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

• Local toxicity, including signs of local inflammation (swelling, warmth, impairment of function), worsening of ulcers or new ulcers or hematomas after MSC administration
• 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.

Inclusion criteria

• Established diagnosis of SSc according to the 2013 ACR/EULAR criteria
• At least one active digital ulcer (painful area, >2 mm in diameter with visible depth and loss of dermis) refractory to intravenous prostacyclins

• 'Refractory to prostacyclins' is defined as
• Worsening of ulcer(s) within 1 month after prostacyclins iv
• No improvement of ulcer(s) after 2 months after prostacyclins iv, as judged by the referring physician
• Recurrence of exactly the same ulcer(s) (same location) within 3 months after prostacyclins iv
• Written informed consent

Exclusion criteria

• Ulcer with underlying calcinosis (ruled out by X-ray prior to screening/inclusion)
• History of neoplasm or malignancy in the past 10 years
• Pregnancy or unwillingness to use adequate contraception during study
• Serious known concomitant disease with life expectancy <1 year
• Uncontrolled hypertension
• Uncontrolled acute or chronic infection with systemic symptoms (e.g. fever)
• Follow-up impossible