfamily C, Member 6 
(TRPC6), patients with primary FSGS, and patients with monogenic FSGS 
as a result of TRPC6 mutations have been selected for this proof of clinical 
principle study to establish TRPC6 inhibition as a potential mechanism to 
reduce excessive proteinuria. 
Trial objectives 
A key objective of this trial is to explore the efficacy of 3 doses  (20 mg, 
40 mg, and 80 mg) of BI 764198 with respect to their benefit to lower 
proteinuria. Additional objectives in this study are to investigate the safety, 
tolerability, and pharmacokinetic and pharmacodynamic profiles of BI 
764198 vs placebo. 
Trial endpoints 
Primary endpoint: 
The primary endpoint is patients achieving at least 25% reduction in 24-
hour urine protein-creatinine ratio (UPCR) relative to baseline at week 12. 
Secondary endpoints: 
The secondary endpoints are; 
• 
Change in 24-hour UPCR relative to visit 3 at week 12 
• 
Change in 24-hour UPCR relative to baseline at week 13 
• 
Change in 24-hour urinary protein excretion relative to baseline  at 
week 12 
• 
The following pharmacokinetic parameters of BI 764198 will be 
determined if feasible: 
- 
Steady state trough concentration Cpre,ss on week 4 and week 12. 
Trial design 
Randomized, double-blind, parallel group study with 3 doses of BI 764198 
(20 mg, 40 mg, and 80 mg) compared to placebo.  

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Total number of 
patients randomized  
60 patients 
Number of patients 
per treatment group 
15 patients in each of the four treatment groups 
Diagnosis 
Patients with primary FSGS, and patients with monogenic FSGS as a result 
of TRPC6 mutations. 
Main inclusion and 
exclusion criteria 
 
Main inclusion criteria: 
• 
Signed and dated informed consent in accordance with ICH-GCP and 
local legislation prior to admission to the study. 
• 
Male and female patients 18 years to 75 years (both inclusive) of age 
on the day of signing informed consent. 
• 
Patients diagnosed with biopsy proven primary FSGS or documented 
TRPC6 gene mutation causing FSGS prior to screening visit. 
• 
UPCR ≥ 1000 mg/g based on first morning void during screening. 
• 
Patients treated with corticosteroids must be on a stable dose for at 
least 4 weeks prior to screening visit with no plan to change the dose 
until end of trial treatment.  
• 
Patients treated with ACE inhibitors, ARBs, finerenone, aldosterone 
inhibitors, or SGLT2 inhibitors should be on a stable dose for at least 
4 weeks prior to screening visit with no plan to change the dose until 
end of trial treatment.  
• 
Body Mass Index (BMI) of ≤ 40 kg/m2 at screening visit. 
• 
Women of childbearing potential must be willing and able to use 
highly effective methods of birth control per ICH M3 (R2) that result 
in a low failure rate of less than 1% per year when used consistently 
and correctly.  
Main exclusion criteria: 
• 
Known monogenic (with the exception of TRPC6 gene mutation) or 
clinical or histologic evidence of secondary FSGS. 
• 
Documented Alport syndrome, Nail Patella syndrome, diabetic 
nephropathy, IgA-nephropathy, lupus nephritis, or monoclonal 
gammopathy (e.g., multiple myeloma). 
• 
Uncontrolled hypertension defined as an average resting systolic blood 
pressure >160 mmHg calculated from the last two of the triplicate 
sitting blood pressure measurements at screening visit. Patients with a 
documented history of white coat hypertension may be included. 
• 
Concomitant use of calcineurin inhibitors within 5 half-lives before 
screening visit.  
• 
Concomitant treatment with cytotoxic agents (cyclophosphamide, 
chlorambucil), or CD20 monoclonal antibody, e.g., rituximab, within 5 
half-lives before screening visit. Note: use of other 
immunosuppression therapies considered as standard of care may be 
allowed as long as the patient remains on stable dose throughout the 
study. 
• 
Treatment with metformin or dofetilide (MATE1 or OCT2 substrates); 
dabigatran or digoxin (P-gp substrates with narrow therapeutic 
window) within 5 half-lives before screening visit. 

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• 
Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 
m2 (CKD-EPI formula based on serum creatinine and cystatin C) at 
screening visit. 
• 
QTc intervals (QTcF) greater than 450 ms in males or greater than 470 
ms in females, or any other clinically relevant ECG findings (at the 
investigator’s discretion) at screening visit. 
Test product 
BI 764198 
 
dose 
20 mg, 40 mg, 80 mg, and matching placebo, q.d. 
 
mode of 
administration 
Oral (p.o) 
Comparator products Matching placebo to BI 764198 
 
dose 
Not applicable 
 
mode of 
administration 
Oral (p.o) 
Duration of treatment 12 weeks 
Statistical methods 
For the primary analysis, descriptive statistics will be provided.  Proportion 
of patients achieving at least 25% UPCR reduction relative to baseline at 
12 weeks will be described. In addition, an ANOVA model for the UPCR 
change from baseline at 12 weeks (and other endpoints as applicable) will 
be used to see difference across arms. The dose-response relationship 
based on reduction in log of UPCR will be explored using a graphical 
approach. 
 
 

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FLOW CHART A – STUDY PROCEDURES  
Trial Periods 
Screening 
Treatment Period 
Follow-up 
Visit1 
1 
2 
3 
4 
5 
EoT2 
FUP1 
EoS3 
Week 
 
0 
 
4 
8 
12 
13 
 
Days from first dose 
-304 
15 
4 
29 
57 
85 
92 
115 
Time window for visits (days) 
 
0 
+3 
±3 
±3 
±3 
±2 
±3 
Informed consent6 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Height7, body weight 
X 
 
 
X 
X 
X 
X 
 
Medical history 
X 
X 
 
 
 
 
 
 
Review of inclusion /exclusion criteria 
X 
X 
 
 
 
 
 
 
Physical exam8 
X 
 
 
X 
 
X 
 
 
Vital signs 
X28 
X 
X 
X 
X 
X 
X 
 
12-lead ECG9 
X 
X 
X 
X 
X 
X 
X 
 
Sampling for safety laboratory (incl. 
serum creatinine/cystatin C for eGFR) 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy testing10 
X 
X 
 
X 
X 
X 
X 
 
Eye exams11 
X 
 
 
 
 
X12 
 
X12 
First morning void (FMV) 
X 
 
 
 
 
 
 
 

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FLOW CHART A – STUDY PROCEDURES (cont.) 
Trial Periods 
Screening 
Treatment Period 
Follow-up 
Visit1 
1 
2 
3 
4 
5 
EoT2 
FUP1 
EoS3 
Week 
 
0 
 
4 
8 
12 
13 
 
Days from first dose 
-304 
15 
4 
29 
57 
85 
92 
115 
Time window for visits (days) 
 
0 
+3 
±3 
±3 
±3 
±2 
±3 
Dispense 24-hr urine collection containers13 
X 
X 
 
 
X 
X 
 
 
24-hour urine collection 
XX14 
 
X15 
 
 
X16 
X17 
 
 
 
Pharmacogenomics20 
 
X 
 
 
 
 
 
 
PK sampling (blood)21 
 
X 
X 
X 
X 
X 
X22 
 
Randomization & dispense trial medication23 
 
X 
 
 
 
 
 
 
Dispense/review of medication diary24 
 
X 
X 
X 
X 
X 
 
 
Medication administration during study visit25 
 
X 
X 
X 
X 
X 
 
 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
All AEs26/SAEs/AESIs 
X 
X 
X 
X 
X 
X 
X 
X 
Return medication /compliance check27 
 
 
X 
X 
X 
X 
 
 
Completion of patient participation 
 
 
 
 
 
 
 
X 

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Footnotes: 
1. Study visits may be completed at the patient’s home for patients participating in the trial remotely via the decentralized clinical trial (DCT) model. All trial 
procedures performed at the clinic can be completed by the mobile research nurse (MRN) at the patient’s home. For eye examinations (see footnotes 11 and 12). 
Please refer to phone call visit schedule in Flow Chart B below. 
2. End of Treatment (EoT) visit. Patients who discontinue trial treatment prematurely should undergo the End of Treatment (EoT) visit procedures as soon as 
possible. 
3. End of Study (EoS) is synonym for End of Trial. EoS will be a telephone visit. For eye exams at EoS, see footnote 12. Patients who discontinue trial treatment 
prematurely should complete follow-up visit (FUP1) and EoS visit. Study site staff will complete the EoS visit by telephone for all patients. 
4. Screening period can be shorter than 30 days. Screening period may also be extended if needed: see section 6.2.1 for more information. 
5. Day of first intake of trial medication. Randomization is completed prior to visit 2 and trial medication is shipped directly to the patient.  For more information, 
see section 4.1.4. 
6. To allow collection of the first morning void sample to determine if the patient’s UPCR meets the protocol inclusion criteria prior to visit 1, patients may sign a 
separate screening consent form (or verbally consent). Patients who are eligible per their UPCR results must sign the main consent form prior to additional 
screening procedures being performed. See section 8.1 for more information on the screening consenting process. Once the patient has consented to collect the 
first morning void  urine sample, the patient is considered to be enrolled in the trial and must be registered in the IRT. 
7. Height measurement collected only at the screening visit. 
8. Physical exam for patients participating in the trial remotely will be performed via telemedicine (section 5.2.1). 
9. ECGs will be recorded at the screening visit. Starting first dosing visit (visit 2) to EoT visit, ECGs will be recorded twice: pre-dose and at 1 to 2 hours post-dose. 
At the FUP1 visit, there will be one ECG recording. See additional guidelines on ECG recordings in section 5.2.4. 
a. ECGs at the screening visit will be recorded in triplicate (3 single ECGs recorded within 180 seconds). The average of the 3 readings will be used to 
determine eligibility (section 3.3.3) 
b. ECGs should be recorded either before or at least 10 minutes after blood sample time points to avoid blood draw related anxiety effects on ECG results. 
c. For patients participating in the trial remotely, the MRN will complete the ECG procedure at the patient’s home. 
10. Serum pregnancy test at screening visit (test performed at central lab), and urine pregnancy test at the study site for other visits (except visit 3 and phone visits). 
Menstrual cycle status (not delayed or missed period) should be checked before the first dose (visit 2). Applicable to only women of childbearing potential. See 
additional guidelines in section 6.1. 
11. Eye exams should be completed at the study site or at another healthcare or eye care facility. If documented medical history of cataract surgery in both eyes is 
available at the time of screening, eye assessments are not required in this trial (section 5.2.5.1).  
12. If cataract surgery in both eyes is confirmed by the eye exam at screening, patients are not required to complete the eye exams at EoT and EoS (section 5.2.5.1). 

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13. Patients will receive instructions on urine collection, storage, and return of the specimens to the study site. If possible, patients should be reminded (e.g., via 
telephone) during screening and ahead of the applicable visits to collect the 24-hour urine samples. More information and instructions for urine collection are 
provided in section 6.1. 
14. Two separate 24-hour urine samples will be collected on separate days prior to visit 2. The 24-hour urine samples should be collected only after confirmation that 
the patient met all the eligibility criteria for the trial, and the collections should be close to visit 2 as much as possible. Visit 2 must be rescheduled if UPCR data 
is not available at least from one 24-hour urine sample.  
15. One 24-hour urine sample should be collected before visit 3. For information and collection time points, see section 6.1. 
16. One24-hour urine samples should be collected before EoT visit. EoT visit must be rescheduled if the 24-hour urine sample is not collected for UPCR 
measurements. For information and collection time points, see section 6.1. 
17. One 24-hour urine sample will be collected before FUP1. For information and collection time points, see section 6.1. 
20. One blood sample for pharmacogenomics will be taken at visit 2.  If the sample is not collected at  visit 2, it can be collected at a later visit. 
21. Refer to Table 10.1: 1 for planned PK sampling schedule.  The date and exact time of trial medication administration will be recorded in the eCRF together with 
the date and exact time when PK samples are drawn.  
22. An additional PK sample will be collected at the FUP1 visit. 
23. Randomization will be performed using the IRT Platform at least a week before the scheduled visit 2 date.  Randomization call must occur only after patient 
eligibility (including UPCR criteria, eye exams) has been confirmed and UPCR data from central lab is available from at least one 24-hour urine sample during 
screening period. Trial medication will be shipped directly to the patient via a courier from a central depot unless not permitted by local/site regulations. First 
dose will be administered at visit 2. A telephone call (video call if possible) from site to patient should occur in about 24 hours (or next working day) after the 
site receives the delivery notification from the courier. For more information, see section 4.1.4. 
24. A medication diary (paper) will be dispensed to the patient. Patient should record the date and time of medication intake at home for the 3 days prior to EoT, and 
for the previous day for all other clinic visits. Patients should bring the diary to the clinic for review. For more information, see section 4.1.4. If possible, a few 
days before the visit patients should be reminded (e.g., via telephone) to complete the medication diary, and to not take the study drug on the day of the study 
visit. 
25. Patient will bring all the trial medication received directly from the central depot to the clinic for visit 2 (first dosing visit). Site will inspect all the trial 
medication and provide instruction to the patient on how medication is administered at home and how the medication should be brought to the clinic visits. Site 
will open the first bottle to administer the first dose in the clinic. When the patient is contacted after the trial medication is delivered to the patient’s home (see 
footnote 23), they should be reminded to bring the trial medication to the clinic for visit 2. If possible, patients should be reminded (e.g. by telephone) to bring 

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the trial medication to the clinic before each visit. Study visits will have to be rescheduled if trial medication is not available during the applicable visits. For 
information on how trial medication will be handled during the course of the trial, see section 4.1.4. 
26. A separate eCRF will be used to collect specific data related to acute kidney injury (section 3.3.4.1). After the FUP1 visit until the individual patient’s end of trial 
only cancers of new histology and exacerbations of existing cancer, all trial drug related SAEs and all trial drug related AESIs will be collected (section 
5.2.6.2.1). 
27. Medication compliance (section 4.3) will be checked by capsule count by study site staff. For information on medication return, see section 4.1.4. 
28. Assessment for uncontrolled hypertension is completed at Visit 1 only. Three blood pressure measurements will be taken approximately 2 minutes apart after the 
patient has rested quietly and is in a seated position for at least 5 minutes. The average of the last two measurements for the triplicate systolic blood pressure 
measurements should be < 160 mmHg for assessment of exclusion criteria 5 at the screening visit. 
 
FLOW CHART B - PHONE CALL VISITS  
 
Phone visits1 
3A 
4A 
5A2 
Week 
2 
6 
10 
Days from first dose 
15 
43 
71 
Window (days) 
±3 
±3 
±3 
Concomitant therapy 
X 
X 
X 
All AEs3/SAEs/AESIs 
X 
X 
X 
 
 
Footnotes: 
1. Patients will be contacted by telephone. If there is any follow-up needed, an unscheduled visit may be scheduled. Patients should be reminded to be compliant with the 
intake of trial medication. 
2. Patient should be reminded to collect the 24-hour urine before EOT visit. 
3. Please see footnote #26 for Flow Chart A.

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TABLE OF CONTENTS 
TITLE PAGE ........................................................................................................................... 1 
CLINICAL TRIAL PROTOCOL SYNOPSIS ..................................................................... 2 
FLOW CHART A – STUDY PROCEDURES ...................................................................... 5 
FLOW CHART B - PHONE CALL VISITS ........................................................................ 9 
TABLE OF CONTENTS ...................................................................................................... 10 
ABBREVIATIONS AND DEFINITIONS ........................................................................... 14 
1. 
INTRODUCTION ............................................................................................... 18 
1.1 
MEDICAL BACKGROUND ............................................................................. 18 
1.2 
DRUG PROFILE ................................................................................................ 19 
1.3 
RATIONALE FOR PERFORMING THE TRIAL ......................................... 23 
1.4 
BENEFIT - RISK ASSESSMENT..................................................................... 24 
1.4.1 
Benefits ................................................................................................................. 24 
1.4.2 
Risks ..................................................................................................................... 24 
1.4.3 
Discussion ............................................................................................................. 26 
2. 
TRIAL OBJECTIVES AND ENDPOINTS ...................................................... 27 
2.1 
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........ 27 
2.1.1 
Main objectives .................................................................................................... 27 
2.1.2 
Primary endpoint ................................................................................................ 27 
2.1.3 
Secondary endpoints ........................................................................................... 27 
2.2.2.2 
Safety endpoints .................................................................................................... 28 
3. 
DESCRIPTION OF DESIGN AND TRIAL POPULATION ......................... 29 
3.1 
OVERALL TRIAL DESIGN ............................................................................. 29 
3.2 
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP ........................................................................................... 29 
3.3 
SELECTION OF TRIAL POPULATION ....................................................... 30 
3.3.1 
Main diagnosis for trial entry ............................................................................ 31 
3.3.2 
Inclusion criteria ................................................................................................. 31 
3.3.3 
Exclusion criteria ................................................................................................ 31 
3.3.4 
Discontinuation of patients from treatment or assessments ........................... 33 
3.3.4.1 
Discontinuation of trial treatment ......................................................................... 33 
3.3.4.2 
Withdrawal of consent to trial participation ......................................................... 34 

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3.3.4.3 
Discontinuation of the trial by the sponsor ........................................................... 34 
4. 
TREATMENTS ................................................................................................... 36 
4.1 
INVESTIGATIONAL TREATMENTS ........................................................... 36 
4.1.1 
Identity of the Investigational Medicinal Products .......................................... 36 
4.1.2 
Selection of doses in the trial .............................................................................. 36 
4.1.3 
Method of assigning patients to treatment groups ........................................... 37 
4.1.4 
Drug assignment and administration of doses for each patient...................... 38 
4.1.5 
Blinding and procedures for unblinding ........................................................... 40 
4.1.5.2 
Unblinding and breaking the code ........................................................................ 40 
4.1.6 
Packaging, labelling, and re-supply................................................................... 41 
4.1.7 
Storage conditions ............................................................................................... 41 
4.1.8 
Drug accountability............................................................................................. 41 
4.2 
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................ 42 
4.2.1 
Other treatments and emergency procedures .................................................. 42 
4.2.2 
Restrictions .......................................................................................................... 42 
4.2.2.1 
Restrictions regarding concomitant treatment ...................................................... 42 
4.2.2.2 
Restrictions on diet and lifestyle ........................................................................... 43 
4.2.2.3 
Contraception requirements .................................................................................. 43 
4.3 
TREATMENT COMPLIANCE ........................................................................ 44 
5. 
ASSESSMENTS .................................................................................................. 45 
5.1 
ASSESSMENT OF EFFICACY ........................................................................ 45 
5.1.1  
Measures of proteinuria ..................................................................................... 45 
5.2 
ASSESSMENT OF SAFETY ............................................................................. 45 
5.2.1 
Physical examination .......................................................................................... 45 
5.2.2 
Vital signs ............................................................................................................. 46 
5.2.3 
Safety laboratory parameters ............................................................................ 46 
5.2.4 
Electrocardiogram .............................................................................................. 50 
5.2.5 
Other safety parameters ..................................................................................... 51 
5.2.5.1 
Ocular safety assessments ..................................................................................... 51 
5.2.6 
Assessment of adverse events ............................................................................. 52 
5.2.6.1 
Definitions of AEs ................................................................................................ 52 
5.2.6.1.1 
Adverse event ........................................................................................................ 52 
5.2.6.1.2 
Serious adverse event ............................................................................................ 52 
5.2.6.1.3 
AEs considered “Always Serious” ........................................................................ 53 
5.2.6.1.4 
Adverse events of special interest ......................................................................... 53 
5.2.6.1.5 
Intensity (severity) of AEs .................................................................................... 53 
5.2.6.1.6 
Causal relationship of AEs .................................................................................... 54 
5.2.6.2 
Adverse event collection and reporting ................................................................ 54 
5.2.6.2.1 
AE Collection ........................................................................................................ 54 
5.2.6.2.2 
AE reporting to the sponsor and timelines ............................................................ 55 

