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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Systemic Sclerosis; Digital Ulcer
• Intervention / Treatment: Drug: Mesenchymal stromal cells; Other: Placebo

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.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Femke van Rhijn, MD; Phone Number: 0031887557329; Email: f.c.c.brouwer-3@umcutrecht.nl

Study Locations

• Netherlands
  • Utrecht, Netherlands, 3584 CX
    • Recruiting
    • Universitair Medisch Centrum Utrecht
    • Principal Investigator: Marianne Verhaar, MD, PhD
    • Sub-Investigator: Jaap van Laar, MD, PhD
    • Sub-Investigator: Femke van Rhijn, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MSC injections; Intramuscular injection of mesenchymal stromal cells (50 million allogeneic MSCs in 0.9% NaCl and 10% human serum albumin).	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).
Placebo Comparator: Placebo injections; Intramuscular injection of placebo (NaCl 0.9% + 10% human serum albumin)	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).

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: UMC Utrecht
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development
• Investigators: Principal Investigator: Marianne Verhaar, MD, PhD, UMC Utrecht

Publications and helpful links

General 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 protocol. BMJ Open. 2018 Aug 20;8(8):e020479. doi: 10.1136/bmjopen-2017-020479.

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2021
• Primary Completion (Estimated): November 1, 2024
• Study Completion (Estimated): November 1, 2024

Study Registration Dates

• First Submitted: April 27, 2017
• First Submitted That Met QC Criteria: July 5, 2017
• First Posted (Actual): July 7, 2017

Study Record Updates

• Last Update Posted (Estimated): December 7, 2023
• Last Update Submitted That Met QC Criteria: December 5, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: mesenchymal stem cell; systemic sclerosis; scleroderma; digital ulcer; vasculopathy; mesenchymal stromal cell
• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Connective Tissue Diseases; Sclerosis; Ulcer; Scleroderma, Systemic; Scleroderma, Diffuse; Skin Ulcer
• Other Study ID Numbers: MANUS; 2015-000168-32 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No