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 protocol

Femke C C van Rhijn-Brouwer, Hendrik Gremmels, Joost O Fledderus, Arnold H Schuurman, Femke Bonte-Mineur, Madelon C Vonk, Alexandre E Voskuyl, Jeska K de Vries-Bouwstra, J Henk Coert, Timothy R D J Radstake, Jacob M van Laar, Marianne C Verhaar, MANUS Study Group, F C C van Rhijn, H Gremmels, J O Fledderus, A H Schuurman, S Zeddies, I C M Slaper-Cortenbach, M J H de Hair, A C A Marijnissen, J Tekstra, E Ton, P M J Welsing, F Bonte-Mineur, M C Vonk, A E Voskuyl, J K de Vries-Bouwstra, J H Coert, T R Radstake, J M van Laar, M C Verhaar, Femke C C van Rhijn-Brouwer, Hendrik Gremmels, Joost O Fledderus, Arnold H Schuurman, Femke Bonte-Mineur, Madelon C Vonk, Alexandre E Voskuyl, Jeska K de Vries-Bouwstra, J Henk Coert, Timothy R D J Radstake, Jacob M van Laar, Marianne C Verhaar, MANUS Study Group, F C C van Rhijn, H Gremmels, J O Fledderus, A H Schuurman, S Zeddies, I C M Slaper-Cortenbach, M J H de Hair, A C A Marijnissen, J Tekstra, E Ton, P M J Welsing, F Bonte-Mineur, M C Vonk, A E Voskuyl, J K de Vries-Bouwstra, J H Coert, T R Radstake, J M van Laar, M C Verhaar

Abstract

Introduction: Systemic sclerosis (SSc) is an autoimmune disease characterised by inflammation, fibrosis and vasculopathy. Digital ulcers (DUs) are a frequent manifestation of vasculopathy in patients with SSc. Despite recent advances in pharmacological treatments, DU still have major health and economic implications. As there is currently no proven therapeutic strategy to promote DU healing, new treatments are urgently needed. Mesenchymal stem or stromal cells (MSCs) may provide a novel therapy for DU in SSc, because of their immunomodulatory and vasculoregenerative properties. Allogeneic MSC therapy involves functionally competent MSCs from healthy donors and may be used as 'off-the-shelf' available treatment. This study will evaluate whether allogeneic MSC therapy is a safe and potentially efficacious treatment for DU of SSc.

Methods and analysis: The MANUS (Mesenchymal stromal cells for Angiogenesis and Neovascularization in digital Ulcers of Systemic Sclerosis) Trial is a double-blind randomised placebo-controlled trial. 20 patients with SSc with refractory DU will be randomised to receive eight intramuscular injections with either placebo or 50*106 MSCs. The primary outcome is the toxicity of the treatment at 12 weeks after administration. Secondary outcomes include (serious) adverse events, number and time to healing of DU, pain, reported hand function, quality of life and SSc disease activity. We will also evaluate changes in nailfold capillaroscopy pattern, as well as biochemical parameters and biomarkers in peripheral blood and skin biopsies. Follow-up visits will be scheduled at 48 hours and 2, 4, 8, 12, 24 and 52 weeks post-treatment. If the results confirm safety, feasibility and potential efficacy, a large multicentre randomised controlled trial with longer follow-up will be initiated focusing on efficacy.

Ethics and dissemination: The study has been approved by the Dutch Central Committee on Research Concerning Human Subjects (protocol no: NL51705.000.15). The results will be disseminated through patient associations and conventional scientific channels.

Trial registration number: NCT03211793; Pre-results.

Keywords: angiogenesis; digital ulcers; mesenchymal stromal cells; systemic sclerosis.

Conflict of interest statement

Competing interests: JMvL received honoraria from Arthrogen, BMS, Eli Lilly, Janssen, MSD, Pfizer, Roche, and research grants from Astra Zeneca, Genentech, MSD.

© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
CONSORT study flow diagram of the MANUS Trial. See table 2 for the schedule of study visits and the assessments conducted at each visit. CONSORT, Consolidated Standards of Reporting Trials; IM, intramuscular; MANUS, Mesenchymal stromal cells for Angiogenesis and Neovascularization in digital Ulcers of Systemic Sclerosis; MSC, mesenchymal stem cell.
Figure 2
Figure 2
injection sites. Mesenchymal stem cells will be intramuscularly injected at these eight sites.

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