Controlled Trial to Evaluate the Safety and Efficacy of CYWC628 (Human Dermal Fibroblast Spheroids) for the Treatment of Refractory Diabetic Foot Ulcers Compared With Standard of Care

This is a prospective, multicentre, randomized clinical trial evaluating the safety, tolerability, and efficacy of up to 12 weeks treatment with SoC + low- or high-dose CYWC628 in treating DFU, compared to SoC only.

Period 1:

After providing voluntary, written informed consent, participants will undergo screening assessments according to the schedule of assessments (SOA). The participant's DFU will be sharply debrided (as needed), dressed with SoC and offloaded. If there is evidence of infection, a skin pathogen test will be performed and topical or systemic antibiotic or antifungal may be administered until the infection is cleared or is at a level defined as acceptable in the eligibility criteria.

After the Screening visit (or the visit at which any DFU infection is deemed cleared or is at a level defined as acceptable in the eligibility criteria), the participant will return two (2) weeks later to confirm eligibility. If the DFU wound area has not decreased in size ≥30% and the participant remains eligible, they will be randomized on Day 1 to one of 3 treatment groups: SoC + low dose CYWC628, SoC + high dose CYWC628, or SoC only.

The treatment period is comprised of weekly visits for allocated study treatment for up to 12 weeks (i.e., up to 12 treatments). At each visit, the DFU will be assessed by the Investigator and measured using the eKare inSight® electronic image capture application, and ABI determined. Vital signs and clinical laboratory testing will be performed at each study visit, from Day 1 until the Week 12 visit or the visit at which the DFU is deemed healed by the Investigator (whichever visit occurs first). Adverse events and concomitant medications/therapies will be recorded at each visit.

The Safety Review Committee (SRC) will review the safety data from the first 2 weeks treatment of the first 20 randomized participants (sentinel group), i.e., data from Day 1, Week 1 and Week 2 visits. If safety and tolerability is confirmed as acceptable, enrolment of the remaining participants will proceed. An interim analysis will be performed when at least 28 randomized participants per treatment group have completed the Week 6 visit, to assess primary safety and efficacy endpoints at Week 6.

Period 1 participants whose DFU heals within the 12-week treatment period (regardless of treatment) will attend 2 follow-up visits 2 weeks apart to confirm healing and attend the end of study visit (EOS) at 6 months post-last treatment. At each follow-up visit, any recurrence of the DFU at the same site will be assessed and recorded.

Period 1 participants randomized to SoC + CYWC628 whose DFU does not heal within 12 weeks, and participants randomized to SoC only whose DFU does not heal within 12 weeks and do not continue with Period 2 treatment with SoC + CYWC628, will revert to their treating physician's care for DFU. Safety follow-up visits for SoC + CYWC628-treated participants with non-healed DFU will be performed at Weeks 14 and 16, with the Week 16 visit considered the EOS for these participants. Safety follow-up visits for SoC only-treated participants with non-healed DFU will be performed at the Week 16 visit only, with this visit considered the EOS for these participants.

Period 2:

Period 1 participants randomized to SoC only whose DFU does not heal within the Period 1 12-week treatment period will be offered up to 12 weeks treatment with SoC + CYWC628 if remaining eligible and at the discretion of the Investigator.

Before participants receive Period 2 treatment with SoC + CYWC628, eligibility must be re-confirmed (Period 1 Week 12 visit assessments may be used with addition of toe systolic pressure measurement; serology and ECG not required unless considered necessary by Investigator). The same 2-week period required between Period 1 Screening and Day 1 randomization will also apply between the Period 1 Week 12 visit and first administration of Period 2 SoC + CYWC628 treatment. Procedures for treatment for infected DFU described for Period 1 Screening will also be applied in Period 2. Eligible participants will receive a dose of CYWC628 if a safe and effective dose has been determined from the interim analysis. Treatment with SoC + CYWC628 and follow-up visits in Period 2 will be as described for Period 1, except that the EOS will be performed 4 weeks after DFU deemed healed by the Investigator (or Period 2 Week 16 visit if unhealed in 12 weeks). Period 2 will not proceed if not approved by the SRC.