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5.2.6.2.3 
Pregnancy .............................................................................................................. 55 
5.2.6.2.4 
Additional Safety monitoring................................................................................ 56 
5.3 
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS ................................................................................... 56 
5.3.1 
Assessment of pharmacokinetics ....................................................................... 56 
5.3.2 
Methods of sample collection ............................................................................. 56 
5.4.2 
Pharmacogenomics biomarkers......................................................................... 58 
5.4.2.1 
Methods and timing of sample collection ............................................................. 59 
5.5 
BIOBANKING .................................................................................................... 59 
5.6 
OTHER ASSESSMENTS................................................................................... 59 
5.7 
APPROPRIATENESS OF MEASUREMENTS .............................................. 59 
6. 
INVESTIGATIONAL PLAN............................................................................. 60 
6.1 
VISIT SCHEDULE ............................................................................................. 60 
6.2 
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................. 63 
6.2.1 
Screening and run-in period .............................................................................. 63 
6.2.2 
Treatment period. ............................................................................................... 64 
6.2.3 
Follow-up period and trial completion.............................................................. 64 
7. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
 ............................................................................................................................... 66 
7.1 
NULL AND ALTERNATIVE HYPOTHESES ............................................... 66 
7.2 
PLANNED ANALYSES ..................................................................................... 66 
7.2.1 
General considerations ....................................................................................... 66 
7.2.2 
Handling of Intercurrent Events ....................................................................... 66 
7.2.3 
Primary endpoint analyses ................................................................................. 67 
7.2.3.1 
Sensitivity analyses ............................................................................................... 67 
7.2.3.2 
Supplemental analysis of primary endpoint .......................................................... 67 
7.2.3.3 
Subgroup analyses................................................................................................. 67 
7.2.4 
Secondary endpoint analyses ............................................................................. 67 
7.2.6 
Safety analyses ..................................................................................................... 68 
7.3 
HANDLING OF MISSING DATA ................................................................... 69 
7.4 
RANDOMIZATION ........................................................................................... 69 

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7.5 
DETERMINATION OF SAMPLE SIZE ......................................................... 70 
8. 
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........ 71 
8.1 
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ........................................................................................................... 71 
8.2 
DATA QUALITY ASSURANCE ...................................................................... 72 
8.3 
RECORDS ........................................................................................................... 73 
8.3.1 
Source documents ............................................................................................... 73 
8.3.2 
Direct access to source data and documents ..................................................... 74 
8.3.3 
Storage period of records ................................................................................... 74 
8.4 
EXPEDITED REPORTING OF ADVERSE EVENTS .................................. 74 
8.5 
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY ........ 74 
8.5.1 
Collection, storage and future use of biological samples and corresponding 
data ....................................................................................................................... 75 
8.6 
TRIAL MILESTONES....................................................................................... 75 
8.7 
ADMINISTRATIVE STRUCTURE OF THE TRIAL ................................... 76 
9. 
REFERENCES .................................................................................................... 77 
9.1 
PUBLISHED REFERENCES ............................................................................ 77 
 
 
10. 
APPENDICES ..................................................................................................... 80 
10.1 
TIME SCHEDULE FOR PK BLOOD SAMPLING ....................................... 80 
11. 
DESCRIPTION OF GLOBAL AMENDMENT .............................................. 83 

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ABBREVIATIONS AND DEFINITIONS  
ACE 
Angiotensin Converting Enzyme 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AHR 
Aryl Hydrocarbon Receptor 
ALT 
Alanine Aminotransferase 
ANOVA 
Analysis of Variance 
ARB 
Angiotensin II Receptor Blockers 
AST 
Aspartate Aminotransferase 
AUC 
Area under the Plasma Concentration Curve 
AUC0-∞ 
Area under the Plasma Concentration Curve from 0 to ∞ 
AUCt1-t2 
Area under the Plasma Concentration Curve from t1 to t2 
AUCt1-t2,ss 
Area under the Plasma Concentration Curve from t1 to t2 at steady state 
BI 
Boehringer Ingelheim 
BMI 
Body Mass Index 
CA 
Competent Authority 
CAR 
Constitutive Androstane Receptor 
CKD 
Chronic Kidney Disease 
CKD-EPI 
Chronic Kidney Disease-Epidemiology Collaboration 
Cmax 
Maximum Plasma Concentration 
Cmax,ss 
Maximum Plasma Concentration at steady state 
Cpre,ss 
Pre-dose Plasma Concentration at steady state 
Ctrough,ss 
Trough Plasma Concentration at steady state 
COVID-19 
Coronavirus Disease 2019 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CSA 
Cyclosporine 
CT Manager 
Clinical Trial Manager 
CTL 
Clinical Trial Leader 
CYP3A4 
Cytochrome P450 3A4 
DCT 
Decentralized Clinical Trial 

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DDI 
Drug-Drug Interaction 
DEX 
Dexamethasone 
DILI 
Drug Induced Liver Injury 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
EoS 
End of Study (corresponds with End of Trial) 
EoT 
End of Treatment 
ES 
Entered Set 
ESKD 
End Stage Kidney Disease 
EudraCT 
European Clinical Trials Database 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSGS 
Focal Segmental Glomerulosclerosis 
FUP1 
Follow-up Visit #1 
GCP 
Good Clinical Practice 
gCV 
Geometric Coefficient of Variation 
GGT 
Gamma-Glutamyl Transferase 
GI 
Gastrointestinal 
gMean 
Geometric Mean 
HA 
Health Authority 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
ICE 
Intercurrent Event 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IgA 
Immunoglobulin A 

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IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISF 
Investigator Site File 
K-EDTA 
Potassium Ethylenediaminetetraacetic Acid 
LOCS III 
Lens Opacities Classification System III 
LPLT 
Last Patient Last Treatment 
MATE1 
Multidrug and Toxin Extrusion 1 
MATE2 
Multidrug and Toxin Extrusion 2 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MMF 
Mycophenolate Mofetil 
MRN 
Mobile Research Nurse 
ms 
Milliseconds 
mRNA 
Messenger RNA 
NEPTUNE 
Nephrotic Syndrome Study Network 
NOAEL 
No Observed Adverse Effect level 
OCT2 
Organic Cation Transporter 2 
P-gp 
Permeability Glycoprotein 
PD 
Pharmacodynamics 
PE 
Physical Exam 
PK 
Pharmacokinetics 
p.o. 
per os (oral) 
q.d. 
quaque die (once a day) 
QT 
Time between start of the Q-wave and end of the T-wave in an 
electrocardiogram 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using the method of Fridericia 
RA 
Regulatory Authority 
SAE 
Serious Adverse Event 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
sFSGS 
Secondary Focal Segmental Glomerulosclerosis 
SGLT2 
Sodium-Glucose Cotransporter-2 

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SOP 
Standard Operating Procedure 
SULT 
Sulfotransferase 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TS 
Treated set 
TRPC6 
Transient Receptor Potential Cation subfamily C Member 6 
TSAP 
Trial Statistical Analysis Plan 
t1/2 
Terminal half-Life of the analyte 
tmax 
Time to Maximum Plasma Concentration 
UGT 
Uridine Diphosphate Glucuronosyl Transferase 
ULN 
Upper Level of Normal 
UPCR 
Urine Protein-Creatinine Ratio 
WOCBP 
Woman of Childbearing Potential 

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1. 
INTRODUCTION  
1.1 
MEDICAL BACKGROUND  
Boehringer Ingelheim (BI) is developing BI 764198, an oral, small-molecule inhibitor of the 
transient receptor potential cation subfamily C Member 6 (TRPC6), for the treatment of 
proteinuric glomerular disease on top of standard of care. 
 
Focal segmental glomerulosclerosis (FSGS) is a leading glomerular cause of End Stage 
Kidney Disease (ESKD) in the United States. FSGS refers to a histologic pattern that is a 
characteristic of perhaps distinct underlying etiologies sharing a common theme of podocyte 
injury and depletion (P17-08386). 
 
FSGS is characterized by histologic lesions as opposed to a specific disease. FSGS is a 
pathophysiological entity which commonly explains the onset of nephrotic syndrome in adult 
or pediatric patients. Histological abnormalities contain sclerosis in segmental (parts) of focal 
(some) glomeruli as assessed by microscopic investigation of kidney biopsies.  
 
FSGS is a frequently found histopathologic lesion in adults with nephrotic syndrome within 
the United States accounting for 35% of all cases and >50% among African Americans  
(R20-3949, and R20-3978).  
 
The classification of FSGS in specific categories is based on various etiologies as defined 
below: 
• Primary (idiopathic) FSGS frequently presenting with nephrotic syndrome. 
• Secondary FSGS (sFSGS) or also referred to as adaptive FSGS, often presenting with 
non-nephrotic proteinuria and, commonly, with some extent of kidney function 
impairment. This category is a common adaptive response to hyperfiltration or 
glomerular hypertrophy and disorders characterized by renal vasodilation and/or 
kidney mass reduction (e.g. unilateral renal agenesis). Drug- or toxin-induced 
(e.g. heroin, interferon, pamidronate) and viral-induced (especially HIV) pathologies 
account for the other causes of sFSGS. 
• Genetic (familial) FSGS, presents generally in early childhood with substantial 
nephrotic syndrome and proteinuria or with less severe proteinuria in adolescence or 
adulthood. 
 
FSGS classification will depend on a multitude of assessments including clinical history, 
laboratory testing, kidney biopsy, and in some cases genetic testing. While considerable 
progress has been achieved with the clinical understanding of FSGS, research is still needed 
to identify plasma factor(s) believed to be responsible for primary FSGS, to assess the 
clinical utility of routine genetic testing, and to find more effective and safer therapeutic 
interventions for FSGS (P17-08386). 
 
A possibly important mechanism related to glomerular dysfunction in proteinuric diseases 
could be the calcium overload of the podocyte. In subjects with TRPC6 mutations increased 

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podocyte foot process detachment and loss has been observed as a consequence of disruption 
of the glomerular filtration barrier [R18-1764, R18-1763]. It is hypothesized that increased 
TRPC6 activity could be a principal mechanism in proteinuric kidney disease driving 
progression to ESKD. Therefore, BI 764198 as TRPC6 inhibitor, may be a novel treatment 
option by limiting TRPC6 channel activity in case of pathological Ca2+ entry which should 
result in preserved podocyte function and reduced podocyte loss. 
 
TRPC6 is expressed in several renal cell types, including podocytes which are key cells for 
glomerular filtration function of the kidney.  Multiple gain of function mutations in TRPC6 
have been demonstrated to cause FSGS by elevating intracellular calcium concentration in 
podocytes and inducing cytoskeletal rearrangements. This has been linked to podocyte 
apoptosis, foot process detachment and loss of podocytes, leading to disruption of the 
glomerular filtration barrier.  The modulation of TRPC6 activity should therefore have the 
potential to improve both podocyte function and survival in proteinuric glomerular diseases 
and specifically in FSGS. 
1.2 
DRUG PROFILE  
BI 764198 is an oral, small-molecule inhibitor of TRPC6. It is being developed for the 
treatment of advanced chronic kidney disease on top of standard of care. 
 
Mode of action: 
BI 764198 is a potent inhibitor of human TRPC6 (IC50: 14.4 nM; IC90: 77 nM), rat TRPC6 
(IC50: 12.9 nM), mouse TRPC6 (IC50: 19.3 nM), dog TRPC6 (IC50: 44.2 nM) and 
cynomolgus monkey TRPC6 (IC50: 10.0 nM) in in vitro manual patch clamp assays using 
human HEK293 cells with inducible TRPC6 expression.  
 
Key pharmacokinetic characteristics: 
Following administration of single and multiple doses ranging from 1 mg to 240 mg in 
humans, BI 764198 was rapidly absorbed into the systemic circulation with maximum plasma 
concentrations occurring in the range of 0.75 h to 2 h post-dose time to maximum plasma 
concentration (tmax).  BI 764198 was cleared from plasma with an apparent t1/2 ranging from 
12.7 h to 17.4 h, independent of the dose. At doses of 10 mg or higher, the exposure of 
BI 764198 was linear. After multiple dose administration, steady state AUC and Cmax values 
increased linearly between 20 mg and 80 mg doses and BI 764198 shows time independent 
PK up to 80 mg. A steady state was achieved by 3-4 days with modest accumulation based on 
AUC0-24h, (1.33-1.48) and Cmax (1.13-1.43). The fraction of BI 764198 excreted unchanged in 
urine over 48 h was between 14% and 30% after single dose administration and 21% to 29% 
over 24 h after multiple dose administration. In study 1434-0002 
), in otherwise 
healthy participants who had renal impairment, gMean BI 764198 AUC increased by 48% 
(moderate impairment) and 78% (severe impairment) and Cmax increased by 14% (moderate 
renal impairment) and 12% (severe renal impairment) after a single dose of 40 mg compared 
with healthy controls. 
 

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After multiple doses of BI 764198 (up to 160 mg), gMeans for AUCτ,ss and Cmax,ss were 
higher by 3-36% and 21-47% respectively, when comparing Japanese (1434-0003) and 
Caucasian (1434-0007) data. This may be related to the lower body weight in Japanese 
subjects (mean weight 63.25 kg vs. 78.08 kg in Caucasian). 
 
The hepatic metabolic clearance of BI 764198 is predicted to be low in humans based on 
in vitro evaluation using human hepatocytes. BI 764198 is 14-30% renally excreted. BI 
764198 is metabolized via glucuronidation (mostly via uridine diphosphate glucuronosyl 
transferase, UGT1A4), oxidation (primarily via cytochrome P450, CYP3A), and amide 
hydrolysis. Although co-administered drugs that inhibit CYP3A or UGT1A4 activity may 
increase BI 764198 plasma exposure, the effect is not expected to be substantial given the 
multiple elimination pathways of BI 764198. With respect to BI 764198’s CYP3A induction 
potential, a clinical drug-drug interaction (DDI) study (
 was conducted to assess 
the compound’s effect (80 mg once daily for 10 days) on the pharmacokinetics of micro-dose 
midazolam, a sensitive CYP3A4 substrate. The geometric mean ratios (90% CI) of AUC0-∞ 
and Cmax of midazolam with and without co-administration of BI 764198 are 1.04 (0.93,1.16) 
and 0.94 (0.84, 1.06), respectively, indicating that 80 mg BI 764198 once daily did not affect 
CYP3A4 activity in vivo. BI 764198 may cause clinically relevant inhibition of P-gp at a 
dose of 80 mg once a day (q.d.). A high fat, high caloric meal did not influence AUC or Cmax. 
Therefore, BI 764198 can be administered with or without food. Relevant restrictions will be 
available in the investigator site file (ISF). 
 
Drug interactions 
As outlined above, 80 mg BI 764198 once daily did not alter the pharmacokinetics of 
midazolam, a CYP3A4 index substrate. Therefore, BI 764198 does not affect CYP3A4 
activity in vivo. Based on the metabolism described above, co-administered drugs that 
modulate CYP3A or UGT1A4 activity may have an impact on BI 764198 plasma exposure. 
Strong inhibitors and strong inducers of CYP3A are excluded. BI 764198 may inhibit OCT2, 
MATE1, or MATE2-K at a dose of ≥40 mg once daily; and P-gp at a dose of ≥80 mg once 
daily. The effect of BI 764198 on the pharmacokinetics of metformin or dofetilide (MATE1/ 
OCT2 substrates), and dabigatran or digoxin (P-gp substrates with narrow therapeutic 
window) will be elucidated when data from DDI studies in healthy subjects become 
available; until then co-administration should be avoided. 
 
BI 764198 is not expected to lead to a clinically relevant reduction in the exposure of oral 
contraceptives due to an increased metabolism via enzyme induction 
). BI 764198 
(80 mg once daily over 10 days) did not change the pharmacokinetics of the sensitive 
CYP3A4 substrate midazolam. Thus, BI 764198 is not considered to be a CYP3A4 inducer in 
vivo. From in vitro studies using human hepatocytes, there is no indication that BI 764198 
activates other nuclear receptors (AHR or CAR) that trigger induction of other drug 
metabolizing enzymes involved in metabolism of oral contraceptive components, such as 
UGTs and sulfotransferases (SULTs). 
 
Residual Effect Period 

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The Residual Effect Period (REP) of BI 764198 is 119 hours, i.e. 5 days, based on 5 times 
23.8 hours, the maximum value for t1/2 in patients with moderate renal impairment 
). This is the period after the last dose with measurable drug levels and/or 
pharmacodynamic effects still likely to be present. 
 
Data from toxicology studies 
The toxicity profile of BI 764198 has been assessed in a comprehensive set of safety 
pharmacology studies, genetic toxicology and phototoxicity studies, repeat dose general 
toxicology studies (up to a duration of 26 weeks  in the rat and 39 weeks in the dog) embryo-
foetal development toxicity studies (rat and rabbit), and a fertility and early embryonic 
development study (in rat). BI 764198 has been well tolerated at clinically relevant plasma 
exposures in toxicity studies. Exposure multiples were calculated based on the human 
estimated steady state Cmax of 3650 nM and AUC0-24hr of 40200 nM•h for a dose of 80 mg 
once daily. 
 
