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MINIMISE-Pilot

Mycophenolate in limited cutaneous systemic sclerosis

15 December 2021

A randomised prospective open label pilot trial comparing mycophenolate mofetil (MMF) with no immunosuppression in adults with limited cutaneous

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Open for recruitment: 08th December 2021
RECRUITMENT TARGET = 120 participants

Trial Information

Background and Design
Systemic sclerosis or scleroderma is an autoimmune condition that cause thickening and hardening of the skin but can also affect internal organs. There are two major subsets of scleroderma: the limited cutaneous systemic sclerosis (lcSSc) that usually affects the skin of the face, neck, lower legs, or lower arms, but can also lead to internal organ complications, and the diffuse cutaneous systemic sclerosis (dcSSc) that may affect blood circulation and internal organs, as well as the skin. To date there is no drug that has been definitively proven to cure or modify the course of scleroderma. However, there is emerging evidence that immunosuppression and specifically mycophenolate mofetil (MMF) may be beneficial in lcSSc.

The MINIMISE-Pilot trial would be an important first step to evaluate the risk and potential benefit to this disease group. MMF as the intervention of choice is both appropriate and timely, as it has been routinely used in the management of dcSSc.

The aim of this pilot trial is to explore whether the immunosuppressive agent MMF can slow down disease progression in patients with lcSSc compared to the current standard of care alone. This pilot trial will also provide critical information for the development of a future large trial that could potentially transform lcSSc patient management.

The MINIMISE-Pilot trial aims to explore whether the immunosuppressive agent mycophenolate mofetil (MMF) at a target dose of 2g daily can slow down disease progression in patients with limited cutaneous systemic sclerosis (lcSSc) compared to the current standard of care alone. This pilot trial will also provide critical information for the development of a future large trial that could potentially transform lcSSc patient management.

The MINIMISE-Pilot trial is a randomised prospective open label trial in which 120 participants, aged 18 and older, with confirmed diagnosis of limited cutaneous systemic sclerosis will be recruited.

Following a screening visit, eligible participants will attend a baseline visit where they will be randomly allocated into one of two groups: MMF or Control. Those in the first group are given mycophenolate mofetil (MMF) taken daily by mouth for up to 96 weeks, in addition to their background Standard of Care medication for SSc related symptoms. Those in the second group will not receive any MMF but will remain on their standard of care medication alone.

Participants will be enrolled from 13 sites across the UK and are expected to be followed up for a minimum of 48 weeks or a maximum of 96 weeks. The trial will involve five (5) clinic visits which are expected to be carried out at the same time of the participants' normal hospital appointment with their scleroderma specialist. Participants from both groups will have the same assessments. Participants are expected to return to the clinics at Week 24, 48, 72 and 96. However, participants allocated to the MMF group will have additional blood samples taken for safety monitoring every 2 weeks for the first 8 weeks, then every 4 weeks for the following 12 weeks. Thereafter, every 12 weeks up to their final visit.

All the participants will receive four (4) routine telephone calls in between their clinic visits.

Who is organising and funding the research? 
This research is being funded by Versus Arthritis (grant reference number 22398).

The trial is being sponsored and co-ordinated by University College London Comprehensive Clinical Trials Unit.

Eligibility criteria

Please find the eligibility criteria for MINIMISE-Pilot below:

Participant Inclusion Criteria

  1. Participants with lcSSc classified by the 2013 EULAR ACR criteria for limited cutaneous subset of SSc
  2. Participants with less than 7 years disease duration from first non-Raynaud's manifestation of SSc
  3. Participants aged 18 years or more (≥ 18 years) at screening visit
  4. If women of childbearing potential, the participant must have a negative pregnancy test at screening and baseline visits
  5. Negative viral screen for HIV, Hepatitis B and C
  6. Ability to provide full informed consent
  7. Registered with a GP practice in the UK
  8. Participants must be willing to attend for follow up visits (at site or remotely) and to comply with study-related procedures

Participant Exclusion Criteria

  1. Having already developed a complication of SSc that requires initiation of MMF or an alternative major immunosuppressive drug for SSc such as methotrexate, cyclophosphamide or azathioprine
  2. Treatment with methotrexate, cyclosporine A, azathioprine, mycophenolate mofetil (MMF), rapamycin, colchicine, D-penicillamine, within ≤ 4 weeks prior to the baseline visit date
  3. Contraindication to MMF (e.g., active infection that would preclude MMF in judgement of investigator), or previous intolerance of MMF
  4. Any clinical condition which the investigator considers would make the patient unsuitable for the trial
  5. Pregnancy (or planned pregnancy during trial participation) and/or breastfeeding
  6. Women of childbearing potential and male participants with a partner of childbearing potential not willing to use adequate contraception as described in section 6.3.1.4 for the duration of trial treatment and within the time points specified following last trial treatment.
  7. Active chronic infection such as COVID-19, tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria. Suitability for enrolment once the participant has recovered from infection will be based on Investigator judgment.
  8. Infection history:
  • Hospitalisation for treatment of infection within ≤ 8 weeks of screening visit date
  • Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or anti-parasitic agents) within ≤ 4 weeks of screening visit date
  1. Receipt of a live-attenuated vaccine within ≤ 12 weeks of screening visit date
  2. Participants enrolled in any other interventional trial within ≤ 4 weeks of the screening visit date (co-enrolment in observational studies is acceptable)
  3. Current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence within ≤ 52 weeks prior to screening visit date.
  4. Any of the following laboratory results at screening visit:
  • Glomerular filtration rate (GFR) <60 ml/min/1.73m²
  • Absolute neutrophil count (ANC) < 1.6 x 10^9/l
  • ALT or AST > 2 x ULN
  1. Participants not willing or unable to attend on-site screening visit.
Outcomes

