Mesenchymal Stromal Cells as Treatment for Digital Ulcers in Systemic Sclerosis

Study Overview
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Brief Summary
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The MANUS Trial aims to examine the safety, feasibility and potential efficacy of intramuscularly injected allogeneic mesenchymal stromal cells as treatment for digital ulcers of systemic sclerosis.

Detailed Description
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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.

Official Title
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Mesenchymal Stromal Cells for Angiogenesis and Neovascularisation in Digital Ulcers of Systemic Sclerosis: the MANUS Trial

Conditions
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Systemic Sclerosis, Digital Ulcer

Intervention / Treatment
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* Drug: Mesenchymal stromal cells
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MSC injections<br>Intramuscular injection of mesenchymal stromal cells (50 million allogeneic MSCs in 0.9% NaCl and 10% human serum albumin). | Drug: Mesenchymal stromal cells<br>* 8 intramuscular injections at designated sites in the hand/forearm muscles of the most affected side. Blinded syringes will be used. Injections will be administered by an experienced clinician (plastic surgeon or hand surgeon).<br>|
| Placebo Comparator: Placebo injections<br>Intramuscular injection of placebo (NaCl 0.9% + 10% human serum albumin) | Other: Placebo<br>* 8 intramuscular injections at designated sites in the hand/forearm muscles of the most affected side. Blinded syringes will be used. Injections will be administered by an experienced clinician (plastic surgeon or hand surgeon).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity of the treatment | 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. | 12 weeks after MSC administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serious adverse events | 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. | 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration | 
| Change in perceived pain based on the Numerical Rating Scale | Change in pain as assessed using the Numerical Rating Scale, | 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) | Change in pain as assessed using the digital ulcer visual analogue scale (part of the S-HAQ). | 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) | Change in pain as assessed using the pain VAS (S-HAQ), use of analgesics. | 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration | 
| Change in perceived pain based on the use of analgesics. | Change in pain as assessed by analyzing the use of analgesics. | 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration | 
| Quality of life - SF-36 | SF-36 questionnaire. | 12, 24 and 52 weeks after MSC administration | 
| Quality of life - Euroqol | EuroQol questionnaire | 12, 24 and 52 weeks after MSC administration | 
| Disability | Assessed with the HAQ-DI questionnaire. | 12, 24 and 52 weeks after MSC administration | 
| Hand function | Cochin Hand Function Score | 12, 24 and 52 weeks after MSC administration | 
| Number (and change in number) of digital ulcers |  | 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration | 
| Healing of digital ulcers | 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. | 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration | 
| Ulcer size | Using sequential pictures, ulcer area and circumference will be measured. | 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration | 
| Time to healing of digital ulcers |  | 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration | 
| Need to alter medication regime | The need to alter the medication regime as determined by the patient's attending rheumatologist. | 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration | 
| Modified Rodnan Skin Score |  | 12, 24 and 52 weeks after MSC administration | 
| Severity of Raynaud's symptoms | Raynaud Condition Score | 12 , 24 and 52 weeks after MSC administration | 
| Changes in capillary morphology and architecture | as visualized with video-assisted nailfold capillaroscopy by a trained investigator. The images will be scored by a certified rheumatologist and a trained investigator. | 2, 12, 24 weeks and 52 weeks after MSC administration | 
| Changes in laboratory parameters | 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. | 48 hours, 2, 4, 8, 12 weeks after MSC administration | 
| Changes in circulating cell populations | Circulating cell populations will be studied by immunofluorescence labelling and analysis using fluorescence assisted cell sorting (FACS Canto machine). | 48 hours, 2, 4, 8, 12 weeks after MSC administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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systemic sclerosis, scleroderma, digital ulcer, vasculopathy, mesenchymal stromal cell, mesenchymal stem cell