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Trial record 29 of 82 for:    scleroderma, systemic sclerosis AND Skin | Recruiting, Not yet recruiting, Available Studies

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

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ClinicalTrials.gov Identifier: NCT03211793
Recruitment Status : Not yet recruiting
First Posted : July 7, 2017
Last Update Posted : June 7, 2018
Sponsor:
Collaborator:
ZonMw: The Netherlands Organisation for Health Research and Development
Information provided by (Responsible Party):
prof dr. M. C. Verhaar, UMC Utrecht

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.

Condition or disease Intervention/treatment Phase
Systemic Sclerosis Digital Ulcer Drug: Mesenchymal stromal cells Other: Placebo Phase 1 Phase 2

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  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Mesenchymal Stromal Cells for Angiogenesis and Neovascularisation in Digital Ulcers of Systemic Sclerosis: the MANUS Trial
Estimated Study Start Date : November 2018
Estimated Primary Completion Date : November 1, 2020
Estimated Study Completion Date : November 1, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Scleroderma

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).




Primary Outcome Measures :
  1. Toxicity of the treatment [ Time Frame: 12 weeks after MSC administration ]
    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.


Secondary Outcome Measures :
  1. Serious adverse events [ Time Frame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration ]
    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.

  2. 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 pain as assessed using the Numerical Rating Scale,

  3. 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 pain as assessed using the digital ulcer visual analogue scale (part of the S-HAQ).

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

  5. 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 ]
    Change in pain as assessed by analyzing the use of analgesics.

  6. Quality of life - SF-36 [ Time Frame: 12, 24 and 52 weeks after MSC administration ]
    SF-36 questionnaire.

  7. Quality of life - Euroqol [ Time Frame: 12, 24 and 52 weeks after MSC administration ]
    EuroQol questionnaire

  8. Disability [ Time Frame: 12, 24 and 52 weeks after MSC administration ]
    Assessed with the HAQ-DI questionnaire.

  9. Hand function [ Time Frame: 12, 24 and 52 weeks after MSC administration ]
    Cochin Hand Function Score

  10. Number (and change in number) of digital ulcers [ Time Frame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration ]
  11. Healing of digital ulcers [ Time Frame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration ]
    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.

  12. Ulcer size [ Time Frame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration ]
    Using sequential pictures, ulcer area and circumference will be measured.

  13. Time to healing of digital ulcers [ Time Frame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration ]
  14. Need to alter medication regime [ Time Frame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration ]
    The need to alter the medication regime as determined by the patient's attending rheumatologist.

  15. Modified Rodnan Skin Score [ Time Frame: 12, 24 and 52 weeks after MSC administration ]
  16. Severity of Raynaud's symptoms [ Time Frame: 12 , 24 and 52 weeks after MSC administration ]
    Raynaud Condition Score

  17. Changes in capillary morphology and architecture [ Time Frame: 2, 12, 24 weeks and 52 weeks after MSC administration ]
    as visualized with video-assisted nailfold capillaroscopy by a trained investigator. The images will be scored by a certified rheumatologist and a trained investigator.

  18. Changes in laboratory parameters [ Time Frame: 48 hours, 2, 4, 8, 12 weeks after MSC administration ]
    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.

  19. Changes in circulating cell populations [ Time Frame: 48 hours, 2, 4, 8, 12 weeks after MSC administration ]
    Circulating cell populations will be studied by immunofluorescence labelling and analysis using fluorescence assisted cell sorting (FACS Canto machine).



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03211793


Contacts
Contact: Femke van Rhijn, MD 0031887557329 f.c.c.brouwer-3@umcutrecht.nl

Locations
Netherlands
Universitair Medisch Centrum Utrecht Not yet recruiting
Utrecht, Netherlands, 3584 CX
Principal Investigator: Marianne Verhaar, MD, PhD         
Sub-Investigator: Jaap van Laar, MD, PhD         
Sub-Investigator: Femke van Rhijn, MD         
Sponsors and Collaborators
UMC Utrecht
ZonMw: The Netherlands Organisation for Health Research and Development
Investigators
Principal Investigator: Marianne Verhaar, MD, PhD UMC Utrecht

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: prof dr. M. C. Verhaar, prof. dr., UMC Utrecht
ClinicalTrials.gov Identifier: NCT03211793     History of Changes
Other Study ID Numbers: MANUS
2015-000168-32 ( EudraCT Number )
First Posted: July 7, 2017    Key Record Dates
Last Update Posted: June 7, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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

Keywords provided by prof dr. M. C. Verhaar, UMC Utrecht:
systemic sclerosis
scleroderma
digital ulcer
vasculopathy
mesenchymal stromal cell
mesenchymal stem cell

Additional relevant MeSH terms:
Sclerosis
Ulcer
Scleroderma, Systemic
Scleroderma, Diffuse
Skin Ulcer
Pathologic Processes
Connective Tissue Diseases
Skin Diseases