Clinical trial NCT03211793: Mesenchymal Stromal Cells as Treatment for Digital Ulcers in Systemic Sclerosis
Official title: Mesenchymal Stromal Cells for Angiogenesis and Neovascularisation in Digital Ulcers of Systemic Sclerosis: the MANUS Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Systemic Sclerosis
Digital Ulcer
Keywords: systemic sclerosis
scleroderma
digital ulcer
vasculopathy
mesenchymal stromal cell
mesenchymal stem cell
Lead sponsor: UMC Utrecht
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
First posted: 2017-07-07
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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

Primary outcomes:
measure: Toxicity of the treatment
timeFrame: 12 weeks after MSC administration
Secondary outcomes:
measure: Serious adverse events
timeFrame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration
measure: Change in perceived pain based on the Numerical Rating Scale
timeFrame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration
measure: Change in perceived pain based on the digital ulcer visual analogue scale (part of the S-HAQ)
timeFrame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration
measure: Change in perceived pain based on the pain VAS ( part of the S-HAQ)
timeFrame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration
measure: Change in perceived pain based on the use of analgesics.
timeFrame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration
measure: Quality of life - SF-36
timeFrame: 12, 24 and 52 weeks after MSC administration
measure: Quality of life - Euroqol
timeFrame: 12, 24 and 52 weeks after MSC administration
measure: Disability
timeFrame: 12, 24 and 52 weeks after MSC administration
measure: Hand function
timeFrame: 12, 24 and 52 weeks after MSC administration
measure: Number (and change in number) of digital ulcers
timeFrame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration
measure: Healing of digital ulcers
timeFrame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration
measure: Ulcer size
timeFrame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration
measure: Time to healing of digital ulcers
timeFrame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration
measure: Need to alter medication regime
timeFrame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration
measure: Modified Rodnan Skin Score
timeFrame: 12, 24 and 52 weeks after MSC administration
measure: Severity of Raynaud's symptoms
timeFrame: 12 , 24 and 52 weeks after MSC administration
measure: Changes in capillary morphology and architecture
timeFrame: 2, 12, 24 weeks and 52 weeks after MSC administration
measure: Changes in laboratory parameters
timeFrame: 48 hours, 2, 4, 8, 12 weeks after MSC administration
measure: Changes in circulating cell populations
timeFrame: 48 hours, 2, 4, 8, 12 weeks after MSC administration
Other outcomes:
Locations:
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
Study officials:
affiliation: UMC Utrecht
name: Marianne Verhaar, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.