The IC50 for hERG inhibition was 7,970 nM, which is 6X human exposure for the predicted 
Cmax for the unbound drug (1329 nM), demonstrating potential for blocking hERG channels 
at clinically relevant concentrations. While no effects to QT intervals were observed after a 
single dose to dogs, there was a dose and time-dependent increase in QTc intervals after 
repeat dosing in the 4-, 13-, and 39-week dog studies. In the 4-week dog study, there was a 
12% increase in QTc interval (+24.9 milliseconds) at 17X human exposure. Prolongations of 
the QTc interval were less prominent in subsequent studies and reproducible only at 25 
mg/kg/day. Additionally, in the 13-week dog study, it was uncertain if second-degree AV 
block in one female at 9X human exposure was due to BI 764198. 
Studies in rats showed dose and time-dependent microscopic lens degeneration that generally 
correlated with cataracts at higher doses or longer duration. In the 26-week study, a dose of 
10 mg/kg/day (1X human exposure) was free of lens findings while the dose of 30 mg/kg/day 
(4X human exposure) as tested in the 13-week study in rats, was considered to represent a 
threshold dose for the irreversible lens degeneration, as the 50 mg/kg/day dose when tested in 
the 26-week rat study was free of adverse effects in males (7X human exposure), but induced 
lens degeneration in females (10X human exposure). No lens effects were observed in dogs at 
doses up to 17X and 9X human exposure, respectively. Lacrimation was observed in both rat 
and dog studies. 
Increases in alanine aminotransferase (ALT) and alkaline phosphatase (ALP) were seen in 
dog and/or rat studies. In the dog, increased ALT correlated with panlobular hepatocellular 
necrosis in a single animal at 17X human exposure. In rats, there have been mild decreases in 
red blood cell parameters and increases in leukocytes. Platelets decreased in dogs in a 2-week 
study, but not in studies with a longer dosing period. Platelets increased and showed 
decreased activation in rats. Increases in cholesterol and decreases in triglycerides have been 
observed in rats. Urinalysis in rat studies showed decreased urine pH and/or increased urine 
protein at 11X human exposure. 
Reversible skin findings were preceded by clinical signs of erythema. Dermal redness was 
observed in rats and dogs at exposures providing 3X human exposure. In rats at higher dose 
levels, dermal redness affecting multiple cutaneous sites was generally accompanied by 

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additional skin and footpad effects such as hair thinning/loss, dermal dryness, single cell 
necrosis, scabbing, and/or epidermal hyperkeratosis, hyperplasia, or acanthosis at 11X human 
exposure. Skin ulceration and swelling were also observed in rats at 22X human exposure. 
Skin swelling was observed for dogs at 9X human exposure. A relation to BI 764198 was not 
excluded for a tricholemmoma in a female mid dose rat (11X human exposure) of the 26-
week study.  In rat studies only, hyperkeratosis affected the tongue at 24X human exposure. 
 
Testing for effects on fertility and early embryonic development in rats revealed NOALEs for 
fertility of 7X human AUC0-24h (males) and 23X human AUC0-24h (females) as well as 
NOAELs for effects on early embryonic development of 7X human AUC0-24h (paternally 
mediated) and 0.4X human AUC0-24h (maternally mediated). In embryo-fetal development 
studies, where pregnant rats and rabbits were dosed BI 764198 from implantation to closure 
of the hard palate, there was embryolethality in rats at 3X human exposure, but no evidence 
of adverse effects to fetal growth or dysmorphogenesis.  There was no embryolethality, effect 
to fetal growth, or dysmorphogenesis in rabbits at dose levels providing up to 26X human 
exposure. There is risk for adverse effects to embryo-fetal development at clinically relevant 
human exposures. 
 
The risk of fetotoxicity induced by systemic exposure to BI 764198 via semen in female 
sexual partners of male trial participants has been assessed based on the recommendations of 
the Clinical Trials Facilitation and Coordination Group CTFG (R20-3402) and as commented 
in a White Paper by Bowman et al (R22-1956). It has been concluded that the exposure of 
female sexual partners and associated risk of fetotoxicity are negligible, indicating that 
condom use is not required for male trial participants with WOCBP partners. 
 
The non-clinical safety package supports administration of BI 764198 to humans for more 
than 6months duration. The NOAEL in the 26-week rat study was 50 mg/kg/day in males 
(Cmax 32,900 nM and AUC0-24h 272,000 nM·h) and 10 mg/kg/day in females males (Cmax 
12,200 nM and AUC0-24h 53,500 nM·h), corresponding to a steady state mean exposure 
multiple of 3X (Cmax) and 1X (AUC0-24h) the human exposure at 80 mg once daily. The 
NOAEL in the 39-week dog study was the high dose, 25 mg/kg/day (Cmax 86,000 and 
71,700nM and AUC0-24h 1,640,000 and 1,240,000 nM·h for males and females, 
respectively), corresponding to a steady state mean exposure multiple of 20X (Cmax) or 31X 
(AUC0-24h) the human exposure at 80 mg once daily. 
Data from clinical studies 
To date, BI 764198 has been studied in a single rising dose trial of up to 240 mg once daily in 
healthy volunteers 
), in a single dose trial in patients with renal impairment 
(
), and in a multiple rising dose/drug-drug interaction trial (midazolam) in healthy 
volunteers treated up to an 160 mg dose once daily for 14 days 
) and in a relative 
bioavailability trial (
). BI 764198 was also administered orally up to 160 mg once 
daily to healthy Japanese volunteers up to 14 days 
). In the completed phase 1 
studies, a total of 171 healthy volunteers and 16 patients with renal impairment have received 
BI 764198. Based on completed Phase 1 clinical trials, BI 764198 was overall well tolerated 
up to a daily dose of 160 mg given up to 14 days in healthy volunteers with no imbalance 

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versus placebo in reported adverse events (AE) leading to discontinuation, drug-related AEs, 
or serious adverse events (SAE). 
 
An electrocardiogram (ECG) analysis based on three Phase I trials in healthy volunteers 
(
), (c
0), and 
) indicated that BI 764198 may cause QT 
prolongation in a dose-dependent manner for doses ≥80 mg BI 764198 once daily. After 
single and multiple doses of BI 764198, a reversible, dose-dependent increase of serum 
creatinine was observed in Phase I trials. It is believed that BI 764198 may increase serum 
creatinine by decreasing renal tubular secretion of creatinine via inhibition of renal 
transporters (e.g. MATE1) without an impact on kidney function as measured by unchanged 
cystatin C levels. Cystatin C (in addition to serum creatinine measurements) will be used to 
assess changes in renal function in patients treated with BI 764198. 
 
Treatment in a proof-of-concept clinical trial 1434-0009 (
) to reduce the 
risk/severity of acute respiratory distress syndrome in patients hospitalized for coronavirus 
disease 2019 (COVID-19) and requiring non-invasive oxygen therapy was terminated early, 
based on an independent data monitoring committee (DMC) recommendations, due to a clear 
lack of benefit in this critically ill patient population and a numerical imbalance of fatal 
events between the active and placebo treatment groups. Fatality rate was still within 
expected range for hospitalised COVID-19 patients on oxygen (R20-3802). Based on the 
totality of the data review from the study, BI has not identified to date any new safety risks 
for BI 764198. No adverse effects were noted to date which would impact the conduct of 
ongoing Phase 1 trials in healthy volunteers or the planning of Phase 2 proof-of-concept trials 
in chronic kidney disease (CKD). 
 
Through favourable effects on glomerulosclerosis, delaying podocyte injury, and improving 
vascular function, a TRPC6 inhibitor may have the potential to slow disease progression 
when used on-top-of optimal therapy including ACEi/ARB. Such a therapy could be 
considered a notable advance in patient health and well-being by slowing progression to 
ESKD, improving clinical outcomes, reducing disease burden, and improving quality of life 
in proteinuric glomerular diseases such as FSGS. 
 
For a more detailed description of the profile, refer to the current version of the IB 
(
). 
1.3 
RATIONALE FOR PERFORMING THE TRIAL  
FSGS is one of the most common forms of acquired glomerular disease leading to ESKD and 
it is one of the most important causes of acquired chronic kidney disease in children and 
adults (R20-3912). Based on a clear biological link between FSGS and gain of function 
mutations of TRPC6 in this disease, BI 764198, based on its TRPC6 inhibitory mechanism of 
action, is expected to reduce proteinuria in FSGS thereby reducing disease burden and 
potential progression.  
 

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Specifically, TRPC6 is expressed in several renal cell types, including podocytes which are 
key cells for glomerular filtration function of the kidney.  Multiple mutations in the TRPC6 
channel have been demonstrated to cause FSGS. This has been linked to podocyte apoptosis, 
foot process detachment and loss of podocytes, leading to disruption of the glomerular 
filtration barrier. The modulation of TRPC6 activity should therefore have the potential to 
improve both podocyte function and survival in proteinuric glomerular disease. 
 
Building on knowledge gained in preclinical investigations and first in human (FIH) phase 1 
clinical studies, this phase 2 study will investigate if TRPC6 inhibition can reduce proteinuria 
by assessing the safety, tolerability, pharmacodynamic and pharmacokinetic profile of 
BI 764198 in patients with FSGS. A reduction of proteinuria in FSGS with TRPC6 inhibition 
will provide a sound basis for the continued investigation of this therapeutic mode of action 
in proteinuric glomerular diseases in future stages of clinical development. 
 
1.4 
BENEFIT - RISK ASSESSMENT  
1.4.1 
Benefits  
There is no direct benefit for individual participants in this study.  The anticipated efficacy of 
BI 764198 in reducing proteinuria has not yet been demonstrated in patients with FSGS.  
However, participation in this study is of major importance to the development of a new oral 
drug that may improve therapeutic options for patients with FSGS and kidney disease 
characterized by excessive proteinuria. 
1.4.2 
Risks  
Procedure-related risks 
Blood draw may be accompanied by mild bruising and in rare cases, by transient 
inflammation of the wall of the vein. In addition, in rare cases a nerve might be injured while 
inserting the needle, potentially resulting in paraesthesia, reduced sensibility, and/or pain for 
an indefinite period. Other observed side effects of blood draw are anxiety, dizziness, 
syncope. 
Drug induced liver injury 
Although rare, a potential for drug induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this study requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure patients´ 
safety. 
 
Safety measures 
The following safety measures will be applied in order to minimize potential risk for the trial 
participants: 
• An extensive safety laboratory will be performed at periodic intervals as specified in the 
Flow Chart A. Safety laboratory tests are listed in Table 5.2.3: 1. 
• Thorough ECG evaluation with central reading at every study visit including pre- and 
post-dose evaluations at expected drug steady state (day 4 of treatment). During the 

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treatment period, ECGs are also collected at the time when Cmax of the drug is expected 
during study visits. Time points for ECG collection can be found in the Flow Chart A. 
ECG collection and central reading processes are described in section 5.2.4. 
• To monitor for cardiac effects and the potential for QTc prolongation, regular ECG is 
evaluated by regular ECG monitoring, and specific exclusion and discontinuation criteria 
are in place for potential risk minimization. See section 3.3.4.1 for conditions under 
which trial treatment will be discontinued due to QT prolongation. 
• Patients who experience clinically relevant conduction disorders (e.g. AV block ≥2nd 
degree, bundle branch block) will be discontinued from study treatment. 
• To monitor for ocular changes, eye exams at screening, end of treatment, and 30 days 
after last dose of trial medication will be performed. Patients diagnosed with cataract 
(Lens Opacities Classification System III (LOCS III) higher than NC1/NO1, C0, P0 
(R99-2093) in slit lamp eye examination will be excluded from the study at screening, 
and if diagnosed after inclusion in study will be discontinued from study treatment. 
• To monitor for renal function, serum cystatin C and serum creatinine levels will be 
assessed at regular intervals and GFR estimation will be based on cystatin C values. 
• There are no risks expected by stopping the study drug during the course of the trial. 
• During the study, patients will be monitored for AEs. 
• Females of childbearing potential who are pregnant, breast-feeding or intend to become 
pregnant or are not using an adequate contraceptive method throughout the trial and until 
5 days after the last dose of the trial medication are excluded from the trial 
(section 4.2.2.3). 
• Set up of an internal study safety review committee who will review unblinded data 
periodically to allow continuous assessment of drug exposure, efficacy, and safety.  The 
safety review committee will include a cardiologist and an ophthalmologist. For more 
information, see section 8.7. 
 
Patient participation in this trial will be consistent with local public health guidance and 
regulations.  During screening, patients with symptoms of COVID-19 or a confirmed severe 
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection will be excluded from 
participation in the trial.  During participation in the study, if a patient is diagnosed with 
COVID-19, trial treatment will be terminated in cases where the patient has severe illness 
(for example patients who require hospitalization, need supplemental oxygen, have 
compromised lung function, etc.) and patients will be discontinued from the study. If a 
patient has a mild SARS-CoV-2 infection, continuation of trial treatment will be at the 
discretion of the investigator. The investigator will make an individual benefit-risk 
assessment on a case-by-case basis considering all aspects and decide if the patient should 
continue treatment or discontinue treatment temporarily or permanently. There are no 
restrictions for trial participant to receive vaccination for COVID-19 during or after the study 
period. 
 
If local regulations require a SARS-Cov-2 test for patients to participate in the trial, the site 
investigator may order a polymerase chain reaction (PCR) test or another approved test at 

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screening or at any time during the study. Patients who test positive will be informed about 
the test result and they will not be eligible to participate in the trial. 
1.4.3 
Discussion  
In summary, BI 764198 has the potential to become an oral treatment for patients with 
proteinuric glomerular disease such as FSGS based on a unique and promising mechanism of 
action with a clear pathophysiological disease link related to TRPC6 mutations in the context 
of FSGS. Patients suffering from FSGS have a high unmet medical need for safe and 
effective therapies to reduce disease severity and progression towards ESKD. 
 
Based on preclinical data and first clinical data for BI 764198, mitigation strategies to 
minimize the potential risk for the participants will be implemented, e.g. close medical 
observation including frequent ECG readings and ophthalmological monitoring.  
 
The proposed dose range selected for efficacy and safety evaluations in this trial has been 
primarily selected based on the tolerability and safety profile of the drug observed in 
completed phase 1 trials including: 
• Trial 1434-0001 (
) a placebo-controlled rising dose study of single doses 
of BI 764198 (1 mg to 240 mg) in healthy volunteers,  
• Trial 1434-0007 (
) a placebo-controlled multiple rising dose study of once 
daily doses of BI 764198 (20/40/80/160 mg) in healthy volunteers,  
• Trial 1434-0002 (
 a placebo-controlled single dose study of BI 764198 
(40 mg) in subjects with normal, moderate and severe renal impairment.  
 
Considering the medical need for an effective treatment in patients with proteinuric 
glomerular disease such as FSGS, the sponsor considers that the benefit outweighs the 
potential risks and justifies exposure of patients with FSGS to BI 764198, given the current 
need of drug development for effective and safe therapies in this disease. 

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2. 
TRIAL OBJECTIVES AND ENDPOINTS  
2.1 
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS  
2.1.1 
Main objectives  
A key objective of this trial is to explore the efficacy of 3 doses  (20 mg, 40 mg, and 80 mg) 
of BI 764198 with respect to their effect in lowering proteinuria. The primary endpoint is the 
proportion of  patients achieving at least 25% reduction in 24-hour urine protein creatinine 
ratio (UPCR) relative to baseline at week 12 in patients with primary FSGS, and patients with 
monogenic FSGS as a result of TRPC6 mutations causing FSGS. Additional objectives in this 
study are to investigate the safety, tolerability, and pharmacokinetic and pharmacodynamic 
profiles of BI 764198 vs placebo. 
 
The primary treatment comparison will be while on treatment, including all data prior to early 
discontinuation or lost to follow-up. 
2.1.2 
Primary endpoint  
The primary endpoint is patients achieving at least 25% reduction in 24-hour urine protein-
creatinine ratio (UPCR) relative to baseline at week 12. For details on efficacy assessments 
and definition of baseline, see section 5.1.1. 
2.1.3 
Secondary endpoints  
The secondary endpoints are: 
• Change in 24-hour UPCR relative to visit 3 at week12 
• Change in 24-hour UPCR relative to baseline at week 13 
• Change in 24-hour urinary protein excretion relative to baseline at week 12 
• The following pharmacokinetic parameters of BI 764198 will be determined if feasible: 
- 
Steady state trough concentration Cpre,ss on week 4 and week 12 
 
For details on efficacy assessments and definition of baseline, see section 5.1.1. 

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2.2.2.2 
Safety endpoints  
• AEs (including clinically relevant findings from the physical examinations) 
• SAEs occurring during the course of the study 
• AEs leading to treatment discontinuation 
• Vital signs (blood pressure, pulse rate) 
• Safety laboratory tests 
• 12-lead ECG 
• Ophthalmological assessments 

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3. 
DESCRIPTION OF DESIGN AND TRIAL POPULATION  
3.1 
OVERALL TRIAL DESIGN  
This multicenter, randomized, double-blind, parallel group study will assess 3 doses of 
BI 764198 compared to placebo administered orally once daily for 12 weeks in patients with 
primary or TRPC6 monogenic FSGS. 
 
After completion of all the screening procedures, eligible patients will be randomized into 
one of the 4 treatment groups stratified by use of corticosteroids, and treated for 12 weeks.  It 
is planned to randomize approximately 15 patients in each treatment group. At the end of the 
treatment period, there will be a follow-up visit at day 7 after end of treatment. A 2nd follow-
up visit will be scheduled via telephone, 30 days from end of treatment. Eye exams (section 
5.2.5.1) will be completed at the 2nd follow-up visit. A schematic illustration of the trial 
design is presented in Figure 3.1: 1. 
 
Figure 3.1: 1 Study design  
 
 
3.2 
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP  
A randomized, double-blind, placebo-controlled design is selected for this study. It is 
standard in studies at this early stage of development to use placebo as a control group in 
order to evaluate efficacy, safety and tolerability. The conduct of this short duration proof of 
clinical principle study will be on top of an array of established standard of care modalities 
including conservative management and steroid-based immunosuppression regimens.  
 
Most FSGS studies on glomerular diseases have used different metrics of proteinuria 
including UPCR. UPCR will be measured from 24-hour urine in this study. 

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UPCR reduction ratio (follow-up vs. baseline) for Cyclosporine A (CSA) and mycophenolate 
mofetil/dexamethasone (MMF/DEX) in a study with adults and children with steroid-resistant 
FSGS was analyzed (P11-13071). At week 8, there were approximately 65% and 
50% reduction of UPCR for CSA and MMF/DEX, respectively. A 12-week treatment to 
identify a reduction in UPCR should therefore be sufficient to demonstrate efficacy in the 
study. In addition, efficacy will further be assessed in this study by the evaluation of 
 
 24-hour proteinuria as secondary endpoints. 
3.3 
SELECTION OF TRIAL POPULATION  
This study will randomize approximately 60 patients with primary FSGS or with TRPC6 
mutations causing FSGS.  It is planned to conduct the study in approximately 55 sites in 
multiple countries. A sufficient number of patients will be screened to meet the 
randomization goal. 
 
Study sites in selected countries will have the option of integrating a decentralized clinical 
trial (DCT) model where the study visits are conducted outside of a dedicated healthcare or 
research facility.  This would allow patients to participate in the trial remotely and complete 
the study in their own home or residence.  The DCT model can bring the clinical trial to 
patient’s homes through telemedicine, a smartphone device, and through the deployment of 
mobile research nurses (MRN). The MRN will visit the patient’s home and complete trial 
procedures in collaboration with the site principal investigator and study staff. 
 
Sites participating in the DCT model would also continue to enroll patients using the 
traditional site-based approach where the patient visits the clinic at the specified time points 
in the protocol. Sites with DCT integration can also allow active ongoing patients in the trial 
to switch to remote participation. Additional operational guidelines will be provided in a 
separate DCT operational manual. A copy of the operational manual will be provided in the 
ISF. 
 
Recruitment of patients for this trial is competitive, i.e. screening for the trial will stop at all 
sites at the same time once a sufficient number of patients has been screened. Investigators 
will be notified about screening completion and will then not be allowed to screen additional 
patients for this trial. Patients already in screening at this time may be allowed to continue to 
randomization if eligible. 
 
A log of all patients enrolled into the trial (i.e. who have signed informed consent including 
patients who signed a screening consent or provided verbal consent) will be maintained in the 
ISF irrespective of whether they have been treated with investigational drug or not. If 
retrospectively it is found that a patient has been randomized in error (did not meet all 
inclusion criteria or met one or more exclusion criteria), the sponsor or delegate should be 
contacted immediately.  Based on individual benefit-risk assessment, a decision will be made 
whether continued trial participation is possible. 

