Global amendment 3 part 1: The following main changes were introduced by the amendment: Modification of flow chart to clarify post-dose electrocardiogram (ECG) at Visit 3 and addition of a footnote explaining the timing of the last dose, for correction and clarification; Extension of the maximum time before randomisation from 28 to 35 days throughout the clinical trial protocol (CTP), to gain more time to allow screening procedures to be repeated where permitted; Specification added for Inclusion Criterion 3 that estimated glomerular filtration rate (eGFR) had to remain ≥20 milliliter (mL)/minute (min)/1.73 square meters (m^2) after Visit 1 up to the start of Visit 3, to ensure patient safety; Rephrasing of Inclusion Criterion 6 from ‘stable on anti-hypertensives, non-steroidal anti-inflammatory drug(s) (NSAIDs), endothelin receptor antagonists, systemic steroids, within at least 4 weeks prior to Visit 1 until start of trial treatment, with no planned change of the therapy during the trial’ to ‘if the patient is taking any of the following medications they should be on a stable dose at least 4 weeks prior to Visit 1 until start of treatment, with no planned change of the therapy during the trial: anti-hypertensives, NSAIDs, endothelin receptor antagonists, systemic steroids or sodium-glucose co-transporter-2 (SGLT2) inhibitors’, for clarification; Modification of Exclusion Criterion 3 from ‘diabetes mellitus’ to ‘diagnosed with diabetes mellitus according to local guidelines’, for clarification; Specification that trial medication shipments were also allowed for regular visits at the patient’s home, for clarification;

Global amendment 3 part 2: The following main changes were introduced by the amendment: Addition of a footnote to concomitant treatments for clarification on use of restricted nitrates in an emergency; Removal of tablet count recording in the case report forms (CRF) since tablet counts were not required for compliance calculation, but were to be provided through accountability procedures at the site; Replacement of the requirement to test non-sterilized women <65 years of age with the requirement to test women of child-bearing potential for pregnancy as it was considered unnecessary for a women who was not of child-bearing potential to undergo pregnancy testing: Addition of a clarification of why a safety laboratory may not be performed at the central laboratory and addition of requirement to check creatinine to the minimum tests at the local laboratory as an important laboratory parameter to monitor kidney function.

Global amendment 4 part 1 - the following main changes were introduced by this amendment: Addition of electrocardiogram (ECGs) at visits where there were previously no ECGs in the flow chart and the flow chart for procedures (3 ECGs at Visits 4 and 5 and 1 ECG at Visits 7 and 8; at Visits 3 and 6 an additional ECG was to be done in addition to the 2 already performed) to introduce more frequent ECG monitoring as a response to recent additional data; Addition of eGFR as a test that patients could be pre-screened for if consent was given, to reduce unnecessary screening procedures for patients who would not be eligible due to eGFR; Inclusion of recent data from trial 1366-0020 in the drug profile to include new information and to serve as rationale for additional measures introduced with the amendment; Inclusion of potential QT-interval (QT interval is the time from the start of the Q wave to the end of the T wave) prolongation in the overview of trial related risks, to reflect new available data; Removal of lactose monohydrate as an example of an excipient in Exclusion Criterion 11 since lactose monohydrate was not used in the Phase II formulation; Addition of the following exclusion criteria to ensure that patients with QTc (QTc is the corrected QT interval) prolongation or with the potential for QTc prolongation would not participate: o Exclusion Criterion 17 (QTcF-interval (QT interval corrected for Fridericia formula) >450 milliseconds (ms) in men or >470 ms in women at screening [Visit 1] until start of treatment); o Exclusion Criterion 18 (family history of long QT syndrome); o Exclusion Criterion 19 (concomitant use of therapies with a known risk of Torsade de Pointes at screening [Visit 1] and throughout screening and baseline run-in or planned initiation of such therapies during the trial);