Primary outcomes:

Feasibility and clinical outcomes will be measured in this trial.

Feasibility outcomes:

  • Recruitment rate (the proportion of eligible participants enrolled into the trial)
  • Adherence to the protocol (by participants and clinicians/research teams at sites)
  • Proportion of participants intolerant to MMF who discontinue therapy
  • Proportion of MMF participants who reduce their dose
  • Proportion of MMF tablets taken
  • Loss to follow up in each group (MMF and Control)
  • Information to guide the design of the definitive double-blind placebo-controlled trial by providing data to:
  1. Estimate the number of centres and the length of the recruitment period that will be required for the definitive double-blind placebo-controlled trial 
  2. Identify any barriers to recruitment
  3. Assess the rate of withdrawal from treatment due to adverse events and the rate of loss to follow up
  • Information to guide the design of the economic evaluation of the definitive double-blind placebo-controlled trial

Clinical outcomes:

  1. Time to clinical worsening of lcSSc defined as development of new clinically significant endpoint:
  • Progressive lung fibrosis
  • Pulmonary hypertension
  • Scleroderma renal crisis 
  • Heart failure 
  • Severe gut involvement causing malnutrition
  • Major vascular complications in the fingers such as gangrene
  • Mortality
Participating Sites / Research contacts

Status: Recruiting
Please contact the local trial teams for more information.

  1. Site 108 - Royal Free Hospital, London
    Principal Investigator: Prof Christopher Denton
    Email: c.denton@ucl.ac.uk
    Tel: 02073177544

Status: Not recruiting yet

  1. Site 101 - Royal United Hospital, Bath
    Principal Investigator: Dr John Pauling
    Email: johnpauling@nhs.net
  2. Site 102 - Queen Elizabeth Hospital, Birmingham
    Principal Investigator: Dr Emma Derrett-Smith
    Email: Emma.Derrett-Smith@uhb.nhs.uk
  3. Site 103 - Southmead Hospital, Bristol
    Principal Investigator: Dr Harsha Gunawardena
    Email: Harsha.Gunawardena@nbt.nhs.uk
  4. Site 104 - Addenbrookes Hospital, Cambridge
    Principal Investigator: Dr Frances Hall
    Email: frances.hall2@nhs.net
  5. Site 105 - Ninewells Hospital, Dundee
    Principal Investigator: Dr Smita Bhat
    Email: smita.bhat@nhs.scot 
  6. Site 106 - Chapel Allerton Hospital, Leeds
    Principal Investigator: Dr Francesco Del Galdo
    Email: F.DelGaldo@leeds.ac.uk
  7. Site 107- Aintree University Hospital, Liverpool
    Principal Investigator: Dr Marina Anderson
    Email: Marina.Anderson@liverpool.ac.uk
  8. Site 109 - Salford Royal Hospital, Manchester
    Principal Investigator: Prof Ariane Herrick
    Email: ariane.herrick@manchester.ac.uk
  9. Site 110 - Freeman Hospital, Newcastle
    Principal Investigator: Dr Bridget Griffiths
    Email: bridget.griffiths@nhs.net 
  10. Site 111 - Nottingham University Hospital
    Principal Investigator: Dr Peter Lanyon
    Email: peter.lanyon@nuh.nhs.uk 
  11. Site 112 - Royal Hallamshire Hospital, Sheffield
    Principal Investigator: Dr Mohammed Akil
    Email: m.akil@sheffield.ac.uk 
  12. Site 113 - New Cross Hospital Wolverhampton
    Principal Investigator: Dr Tom Sheeran
    Email:  t.sheeran@nhs.net
Meet the MINIMISE-Pilot Team

Prof Christopher Denton
Chief Investigator

Felicia Ikeji
Clinical Project Manager

Amalia Ndoutoumou
Clinical Trial Manager

Katie Thompson
Data Manager

Trial Additional Information

Additional information about our trial on clinicaltrials.gov/ct2/show/NCT04927390 - a service of the U.S. National Institutes of Health.

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EudraCT: 2019-004139-21
ClinicalTrials.gov: NCT04927390
REC: 20/LO/0352
IRAS: 275187