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3.3.1 
Main diagnosis for trial entry  
The study will include patients with primary FSGS, and patients with monogenic FSGS as a 
result of TRPC6 mutations. 
 
Refer to section 8.3.1 for the documentation requirements pertaining to the inclusion and 
exclusion criteria. 
3.3.2 
Inclusion criteria  
1. Signed and dated informed consent in accordance with ICH-GCP and local legislation 
prior to admission to the study. 
2. Male and female patients 18 years to 75 years (both inclusive) of age on the day of 
signing informed consent. 
3. Patients diagnosed with biopsy proven primary FSGS or documented TRPC6 gene 
mutation causing FSGS prior to screening visit. 
4. UPCR ≥ 1000 mg/g based on first morning void urine sample during screening. 
5. Inclusion criterion 5 removed in global amendment 2. Numbering of subsequent criteria 
was not changed.  
6. Patients treated with corticosteroids must be on a stable dose for at least 4 weeks prior to 
screening visit with no plan to change the dose until end of trial treatment. 
7. Patients treated with ACE inhibitors, ARBs, finerenone, aldosterone inhibitors, or SGLT2 
inhibitors should be on a stable dose for at least 4 weeks prior to screening visit with no 
plan to change the dose until end of trial treatment. 
8. Body Mass Index (BMI) of ≤ 40 kg/m2 at screening visit. 
9. Women of childbearing potential (WOCBP1) must be willing and able to use highly 
effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less 
than 1% per year when used consistently and correctly.  A list of contraception methods 
meeting these criteria is provided in the informed consent form (ICF) and in section 
4.2.2.3.  
3.3.3 
Exclusion criteria  
1. Known monogenic (with the exception of TRPC6 gene mutations) or clinical or 
histologic evidence of secondary FSGS. 
2. Documented Alport syndrome, Nail Patella syndrome, diabetic nephropathy, 
IgA-nephropathy, lupus nephritis, or monoclonal gammopathy (e.g., multiple myeloma). 
3. Genito-urinary malformations with vesicoureteral reflux or renal dysplasia. 
4. A history of organ transplantation or planned transplantation during the course of the 
study. 
 
1A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy. Tubal ligation is NOT a method of permanent sterilisation. A postmenopausal state is defined as no 
menses for 1 year without an alternative medical cause. 

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5. Uncontrolled hypertension defined as an average resting systolic blood pressure 
>160 mmHg calculated from the last two of the triplicate sitting blood pressure 
measurements at screening visit. Patients with a documented history of white coat 
hypertension may be included. 
6. Concomitant use of calcineurin inhibitors within 5 half-lives before screening visit.  
7. Concomitant treatment with cytotoxic agents (cyclophosphamide, chlorambucil), or 
CD20 monoclonal antibody, e.g., rituximab, within 5 half-lives before screening visit. 
Note: use of other immunosuppression therapies considered as standard of care may be 
allowed as long as the patient remains on stable dose throughout the study. 
8. Treatment with metformin or dofetilide (MATE1 or OCT2 substrates); dabigatran or 
digoxin (P-gp substrates with narrow therapeutic window) within 5 half-lives before 
screening visit. 
9. Treatment with strong inhibitors or strong inducers of CYP3A within 1 week or 
5 half-lives before screening visit (whichever is longer). 
10. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 (CKD-EPI formula 
based on serum creatinine and cystatin C) at screening visit. 
11. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) >3X the upper limit of 
normal (ULN) at screening visit. 
12. Clinically significant laboratory abnormalities or medical conditions which pose a safety 
risk for the patient or may interfere with the trial objectives in the investigator’s opinion 
(except for renal function tests or deviation of clinical laboratory values that are related to 
FSGS) at screening visit. 
13. QTc intervals (QTcF) greater than 450 ms in males or greater than 470 ms in females, or 
any other clinically relevant ECG findings (at the investigator’s discretion) at screening 
visit. 
14. History of congenital long QT syndrome, previous drug-induced QT prolongation, or 
other risk factors for Torsade de pointes (e.g. hypokalemia, bradycardia, heart failure). 
15. Detection of graded cataract by LOCS III higher than NC1/NO1, C0, P0 in the slit lamp 
eye examination at screening visit.  Planned cataract surgery during participation in the 
study. Patients with cataract who have undergone lens replacement are not excluded. 
16. A history of gastrointestinal (GI) surgery or GI disorders that could interfere with 
absorption of trial medication in the investigator’s opinion. 
17. Major surgery (major according to the investigator’s assessment, e.g. hip replacement) 
performed 3 months before the screening visit or planned within 6 months after entering 
the study. 
18. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to screening visit, except appropriately treated basal cell carcinoma of the skin or in 
situ carcinoma of uterine cervix. 
19. History of relevant allergy or hypersensitivity according to the investigator´s clinical 
judgment (e.g. systemic hypersensitivity reactions including anaphylaxis and 
anaphylactoid reactions to the excipients or any other systemically administered agent). 
20. Patients who need to use restricted medications (section 4.2.2.1) or any drug considered 
likely to interfere with the safe conduct of the study, e.g. drugs with known 
QT-prolongation effects. 

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21. Patients not expected to comply with the protocol requirements or not expected to 
complete the study as scheduled (e.g. chronic alcohol or drug abuse or any other 
condition that, in the investigator’s opinion, makes the patient an unreliable study 
participant). 
22. Previous enrollment in this trial, or currently enrolled in another study investigating a 
device or drug, or less than 30 days or 5 times half-life of the investigational drug 
(whichever is longer) since ending another investigational drug study. Patients 
participating in observational studies will not be excluded. 
23. Women who are pregnant, nursing, or who plan to become pregnant while in the study. 
24. A positive test for SARS-CoV-2 during the screening period and up to the randomization. 
3.3.4 
Discontinuation of patients from treatment or assessments  
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole 
(“withdrawal of consent”) with very different implications; see sections 3.3.4.1 and 3.3.4.2 
below.  Every effort should be made to keep the patients in the trial.  Measures to control the 
withdrawal rate include careful patient selection, appropriate explanation of the trial 
requirements and procedures prior to trial enrollment, as well as the explanation of the 
consequences of withdrawal.  The decision to discontinue trial treatment or withdraw consent 
to trial participation and the reason must be documented in the patient files and electronic 
case report forms (eCRF). If applicable, consider the requirements for AE collection 
reporting (section 5.2.6.2). 
3.3.4.1 
Discontinuation of trial treatment  
An individual patient will discontinue trial treatment if: 
• The patient wants to discontinue trial treatment. The patient will be asked to explain the 
reasons but has the right to refuse to answer. 
• The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, the safety of the 
patient cannot be guaranteed as he/she is not willing or able to adhere to the trial 
requirements in the future.  
• The patient needs to take concomitant medication which may increase their risk of 
adverse effects or interfere with the investigational medicinal product (section 4.2.2.). In 
cases where treatment is expected to be temporary (short course), the case should be 
discussed with the sponsor and a decision will be made on potentially restarting trial 
medication. 
• The patient can no longer receive trial treatment for medical reasons (such as surgery, 
serious or severe drug induced liver injury attributable to the trial drug (section 5.2.6.1.4), 
other AEs, other diseases, or pregnancy).  
• The patient experiences confirmed QT prolongation of QTcF intervals greater than 
500 ms or an increase of >60 ms compared to baseline (defined as visit 2, pre-dose 
measurement). 
• The patient experiences clinically relevant conduction disorders (e.g. AV block ≥2nd 
degree, bundle branch block). 

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• The patient is diagnosed with cataract (graded by LOCS III higher than NC1/NO1, C0, 
P0) during study treatment. 
• eGFR below 25 mL/min/1.73 m2 (CKD-EPI formula based on serum cystatin C) and not 
improved by resolution of transient events (e.g. dehydration). 
Patient experiences acute kidney injury as per clinical judgement by the investigator 
and/or according to the modified Kidney Disease: Improving Global Outcomes (KDIGO) 
definition (R17-2439) and adapted for cystatin C as opposed to serum creatinine (R14-
1203, R15-5270). 
o Increase in cystatin C to ≥ 1.5 times the baseline value, which is known or 
presumed to have occurred within the prior 7 days. 
• The patient is diagnosed with severe COVID-19 (for example patients who require 
hospitalization, need supplemental oxygen, have compromised lung function, etc.). If the 
patient has mild illness, continuation of trial treatment is at the discretion of the 
investigator. Testing for SARS-CoV-2 infection must be done locally and not at the 
central lab. Positive test should be reported as an AE, and reason for premature 
withdrawal should be recorded as “other AE” if applicable. 
 
If new efficacy/safety information becomes available, BI will review the benefit-risk-
assessment and, if needed, pause or discontinue the trial treatment for all patients or take any 
other appropriate action to guarantee the safety of the trial patients.  
 
If the trial treatment is permanently discontinued, patient should complete the EoT, follow-up 
(FUP1), and EoS visits as outlined in the Flow Chart A. 
3.3.4.2 
Withdrawal of consent to trial participation  
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision. 
 
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation. Investigator should also explain the options for 
continued follow-up after trial treatment discontinuation. 
3.3.4.3 
Discontinuation of the trial by the sponsor  
BI reserves the right to discontinue the trial overall or at a particular trial site at any time for 
the following reasons: 
1. Failure to meet expected enrollment goals overall or at a particular trial site. 
2. New efficacy or safety information invalidating the earlier positive benefit-risk-
assessment. 
3. Deviations from Good Clinical Practice (GCP), the trial protocol, or the contract 
impairing the appropriate conduct of the trial. 
 

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The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason). 

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4. 
TREATMENTS  
4.1 
INVESTIGATIONAL TREATMENTS  
The BI investigational products are provided by Boehringer Ingelheim Pharma GmbH & Co. 
KG. 
4.1.1 
Identity of the Investigational Medicinal Products  
Table 4.1.1: 1 
Test product 1  
Substance: 
BI 764198 
Pharmaceutical formulation: 
Capsule 
Unit strength: 
20 mg, 40 mg, and 80 mg 
Posology: 
q.d. 
Mode of administration: 
Oral (p.o.) 
 
Table 4.1.1: 2 
Test product 2  
Substance: 
Placebo to match BI 764198 
Pharmaceutical formulation: 
Capsule 
Unit strength: 
Not applicable 
Posology: 
q.d. 
Mode of administration: 
Oral (p.o.) 
 
4.1.2 
Selection of doses in the trial  
The proposed doses in this study, 20 mg, 40 mg, and 80 mg were chosen based on acceptable 
Phase 1 clinical trial safety data generated with 80 mg for up to 14 days of daily dosing in 
healthy volunteers and safety margins based on nonclinical toxicological findings 
(
). 
 

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The human therapeutic dose in patients with CKD has been estimated based on plasma 
exposures demonstrating efficacy in a mouse unilateral ureteral obstruction model in which 
BI 764198 levels above the mouse manual patch-clamp IC90 value (after correcting for 
plasma protein binding) produced a significant pharmacological effect. Coverage of the 
human manual patch-clamp IC90 value of 212 nM (equivalent to 77 nM unbound, considering 
an unbound fraction of 36.4% in human plasma (
)) is predicted to be required in 
patients to provide therapeutic benefit.  The conservative assumption is that the Ctrough,ss value 
needs to be above the IC90 value.  
 
In the multiple rising dose (MRD) study (
), the gMean (gCV%) Ctrough,ss values of 
dose groups 20 mg, 40 mg and 80 mg were 164 nM (28.6), 351 nM (20.2) and 731 nM 
(29.1), respectively. Patients with primary FSGS likely have slightly higher exposures due to 
their impaired renal function relative to healthy subjects (see section 1.2). Simulations for 
patients with an eGFR of 60 mL/min/1.73 m2 were performed based on a population PK 
analysis including studies 1434-0001 
), 1434.0002 (
), and 1434-0007 
(
). The predicted median Ctrough,ss (95% prediction interval) of dose groups 20 mg, 
40 mg and 80 mg were 221 nM (134 - 356 nM), 432 nM (264 - 710 nM) and 867 nM (529 - 
1381 nM), respectively. 
 
Thus, the therapeutic dose of BI 764198 is estimated to be between 20 and 40 mg. However, 
in the absence of the possibility to assess target engagement in humans and given the 
uncertainty of a demonstrable pharmacodynamic effect solely based on in vitro dose 
estimation, a higher exposure (at multiples of IC90) may be needed to observe a therapeutic 
response in vivo.  
 
From an efficacy perspective, in this mechanistic study, we intend to investigate high doses 
of BI 764198 (above the anticipated therapeutic dose) in order to explore whether TRPC6 
inhibition induces a clinically meaningful UPCR response in patients with primary or TRPC6 
monogenic FSGS. Beyond the establishment of the proof of clinical principle, which is a key 
objective in this trial, future studies, including a dedicated Phase 2 dose finding trial will 
enable a thorough investigation of therapeutic doses and the establishment of the minimum 
effective dose. 
4.1.3 
Method of assigning patients to treatment groups  
After the assessment of all inclusion and exclusion criteria, each eligible patient will be 
randomized to one of the treatment groups according to the randomization plan in a 1:1:1:1 
ratio via Interactive Response Technology (IRT).  Randomization will be stratified by use of 
corticosteroids. 
 
Note that the trial medication number is different from the patient number (the latter is 
generated during screening via the IRT System). A total of 60 patients will be randomized 
with approximately 15 patients in each treatment group. Patients randomized by error and did 
not receive any trial medication may be replaced.  

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4.1.4 
Drug assignment and administration of doses for each patient  
Table 4.1.4: 1 shows the trial medication schedule for each treatment group. 
Table 4.1.4: 1 
BI 764198 and placebo treatments  
Dose 
group 
Substance 
Pharmaceutical 
form 
Unit strength 
Number of capsules  
per administration 
Total daily 
dose 
1 
BI 764198 
Capsule 
20 mg 
1 capsule q.d. for 12 weeks 
20 mg 
2 
BI 764198 
Capsule 
40 mg 
1 capsule q.d. for 12 weeks 
40 mg 
3 
BI 764198 
Capsule 
80 mg 
1 capsule q.d. for 12 weeks 
80 mg 
1-3 
Placebo* 
Capsule 
-- 
Matching placebo for 12 weeks 
-- 
* Subjects receiving placebo are equally distributed across all three treatment groups. 
After eligibility of the patient is confirmed during the screening period, patient will be 
randomized in the IRT Platform at least 7 days before the scheduled visit 2 date. 
Randomization will initiate the direct shipment of trial medication to the patient. Each patient 
will receive trial medication from an external depot contracted by the sponsor. Patient’s name 
and address will not be made available to the sponsor. Patient will receive sufficient trial 
medication for the entire 12-week duration of the treatment period.  
 
Prior to shipment of the trial medication, study site staff will train the patient on handling, 
storage, and use of the trial medication. Site staff should contact the patient by telephone 
(video call if possible) in about 24 hours (or next working day) after the site receives the 
delivery notification from the courier. During this contact, the site should remind the patient 
of the proper storage requirements for the medication. The patient should also be instructed 
not to open the trial medication package and to bring all the medication to the clinic for 
visit 2. 
 
Medication from one of the bottles will be used to dose the patient at visit 2. Site staff will 
inspect the shipment to ensure patient has received all the medication. All trial medication 
(except the capsule used for dosing at visit 2) will be returned to the patient with instructions 
for administration of medication at home. 
 
• Patient will self-administer the trial medication at home. On study visit days, patient 
must receive the dose during the study visit (at the clinic or at home) after the pre-
dose PK sample is taken. 
• Patients should take one capsule a day with or without food, preferably at the same 
time of the day in the mornings. 
• In case dosing occurs before 18:00 hours (6 p.m.), the next dose should be in the 
morning the next day (followed by morning dosing thereafter). 
• In case dosing occurs before midnight, the next dose should be at about noon the next 
day (followed by morning dosing thereafter). 
• If dosing does not occur on a particular day (not taken until midnight), the next dose 
should be in the morning the next day (followed by morning dosing thereafter). 

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The route of administration is by mouth (p.o.). Trial treatment may be restarted after 
temporary discontinuation (section 3.3.4.1). Dose reduction or increase are not allowed. 
 
On study visit days, trial medication will be administered at the specified time (see Table 
10.1: 1). Patient should be instructed to bring all used and unused bottles to the clinic for each 
study visit.  Site staff will inspect all the trial medication and also calculate compliance 
(section 4.3) by capsule count. Site will destroy the empty bottles with documentation and 
re-dispense the remaining medication to the patient at each study visit. At the EoT visit all 
remaining used and unused bottles with trial medication will be collected from the patient. 
Study visits should be rescheduled if trial medication is not available for dosing the patient 
after the pre-dose PK sample is drawn.  
  
If local regulations or site procedures or if the patient does not permit shipment of the trial 
medication directly to the patient, medication can be shipped to the study site. Randomization 
will still be completed at least 7 days before the scheduled visit 2 date to initiate trial 
medication shipment to the site. Site staff will dispense the trial medication to the patient. For 
storage conditions, see section 4.1.7. 
 
Unscheduled supply of trial medication can be initiated by the study site in the IRT. Patient 
should contact the site if a need for additional medication supply arises. 
 
A paper diary will be dispensed and collected at time points shown in the Flow Chart A. 
Patient will record the date and time of trial medication intake in the diary on the 3 days 
before EoT visit, and on the previous day for all other visits. Patients should be instructed to 
bring the completed diary for review by the site staff.  Date and time of medication intake for 
the 3 days prior to EoT as well as the previous day for all other visits will be entered in the 
eCRF. Date and time of medication intake during the study visit will also be entered in the 
eCRF. A copy of the paper diary will be placed in the ISF. 
 
For patients participating in the trial remotely via the DCT model, the MRN will visit the 
patient’s home for the study visit and complete the trial procedures including inspection of 
the trial medication, providing instructions for administration of medication at home, 
administering trial medication at the specified time during the study visit, and review of the 
paper diary.  Additional guidance on remote study visits will be provided in a separate DCT 
operational manual which will include instructions for handling used empty bottles and 
unused trial medication. 
 
COVID-19 pandemic - contingency plan: 
 
During the COVID-19 pandemic physical visits to the sites (for patients not participating in 
the DCT model) may need to be restricted to ensure patient safety.  Based on a thorough 
assessment of the benefits and risks, the investigator may still decide to continue the trial 
treatment, after discussion with the sponsor. 

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4.1.5 
Blinding and procedures for unblinding  
The trial has a double-blind design. The randomization schemes and medication kit lists 
(i.e. the treatment information) will be handled according to the sponsor’s Standard Operating 
Procedures (SOPs).  
 
 
Refer to section 4.1.5.2 for rules of breaking the code for an individual or for all patients in 
emergency situations. 
4.1.5.2 
Unblinding and breaking the code  
Emergency unblinding will be available to the investigator via IRT. It must be used only in 
an emergency situation when the identity of the trial drug must be known to the investigator 
in order to provide appropriate medical treatment or otherwise assure safety of trial 
participants.  The reason for unblinding must be documented in the source documents and/or 
appropriate CRF page.  If the patient is unblinded by the investigator, patient will have to be 
discontinued from the trial.  Discontinued patients will complete the EoT and follow-up 
visits. 
 
