Clinical trial NCT05785065: Mycophenolate Mofetil in Systemic Sclerosis With Subclinical Interstitial Lung Disease
Official title: Randomized Double-Blind Placebo-Controlled Clinical Trial to Assess the Efficacy of Mycophenolate Mofetil in Subclinical Interstitial Lung Disease Associated With Systemic Sclerosis: a Feasibility Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Systemic Sclerosis With Lung Involvement
Systemic Sclerosis
Interstitial Lung Disease
Keywords: Systemic sclerosis
Mycophenolate mofetil
Interstitial lung disease
Lead sponsor: Centre hospitalier de l'Université de Montréal (CHUM)
Sponsor class: OTHER
Collaborators: name: McGill University
name: University of Calgary
name: Jewish General Hospital
name: Canadian Institutes of Health Research (CIHR)
name: Sclérodermie Québec
name: Institut universitaire de cardiologie et de pneumologie de Québec, University Laval
First posted: 2023-03-27
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients will be randomized to treatment group or placebo group in a 1:1 ratio and stratified according to the presence of anti-topoisomerase I autoantibody.
Primary purpose: OTHER

Brief summary: The goal of this pilot study is to assess the feasibility of a larger study on the efficacy of mycophenolate mofetil in people diagnosed with systemic sclerosis with mild lung involvement. Participants will be recruited over 12 months at 3 academic centers and assigned randomly to receive either mycophenolate mofetil or placebo, a look-alike substance that contains no active drug, for 96 weeks.

Detailed description: Background: Systemic sclerosis (SSc, scleroderma) is a rare but life-threatening systemic autoimmune disease characterized by microvasculopathy, serum autoantibodies, inflammation and fibrosis of the skin and internal organs. Early rapidly progressive SSc remains the most lethal autoimmune rheumatic disease, with over 60% mortality at 5 years in high-risk patients. Interstitial lung disease (ILD) is the leading cause of SSc-related mortality and affects over half of SSc patients. SSc-ILD is currently treated with immunosuppressive and anti-fibrotic drugs, with the first-line treatment being mycophenolate mofetil (MMF), although treatments have modest benefits when initiated in advanced stages of disease. Emerging data suggest that earlier treatment, when lung function is still normal despite evidence of ILD on computed tomography scan ("subclinical SSc-ILD"), may lead to improved outcomes, suggesting a window of treatment opportunity.

Research Aims: The goal of the proposed pilot RCT is to establish the feasibility of a phase III RCT that will assess the efficacy of MMF in subclinical SSc-ILD. Specifically, we aim to:

1. Determine the rate of patient recruitment at three centers over one year, and identify barriers and solutions to recruitment;
2. Determine the proportion of participants receiving the allocated treatment and with complete primary efficacy outcome data at 48 and 96 weeks; and
3. Generate preliminary data on clinical efficacy outcomes that will contribute information to the analysis of the phase III trial through a Bayesian inference framework.

Methods: Participants will be adults with SSc, ILD diagnosed within the past 3 years and a normal forced vital capacity (≥ 80%). Participants will be recruited over 12 months at 3 academic centers affiliated to the Canadian Scleroderma Research Group. Eligible participants will be assigned using stratified randomization to receive either MMF (up to 2 grams daily) or placebo for 96 weeks. The primary feasibility outcome will be the rate of recruitment per site over 12 months. A Bayesian approach will be used to estimate the probability of reaching the target sample size based on observed recruitment rates, with decision rules to continue, adapt, or stop the trial. Data collected on the primary clinical efficacy outcome (annual rate of decline in forced vital capacity over 96 weeks) will be used to inform the analysis of the phase III trial (as an informative prior) through a Bayesian inference framework.

Eligibility criteria: Inclusion Criteria:

1. Able and willing to provide informed consent and adhere to study protocol;
2. Women and men of all race/ethnicity, aged 18 years and older;
3. SSc based on 2013 ACR-EULAR classification criteria;
4. Presence of interstitial lung disease on HRCT scan, obtained within 12 months before screening, that shows fibrosis affecting less than 20% of the lungs, as confirmed by an expert radiologist;
5. Diagnosis of ILD within 7 years before screening;
6. Forced vital capacity of 80% predicted and above, on pulmonary function tests obtained within 6 months before screening;
7. Able to communicate in French or English;

Exclusion Criteria:

1. Progressive pulmonary fibrosis, defined as at least two of three criteria (worsening symptoms, radiological progression, and physiological progression) occurring within the past year with no alternative explanation, as defined by the 2022 ATS/ERS/JRS/ALAT Clinical Practice Guideline;
2. Use of medications with putative lung disease-modifying properties:

   1. Current use of MMF, mycophenolic acid, azathioprine, calcineurin inhibitors (e.g. tacrolimus, cyclosporin A), tocilizumab, nintedanib, pirfenidone or corticosteroids (Prednisone equivalent dose \>10 mg/day) at time of screening
   2. Cyclophosphamide within one year prior to screening
   3. Rituximab within 6 months prior to screening
   4. Cell therapies (including stem cell transplantation) within one year prior to screening
3. Current use of other biological, targeted synthetic or investigational products with immunosuppressive effects (e.g. TNF inhibitors, abatacept, tofacitinib) at time of screening
4. Any contraindication to MMF, including:

