Mycophenolate in Limited Cutaneous Systemic Sclerosis (MINIMISE-Pilot)

A Randomised Prospective Open Label Pilot Trial Comparing Mycophenolate Mofetil (MMF) With no Immunosuppression in Adults With Limited Cutaneous Systemic Sclerosis

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.

This is an open label randomised prospective trial that will recruit 120 participants aged 18 and older with limited cutaneous systemic sclerosis across 13 sites in the UK. 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 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.

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 child bearing 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 -

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 child bearing potential and male participants with a partner of child bearing 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:

   i. Hospitalisation for treatment of infection within ≤ 8 weeks of screening visit date

   ii. Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or anti-parasitic agents) within ≤ 4 weeks of screening visit date

9. Receipt of a live-attenuated vaccine within ≤ 12 weeks of screening visit date

10. Participants enrolled in any other interventional trial within ≤ 4 weeks of the screening visit date (co-enrolment in observational studies is acceptable)

11. 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.

12. 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

13. Participants not willing or unable to attend on-site screening visit.