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance group to 
access the randomization code for individual patients during trial conduct. The access to the 

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code will only be given to authorized Pharmacovigilance representatives for processing in the 
PV database system and not be shared further.  
4.1.6 
Packaging, labelling, and re-supply  
The investigational medicinal products will be provided by BI or a designated contract 
research organization (CRO). They will be packaged and labelled in accordance with the 
principles of Good Manufacturing Practice. Re-supply (if necessary) will be managed via the 
IRT system. For details of packaging and the description of the label, refer to the ISF. 
4.1.7 
Storage conditions  
Drug supplies will be kept in their original packaging according to the recommended storage 
conditions on the medication label. Patients will be instructed to store the medication in a 
secure area. Site staff will train the patients on storage conditions. Patients will not maintain a 
temperature log. 
 
If shipment of trial medication to the site becomes necessary (section 4.1.4), sites should 
store the medication in a secure limited access storage area according to the recommended 
storage conditions on the medication label, and maintain a temperature log until the 
medication is dispensed to the patient. If the storage conditions are found outside the 
specified range, procedure described in the ISF has to be followed and a Clinical Research 
Associate (CRA) should be contacted immediately. 
4.1.8 
Drug accountability  
The patient will receive the investigational drug delivered by the sponsor when the following 
requirements are fulfilled at the study site: 
• Approval of the clinical trial protocol by the Institutional Review Board (IRB) / ethics 
committee, 
• Availability of a signed and dated clinical trial contract between the sponsor or delegate 
and the investigational site, 
• Approval/notification of the regulatory authority, e.g. competent authority, 
• Availability of the curriculum vitae of the Principal Investigator, 
• Availability of a signed and dated clinical trial protocol, 
• Availability of the proof of a medical license for the Principal Investigator,  
• Availability of Food and Drug Administration (FDA) Form 1572 (if applicable), 
• Study site has obtained a signed informed consent from the patient. 
 
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
all unused investigational drug. 
 
The investigator or designee must maintain records of the product’s delivery to the patient, 
the use by each patient, and the return to the sponsor or warehouse / drug distribution center 

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or alternative disposal of unused products. If applicable, the sponsor or warehouse / drug 
distribution center will maintain records of the disposal. These records will include dates, 
quantities, batch / serial numbers, expiry (‘use-by’) dates, and the unique code numbers 
assigned to the investigational medicinal product and trial patients. The investigator or 
designee will maintain records that document adequately that the patients were provided the 
doses specified by the Clinical Trial Protocol and reconcile all investigational medicinal 
products the patient received from the sponsor. At the time of return to the sponsor and/or 
appointed CRO, the investigator or designee must verify that all unused or partially used drug 
supplies have been returned by the patient and that no remaining supplies are in the 
investigator’s possession. 
4.2 
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS  
4.2.1 
Other treatments and emergency procedures  
There are no special emergency procedures to be followed in this trial. 
4.2.2 
Restrictions  
4.2.2.1 
Restrictions regarding concomitant treatment  
Medication or class of medications 
Restriction needs and time  
Strong inhibitors and strong inducers of 
CYP3A4/5; immunosuppressive agents, 
drugs with UGT1A4 activity, drug which are 
known P-gp substrates of narrow therapeutic 
window, and OCT2, MATE1, or MATE2-K 
substrates. 
Not allowed 1 week or 5 half-lives 
(whichever is longer) prior to randomization 
through 5 days after EOT 
 
Investigational device or drug  
Not allowed 30 days or 5 half-lives 
(whichever is longer) prior to 
randomization through 5 days after EOT  
Agents known to prolong the QT interval 
Not allowed 1 week or 
 5 half-lives (whichever is longer)  prior to 
randomization through 5 days after EOT 
Systemic corticosteroids 
Dose must be stable for at least 4 weeks 
prior to screening visit. Dose should not 
change during the screening and treatment 
period unless the investigator feels a dose 
change is necessary to ensure the patient’s 
safety.   
 

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Additional information, including a list of drugs that should be avoided, is provided in the 
ISF for the following classes of medications: immunosuppressive agents, strong 
inhibitors/inducers of CYP3A4/5, UGT1A4, drugs which are known P-gp substrates of 
narrow therapeutic window, and OCT2, MATE1, or MATE2-K substrates as well as agents 
known to prolong the QT interval. 
 
Medications listed under the exclusion criteria (section 3.3.3), are not allowed during the 
trial.  When possible, use of restricted medications and impact on treatment discontinuation 
should be discussed with the sponsor. There are no restrictions for trial participant to receive 
vaccination for COVID-19 during or after the study period. 
4.2.2.2 
Restrictions on diet and lifestyle  
Patients should avoid high protein, high salt diet. Avoidance of dietary protein load and 
strenuous exercise is especially important within 24 hours prior to the start and until the 
completion of the 24-hour urine collections. 
4.2.2.3 
Contraception requirements  
Female Patients 
WOCBP (for definition refer section 3.3.2) and their male sexual partner must use two 
medically approved methods of birth control during the treatment period and for a period of 
at least 5 days after last trial drug intake. Male partner of a WOCBP trial participant who is 
able to father a child must use a condom. 
WOCBP (trial participant) must use a highly effective method of birth control per ICH M3 
(R2) that results in a low failure rate of less than 1% per year when used consistently and 
correctly. Birth control methods with low user dependency, as indicated with an asterisk (*) 
below are preferable. 
• Combined (estrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal) 
• Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable*) 
• Intrauterine device (IUD)* or intrauterine hormone-releasing system (IUS)* 
• Bilateral tubal occlusion* 
Acceptable methods of birth control will include abstinence from male-female sex or having 
a vasectomized partner, provided that partner is the sole sexual partner of the trial participant 
who is a WOCBP, and that the vasectomized partner has received medical assessment of the 
surgical success. 
Abstinence from male-female sex is defined as being in line with the preferred and usual 
lifestyle of the patient. Periodic abstinence e.g. calendar, ovulation, symptothermal, post-
ovulation methods; declaration of abstinence for the duration of exposure to study drug; and 
withdrawal are not acceptable. 

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Since BI 764198 is not expected to lead to a clinically relevant reduction in the exposure of 
oral contraceptives due to an increased metabolism via enzyme induction (section 1.2), oral 
contraceptives are allowed in this trial. 
 
 
 
 
4.3 
TREATMENT COMPLIANCE  
Patients are requested to bring all remaining trial medication including empty bottles with 
them when attending visits. Based on capsule counts, treatment compliance will be calculated 
as shown in the formula below.  
Treatment compliance (%) = 
 
Number of capsules actually taken  100 
     Number of capsules should have been taken as 
directed by the investigator 
Compliance will be verified by the CRA authorized by the sponsor or delegate. The target for 
medication compliance should be 100%. If patient is non-compliant, site staff will explain to 
the patient the importance of treatment compliance. Randomized patients will not be 
discontinued from the trial for poor medication compliance without prior discussion with the 
Clinical Trial Manager (CT Manager) appointed by the sponsor. 
For patients participating in the trial remotely via the DCT model, compliance will be 
calculated by the MRN, and all unused trial medication and empty bottles will be collected by 
the MRN and returned to the study site or an alternative location for disposal. Shipment 
schedule and guidelines will be described in the DCT operational manual.  The investigator 
or designee must verify that all unused trial medication has been returned by the patient and 
that no remaining supplies are at the patient’s home. 

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5. 
ASSESSMENTS  
5.1 
ASSESSMENT OF EFFICACY  
5.1.1  
Measures of proteinuria  
The primary endpoint is patients achieving at least 25% reduction in UPCR from 24-hour 
urine relative to baseline after 12 weeks of treatment. The baseline UPCR will be from the 
average of two 24-hour urine samples collected before visit 2. 
 
Secondary and 
 are listed in sections 2.1.3 and 
., respectively, and they 
will be assessed as follows:  
 
• Change in UPCR relative to visit 3 at week 12: the samples will be from the 24-hour 
urine samples collected at visits 3 and 12. 
• Change in UPCR relative to baseline at week 13: the samples will be the 24-hour 
urine samples collected at baseline and week 13. 
• Change in 24-hour urinary protein excretion relative to baseline at week 12. 
For additional information on urine sample collections and the time points, see section 6.1 
and Flow Chart A. 
5.2 
ASSESSMENT OF SAFETY  
5.2.1 
Physical examination  
A complete physical examination will be performed at the time points specified in the Flow 
Chart A. It includes at a minimum general appearance, neck, lungs, cardiovascular system, 
abdomen, extremities, and skin. Measurement of height and body weight will be performed at 
the time points specified in the Flow Chart A. The results must be included in the source 
documents available at the site.  
 
For patients participating in the trial remotely via the DCT model, a physical examination per 
protocol will be performed at the patient’s home at the time points specified in the study 
protocol. The investigator or a designee (as indicated in the site trial staff list) will supervise 

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the physical examination remotely.  A MRN will facilitate the physical examination in the 
patient’s home.  
 
For patients participating in the trial remotely, if during the physical examination (PE) or at 
any time during the trial it is deemed that the patient requires in-person follow-up, the patient 
will be advised to visit the study site or their healthcare provider or a local facility for 
consultation. When applicable, the study site staff will contact the local healthcare facility to 
obtain the medical records. 
5.2.2 
Vital signs  
Vital signs will be evaluated at the time points specified in the Flow Chart A, prior to blood 
sampling. This includes systolic and diastolic blood pressure and pulse rate (electronically or 
by palpation count for 1 minute) in a seated position after 5 minutes of rest. Assessment for 
uncontrolled hypertension is completed at Visit 1 only. Three blood pressure measurements 
will be taken approximately 2 minutes apart after the patient has rested quietly and is in a 
seated position for at least 5 minutes. The average of the last two measurements for the 
triplicate systolic blood pressure measurements should be < 160 mmHg for assessment of 
exclusion criteria 5 at the screening visit. For subsequent visits, triplicate measurements are 
needed only if the first reading is >160mmHg, the average of the last two measurements are 
taken as the final reading. The results must be included in the source documents available at 
the site. 
5.2.3 
Safety laboratory parameters  
Safety laboratory parameters to be assessed are listed in Table 5.2.3: 1. Sampling time points 
are provided in the Flow Chart A. 
 
All analyses will be performed by a central laboratory, and the respective reference ranges 
will be provided in the laboratory manual. Instructions regarding sample collection, sample 
handling, processing, and shipping are provided in the laboratory manual. 
 
If central lab services or the lab kits provided by the central lab are not available at the study 
site, safety labs may be done at a local lab. The results of the lab tests should be entered in the 
eCRF. Please note the local labs should be used only if it becomes necessary, and the 
CT Manager should be informed. 
 
For patients participating in the trial remotely via the DCT model, laboratory kits will be 
made available at the patient’s home for the respective visits. The MRN will collect, process, 
and ship lab samples to the central laboratory or the study site (when applicable). Additional 
information will be provided in the DCT operations manual. 
 
Patients do not have to be fasted for the blood sampling for the safety laboratory.  
 

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The central laboratory will send laboratory reports to the investigator. It is the responsibility 
of the investigator to evaluate the reports. Clinically relevant abnormal findings as judged by 
the investigator will be reported as AEs (refer to section 5.2.6). 
 
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (section 5.2.6.1 and the DILI Checklist provided in the electronic data capture 
(EDC) system. The amount of blood taken from the patient concerned will be increased due 
to this additional sampling for DILI assessments. The central laboratory will transfer the data 
to the sponsor periodically. 
 
For assessment of eGFR exclusion criterion (section 3.3.3), the CKD-EPI formula based on 
serum creatinine and serum cystatin C will be used. The serum cystatin C-based CKD-EPI 
formula will be used for the calculation of eGFR in the evaluation of efficacy. 
 
 
. 
 
 

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Table 5.2.3: 1 
Safety laboratory tests  
 
Functional lab group 
Test name 
Haematology 
Haematocrit 
Haemoglobin 
Red blood cells (RBC) 
White blood cells (WBC) 
Platelet count 
MCV 
MCH 
MCHC 
RDW 
Automatic WBC differential 
(relative and absolute) 
Neutrophils total 
Lymphocytes total 
Eosinophils 
Basophils 
Monocytes 
Lymphocytes 
Manual differential WBC  
(if automatic differential WBC is 
abnormal) 
Polymorphonuclear neutrophils (segs), band neutrophils 
(stabs), eosinophils, basophils, monocytes, lymphocytes 
Coagulation 
Activated partial thromboplastin time (aPTT) 
Prothrombin Time (PT) 
International Normalised Ratio (INR) 
Enzymes 
Aspartate aminotransferase (AST)  
Alanine aminotransferase (ALT)  
Alkaline phosphatase (ALP) 
Gamma-glutamyl transferase (GGT)   
Creatine Kinase (CK) 
Creatine kinase – MB fraction (CK-MB1) 
Lactate dehydrogenase 
Lipase 
Amylase 
Troponin I1 
Substrates 
Glucose 
HbA1c (at screening and EoT)  
Creatinine (enzymatic method)2 
Cystatin C 
eGFR - CKD-EPI formula based on serum creatinine and 
cystatin C3  
eGFR - CKD-EPI based on serum creatinine 
eGFR – CKD-EPI based on serum cystatin C4 
Urea 
Uric Acid 

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Table 5.2.3: 1  
 
Safety laboratory tests (cont.) 
 
Functional lab group 
Test name 
Substrates (cont.) 
Total bilirubin  
Direct bilirubin 
Total protein 
Triglycerides 
Albumin 
Globulin 
Albumin / Globulin ratio 
C-Reactive Protein (CRP)  
Total cholesterol 
Infectious serology5 
Hepatitis B surface antigen 
Hepatitis C antibodies 
HIV-1/2 combination 
Electrolytes 
Calcium 
Sodium 
Potassium 
Magnesium 
Chloride 
Phosphate 
Bicarbonate  
(calculated) anion gap 
Urinalysis 
Urine nitrite 
Urine protein 
Urine glucose 
Urine ketone 
Urine bilirubin 
Urine Blood 
Urine leukocyte esterase 
Urine pH 
Specific gravity 
Urine drug screen (screening visit only) 
Cannabis 
Cocaine 
Benzodiazepine 
Amphetamines 
Barbiturates 
Methadone 
Opiates 
Urine sediment (microscopic 
examination if erythrocytes, 
leukocytes, nitrate or protein are 
abnormal in urine) 
Only positive findings will be reported (e.g. presence of 
sediment bacteria, casts in sediment, squamous epithelial 
cells, erythrocytes, leukocytes). 
 
Serum Pregnancy test (only for female 
participants of childbearing potential) 
at Visit 1, and if urine pregnancy test 
is positive at other visits. 
Human Serum Chorionic Gonadotropin 
 
Urine pregnancy test 
Human Serum Chorionic Gonadotropin 

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1. If initial CK is elevated, re-test CK with CK-MB and troponin I. 
2. Reported to the investigator only up to visit 2. 
3. eGFR based on serum creatinine and cystatin C will be reported to the investigator only up to visit 2. 
4. eGFR based on serum cystatin C will be reported to the investigator from visit 2 onwards. 
5. Only at screening visit. 
5.2.4 
Electrocardiogram  
Centralized ECG services will be provided by an external vendor. Standardized equipment 
and a quick guide will be provided by the vendor. ECGs should be collected according to the 
study-specific recommendations, using the standardized equipment provided by the vendor. 
 
The 12-lead ECGs will be recorded at the time points shown in the Flow Chart A. ECGs 
should be recorded before or at least 10 minutes after blood samples are drawn. Patients 
should be supine for approximately 5 to 10 minutes before ECG collection.  Patients should 
remain supine, but awake, during the ECG collection process. 
 
After the screening visit, the investigator must review the ECG results from central reading to 
ensure that patient is eligible to participate in the study. Starting at visit 2, ECGs will be 
recorded at two time points at each study visit: pre-dose and at 1 to 2 hours post-dose. ECGs 
may be repeated for quality or safety reasons.  
 
ECG recordings will be transmitted electronically to a vendor for central reading.  ECGs will 
be centrally evaluated and rated as normal, abnormal, or unable to evaluate, and the results 
will be sent to the study site.  The investigator should review the report from central reading.  
If the ECG is rated as abnormal, the investigator will determine if the abnormal findings are 
clinically significant.  The investigator will have the responsibility to follow up with the 
patient if there are any clinically significant findings in the ECG report. 
 
At the screening visit, ECGs are done in triplicate (3 single ECGs recorded within 
180 seconds). The QTcF value used to check eligibility at the screening visit is the average of 
the three recordings.  Any pre-existing conditions should be recorded as baseline conditions.   
 
Pre-dose ECGs at the first dosing visit should be evaluated by the investigator before the 
patient receives the first dose.  If abnormalities are observed by the investigator in the ECG 
readings at the first dosing visit, the investigator may wait until the results from central 
reading are available, and the first dosing visit may be rescheduled. 
 
After the first dose is taken at visit 2, ECG will be done 1 to 2 hours post-dose. In each of the 
remaining study visits until EoT, ECG will be recorded pre-dose and 1 to 2 hours post-dose. 
At the FUP1 visit, ECG will be recorded only once. ECGs will not be recorded at EoS visit. 
 
After the patient receives the first dose, if a clinically significant increase in the QTcF 
interval from baseline (defined as visit 2, pre-dose measurement) or any other clinically 
significant quantitative or qualitative change from baseline is identified the investigator will 
assess the symptoms (e.g., palpitations, near syncope, or syncope) and decide if the patient 

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will continue in the trial.  The investigator must also check if the patient meets any of the 
treatment discontinuation criteria (section 3.3.4.1). Any new pathological findings (including 
clinically relevant abnormal ECG findings) or deterioration of previous findings observed 
during the trial will be recorded as AEs or SAEs, and should be followed up and/or treated as 
medically appropriate per local standards. 
 
Although the ECGs are transmitted to the vendor for central reading, the investigator has the 
responsibility to complete an initial review of the ECG recordings the same day as the study 
visit. At any time during the trial, the investigator may decide to place a hold on further 
dosing of the patient if there is an indication of any new pathologic abnormalities in the ECG, 
and would prefer to wait until the results from the central reading are available. 
 
All ECGs that are read in the central location will be stored in the vendor’s database and will 
be transmitted to the sponsor periodically. 
 
For patients participating in the trial remotely via DCT, ECGs are completed at the patient’s 
home. The MRN will upload the ECGs to the DCT Platform (when applicable), and they will 
be available for the investigator or the site staff for review. If necessary, the MRN should 
consult with the investigator or designee before dosing the patient.  
5.2.5 
Other safety parameters  
5.2.5.1 
Ocular safety assessments  
Eye exams including the evaluation of cataract by slit lamp will be performed by an 
ophthalmologist or an optometrist in both eyes to evaluate the presence of lens disorders and 
cataract during the screening period. Results from the eye exams must be available to the 
investigator before the patient is randomized in the IRT and trial medication shipment is 
initiated.  The eye assessments will be repeated at EoT, and 30 days after last dose of trial 
medication (EoS) to monitor eye health and to observe any changes from baseline. 
 
