Global Amendment 1 (15 Jul 2021): Issued before the first patient screening, this amendment added Exclusion Criterion #2 to ensure that trial participants had alcohol-related liver disease by excluding those with other chronic liver diseases (e.g., NASH, HBV, untreated HCV, autoimmune liver disease, Wilson’s disease, etc.). It also updated Exclusion Criterion #19 to adjust the contraindication for FibroScan® to apply only in countries where local regulations still restricted its use in patients with active implantable devices. For further details, refer to Section 8.1, CTP Version 7 - Section 11.1.

Global Amendment 2 (21 Sep 2021) was issued before screening the first patient and included several changes outlined in Section 8.1, CTP Version 7 - Section 11.2. Version 3 of the CTP, the first version submitted to IECs/IRBs and CAs across all participating countries (previous versions were only submitted in some), incorporated new data from trial 1366-0020 showing Avenciguat's effect on the placebo-corrected change in QTcF (ΔΔQTcF). As a precaution, exclusion and discontinuation criteria were added, along with more frequent ECG monitoring and restricted concomitant therapies, to mitigate potential QT-prolongation risks of Avenciguat. A new exclusion criterion (#18) was added: “QTcF-interval > 450 ms in men or > 470 ms in women at screening (Visit 1a), a family history of long QT syndrome, or concomitant use of therapies with a known risk of Torsade de Pointes at screening (Visit 1a) or planned initiation of such therapies during the trial (refer to Section 4.2.2.1).” Additionally, a new discontinuation criterion was added: “patients with a QT or QTcF interval >500 ms, or an increase of QT or QTcF of >60 ms from the value at Visit 2/randomisation (baseline). Such cases must be reported as AEs.” Also, the wording of exclusion criterion #3 was adjusted to include and remove specific text: “Has received curative anti-viral therapy with direct-acting anti-virals within the last 2 years for HCV, or, if treatment was >2 years ago, and no sustained virological response (SVR) at screening (Visit 1a), or, must take curative anti-viral therapy with direct-acting anti-virals throughout the trial (refer to Section 4.2.2.1).

Global Amendment 3 (07 Jul 2022) was issued after the first patient was screened and included important changes outlined in Section 8.1, CTP Version 7 - Section 11.3. This amendment added a description of the potential for drug-drug interaction with CYP2C8 substrates, highlighting related risks and the need for monitoring adverse events (AEs) associated with CYP2C8 substrates when administered as concomitant therapy.

Global Amendment 4 (16 Aug 2022) was issued after the first patient was screened and included important changes outlined in Section 8.1, CTP Version 7 - Section 11.4. Due to recruitment difficulties, the requirement for complete abstinence from alcohol prior to the first trial visit was changed to allow screening of patients without significant alcohol misuse/abuse (as judged by the Investigator). The abstinence timeframe was reduced from 6 months to 2 months, though patients were still required to abstain from alcohol during the trial as excessive consumption could cause hypotension when taken with Avenciguat. The wording of inclusion criterion #6 was adjusted as follows: “Abstinence from significant alcohol misuse/abuse for a minimum of 6 months prior to screening (Visit 1a), and the ability, based on Investigator judgement, to abstain from alcohol throughout the trial (both evaluated based on Investigator judgement).” In alignment with this change, the wording of exclusion criterion #4 was also adjusted: “ARLD without adequate treatment (e.g., lifestyle modification) or with ongoing pathological drinking behaviour (misuse/abuse based on Investigator judgement).

Global Amendment 5 (14 Dec 2022) was issued after the first patient was screened and included several important changes outlined in Section 8.1, CTP Version 7 - Section 11.5. To assist sites with scheduling difficulties for required screening assessments, the permitted duration of the screening period was extended from 4 to 6 weeks. To increase trial efficiency while preserving the probability of observing a 20% HVPG reduction between at least one dose group of Avenciguat and placebo, the total number of patients randomised was adjusted from 150 to 105, and the number of patients per treatment group was adjusted from 50 to 35. The number of patients expected to be randomised at each site was reduced from 2-3 to 2, with updated probabilities for achieving the assumed treatment effects in the final analysis. Additionally, the conditions for using a historical gastroscopy were modified to ease recruitment due to its invasive nature. The admissibility limit for prior gastroscopy was extended from 3 to 6 months before screening, and if therapy with NSBBs/carvedilol had been initiated after a historical gastroscopy, the requirement for a further gastroscopy to confirm the persistence of varices was removed. This change affected the wording of inclusion criterion #3 and other sections. The length of time required for a stable dose of NSBBs or carvedilol prior to screening was reduced from 3 months to 1 month to ease recruitment difficulties, affecting inclusion criterion #9 and other sections. Finally, systemic sclerosis (SSc) was added as a third intended indication for Avenciguat based on an IB update.

Global Amendment 6 (02 Nov 2023) was issued after the first patient was screened and included several important changes outlined in Section 8.1, CTP Version 7 - Section 11.6. The total number of patients randomised was reduced from 105 to 78, with the number of patients per treatment group adjusted from 35 to 26. Corresponding probabilities for achieving the assumed treatment effects (a difference of at least 15% HVPG reduction from baseline between at least one dose group of avenciguat and placebo) in the final analysis were updated. These changes were made because a smaller sample size was now required to observe a 15% HVPG reduction, as more recent data indicated that even a 10% reduction in portal pressure positively impacted outcomes. Initially, a 20% reduction was chosen based on academic guidelines for clinical development in pulmonary hypertension (PH) at the start of development in 2018. Additionally, a correction/clarification of exclusion criterion #2 was made, now reading: "History of other forms of chronic liver disease (e.g., non-alcoholic steatohepatitis [NASH], Hepatitis B virus [HBV], untreated HCV, autoimmune liver disease, primary biliary cholangitis, primary sclerosing cholangitis, Wilson’s disease, haemochromatosis, alpha-1 antitrypsin [A1At] deficiency).