Mesenchymal Stromal Cells as Treatment for Digital Ulcers in Systemic Sclerosis

Phase 2RecruitingNCT03211793

UMC Utrecht20 enrolled

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.

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Systemic Sclerosis Digital Ulcer

Interventions

Mesenchymal stromal cellsDRUG

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).

PlaceboOTHER

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (1)

Universitair Medisch Centrum Utrecht

Utrecht, Netherlands

RECRUITING

Outcomes

Primary Outcomes

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.

Time frame: 12 weeks after MSC administration

Secondary Outcomes

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.

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

Change in pain as assessed using 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)

Change in pain as assessed using 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)

Change in pain as assessed using the pain VAS (S-HAQ), use of analgesics.

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.

Central Contacts

Femke van Rhijn, MD

CONTACT

0031887557329 f.c.c.brouwer-3@umcutrecht.nl

Data from ClinicalTrials.gov

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