Mesenchymal Stromal Cells as Treatment for Digital Ulcers in Systemic Sclerosis

The MANUS Trial is a randomized double-blind, placebo-controlled clinical trial. Patients with systemic sclerosis (SSc) and digital ischemia with intractable ischemic digital ulcers refractory to conventional treatments are eligible to participate.

20 participants will be randomised (1:1) to undergo intramuscular injection (8 sites) of allogeneic bone marrow derived mesenchymal stromal cells (BM-MSC) (45-50\*10\^6) or placebo in the most affected limb.

Main study parameters/endpoints: The primary outcome is the toxicity of the treatment at 12 weeks after MSC administration, defined as

1. Local toxicity, including signs of local inflammation (swelling, warmth, impairment of function), worsening of ulcers or new ulcers or hematomas after MSC administration 2. Other adverse events, graded according to the Common Terminology Criteria for Adverse Events version 4.0, expressed as maximum grade toxicity per organ system.

Secondary outcome measures are: number of serious adverse events, pain and disability parameters; healing, time to healing and reduction of new ischemic digital ulcers; modified Rodnan skin score; Scleroderma Health Assessment Questionnaire (S-HAQ) including visual analogue scales (VAS) for scleroderma-specific symptoms; Quality-of-life (SF-36, EuroQol (EQ-5D); Cochin hand function score. We will also evaluate changes in capillary morphology and architecture using capillaroscopy; biochemical parameters; markers for endothelial activation and injury, inflammation, oxidative stress, circulating cells including endothelial cells, hematopoietic and endothelial progenitor cells, cytokines and growth factors, immunological responses. Follow-up visits will be scheduled at 48 hours and 2, 4, 8, 12, 24 and 52 weeks post-treatment.

• Serious adverse events [Срок оценки: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration]
• Change in perceived pain based on the Numerical Rating Scale [Срок оценки: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration]
• Change in perceived pain based on the digital ulcer visual analogue scale (part of the S-HAQ) [Срок оценки: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration]
• Change in perceived pain based on the pain VAS ( part of the S-HAQ) [Срок оценки: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration]
• Change in perceived pain based on the use of analgesics. [Срок оценки: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration]
• Quality of life - SF-36 [Срок оценки: 12, 24 and 52 weeks after MSC administration]
• Quality of life - Euroqol [Срок оценки: 12, 24 and 52 weeks after MSC administration]
• Disability [Срок оценки: 12, 24 and 52 weeks after MSC administration]
• Hand function [Срок оценки: 12, 24 and 52 weeks after MSC administration]
• Number (and change in number) of digital ulcers [Срок оценки: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration]
• Healing of digital ulcers [Срок оценки: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration]
• Ulcer size [Срок оценки: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration]