Mesenchymal Stromal Cells as Treatment for Digital Ulcers in Systemic Sclerosis
For patients and families
In plain language
An automatic summary of structured registry data. It is an orientation aid, not a substitute for the official protocol or a physician assessment.
- What is being studied
- The protocol lists: Mesenchymal stromal cells, Placebo.
- Who it may be relevant to
- Registry conditions: Systemic Sclerosis, Digital Ulcer. Basic parameters: from 18 years · All.
- What needs checking
- Age, condition and sex are only basic indicators. Prior treatment, laboratory values and other mandatory requirements appear in the eligibility criteria below.
- Where it takes place
- Netherlands
- Next step
- Save the trial, show it to the treating physician, and confirm current recruitment with the study center. Costs, documents and travel →
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Official title
Mesenchymal Stromal Cells for Angiogenesis and Neovascularisation in Digital Ulcers of Systemic Sclerosis: the MANUS Trial
Overview
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
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.
Interventions
- Drug Mesenchymal stromal cells
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). - Other Placebo
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).
Primary outcome measures
- Toxicity of the treatment [Time frame: 12 weeks after MSC administration]
Secondary outcome measures (12)
- Serious adverse events [Time frame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration]
- 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 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 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 perceived pain based on the use of analgesics. [Time frame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration]
- Quality of life - SF-36 [Time frame: 12, 24 and 52 weeks after MSC administration]
- Quality of life - Euroqol [Time frame: 12, 24 and 52 weeks after MSC administration]
- Disability [Time frame: 12, 24 and 52 weeks after MSC administration]
- Hand function [Time frame: 12, 24 and 52 weeks after MSC administration]
- 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]
- Ulcer size [Time frame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration]
Eligibility criteria
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
Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.
Healthy volunteers: No
Study design
- Allocation
- Randomized
- Model
- Parallel assignment
- Masking
- Quadruple blind
- Primary purpose
- Treatment
Study locations
Netherlands · 1 center
- Universitair Medisch Centrum Utrecht — Utrecht
Publications
- van Rhijn-Brouwer FCC, Gremmels H, Fledderus JO, Schuurman AH, Bonte-Mineur F, Vonk MC, Voskuyl AE, de Vries-Bouwstra JK, Coert JH, Radstake TRDJ, van Laar JM, Verhaar MC; MANUS Study Group. A randomised placebo-controlled double-blind trial to assess the safety of intramuscular administration of allogeneic mesenchymal stromal cells for digital ulcers in systemic sclerosis: the MANUS Trial protoco PMID 30127049
Identifiers
NCT: NCT03211793 · MANUS · 2015-000168-32