Mesenchymal Stromal Cells as Treatment for Digital Ulcers in Systemic Sclerosis (MANUS)

• Toxicity of the treatment [ Time Frame: 12 weeks after MSC administration ]
  Toxicity of the treatment is 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.
  
  

• Serious adverse events [ Time Frame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration ]
  Any treatment-related serious adverse events (SAE) defined as events leading to hospitalization, death, or persistent or significant disability. To establish the presence or absence of a causal relationship, the World Health Organisation guidelines for pharmacovigilance will be followed.
  
  
• Change in perceived pain based on the Numerical Rating Scale [ Time Frame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration ]
  Change in pain as assessed using the Numerical Rating Scale,
  
  
• Change in perceived pain based on the digital ulcer visual analogue scale (part of the S-HAQ) [ Time Frame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration ]
  Change in pain as assessed using the digital ulcer visual analogue scale (part of the S-HAQ).
  
  
• Change in perceived pain based on the pain VAS ( part of the S-HAQ) [ Time Frame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration ]
  Change in pain as assessed using the pain VAS (S-HAQ), use of analgesics.
  
  
• Change in perceived pain based on the use of analgesics. [ Time Frame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration ]
  Change in pain as assessed by analyzing the use of analgesics.
  
  
• Quality of life - SF-36 [ Time Frame: 12, 24 and 52 weeks after MSC administration ]
  SF-36 questionnaire.
  
  
• Quality of life - Euroqol [ Time Frame: 12, 24 and 52 weeks after MSC administration ]
  EuroQol questionnaire
  
  
• Disability [ Time Frame: 12, 24 and 52 weeks after MSC administration ]
  Assessed with the HAQ-DI questionnaire.
  
  
• Hand function [ Time Frame: 12, 24 and 52 weeks after MSC administration ]
  Cochin Hand Function Score
  
  
• Number (and change in number) of digital ulcers [ Time Frame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration ]
  
• Healing of digital ulcers [ Time Frame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration ]
  Healing of ulcers is defined as complete epithelialization, regardless of residual pain. This will be established using sequential pictures in addition to the clinical examination.
  
  
• Ulcer size [ Time Frame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration ]
  Using sequential pictures, ulcer area and circumference will be measured.
  
  
• Time to healing of digital ulcers [ Time Frame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration ]
  
• Need to alter medication regime [ Time Frame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration ]
  The need to alter the medication regime as determined by the patient's attending rheumatologist.
  
  
• Modified Rodnan Skin Score [ Time Frame: 12, 24 and 52 weeks after MSC administration ]
  
• Severity of Raynaud's symptoms [ Time Frame: 12 , 24 and 52 weeks after MSC administration ]
  Raynaud Condition Score
  
  
• Changes in capillary morphology and architecture [ Time Frame: 2, 12, 24 weeks and 52 weeks after MSC administration ]
  as visualized with video-assisted nailfold capillaroscopy by a trained investigator. The images will be scored by a certified rheumatologist and a trained investigator.
  
  
• Changes in laboratory parameters [ Time Frame: 48 hours, 2, 4, 8, 12 weeks after MSC administration ]
  A range of haematological and chemical parameters will be measured for safety assessment. Additionally, serum, plasma and peripheral blood mononuclear cells will be collected and stored for analysis at a later time point. Samples will be analysed and used to assess markers for endothelial activation and injury, proangiogenic factors, inflammation and oxidative stress. The presence of HLA-antibodies will be determined as well.
  
  
• Changes in circulating cell populations [ Time Frame: 48 hours, 2, 4, 8, 12 weeks after MSC administration ]
  Circulating cell populations will be studied by immunofluorescence labelling and analysis using fluorescence assisted cell sorting (FACS Canto machine).
  
  

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.