Global amendment 4 part 2 - the following main changes were introduced by this amendment: Clarification that the Kidney Disease: Improving Global Outcomes (KDIGO) definition should be used ‘for guidance’ when assessing the criterion for treatment discontinuation in case of Acute Kidney Injury (AKI), to reflect that the KDIGO guidelines are for use within a clinical setting, and patients with low urine output for reasons other than AKI could potentially have been incorrectly discontinued; Modification of the criterion for treatment discontinuation in case of intake of concomitant medication that interferes with the safety of the investigational medicinal product to include sponsor review and decision on a case-by-case basis, to enable patients to remain on trial treatment in exceptional cases if using restricted medication, if there were no safety concerns; Addition of a criterion for treatment discontinuation for patients with a QT or QTcF interval >500 ms, or an increase of QT or QTcF of >60 ms from the pre-dose value at Visit 3 and specification that such cases had to be reported as Adverse Events (AEs), as an additional safety measure; Addition of concomitant therapies with a known risk of Torsade de Pointes as restricted medications, with criteria for temporary stop and re-start of trial medication in the event of temporary concomitant use of such a therapy, to exclude use of medications that could impact QTc; Specification that vital signs were to be assessed prior to ECG and blood sampling, to ensure vital signs were assessed prior to ECG; Addition of high density lipoprotein (HDL) cholesterol laboratory test to correct erroneous omission; Addition of details on ECG timing, review, collection, and storage, to ensure ECGs were accurate and any anomalies were correctly reported, and to include a new storage procedure.

Global amendment 5 part 1 - the following main changes were introduced by this amendment: Modification of the lay title of the CTP to be consistent with revisions made to the eligibility criteria; Changes of inclusion criteria to allow enrolment of patients with other non-diabetic kidney diseases whose prognosis and treatment were similar, and who therefore may have benefited from treatment with a soluble Guanylate Cyclase (sGC) activator: Expansion of Inclusion Criterion 8 by replacing ‘...hypertensive kidney disease or chronic glomerulonephritis defined as one of the following (...)’ with ‘...any kind of diagnosed chronic kidney disease1 whose primary cause is clinically not considered to be of diabetic origin’ (with footnote indicating that diagnosis could be reached by standard clinical methods, not requiring biopsy); Removal of Inclusion Criterion 7 (diagnosis of CKD as defined by KDIGO definition) due to redundancy with Inclusion Criterion 8; Replacement of ‘phosphodiesterase inhibitors’ with ‘Phosphodiesterase-5-inhibitors, non-specific phosphodiesterase inhibitors (such as dipyridamole and theophylline)’ in Exclusion Criterion 1 and in the restricted concomitant medications, since nitric oxide (NO)-sGC- cyclic guanosine monophosphate (cGMP) pathway activating drugs were not to be administered due to possible synergistic effects with avenciguat; Replacement of ‘diabetes mellitus’ with ‘diagnosed with diabetic kidney disease1’ in Exclusion Criterion 3 (with footnote indicating that diagnosis could be reached by standard clinical methods, not requiring biopsy) to be consistent with the revised inclusion criteria which allowed patients with diabetes mellitus as long as the primary cause of kidney disease was not of diabetic origin;

Global amendment 5 part 2 - the following main changes were introduced by this amendment: Addition of Exclusion Criterion 20 (patients with one of the following aetiologies as the underlying cause: Chronic Kidney Disease (CKD) secondary due to malignancy [e.g. cast-nephropathy, AL-amyloidosis], CKD secondary to infectious disease [e.g. hepatitis- or human immunodeficiency virus (HIV)-associated], autosomal-dominant polycystic kidney disease) as a clarification to ensure patients with certain causes of kidney disease, where sufficient benefit of this treatment was not expected, did not participate; Limitation of criterion for treatment discontinuation for patients with severe Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) to those infections that ‘precluded their safe participation in the trial’ to avoid discontinuing trial treatment if it was deemed safe for patients to continue on treatment; Addition of ‘other anti-diabetic treatment (e.g. glucagon-Like Peptide 1 receptor (GLP1R) agonists)’ to restricted medications to consider that patients may have been on diabetic treatment due to broadening of inclusion criteria for diagnosis of CKD. This was added to align with restrictions on other anti-diabetic medications and allow treatment if on stable dose; Inclusion of a sentence allowing the option to complete unscheduled visits or visits outside visit window for exceptional home visits or telemedicine contacts in the case that COVID-19 or similar pandemic restrictions were in place, to allow more flexibility.

Global amendment 6 - the following main change was introduced by this amendment: Modification of Exclusion Criterion 1 to exclude patients treated with NO donors including nitrates and inclusion of NO donors including nitrates as restricted medications, to ensure that no NO-sGC-cGMP pathway-activating drugs were administered due to possible synergistic effects with avenciguat.