Table 2 Summary of protocol amendments to SEPCELL study

1

[17/11/2016]

1. Study objectives updated to incorporate an additional secondary objective to explore longer-term safety:

Follow-up safety (only SAEs) at months 6 and 12 after the first IMP dose administration (day 1)

2. Study objectives updated to incorporate an exploratory objective to explore longer-term safety:

Safety data collection (SAEs collection via phone call) at months 18 and 24

These changes were made to meet the requests received from the Spanish regulatory agency (AEMPS) where the clinical trial application was submitted and approved.

2

[01/08/2017]

1. Clinical study protocol updated so CryoStor® CS10, an excipient of Cx611, was also used in the placebo arm:

DMSO in CryoStor® CS10 is chemically changed by the human body and subsequently secreted, causing a distinct garlic odor to be exhaled approximately 48 h after administration. To reduce the chances of accidental unblinding, CryoStor® CS10 was added to the placebo arm. New placebo kits provided to study sites included CryoStor® CS10 and Ringer lactate solution

2. ICFs for subject, legal representative and independent physicians were also updated to highlight changes made to the placebo arm

3

[28/05/2018]

1. Contraception language amended to follow the Clinical Trial Facilitation Group 2014 recommendations related to contraception and pregnancy testing in clinical trials

2. Exclusion criteria updated to exclude patients with a history of malignancy within 5 years before enrolment

3. ICF updated to incorporate updated European data privacy laws (General Data Protection Regulation)

These changes were made to meet requirements and implement feedback received from European regulatory agencies/ethics committees where the clinical trial application was submitted and approved.

4

[04/09/2019]

1. Safety reporting contact details and process were updated

2. Information regarding IMP shelf life was updated to reflect product re-test period had been extended (previous re-test period of 18 months if stored at − 140 °C or below) and updated expiry dates were reflected in the IRT

5

[19/12/2019]

1. Early closure of study enrolment

Due to persistent recruitment challenges throughout the study and to avoid not meeting study enrolment goals in a sufficient period of time, enrolment will be closed early^a

2. Secondary objective was updated to an exploratory objective (understand the MoA of Cx611 in patients with sCABP by identifying the pro-inflammatory and anti-inflammatory pathways through which Cx611 may affect the underlying processes of sepsis)

Due to reduced number of subjects enrolled in the study, data analysis will no longer be powered to detect statistical difference, but they will provide useful information on trends. Also tests that are no longer of interest will be removed to allow flexibility to test for specific biomarkers of most interest nearer the time of sample analysis

3. Study unblinding will occur after day 90 data has been collected and analysed for all subjects

To allow the investigators to be unblinded earlier, efficacy assessments post-day 90 will be removed (previously at day 180 and day 365). Safety assessments at day 180, day 365, month 18 and month 24 will remain

4. Safety and efficacy data will be summarised via descriptive statistics only

Due to early closure of enrolment, the total number of enrolled subjects will be too low to detect any safety and efficacy signals, and, therefore, any statistical inference including 95% CIs and p values may be misleading