The eye exams do not have to be completed on the same day of the study visits. At study 
entry, eye exams can be completed during the screening period. For EoT and EoS visits, 
patients should try and complete the eye exams within the protocol allowed window 
(±3 days) for the respective visits. Eye exams should be completed at the study site or at 
another healthcare or eye care facility. 
 
Eye assessments will be performed according to the Eye Examination Worksheet provided by 
the sponsor. All cataracts will be graded using LOCS III. A copy of the worksheet will be 
available in the ISF. The results from the eye exams should be entered in a separate eCRF.  
Safety related findings will be reported as AEs if applicable. If documented medical history 
of cataract surgery in both eyes is available at the time of screening, eye assessments are not 
required, and patient will not undergo eye exams during the screening period, EoT, and EoS. 
If it is confirmed at the screening visit (by slit lamp exam) that the patient had cataract 
surgery in both eyes, eye assessments are not required at EoT and EoS.  

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Patients participating in the trial remotely via the DCT model will complete the eye exams at 
a facility referred to by the investigator or patient could complete these exams at a local 
healthcare facility close to the patient’s home.  Results from the eye exams must be sent to 
the study site. 
5.2.6 
Assessment of adverse events  
5.2.6.1 
Definitions of AEs  
5.2.6.1.1 
Adverse event  
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment. 
 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
 
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable): 
• Worsening of the underlying disease or of other pre-existing conditions. 
• Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator. 
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only. 
5.2.6.1.2 
Serious adverse event  
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria: 
- 
results in death, 
- 
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe, 
- 
requires inpatient hospitalization or prolongation of existing hospitalization 
- 
results in persistent or significant disability or incapacity,  
- 
is a congenital anomaly / birth defect, 
- 
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse. 

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5.2.6.1.3 
AEs considered “Always Serious”  
In accordance with the European Medicines Agency initiative on Important Medical Events, 
BI has set up a list of AEs, which by their nature, can always be considered to be “serious” 
even though they may not have met the criteria of an SAE as defined above. 
 
The latest list of “Always Serious AEs” can be found in the EDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described in section 5.2.6.2. 
 
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in 5.2.6.2, “AE Collection” and “AE reporting to sponsor and timelines”. 
5.2.6.1.4 
Adverse events of special interest  
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, see section 
5.2.6.2.2. 
 
The following are considered as AESIs: 
Potential severe DILI 
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up defined by the 
following alterations of hepatic laboratory parameters:  
• an elevation of AST and/or ALT ≥3 fold upper limit normal (ULN) combined with an 
elevation of total bilirubin ≥2 fold ULN measured in the same blood draw sample, or in 
samples within 30 days of each other, or 
• ALT and/or AST elevations ≥10-fold ULN. 
 
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the EDC.  
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed. 
5.2.6.1.5 
Intensity (severity) of AEs  
The intensity (severity) of the AE should be judged based on the following: 
 
Mild:  
Awareness of sign(s) or symptom(s) that is/are easily tolerated. 
Moderate: 
Sufficient discomfort to cause interference with usual activity. 

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Severe: 
Incapacitating or causing inability to work or to perform usual activities. 
5.2.6.1.6 
Causal relationship of AEs  
Medical judgement should be used to determine the relationship between the adverse event 
and the BI investigational compound, considering all relevant factors, including pattern of 
reaction, temporal relationship, de-challenge or re-challenge, confounding factors such as 
concomitant medication, concomitant diseases and relevant history.  
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be: 
• The event is consistent with the known pharmacology of the drug.  
• The event is known to be caused by or attributed to the drug class. 
• A plausible time to onset of the event relative to the time of drug exposure. 
• Evidence that the event is reproducible when the drug is re-introduced. 
• No medically sound alternative aetiologies that could explain the event 
(e.g. pre-existing or concomitant diseases, or co-medications). 
• The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome). 
• An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced). 
 
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be: 
• No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned). 
• Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). 
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger. 
• Additional arguments amongst those stated before, like alternative explanation 
(e.g. situations where other drugs or underlying diseases appear to provide a more 
likely explanation for the observed event than the drug concerned). 
• Disappearance of the event even though the trial drug treatment continues or remains 
unchanged. 
5.2.6.2 
Adverse event collection and reporting  
5.2.6.2.1 
AE Collection  
The investigator shall maintain and keep detailed records of all AEs in the patient files. 
 
The following must be collected and documented on the appropriate CRF(s) by the 
investigator: 

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• 
From signing the informed consent onwards until the follow-up visit: all AEs (serious and 
non-serious) and all AESIs.  
• 
After follow-up-visit 1 until the individual patient’s end of trial: cancers of new histology 
and exacerbations of existing cancer, all trial drug related SAEs and all trial drug related 
AESIs. 
• 
After the individual patient’s end of trial: the investigator does not need to actively 
monitor the patient for new AEs but should only report any occurrence of cancer and trial 
treatment related SAEs and trial treatment related AESIs of which the investigator may 
become aware of by any means of communication, e.g. telephone call. Those AEs should 
be reported on the BI SAE form (section 5.2.6.2.2), but not on the CRF. 
5.2.6.2.2 
AE reporting to the sponsor and timelines  
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form to the sponsor’s unique entry point within 24 
hours of becoming aware of the event. Country specific process will be specified in the ISF. 
The same timeline applies if follow-up information becomes available. In specific occasions, 
the investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete the BI SAE form. 
 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable”, or no 
further information can be obtained. 
5.2.6.2.3 
Pregnancy  
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point. 
 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Studies (Part B). The ISF will contain the Pregnancy Monitoring Form for 
Clinical Studies (Part A and B). 
 
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition. 

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5.2.6.2.4 
Additional Safety monitoring  
In addition to the standard AE and SAE reporting, additional information will be collected in 
a separate eCRF on the following: 
• Acute kidney injury (defined in section 3.3.4) 
• Cataract 
5.3 
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS  
5.3.1 
Assessment of pharmacokinetics  
Blood samples for PK will be collected according to planned dates and times provided in 
Table 10.1: 1. The date and clock times of drug administration and pharmacokinetic sampling 
will be recorded in the eCRF. The actual sampling times will be used for determination of 
pharmacokinetic parameters as defined in section 2.1.3.  PK samples collected from this 
study will be also used for population PK and/or PK/PD analyses. 
5.3.2 
Methods of sample collection  
For the quantification of BI 764198 plasma concentrations, blood samples will be collected at 
time points indicated in Table 10.1: 1 and the Flow Chart A. The actual sampling times and 
time of dosing will need to be recorded in the eCRF. At selected sites, additional samples will 
be taken for the exploratory investigation of the metabolite CD 7949. These additional 
samples will be acidified as described in the laboratory manual. 
 
Plasma samples should be shipped to the central laboratory preferably on the same day of 
collection. Samples should be stored at approximately -20°C or below. Detailed instructions 
on sampling, preparation, processing, shipment and storage are provided in the laboratory 
manual. 
 
After completion of the trial the plasma samples may be used for further methodological or 
exploratory investigations, e.g. for stability and metabolite testing. However, only data 
related to the analyte and/or its metabolites will be generated by these additional 
investigations. The study samples will be discarded after completion of the additional 
investigations but not later than 5 years after the final study report has been signed. 

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5.4.2 
Pharmacogenomics biomarkers  
Pharmacogenomics investigates genetic variations to explain and to predict an individual’s 
response to drugs. Therefore, a blood sample for pharmacogenomic testing will be taken from 
each subject. In case of unexplainable variability of PK or PD parameters, DNA may be 
extracted from these samples and used for exploratory analysis of variants of genes with 
known association with FSGS, in particular TRPC6, and/or genes involved in absorption, 
distribution, metabolism and excretion of drugs. 
 
It is not intended to include these data in the clinical trial report. However, the data may be 
part of the report if necessary. All DNA samples will be destroyed one year after the last 
patient has completed the trial. 
 

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Detailed instructions for pharmacogenomics sampling, handling, and shipment of samples 
will be provided in the laboratory manual. 
5.4.2.1 
Methods and timing of sample collection  
One blood sample will be taken from an arm vein into a PAXgene blood DNA drawing tube, 
preferably at Visit 2. 
5.5 
BIOBANKING  
Not applicable. 
5.6 
OTHER ASSESSMENTS  
Not applicable. 
 
5.7 
APPROPRIATENESS OF MEASUREMENTS  
All measurements except for the exploratory biomarker measurements performed during this 
trial are standard measurements and will be performed in order to monitor patients’ safety 
and to determine pharmacokinetic and pharmacodynamic parameters. Sampling for the 
exploratory biomarkers is not associated with any additional risks. The risks related to eye 
exams are minimal.  
 
The scheduled procedures and measurements will allow monitoring of changes in vital signs, 
standard laboratory values, eye health, and ECG parameters that might occur as a result of 
administration of study drug. The safety assessments are standard, and are accepted for 
evaluation of safety and tolerability, and are widely used in clinical trials. The 
pharmacokinetic parameters and measurements outlined are generally used for assessments of 
drug exposure.  Approximately 200 mL (14 tablespoons) of blood will be collected from a 
patient during the course of the study. 
 

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6. 
INVESTIGATIONAL PLAN  
6.1 
VISIT SCHEDULE  
The trial consists of a screening period, treatment period, and a follow-up period.  Following 
the screening period, patients will be randomized (prior to visit 2) to one of the four treatment 
arms.  The treatment period is followed by a 30-day follow-up period which consists of 
2 follow-up visits.  The 2nd follow-up visit which is also the EoS visit will be completed by 
telephone except for the eye exams. Visit schedule and trial procedures are provided in the 
Flow Charts A and B. Schedule for PK sampling is presented in Table 10.1: 1. 
 
Patients should make all efforts to complete the trial which includes the 2 follow-up visits.  
Investigators should encourage treatment compliance, and adherence to the protocol 
procedures.  All patients should adhere to the visit schedule as specified in the Flow Charts A 
and B.  Any deviations from the planned visit schedule should be documented. 
 
All study visits should start preferably in the morning. Patients should be instructed to not 
take their trial medication at scheduled clinic visit days (from visit 2 to EoT visit). Trial 
medication must be administered during the clinic study visit as the time points specified in 
Table 10.1:1. 
 
If any visit after the first dosing visit (visit 2) is rescheduled or missed, subsequent visits 
should follow the original visit date.  The total treatment period (visit 2 to EoT visit) should 
be 12 weeks. 
 
Unscheduled visits may be arranged, and it will be at the discretion of the investigator in 
order to check the safety or for other reasons. 
 
ECGs should be recorded before blood samples are taken. Post-dose ECGs should be 
recorded before the PK sample is taken. 
 
Eye exams should be completed at the study site or at another healthcare facility (section 
5.2.5.1). 
 
For patients participating in the trial remotely via the DCT model, study visits and procedures 
(except eye exams) will be performed by a MRN deployed by a CRO authorized by BI.  
Home visits may also be performed by an appropriately qualified member of the 
investigational site staff (e.g. investigator, study nurse). Investigative sites may also contract 
their own mobile research nurse to perform the study visits at the patient’s home. Phone visits 
conducted in Flow Chart B should be conducted by site staff.  
 
The remote visits must adhere to the visit schedule as specified in the Flow Chart A.  The 
EoS visit by telephone will be completed by the study site staff. 
 

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In the event of force majeure or other disruptive circumstances (e.g. pandemic, war) the 
investigational plan as per this clinical trial protocol may not be feasible at a site. With the 
consent of the patient, sponsor and investigator may agree on alternative, back-up or rescue 
methodology which may include but will not be limited to virtual patient visits and 
assessments, and home healthcare nurse visits. The implementation of these measures will 
depend on patient’s consent, operational feasibility, local law and regulations. If alternative 
methodology is implemented, the deviations from the original plan will be precisely 
documented. 
 
First morning void – urine collection: 
 
First morning void sample is collected during the screening period to obtain the UPCR 
needed to determine eligibility for the trial. The first morning void is the urination after the 
patient wakes up to start their day. If the patient goes back to sleep after urinating early in the 
morning e.g. at 4am, this void does not need to be collected and this does not need to be 
documented. This applies also to any urinations earlier during the night in patients who have 
nocturia. However, if the patient is an early riser and gets up ‘for good’ e.g. at 4am, this 
would qualify as their first morning void. There may be cases when a patient might go back 
to bed after their usual rising time. In those cases, the void after the usual rising time 
constitutes the first morning void. The FMV sample can be brought to the site by the patient 
or may be shipped to the study site via a courier when possible. 
 
Patients can sign a separate screening consent for the purpose of collecting the first morning 
void urine sample during the screening period or provide a verbal consent (section 8.1). Site 
will process the urine samples and send them to central lab for UPCR analysis. The UPCR 
value obtained from the first morning void urine sample will be used to assess eligibility of 
the patient for the trial (section 3.3.2). Site staff should ensure sufficient time is available to 
get the UPCR results from central lab to complete the screening period within the protocol 
allowed window. If the patient did not meet the inclusion criteria for UPCR from the first 
morning void, the patient may repeat the assessment once, and the UPCR value obtained 
from the 2nd first morning void urine sample can be used to determine eligibility for the 
study. 
 
24-hour urine collection: 
The schedule for 24-hour urine collection and the time points for dispensing urine collection 
containers are provided in the Flow Chart A. The start and end time of the 24-hour urine 
collection will be recorded. Patients will be asked to empty their bladders outside the 
container before start of sampling and into the container during and at the end of the 24-hour 
collection period. Patients will receive detailed instructions on the collection, storage, and 
transportation of the urine samples. Processing and analyses of the 24-hour urine samples will 
be described in the laboratory manual. 
 
The 24-hour urine samples where collection started the day before the study visits should be 
brought to the clinic by the patient for the respective study visits. Other 24-hour urine 

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samples (collected during the screening period) can be brought to the site by the patient or 
may be shipped to the study site via a courier when possible. 
 
During the screening period, patient will collect 24-hour urine samples at two separate 
occasions. The 24-hour urine samples should be collected only after confirmation that the 
patient met all the eligibility criteria for the trial, and the collections should be close to visit 2 
as much as possible. Visit 2 must be rescheduled if UPCR data is not available from at least 
one 24-hour urine sample. 
 
For visits 3, EoT, and FUP1, one 24-hour urine sample will be collected. Collection should 
start preferably the day before the respective study visit and end on the day of the visit. 
 
Visit 2 must be rescheduled if at least one of the 24-hour urine sample is not collected. The 
EoT visit must be rescheduled if the 24-hour urine sample is not collected before the visit. 
Visits must be rescheduled as soon as possible. 
 
For patients participating in the trial remotely via the DCT model, urine collection containers 
for all the study visits will be sent to the patient’s home, and the urine samples will be 
shipped to the study site via a courier. If patients live close to the study site, they may also 
pick up the urine collection containers from the study site and bring the 24-hour urine 
samples to the study site. 
 
If possible, patients should be reminded (e.g. via telephone) during the screening period and 
ahead of the applicable visits to collect the 24-hour urine samples. 
 
Collection of 24-hour urine samples may be repeated for logistical reasons (e.g. samples lost 
or patient could not complete the 24-hour collection) or technical issues (e.g. sample not fit 
for analysis). 
 
Pregnancy tests 
 
All WOCBP will undergo serum pregnancy test at the screening visit (visit 1).  Patients who 
test positive for the serum pregnancy test will be excluded from the trial.  If the patient is a 
WOCBP, the status of the menstrual cycle should be assessed before the administration of the 
first dose of trial medication (visit 2): in case of a delayed or missed period, the PI should use 
their clinical judgement and the results of the pregnancy test at visit 2 to assess the 
participants pregnancy status and confirm eligibility before intake of trial drug.  
 
Urine pregnancy tests will be done at all study visits starting from visit 2 (except visit 3 and 
phone visits). If the urine pregnancy test is positive, trial medication will be stopped and a 
serum pregnancy test will be performed to confirm pregnancy. If the serum pregnancy test is 
positive, the patient will be discontinued from the trial. EoT visit will be scheduled as soon as 
possible, and patient should complete the EoS visit. If serum pregnancy is negative, patient 
may continue in the trial and resume treatment with trial medication.  If the urine pregnancy 

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test is positive at the first dosing visit (visit 2), the patient must not be dosed unless the serum 
pregnancy test is negative. 
6.2 
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS  
6.2.1 
Screening and run-in period  
Trial procedures to be performed during the screening period can be found in the Flow Chart 
A. Screening period is defined as the time between the date of informed consent (or the 
screening consent) to the date of first dose (visit 2). No trial procedures should be performed 
until the patient has consented to take part in the trial.  The separate screening consent is to 
allow collection of the first morning void urine sample to obtain the UPCR needed to check 
eligibility criteria (section 3.3.2 and 8.1). Each patient will be assigned a unique patient 
number and enrollment will be recorded in eCRF. 
 
For patients participating in the trial via the DCT model, the consenting process may be 
completed electronically (via eConsent) within the DCT Platform. Screening consent when 
applicable will be administered outside the DCT Platform. Prior to initiating the eConsent 
process, eligibility of potential patients will be assessed after review of medical records by 
the investigator or site staff. Once this preliminary eligibility is confirmed, a study informed 
consent discussion will be scheduled.  The informed consent materials will be presented in 
the DCT Platform. The patient will review the documents and during this telephone call with 
the investigator or designee will have the opportunity to discuss the study, and have their 
questions answered. If patient agrees to participate in the trial, an electronic signature will be 
obtained. 
 
Once the patient has consented to collect the first morning void  urine sample for screening 
purposes, the patient is considered to be enrolled in the trial. The patient should be recorded 
on the enrollment log and be registered in the IRT. 
 
Baseline conditions, medical history, and eligibility criteria will be assessed at visit 1.  
Concomitant therapy and AE (if any) will be recorded.  At the conclusion of visit 1, patients 
should receive instructions on procedures to be followed during the screening period. 
 
If all the eligibility criteria are met, randomization will be completed by calling the IRT. 
Randomization will initiate trial medication shipment to the patient and visit 2 will be 
scheduled. For more information on medication administration, see section 4.1.4. 
 
Screening period may be extended for administrative reasons with approval from the 
CT Manager. 
 
If screening period exceeds 30 days, the investigator should review the laboratory reports 
from the screening visit (visit 1) and make a determination if any labs specified in the 
protocol must be repeated before the first dosing visit.  If deemed necessary, test samples 
should be drawn and sent to the central laboratory.   

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Discontinuation during the screening period 
 
If patients discontinue from the trial during the screening period, no additional study visits 
are required, and they will be marked as screen failures.  Patient will be registered as a screen 
failure in IRT. 
 
Rescreening and retesting 
 
Patients who screen failed due to a reason that was reversible and has since been resolved or 
those who were screen failed for administrative reasons (e.g., extended travel, life events) 
may be rescreened once with approval from the CT Manager or designee. 
 
If the investigator believes that a lab test result is due to an error or other extenuating 
circumstances, the lab test can be repeated once without the patient having to be rescreened. 
6.2.2 
Treatment period.  
Treatment period will begin at visit 2 and will continue for 12 weeks. Procedures to be 
completed at each study visit can be found in the Flow Charts A and B. There will be three 
phone call visits during the treatment period: visits 3A, 4A, and 5A. Please refer to Flow 
Chart B for details on the phone call visits. 
 
