Systemic SclerosisPhase 1/2MANUSNCT03211793
Mesenchymal Stromal Cells as Treatment for Digital Ulcers in Systemic Sclerosis
A Phase 1/2 study testing Mesenchymal stromal cells in people with Systemic Sclerosis and Digital Ulcer, run by UMC Utrecht at 1 site in Netherlands.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Systemic Sclerosis, Digital Ulcer
- What is being tested?
- Mesenchymal stromal cells
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 20 participants
- Where
- 1 siteNetherlands
- Study dates
- 6 Oct 2021to 1 Nov 2026
- Phase
- Phase 1/2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Netherlands1 site, 1 recruiting
- Recruiting
Universitair Medisch Centrum Utrecht
Utrecht, 3584 CX
Marianne Verhaar, MD, PhD
Jaap van Laar, MD, PhD
About this study
Official title: 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.
Read the 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
- Local toxicity, including signs of local inflammation (swelling, warmth, impairment of function), worsening of ulcers or new ulcers or hematomas after MSC administration
- 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.
- Conditions
- Systemic Sclerosis, Digital Ulcer
- Being tested
- Mesenchymal stromal cells, Placebo
- Keywords
- systemic sclerosis, scleroderma, digital ulcer, vasculopathy, mesenchymal stromal cell, mesenchymal stem cell
- Medical subject headings
- Scleroderma, Systemic, digital ulcers, Scleroderma, Diffuse, Vascular Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
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
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).
| Study group | Role | What they receive |
|---|---|---|
| MSC injections | Experimental | Intramuscular injection of mesenchymal stromal cells (50 million allogeneic MSCs in 0.9% NaCl and 10% human serum albumin). Receives: Drug: Mesenchymal stromal cells |
| Placebo injections | Placebo comparator | Intramuscular injection of placebo (NaCl 0.9% + 10% human serum albumin) Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 12 weeks after MSC administration
Secondary outcomes (19)
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.
Measured: 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,
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration
Quality of life - SF-36
SF-36 questionnaire.
Measured: 12, 24 and 52 weeks after MSC administration
Quality of life - Euroqol
EuroQol questionnaire
Measured: 12, 24 and 52 weeks after MSC administration
Disability
Assessed with the HAQ-DI questionnaire.
Measured: 12, 24 and 52 weeks after MSC administration
Hand function
Cochin Hand Function Score
Measured: 12, 24 and 52 weeks after MSC administration
Number (and change in number) of digital ulcers
Measured: 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.
Measured: 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.
Measured: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration
Time to healing of digital ulcers
Measured: 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.
Measured: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration
Modified Rodnan Skin Score
Measured: 12, 24 and 52 weeks after MSC administration
Severity of Raynaud's symptoms
Raynaud Condition Score
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 48 hours, 2, 4, 8, 12 weeks after MSC administration
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Jul 2017
- Study start6 Oct 2021
- Primary completion1 Nov 2026 (estimated)
- Study completion1 Nov 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Systemic SclerosisStudies of the same condition, open and under way.
- More trials run by UMC UtrechtThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 20 participants (estimated)
Sponsor and investigators
- Lead sponsor
- UMC Utrecht
- Sponsor type
- University, hospital or other
- Collaborators
- ZonMw: The Netherlands Organisation for Health Research and Development
- Responsible party
- Principal investigator, prof dr. M. C. Verhaar, UMC Utrecht
- Investigators
- Marianne Verhaar, MD, PhD, Principal investigator, UMC Utrecht
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03211793
- Sponsor's protocol ID
- MANUS
- Other IDs
- 2015-000168-32, 2015
- Acronym
- MANUS
- Status last verified
- Sep 2025
- First submitted
- 27 Apr 2017
- Last updated
- 10 Sep 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
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.
PubMed 30127049
Study at a glance
From the registry record, last updated by the sponsor on 10 Sep 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Mesenchymal Stromal Cells for Angiogenesis and Neovascularisation in Digital Ulcers of Systemic Sclerosis: the MANUS Trial
- ClinicalTrials.gov ID
- NCT03211793
- Acronym / sponsor ID
- MANUS / MANUS
- Conditions
- Systemic Sclerosis, Digital Ulcer
- Keywords
- systemic sclerosis, scleroderma, digital ulcer, vasculopathy, mesenchymal stromal cell, mesenchymal stem cell
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 20 participants (estimated)
- Lead sponsor
- UMC UtrechtUniversity, hospital or other
- Collaborators
- ZonMw: The Netherlands Organisation for Health Research and Development
- Study start
- 6 Oct 2021 (actual)
- Primary completion
- 1 Nov 2026 (estimated)
- Study completion
- 1 Nov 2026 (estimated)
- First posted
- 7 Jul 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
- Local toxicity, including signs of local inflammation (swelling, warmth, impairment of function), worsening of ulcers or new ulcers or hematomas after MSC administration
- 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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| MSC injections | Experimental | Drug: Mesenchymal stromal cellsIntramuscular injection of mesenchymal stromal cells (50 million allogeneic MSCs in 0.9% NaCl and 10% human serum albumin). |
| Placebo injections | Placebo comparator | Other: PlaceboIntramuscular injection of placebo (NaCl 0.9% + 10% human serum albumin) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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
- Written informed consent
Key exclusion criteria (7 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Mesenchymal stromal cells8 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). | Drug | MSC injections |
| Placebo8 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). | Other | Placebo injections |
Primary outcome
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.
19 secondary outcomes
Serious adverse events
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
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)
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)
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.
Time frame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration
Quality of life - SF-36
Time frame: 12, 24 and 52 weeks after MSC administration
Quality of life - Euroqol
Time frame: 12, 24 and 52 weeks after MSC administration
Disability
Time frame: 12, 24 and 52 weeks after MSC administration
Hand function
Time frame: 12, 24 and 52 weeks after MSC administration
Number (and change in number) of digital ulcers
Time frame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration
Healing of digital ulcers
Time frame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration
Ulcer size
Time frame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration
Time to healing of digital ulcers
Time frame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration
Need to alter medication regime
Time frame: 48 hours, 2, 4, 8, 12, 24 weeks and 52 weeks after MSC administration
Modified Rodnan Skin Score
Time frame: 12, 24 and 52 weeks after MSC administration
Severity of Raynaud's symptoms
Time frame: 12 , 24 and 52 weeks after MSC administration
Changes in capillary morphology and architecture
Time frame: 2, 12, 24 weeks and 52 weeks after MSC administration
Changes in laboratory parameters
Time frame: 48 hours, 2, 4, 8, 12 weeks after MSC administration
Changes in circulating cell populations
Time frame: 48 hours, 2, 4, 8, 12 weeks after MSC administration
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Sep 2025.
- Derived from this study: PubMed 30127049van 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.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Marianne Verhaar, MD, PhD principal investigator
UMC Utrecht
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Mesenchymal stromal cells in people with Systemic Sclerosis and Digital Ulcer, run by UMC Utrecht at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 10 Sep 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Femke van Rhijn, MD (0031887557329, f.c.c.brouwer-3@umcutrecht.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Toxicity of the treatment (time frame: 12 weeks after MSC administration). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03211793, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Sep 2025.