Protocol v5.0 with the following changes to v4.0: - Inclusion criterion 3 was specified in more detail; inclusion criterion 4 was changed (maximum wound size of 20 cm² instead of 10 cm²), wording of inclusion criterion 9 was changed (from “Patients with hypertension, if they are treated…” to “If patients are hypertensive, they have to be treated…”) - Exclusion criterion 6 was changed (from “…with bone exposure” to “…with exposure of destructive bone lesion”), exclusion criterion 7 was split into 2 criteria and specifying details were added; the numbering of subsequent exclusion criteria was changed accordingly - The option to use intravenous injections of strong analgesics upon subject request and longer safety observation time in case of strong analgesics use at the discretion of the investigator was added - The use of vitamin K and direct oral anticoagulants as concomitant medications was specified in more detail - The visit window for screening was changed (from “14 days to 7 days before treatment” to “21 days to 7 days before treatment”).

Protocol v6.0 with the following changes to v5.0: - Exclusion criterion 6 was rephrased (from “… with ulcers with exposure of destructive bone lesions” to “…with osteomyelitis at ulceration”).

Protocol v7.0 with the following changes to v6.0: - The trial was changed from a national (Germany) to an international trial with additional sites in the United Kingdom, Austria, Czech Republic, and Poland - Inclusion criterion 3 was changed to allow angiography results not older than 6 months (formerly 3 months) - The safety observation time after IMP injection was specified to be at least 2 hours; accordingly, vital signs were to be assessed the earliest 2 hours after the IMP administration - Unblinding via randomization envelopes was changed to unblinding via the electronic case report form system.

Protocol v8.0 with the following changes to v7.0: - The specification that no minimal number of subjects with diabetes or without diabetes was added - Inclusion criterion 7 was changed (from “No evidence of change of wound size of more than 25% for at least 6 weeks before screening” to “No evidence of wound healing after standard of care treatment for at least 1 week before screening”) - Exclusion criterion 1, the origin of skin lesions was rephrased (from “mixed anterior-venous” to “leading venous”) - Exclusion criterion 9 was changed to include subjects with surgical/interventional reconstruction more than 1 week before screening or with not successful revascularization - Exclusion criterion 10 was changed to include subjects with major amputations of lower extremities within 12 months before screening - Exclusion criterion 22 was changed to allow previous use of glucocorticoid-medication above the cushing threshold dose. Medications that might influence wound healing, hyperbaric oxygen therapy, spinal cord stimulation and sympathectomy, as well as vasoactive substances other than the test drug, haemodilution or rheological therapy were not allowed from screening until Week 12 - Octenisept for wound care was only to be used in subjects without a history of allergic reactions to the product - The visit window for screening was changed (from “21 days to 7 days before treatment” to “21 days to 2 days before treatment”) - The examination of injection sites was added for Visits 2-9 - Relationship assessment of adverse events to the procedure was added - Suspected unexpected serious adverse reaction reporting was expanded from German legislation to include applicable European and other applicable national regulatory requirements.

In Czech Republic, subjects were studied on protocol version CZE 3.0, dated 05-Apr-2019, which corresponds to Version 8.0, dated 07-Feb-2019, except that only subjects aged 45 to 75 years were to be included.