Unscheduled visits may be arranged if necessary.  Procedures completed during an 
unscheduled visit will depend on the circumstances under which the visit was scheduled, and 
at the discretion of the investigator. 
 
EoT must be rescheduled if the 24-hour urine sample is not collected for UPCR 
measurements. After completion of the treatment period, the patient will enter the 30-day 
follow-up period. 
 
Discontinuation during the treatment period 
 
For discontinued patients, EoT visit must be scheduled as soon as possible. After completion 
of the EoT visit, patient will complete both follow-up visits (FUP1 and EoS). 
6.2.3 
Follow-up period and trial completion  
The 30-day follow-up period extends from the EoT visit until the EoS phone call visit. The 
FUP1 visit should be scheduled 7 days after the EoT visit, and EoS phone call visit should be 
scheduled 30 days after the EoT visit.  The EoS visit will be a telephone visit for all patients. 
For patients participating in the trial remotely, the study site staff will complete EoS visit by  
telephone. Procedures to be completed at the follow-up visits can be found in the Flow Chart 
A. Investigator should ensure that eye exams (if applicable) are completed as part of the EoS 
visit and the results are reviewed. 
 

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The last study visit will be the EoS visit and this will mark the end of observation period, and 
the patient has completed the trial. 

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7. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE  
7.1 
NULL AND ALTERNATIVE HYPOTHESES  
No confirmatory testing will be performed and hence no null and alternative hypotheses are 
defined since this is a non-confirmatory study. 
7.2 
PLANNED ANALYSES  
7.2.1 
General considerations  
The following analysis sets will be defined for statistical analyses: 
 
• Entered Set (ES): This patient set includes all patients who signed informed consent. 
The ES will be used for the analysis of patient disposition. 
 
• Randomized Set (RS): This patient set includes all patients who signed the informed 
consent form and were also randomized, regardless whether the patient was treated 
with trial medication or not. 
 
• Treated Set (TS): This patient set includes all patients who received at least one dose 
of trial medication. The TS is used for safety analyses as well as demographics and 
baseline characteristics. 
 
• Full Analysis Set (FAS): This patient set includes all patients who were randomized 
and treated with evaluable measurements UPCR at baseline and at least one UPCR 
measurement after first dose. The FAS is the main analysis set for the analysis of 
efficacy. 
 
• Pharmacokinetic Analysis Set (PKS): This patient set includes all patients in the TS 
who provide at least one PK endpoint that was not excluded due to protocol violation 
relevant to the evaluation of PK or due to PK non-evaluability. 
 
For the analysis of efficacy, patients will be analyzed as randomized, without regard to any 
treatment changes. 
7.2.2 
Handling of Intercurrent Events  
An intercurrent event (ICE) is defined as an event of, 
• early discontinuation,  
• lost to follow-up, or 
• death. 
 
The strategies for handling intercurrent events in this trial are as follows: 

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• Hypothetical estimand: assuming all subjects remained adherent to the assigned trial 
medication and the study protocol. This strategy will include all data collected until 
time of an ICE. 
• Treatment policy estimand: using all available data including data collected after an 
ICE. 
7.2.3 
Primary endpoint analyses  
An exploratory inferential analysis for the primary endpoint, in terms of proportion of 
patients achieving at least 25% UPCR reduction relative to baseline at 12 weeks, will be 
conducted by providing 95% confidence intervals from each treatment group. The primary 
estimand of interest is the treatment effect assuming all subjects remained adherent to the 
assigned trial medication and the study protocol using a hypothetical approach, i.e., study 
drug is taken as directed. This analysis will include all data collected until time of an ICE. 
 
In addition, an analysis of variance (ANOVA) model (for the UPCR change from baseline at 
week 12) will be used to see difference across arms. Dose-response relationship based on 
reduction in log of UPCR may be explored using graphical approach. 
7.2.3.1 
Sensitivity analyses  
Sensitivity analyses to be conducted to assess the robustness of the primary analysis outcome 
will be described in the trial statistical analysis plan (TSAP). 
7.2.3.2 
Supplemental analysis of primary endpoint  
An additional assessment of the primary endpoint will be conducted using the treatment 
policy estimand, i.e., effectiveness/intention to treat. The treatment policy estimand will use 
all available data including data collected after an ICE. All attempts will be made to collect 
all data per protocol. 
7.2.3.3 
Subgroup analyses  
No subgroup analysis planned. 
7.2.4 
Secondary endpoint analyses  
All secondary endpoints in Section 2.1.3 except pharmacokinetic parameters of BI 764198 
will be analysed by using descriptive statistics and figures.  
 
Further details will be given in the TSAP. 

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7.2.6 
Safety analyses  
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of study, which include a 5-day period after 
last dose of trial medication, will be assigned to the on-treatment period for evaluation. 
 
All treated patients (i.e., all patients who received at least one dose of trial medication) will 
be included in the safety analysis. In general, safety analyses will be descriptive in nature and 
will be based on BI standards. No hypothesis testing is planned.  
 
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 
study. Adverse events that start before first intake of trial medication and deteriorate under 
treatment will also be considered as ‘treatment-emergent’.  
 
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the MedDRA 
at the database lock.  
 
Laboratory data will be analyzed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarized. 
Treatment groups will be compared descriptively with regard to distribution parameters as 
well as with regard to frequency and percentage of patients with abnormal values or clinically 
relevant abnormal values.  
 
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the study and at the end-of-study evaluation will be assessed 
with regards to possible changes compared to findings before start of treatment. 

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7.3 
 HANDLING OF MISSING DATA   
No missing data will be imputed in the UPCR, 
, and urinary protein excretion, 
analyses. Handling of missing PK data will be performed according to the relevant Corporate 
Procedure.  PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed. Further details will be specified in the TSAP. 
7.4 
RANDOMIZATION  
The study will be performed as a double-blind design with respect to the 3 different doses of 
BI 764198 and placebo in a 1:1:1:1 ratio stratified by use of corticosteroids.  Patients will be 
randomized in blocks to double-blind treatment via the IRT system. 
 

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The sponsor will arrange for the randomization as well as packaging and labelling of trial 
medication. The randomization list will be generated using a validated system that uses a 
pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable. 
7.5 
DETERMINATION OF SAMPLE SIZE  
To explore the clinical principle of BI 764198 it is planned to include a total of 60 patients 
with FSGS. The planned sample size is not based on a power calculation. The size of 
15 patients per treatment arm is considered to be sufficient to detect differences between the 
different treatment groups and placebo in terms of the primary endpoint. 
 
The goal of the trial is to determine if the difference in UPCR response between at least one 
dose after baseline and placebo is greater than 25%. Assuming that approximately 40%, 30%, 
20% of patients in 80mg, 40mg, 20mg treatment groups, respectively, achieve at least 25% 
UPCR reduction at 12 weeks while 9 % of patients in placebo group achieve 25% UPCR 
reduction, the proposed sample size provides 73.4% probability for the difference in 
responder rates between at least one treatment arm and placebo to be greater than 25%.  
 
Calculations were performed using R3.6.1. 
 

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8. 
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE  
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for GCP, 
relevant BI SOPs, the EU directive 2001/20/EC /EU regulation 536/2014, and other relevant 
regulations. Investigators and site staff must adhere to these principles. Deviation from the 
protocol, the principles of ICH GCP or applicable regulations as will be treated as “protocol 
deviation”. 
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient. 
 
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP. 
 
The BI transparency and publication policy can be found on the following web page: 
trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor with regard 
to publication of the results of this trial are described in the investigator contract.  As a rule, 
no trial results should be published prior to finalisation of the Clinical Trial Report. 
8.1 
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT  
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB / Independent Ethics Committee (IEC) and competent 
authority (CA) according to national and international regulations. The same applies for the 
implementation of changes introduced by amendments. 
 
Prior to patient participation in the trial, informed consent must be obtained from each patient 
(or the patient’s legally accepted representative) according to ICH-GCP and to the regulatory 
and legal requirements of the participating country. Each signature must be personally dated 
by each signatory on the informed consent and any additional patient-information form 
retained by the investigator as part of the trial records. A signed copy of the informed consent 
and any additional patient information must be given to each patient. For patients who are 
also participating in the National Institutes of Health sponsored Nephrotic Syndrome Study 
Network (NEPTUNE), their NEPTUNE TrialLink identification number will be collected in 
the eCRF to enable sharing their trial data with NEPTUNE, appropriate data linkages for 
post-hoc analysis, and for quality assurance. For additional information on consenting 
patients participating in the trial remotely via the DCT model, refer to section 6.1. 
 
The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent (or eConsent) of the patient’s own free will 
with the informed consent form after confirming that the patient understands the contents. 
The investigator or 
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form. If a trial collaborator has given a supplementary explanation, the trial collaborator also 
signs (or places a seal on) and dates the informed consent. 
 
When possible, a screening consent process can be used prior to signing the full consent to 
permit collection of the first morning void urine sample from the patient that is needed during 
the screening process. A screening consent form will be mailed/faxed/emailed to the patient, 
and site staff will discuss the urine collection process over the phone/video call. A signed 
screening consent form is mailed/faxed/emailed back to the site. Once the signed screening 
consent form is received, urine collection containers and instructions will be sent to the 
patient. 
 
When it is not possible to send/return a signed screening consent form, the study site staff 
will verbally describe the procedure over a phone/video call and obtain a verbal consent.  Site 
will document the conversation in medical notes. Patient will sign the screening consent form 
in person during the screening visit.  The date of the screening consent obtained over the 
phone/video call is regarded as the date of screening consent. The investigator or delegated 
site staff will sign and date the screening consent form. All phone/video call screening 
consents should be documented by the site staff in patient’s medical record. If a patient signs 
a screening consent and does not provide the first morning void urine sample before the 
screening visit, or if the patient did not sign a screening consent, patient will receive 
instructions and urine collection containers at the screening visit. 
 
Patients participating in the trial remotely via the DCT model will follow the same screening 
consenting process administered by the study site staff. 
 
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.  The consent and re-consenting 
process should be properly documented in the source documentation. 
8.2 
DATA QUALITY ASSURANCE  
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk. Continuous risk review and assessment may lead to adjustments in 
trial conduct, trial design or monitoring approaches.  
 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial. 

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8.3 
RECORDS  
CRFs for individual patients will be provided by the sponsor. See section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to section 4.1.8. 
8.3.1 
Source documents  
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail). Data reported on 
the CRF must be consistent with the source data or the discrepancies must be explained. 
 
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable. 
 
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file. 
For the CRF, data must be derived from source documents, for example: 
• Patient identification: gender, year of birth (in accordance with local laws and 
regulations) 
• Patient participation in the trial (substance, trial number, patient number, date patient was 
informed) 
• Dates of patient’s visits, including dispensing of trial medication 
• Medical history (including trial indication and concomitant diseases, if applicable) 
• Medication history 
• Adverse events and outcome events (onset date (mandatory), and end date (if available)) 
• Serious adverse events (onset date (mandatory), and end date (if available)) 
• Concomitant therapy (start date, changes) 
• Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available) 
• Completion of patient’s participation in the trial (end date, in case of premature 
discontinuation document the reason for it) 
• Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial 
 

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Data collected from patients participating in the trial remotely via the DCT model, will be 
entered in a DCT Platform built for this trial. The data from the DCT Platform will be 
transcribed into the BI EDC system by the site staff. 
8.3.2 
Direct access to source data and documents  
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP. 
 
Remote source data verification is acceptable in rare cases where onsite monitoring visits 
cannot take place due to the COVID-19 pandemic or other unforeseen circumstances.  
Remote source data verification must first be approved by the CT Manager and must be 
aligned with local laws and regulations. 
8.3.3 
Storage period of records  
Trial sites: 
The trial sites must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer). 
Sponsor: 
The sponsor must retain the essential documents according to the sponsor’s SOPs. 
8.4 
EXPEDITED REPORTING OF ADVERSE EVENTS  
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.  
8.5 
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY  
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the World Health 
Organization GCP handbook.  
 
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions: 
Personalised treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities. 

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8.5.1 
Collection, storage and future use of biological samples and corresponding 
data  
Measures are in place to comply with the applicable rules for the collection, and future use of 
biological samples and clinical data, in particular: 
• The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials 
• An appropriate sample and data management system, incl. audit trial for clinical data 
and samples to identify and destroy such samples according to ICF is in place 
• A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage 
• A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data 
8.6 
TRIAL MILESTONES  
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent. 
 
The end of the trial is defined as the date of the last visit of the last patient in the whole trial 
(Last Patient Completed).  
 
The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last 
patient in the whole trial is administered the last dose of trial treatment (as scheduled per 
protocol or prematurely). Individual investigators will be notified of SUSARs occurring with 
the trial medication until 30 days after LPLT at their site. 
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol. 
 
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it. 
 
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
(HA) request. 
 
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws. 
 
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.  
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU). 

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8.7 
ADMINISTRATIVE STRUCTURE OF THE TRIAL  
The trial is sponsored by Boehringer Ingelheim (BI).  
 
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract.  
 
The sponsor will establish an internal safety review committee which will include a 
cardiologist, ophthalmologist, member from global pharmacovigilance, and other trial or 
project team members. The committee will review individual and aggregated unblinded 
safety data at regular intervals.  The primary objective of this committee will be to monitor 
the safety and tolerability of BI 764198. ECG data (from central reading) will be reviewed at 
this meeting. The safety review committee will operate under a data review plan. Information 
on tables, figures, and listings to be reviewed by the committee will be described in this 
document. An independent data monitoring committee will not be established to monitor this 
trial. 
 
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF. The investigators will have access to the BI web portal 
Clinergize to access documents provided by the sponsor. 
BI has appointed a Clinical Trial Leader (CTL), responsible for coordinating all required 
activities, in order to  
- 
manage the trial in accordance with applicable regulations and internal SOPs, 
- 
direct the clinical trial team in the preparation, conduct, and reporting of the trial, 
- 
ensure appropriate training and information of CT Managers, CRAs, and investigators 
of participating countries. 
 
In the participating countries the trial will be performed by the respective local or regional 
BI-organization (Operating Unit) in accordance with applicable regulations and BI SOPs, or 
by a CRO based on a contract. 
 
Data Management and Statistical Evaluation will be done by BI according to BI SOPs. 
 
Tasks and functions assigned in order to organize, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF. 
 
A central laboratory service, a central ECG service, and an IRT vendor will be used in this 
trial. Details will be provided in the central laboratory manual, quick guide for ECG, and 
quick reference documents for IRT, respectively. 

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9. 
REFERENCES  
9.1 
PUBLISHED REFERENCES  
 
P11-13071 
Gipson DS, et al. Clinical trial of focal segmental glomerulosclerosis in 
children and young adults. Kidney Int 2011;80(8):868-878.  
 
P17-08386 
Rosenberg AZ, Kopp JB. Focal segmental glomerulosclerosis. Clin J Am 
Soc Nephrol 2017;12(3):502-517.  
 
R14-1203 
Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, 
Kusek JW, Manzi J, Lente F van, Zhang YL, Coresh J, Levey AS, CKD- 
EPI Investigators. Estimating glomerular filtration rate from serum 
creatinine and cystatin C. N Engl J Med 2012;367(1):20-29.  
 
R15-5270 
Levey AS, Becker C, Inker LA. Glomerular filtration rate and albuminuria 
for detection and staging of acute and chronic kidney disease in adults: a 
systematic review. JAMA 2015;313(8):837-846.  
 
R17-2439 
Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney 
Injury Work Group. KIDGO clinical practice guideline for acute kidney 
injury. Kidney Int Suppl 2012;2(1):1-138.  
 
R18-1763 
Jiang L, Ding J, Tsai H, Li L, Feng Q, Miao J, et al. Over-expressing 
transient receptor potential cation channel 6 in podocytes induces 
cytoskeleton rearrangement through increases of intracellular Ca2+ and 
RhoA activation. Exp Biol Med (Maywood) 2011;236:184-193.  
 
R18-1764 
Tian D, Jacobo SMP, Billing D, Rozkalne A, Gage SD, Anagnostou T, et 
al. Antagonistic regulation of actin dynamics and cell motility by TRPC5 
and TRPC6 channels. Sci Signal 2010;3(145):ra77.  
 
R20-3402 
Recommendations related to contraception and pregnancy testing in clinical 
trials (version 1.1, CTFG 21/09/2020). Website: 
hma.eu/fileadmin/dateien/Human_Medicines/01 
About_HMA/Working_Groups/CTFG/2020_09_HMA_CTFG_Contracepti
on_guidance_Version_1.1.pdf (access date: 16 October 2020); Clinical 
Trial Facilitation Group (CTFG), Head of Medicine Agencies (HMA); 
2020.  
R20-3802 
Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et 
al, ACTT-1 Study Group Members. Remdesivir for the treatment of Covid-
19 - final report. N Engl J Med 2020;383(19):1813-1826.     
 

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R20-3912 
Kiffel J, Rahimzada Y, Trachtman H. Focal segmental glomerulosclerosis 
and chronic kidney disase in pediatric patients. Adv Chronic Kidney Dis 
2011;18(5):332-338.  
 
R20-3949 
Haas M, Meehan SM, Karrison TG, Spargo BH. Changing etiologies of 
unexplained adult nephrotic syndrome: a comparison of renal biopsy 
findings from 1976 - 1979 and 1995 - 1997. Am J Kidney Dis 1997;30(5) 
:621-631.  
 
R20-3978 
Kitiyakara C, Eggers P, Kopp JB. Twenty-one-year trend in ESRD due to 
focal segmental glomerulosclerosis in the United States. Am J Kidney Dis 
2004;44(5):815-825.  
 
R22-1956 
Bowman CJ, Becourt-Lhote N, Boulifard V, et al. Science-based approach 
to harmonize contraception recommendations in clinical trials and 
pharmaceutical labels. Clin Pharmacol Ther 2022. doi:10.1002/cpt.2602  
R99-2093 
Chylack LT, Wolfe JK, Singer DM, Leske MC, Bullimore MA, Bailey IL, 
Friend J, McCarthy D, Wu SY, Longitudinal Study of Cataract Study 
Group. The lens opacities classification system III. Arch Ophthalmol 
(Chicago) 1993;111:831-836.  
 
 

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10. 
APPENDICES  
10.1 
TIME SCHEDULE FOR PK BLOOD SAMPLING  
PK blood samples will be taken according to the time schedule below. 
Table 10.1: 1 
Time schedule for PK blood sampling during treatment course  
Trial 
Periods 
Visit 
Day 
Time Point [hh:min] 
Planned 
Time 
Event 
Treatment 
period  
2 
1 
 Within 30 min before drug 
admin. 
-0:30 
PK Blood 
0:00 
0:00 
Drug admin. 
0:303 
0:30 
PK Blood 
1:001,3 
1:00 
PK Blood 
2:003 
2:00 
PK Blood 
 
 
 
 
 
 
3 
4 (+3) 
Within 5 min before drug admin. 
71:55 
PK Blood 
0:00 
72:00 
Drug admin. 
1:003 
73:00 
PK Blood 
4 
29 (+3) 
Within 5 min before drug admin. 
671:55 
PK Blood 
0:00 
672:00 
Drug admin. 
 
