Mesenchymal stromal cell infusions of umbilical cord-derived mesenchymal stromal cells in children with recessive dystrophic epidermolysis bullosa (MissionEB): a randomised, double-blind, placebo controlled, crossover, phase 3 trial with an internal phase 1 dose de-escalation phase.
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BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic disorder characterised by extensive mucocutaneous blistering. This study aimed to generate evidence to inform commissioning decisions on umbilical cord-derived mesenchymal stromal cells, UC-MSCs, (CORDStrom™) for RDEB. METHODS: In this double-blinded, randomised (1:1), placebo-controlled, two-period crossover phase 3 trial, children aged 6 months to 16 years of age with RDEB were enrolled at two UK specialist centres for epidermolysis bullosa (EB). Individuals were excluded if they had received oral or topical corticosteroids for more than 7 consecutive days within 30 days of enrolment into this study, excluding oral viscous budesonide and inhaled fluticasone used as prophylaxis to relieve oesophageal symptoms, an active infection that required treatment with oral or intravenous antibiotics within 7 days of screening, medical history or evidence of active malignancy, the presence of both positive collagen VII ELISA and a positive indirect immunofluorescence (IIF) with binding to the base of salt split skin, administration of MSCs from any source in the previous 9 months and participation in any other interventional trial within 3 months of enrolment into this study. This trial included an internal dose de-escalation (IDD) phase for safety gatekeeping. During IDD, 4 participants were randomised (3:1) to receive two infusions (2-3 × 106 cells/kg/infusion or placebo) on days 0 and 14 before the next participant begun treatment. The primary outcome was toxicity defined as a suspected unexpected serious adverse reaction (SUSAR) within 48 h of receiving an infusion. The DMEC reviewed the data and if one (or fewer) patients receiving the active treatment experienced a SUSAR, the dose would be reduced and toxicity evaluated in a further 5 patients randomised (3:2) to UC-MSCs or placebo. If there were no further toxicities, the trial progressed to the main two period crossover study. In the main crossover, patients were randomly assigned (1:1) using a web-based randomisation system SCRAM to receive two intravenous infusions (days 0 and 14), at a dose of 2-3x106 cells/kg UC-MSCs or placebo. There were 2 follow-up periods each of 6 months with a 3 month interval between periods, giving a 9 month duration between doses. Clinicians, caregivers, patients, and clinical trial personnel were fully blinded to treatment groups. Trial pharmacists and a team or independent research nurses who only performed administration of the infusion were unblinded to perform security checks of the product but were not involved in any assessments. The primary endpoint was change in disease severity as measured by Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) at three months post infusion assessed in the modified intention to treat (mITT) population (participants providing data at both period baselines and at least one 3-month follow-up). Prespecified subgroups included RDEB severity and age. Safety data were collected for all participants and safety assessment was based on all treatment emergent events in the safety population (those receiving at least one active or placebo infusion). This trial is registered with ISRCTN, ISRCTN14409785. FINDINGS: Between OCT 06, 2021, and JUL 15, 2024, 44 participants were screened; 37 were randomised (18 UC-MSCs/placebo; 19 Placebo/UC-MSCs), with 34 receiving at least one infusion and 30 in the mITT analysis (14 UC-MSCs/placebo; 16 placebo/UC-MSCs). No toxicities were seen in the IDD phase (primary outcome). At three months no changes in favour of UC-MSCs were seen in the primary outcome EBDASI. The between arm difference in EBDASI at 3 months showed a 3.75 point difference (effect size 0.06) in favour of placebo (95% CI of -1.46, 8.96, p = 0.15) with corresponding figures for UC-MSCs/Placebo and Placebo/UC-MSCs of 5.5 (95% CI of -2.53 to 13.53, p = 0.16) and 2 (95% CI of -5.33 to 9.33, p = 0.58). No serious adverse events were associated with UC-MSCs. INTERPRETATION: UC-MSCs infusions were safe and the primary outcome (EBDASI) did not show MSCs were beneficial. Further evaluation of the long-term efficacy of UC-MSCs is planned. The main strength is that Mission EB is the largest cell therapy study to date providing the most robust evidence on the safety and efficacy of UC-MSCs in children with RDEB. A limitation is that there are no robust validated outcome measures for RDEB. FUNDING: National Research Collaboration Programme, an NHS England and NIHR partnership (NIHR 127963) and Cure EB.