 
 
1:003 
673:00 
PK Blood2 
5 
57 (±3) 
Within 5 min before drug admin. 
1343:55 
PK Blood2 
0:00 
1344:00 
Drug admin. 
1:003 
1345:00 
PK Blood 
EoT 
85 (±3)  Within 5 min before drug admin. 
2015:55 
PK Blood 
0:00 
2016:00 
Drug admin. 
0:303 
2016:30 
PK Blood 
1:001,3 
2017:00 
PK Blood 
2:003 
2018:00 
PK Blood 
4:003 
2020:00 
PK Blood 
6:003 
2022:00 
PK Blood2 
Follow-up 
period 
FUP 1 
92 (±2) 
One PK sample during the visit 
2184:00 
PK Blood 
1  Post dose ECG should be performed either before or at least 10 min after PK blood 
sample.2 At selected sites, additional PK samples at planned times 673:00, 1343:55 and 
2022:00 will be taken and acidified for CD 7949 quantification. Details on the handling and 
acidification of these specific samples will be provided in the laboratory manual. 
3 +/- 15 minutes for post dose sample draws. 
 

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11. 
DESCRIPTION OF GLOBAL AMENDMENT  
 
Date of amendment 
 
01 December 2021 
EudraCT number 
 
2020-000384-23 
BI Trial number 
 
1434-0004 
BI Investigational Medicinal 
Product 
 
BI 764198 
Title of protocol 
 
A multicenter, randomized, double-blind, parallel 
group, placebo-controlled study to assess safety, 
tolerability, pharmacokinetics  and 
pharmacodynamics of BI 764198 administered 
orally once daily for 12 weeks in patients with 
focal segmental glomerulosclerosis. 
Global Amendment due to urgent safety reasons 
 
Global Amendment 
 
Section to be changed 
 
Sections 1.2 and 4.1.2 
Description of change 
 
Drug profile 
a) Sections on drug interactions updated. 
Sections on toxicology and clinical studies 
updated. 
b) REP changed from 4 to 5 days. 
c) In section 4.1.2, preliminary results from the 
renal impairment study (
) is 
updated with final results. 
Rationale for change 
 
a) Updates based on additional data that became 
available. 
b) REP for BI 764198 is longer in patients with 
moderate renal impairment. 
c) Updated with final results consistent with the 
IB. 
Sections to be changed 
 
All applicable sections 
Description of change  
 
Patient Population 
Patients with primary or monogenic FSGS or with 
TRPC6 mutations causing FSGS will be included 
in the study. 
Rationale for change 
 
To include patients with TRPC6 associated 
FSGS. 
Section to be changed 
 
a) Flow Chart 
b) Table 5.2.3.1 
c) Section 6.1 
Description of change 
 
Trial Procedures 
a) Pregnancy test at visit 3 removed. 

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b) Urine drug screening added for screening 
visit. 
c) If urine pregnancy test is positive, trial 
medication should be suspended until serum 
pregnancy test result is available. 
Rationale for change 
 
a) Pregnancy test done 3 days before at visit 2. 
b) Additional safety labs added at screening. 
c) To ensure patient safety. 
Section to be changed 
 
a) Section 1.2 
b) Sections 1.4.2, 3.3.2, and 4.2.2.3 
c) Section 6.1 
d) Section 4.2.2.3 
Description of change 
 
Contraception requirements 
a) Rationale for permitting oral contraceptives 
added.  
b) Men must use condoms, including those who 
are vasectomized. 
c) Menstrual cycle status checked at 
randomization visit in WOCBP. 
d) Preferable methods of birth control for 
WOCBP indicated. 
Rationale for change 
 
a) BI 764198 is not expected to lead to a 
clinically relevant reduction in the exposure of 
oral contraceptives due to an increased 
metabolism. 
b) Potential male-mediated exposure to 
BI 764198 in females would be conveyed by 
seminal fluid rather than the genetic material 
in the sperm cells. Therefore, the use of 
condoms is also required in vasectomized trial 
participants.  
c) To ensure exclusion of pregnant patients. 
d) Birth control methods with low user 
dependency are preferred. 
Section to be changed 
 
a) Section 2.2.2.2 
b) Sections 2.1.3, 5.1.1,
c) Section 5.1.1 
Description of change 
 
Endpoints 
a) Ophthalmological assessments added to safety 
endpoints. 
b) Change in 24-hour urinary albumin excretion 
deleted. 
 
 
 
. 

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Rationale for change 
 
a) To monitor any changes in the ocular 
assessments. 
b) 
Section to be changed 
 
Section 3.3.3 
Description of change 
 
Exclusion criteria 
Cataract is graded by LOCS III system. 
Rationale for change 
 
To allow patients with age-related mild cataract to 
participate in the study. 
Section to be changed 
 
Section 3.3.4.1 
Description of change 
 
Discontinuation criteria 
Added two additional criteria: 
1. The patient experiences clinically relevant 
conduction disorders (e.g. AV block ≥2nd 
degree, bundle branch block). 
2. The patient is diagnosed with cataract during 
study treatment. 
Rationale for change 
 
Additional safety measures added for patients 
during their participation in the study. 
Section to be changed 
 
Section 4.2.2.1 
Description of change 
 
Restrictions 
List of medications or class of medications 
updated. 
Rationale for change 
 
Align with restricted medication guidance 
provided in the ISF. 
Section to be changed 
 
a) Section 5.2.5.1 
b) Various 
Description of change 
 
Ocular safety assessments 
a) Eye assessments will be performed according 
to the Eye Examination Worksheet provided 
by the sponsor. 
b) Slit lamp eye exam changed to “eye exams”. 
Rationale for change 
 
Characterization of cataract using the LOCS III 
grading. 
Section to be changed 
 
a) Section 3.3 
b) Section 3.3.4.1 
c) Section 5.2.3 
d) Section 8 
e) Section 9.2 
f) Entire document 
g) Flow Chart and synopsis 

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Description of change 
 
Administrative 
a) Multinational study 
b) Cystatin C – compared to baseline 
c) Assessment of eGFR at screening and for 
other visits defined. Formulas to calculate 
eGFR has been removed: will be included in 
the central lab specifications document. 
d) European Union specific requirements are 
added. Collection of NEPTUNE TrialLink 
identification number added. 
e) References added. 
f) Abbreviations updated and typographical 
errors corrected. Clarifications and corrections 
made. Applicable changes throughout the 
document to reflect the changes described in 
Section 11. 
g) Changes in the main protocol have also been 
addressed in the Flow Chart and synopsis 
when applicable. 
Rationale for change 
 
Administrative 
 
 
 
 

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Date of amendment 
25 October 2022 
EudraCT number 
2020-000384-23 
BI Trial number 
1434-0004 
BI Investigational Medicinal Product 
BI 764198 
Title of protocol 
A multicenter, randomized, double-blind, 
parallel group, placebo-controlled study 
to assess efficacy, safety, tolerability, 
pharmacokinetics  and 
pharmacodynamics of BI 764198 
administered orally once daily for 12 
weeks in patients with focal segmental 
glomerulosclerosis. 
Global Amendment due to urgent safety 
reasons 
 
Global Amendment 
 
Section to be changed 
Title page and Synopsis 
Description of change 
Title of the protocol is revised to include 
efficacy assessment. 
Change in Clinical Trial Leader 
Rationale for change 
Primary endpoint includes efficacy 
assessment. 
Change in Clinical Trial Leader 
Section to be changed 
Sections 1.2, 1.4.2, and 3.3.4.1  
Description of change 
Drug Profile:  
Key pharmacokinetic characteristics 
updated. 
Data from clinical studies updated. 
Risks, Discontinuation of trial 
treatment: 
Severe Covid-19 infection defined and 
provided as a reason patients should be 
discontinued from trial treatment. 
Rationale for change 
Updates were made based on new clinical 
data. 

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Section to be changed 
Section 3.3.1 
Also clarified in the synopsis under trial 
rationale. 
Description of change 
Main diagnosis for trial entry: 
Patients with primary or monogenic 
FSGS as a result of TRPC6 mutations. 
Changed to 
Patients with primary FSGS, and patients 
with monogenic FSGS as a result of 
TRPC6 mutations. 
Rationale for change 
Clarification 
Section to be changed 
Synopsis 
Sections 2.1.1, 2.1.2, 2.1.3, 
, 
, 5.1.1, and 5.3.4. 7.2.1, 7.2.3, 
7.2.5, 7.5 
Description of change 
Trial objectives and endpoints: 
Main objectives: updated to include 
efficacy as an objective.  
Primary endpoint: baseline will be based 
on 24-hour urine samples collected before 
first dose. 
Secondary endpoints: changed to align 
with revised 24-hour urine collection 
schedule. 
Rationale for change 
Decision to have UPCR collected before 
first dose as the baseline for primary 
endpoint. 
Section to be changed 
Synopsis, Flow Chart A, Sections 3.3.2, 
6.1, and 6.2.1 

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Description of change 
Inclusion criteria: 
Inclusion criteria 4, UPCR for inclusion 
criteria changed to 1000mg/g and will be 
based on first morning void. Section 6.1 
provides instructions for the collection of 
morning void. 
Inclusion criteria 5 removed and 6 
revised. 
Rationale for change 
UPCR from first morning void is 
sufficient to determine inclusion in the 
study. 
Inclusion criteria 6 revised to allow 
patients taking corticosteroids in the study 
if they are on a stable dose for 4 weeks.  
Section to be changed 
Synopsis and Section 3.3.3 
Description of change 
Exclusion criteria: 
Exclusion 6: exclusionary timeframe for 
calcineurin inhibitors prior to screening 
added 
Exclusion 7: stable therapeutic dose 
changed to stable dose 
Exclusion 19: revised to describe the 
assessment of relevant allergy or 
hypersensitivity. 
Exclusion 24:  revised to clarify eligibility 
relative to covid-19 infection. 
Rationale for change 
Clarifications 
Section to be changed 
Section 4.2.2.1, 4.2.2.3 
Description of change 
Restrictions on concomitant treatment: 
restriction needs and time described in the 
protocol. Restriction guidelines for 
systemic corticosteroids added. 
Restriction of agents known to prolong 
QT interval is specified. 
Contraception Requirements:  
Vasectomized partner added as acceptable 
method of contraception. 
Rationale for change 
Additional information and guidance 
added to restricted medications. 

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Section to be changed 
Flow Charts A and B, Section 6.1, 6.2.1, 
6.2.2, 8.1 
Description of change 
Study visits 
Visits 4, 6, and 8 removed and visit 
numbers changed. 
Visits 3A, 4A, and 5A added as phone 
visits. 
Dispensing 24-hour urine collection kits 
aligned with scheduled collections. 
 
Footnotes renumbered.  
FMV added during screening for 
determination of eligibility before 
proceeding with other screening 
procedures.  
Broadened potential reasons for 
rescreening after screen failure. 
Rationale for change 
Reduced the frequency of clinic visits to 
reduce patient burden. Phone visits have 
been added to follow patient safety. 
Section to be changed 
Table 10.1.1, Sections 4.1.4, and 5.3 
Description of change 
PK sampling schedule changed. Serial PK 
will be done only at EoT. 
Additional PK samples will be collected 
at selected sites for quantification of the 
CD 7949 metabolite. 
Schedule to record date and time of trial 
medication intake in the paper diary 
changed.  
Rationale for change 
Two serial PK visits removed to reduce 
patient burden. 
Additional samples were needed to 
quantify metabolite CD 7949. 
Paper diary is aligned with revised PK 
sampling schedule. 
Section to be changed 
Flow Chart A, Sections 1.3, 
, 5.5, 
and 8.5.1 
Description of change 
Optional biobanking samples will not be 
collected. 

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Rationale for change 
Biobanking samples will be collected in 
future trials. 
Section to be changed 
Table 5.2.3: 1 
Description of change 
Infectious serology added to safety 
laboratory tests. 
Added to table: eGFR - CKD-EPI formula 
based on serum creatinine and cystatin C 
Rationale for change 
Additional safety parameters added. 
eGFR formula added for consistency with 
inclusion criterion. 
Section to be changed 
Flow Chart A, Section 1.4.2 
Description of change 
ECG will be performed only at clinic 
visits. 
Rationale for change 
To align with changes in the clinic visit 
schedule. 
Section to be changed 
Section 5.4.1.3 
Description of change 
Urine biomarkers will not be collected if 
study visits are conducted remotely. 
Rationale for change 
Logistical reasons in processing the urine 
samples at remote visits (e.g., patient’s 
home) before shipment to central 
laboratory. 
Section to be changed 
Section 7.2.3 
Description of change 
Added 95% confidence intervals for 
proportion of patients achieving at least 
25% UPCR reduction relative to baseline 
at 12 weeks  from each treatment group. 
Rationale for change 
To have more informative statistics 
besides simple descriptive statistics. 
Section to be changed 
Sections 3.1, 4.1.3, 7.4 
Description of change 
Patients will be stratified by use of 
corticosteroids at randomisation. 
Rationale for change 
Ensure even distribution of patients taking 
corticosteroids across treatment groups. 
Section to be changed 
Sections 3.3, 4.1.1, 4.1.2, and 5.7 
Description of change 
Added more sites 

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Source for Investigational Medicinal 
Products is corrected. 
Reference to 1434-0002 removed in 
Section 4.1.2. 
Blood volume corrected to align with the 
revised blood sampling schedule. 
Rationale for change 
Administrative 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Date of amendment 
14 Jul 2023 
EudraCT number 
2020-000384-23 
BI Trial number 
1434-0004 
BI Investigational Medicinal Product 
BI 764198 
Title of protocol 
A multicenter, randomized, double-blind, 
parallel group, placebo-controlled study 
to assess efficacy, safety, tolerability, 
pharmacokinetics  and 
pharmacodynamics of BI 764198 
administered orally once daily for 12 
weeks in patients with focal segmental 
glomerulosclerosis. 
Global Amendment due to urgent safety 
reasons 
 
Global Amendment 
 
Section to be changed 
Title page  
Description of change 
1. Universal Trial Number added 
2. Change in Clinical Trial Leader 
3. Change in Coordinating Investigator 
Rationale for change 
Administrative update 
Section to be changed 
Protocol Synopsis 
Description of change 
Removal of male participant 
contraception use if female partner is 
WOCBP 
Rationale for change 
Based on emergent animal study results, 
the exposure of female sexual partners 
and associated risk of fetotoxicity are 
negligible, indicating that condom use is 
not required for male trial participants 
with WOCBP partners 
Section to be changed 
Flowchart footnotes 

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Description of change 
1. Timing of collection of ECG relative to 
blood sampling 
2. Urine pregnancy testing clarity 
3. Addition of triplicate systolic blood 
pressure measurements at screening to 
support assessment of exclusion criteria 5 
Rationale for change 
1. Clarity to avoid ECG collection no 
sooner than 10 minutes after blood 
sampling to avoid anxiety related findings 
on ECG results 
2. Urine pregnancy testing is not done at 
phone visits 
3. Guidance for assessment of 
uncontrolled hypertension in exclusion 
criteria 5 
Section to be changed 
1.2 Drug Profile 
Description of change 
Alignment with Investigator Brochure 
version 7 based on completed toxicology 
animal study data 
Rationale for change 
Alignment with Investigator Brochure 
version 7 based on completed toxicology 
animal study data 
Section to be changed 
1.4.2 Risks 
Description of change 
Removal of male participant 
contraception use if female partner is 
WOCBP 
Rationale for change 
Based on emergent animal study results, 
the exposure of female sexual partners 
and associated risk of fetotoxicity are 
negligible, indicating that condom use is 
not required for male trial participants 
with WOCBP partners 
Section to be changed 
3.3.2 Inclusion criteria 
Description of change 
Removal of male participant 
contraception use if female partner is 
WOCBP 
Rationale for change 
Based on emergent animal study results, 
the exposure of female sexual partners 
and associated risk of fetotoxicity are 

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negligible, indicating that condom use is 
not required for male trial participants 
with WOCBP partners 
Section to be changed 
4.1.4 Drug assignment and 
administration of doses for each patient 
Description of change 
Update reason why study medication may 
be shipped to the site instead of patient’s 
home 
Rationale for change 
Update reason why study medication may 
be shipped to the site instead of patient’s 
home 
Section to be changed 
4.2.2.3 Contraception requirements 
Description of change 
Removal of male participant 
contraception use if female partner is 
WOCBP 
Rationale for change 
Based on emergent animal study results, 
the exposure of female sexual partners 
and associated risk of fetotoxicity are 
negligible, indicating that condom use is 
not required for male trial participants 
with WOCBP partners 
Section to be changed 
5.2.2 Vital Signs 
Description of change 
Addition of triplicate systolic blood 
pressure measurements at screening to 
support assessment of exclusion criteria 5 
Rationale for change 
Guidance for assessment of uncontrolled 
hypertension in exclusion criteria 5 
Section to be changed 
5.2.4 Electrocardiogram 
Description of change 
Timing of collection of ECG relative to 
blood sampling 
Rationale for change 
Clarity to avoid ECG collection no sooner 
than 10 minutes after blood sampling to 
avoid anxiety related findings on ECG 
results 
Section to be changed 
5.2.6.2.3 Pregnancy 
Description of change 
Removal of male participant 
contraception use if female partner is 

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WOCBP and a pregnant partner informed 
consent form is no longer needed 
Rationale for change 
Based on emergent animal study results, 
the exposure of female sexual partners 
and associated risk of fetotoxicity are 
negligible, indicating that condom use is 
not required for male trial participants 
with WOCBP partners 
Section to be changed 
6.1 Visit schedule 
Description of change 
Urine pregnancy testing clarity 
Rationale for change 
Urine pregnancy testing is not done at 
phone visits 
Section to be changed 
9.1 Published references 
Description of change 
Added references 
Rationale for change 
Administrative update 
Section to be changed 
10.1 Time schedule for PK blood 
sampling 
Description of change 
1. Addition of out of window allowance 
for post dose sampling 
2. Clarity to avoid ECG collection no 
sooner than 10 minutes after blood 
sampling 
Rationale for change 
Allowance of out of window for post dose 
PK sampling and ECG collection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Date of amendment 
08 Jan 2024 
EudraCT number 
2020-000384-23 
BI Trial number 
1434-0004 
BI Investigational Medicinal Product 
BI 764198 
Title of protocol 
A multicenter, randomized, double-blind, 
parallel group, placebo-controlled study 
to assess efficacy, safety, tolerability, 
pharmacokinetics  and 
pharmacodynamics of BI 764198 
administered orally once daily for 12 
weeks in patients with focal segmental 
glomerulosclerosis. 
Global Amendment due to urgent safety 
reasons 
 
Global Amendment 
 
Section to be changed 
Title Page 
Description of change 
Change in Document Number 
Change in Clinical Trial Protocol 
Revision Date  
Change in Clinical Trial Leader 
Rationale for change 
Administrative change 
Section to be changed 
Protocol Synopsis 
Description of change 
Change in Clinical Trial Protocol 
Revision Date  
Rationale for change 
Administrative change 

Boehringer Ingelheim 
                       08 Jan 2024 
BI Trial No.: 1434-0004 
c30500151-06 
                                                   Clinical Trial Protocol 
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