   1. Pregnancy and/or breastfeeding
   2. Female of childbearing potential not using reliable method of contraception
   3. Persistent leucopenia (white blood cell count \<3.0 x103/μL)
   4. Persistent thrombocytopenia (platelet count \<100 x103/μL)
   5. Persistent anemia (hemoglobin \<100 g/L)
   6. Baseline liver enzymes (alanine transaminase (ALT) or aspartate transaminase (AST)) or bilirubin \>1.5 times the upper limit of normal, other than due to Gilbert's disease
   7. Uncontrolled congestive heart failure
   8. Active infection (lung or elsewhere)
   9. Active solid or hematological malignancy (other than basal cell cancer of the skin or cervical carcinoma in situ removed entirely by biopsy)
   10. Active peptic ulcer disease
   11. Other serious concomitant medical illness, unreliability or drug abuse that might compromise the patient's ability to safely take MMF
   12. Use of drugs or products with significant interactions with MMF

Primary outcomes:
measure: Total number of potentially eligible patients identified per site
timeFrame: Over one year
measure: Proportion of potentially eligible patients who provide consent per site
timeFrame: Over one year
measure: Proportion of consented participants who meet the eligibility criteria per site
timeFrame: Over one year
measure: Monthly rate of randomized participants per site
timeFrame: Over one year
measure: Adherence to treatment as assessed by Participant Dosing Diaries
timeFrame: From the first dose to the last dose taken for each participant, up to 96 weeks
measure: Drug adherence rate as assessed by Pharmacy Accountability Logs
timeFrame: From the first dose to the last dose taken for each participant, up to 96 weeks
measure: Adherence to the study protocol as assessed by the number of protocol deviations
timeFrame: Over total study period (up to 96 weeks per participant)
measure: Proportion of participants intolerant to the study drug who discontinue trial treatment
timeFrame: Over total study period (up to 96 weeks per participant)
measure: Proportion of participants receiving the allocated treatment at 48 weeks
timeFrame: At 48 weeks
measure: Proportion of participants receiving the allocated treatment at 96 weeks
timeFrame: At 96 weeks
measure: Proportion of participants with complete primary efficacy outcome data at 48 weeks
timeFrame: At 48 weeks
measure: Proportion of participants with complete primary efficacy outcome data at 96 weeks
timeFrame: At 96 weeks
measure: Proportion of participants lost to follow-up
timeFrame: Over total study period (up to 96 weeks per participant)
Secondary outcomes:
measure: Frequency of treatment-related adverse events
timeFrame: Over total study period (up to 96 weeks per participant)
Other outcomes:
measure: Annual rate of decline in percent (%) predicted forced vital capacity (FVC) over 48 weeks
timeFrame: Over 48 weeks
measure: Annual rate of decline in percent (%) predicted forced vital capacity (FVC) over 96 weeks
timeFrame: Over 96 weeks
measure: Proportion of participants having clinically meaningful progression
timeFrame: Over total study period (up to 96 weeks per participant)
measure: Time to clinically meaningful progression
timeFrame: Over total study period (up to 96 weeks per participant)
measure: Proportion of participants having an absolute decrease in FVC of at least 3.3% predicted
timeFrame: Over total study period (up to 96 weeks per participant)
measure: Time to an absolute decrease in FVC of at least 3.3% predicted
timeFrame: Over total study period (up to 96 weeks per participant)
measure: Proportion of participants having progressive pulmonary fibrosis
timeFrame: Over total study period (up to 96 weeks per participant)
measure: Time to progressive pulmonary fibrosis
timeFrame: Over total study period (up to 96 weeks per participant)
measure: Annual rate of decline in percent (%) predicted total lung capacity over 48 weeks
timeFrame: Over 48 weeks
measure: Annual rate of decline in percent (%) predicted total lung capacity over 96 weeks
timeFrame: Over 96 weeks
measure: Annual rate of decline in percent (%) predicted diffusion capacity for carbon monoxide (DLCO) over 48 weeks
timeFrame: Over 48 weeks
measure: Annual rate of decline in percent (%) predicted DLCO over 96 weeks
timeFrame: Over 96 weeks
measure: Change from baseline in percent (%) extent of ILD, ground-glass opacities, reticular infiltrates and honeycombing, and in pulmonary vessel volume at 48 weeks
timeFrame: At 48 weeks
measure: Change from baseline in percent (%) extent of ILD, ground-glass opacities, reticular infiltrates and honeycombing, and in pulmonary vessel volume at 96 weeks
timeFrame: At 96 weeks
measure: Change from baseline in St-George Respiratory Questionnaire at 48 weeks
timeFrame: At 48 weeks
measure: Change from baseline in St-George Respiratory Questionnaire at 96 weeks
timeFrame: At 96 weeks
measure: Change from baseline in Leicester Cough Questionnaire at 48 weeks
timeFrame: At 48 weeks
measure: Change from baseline in Leicester Cough Questionnaire at 96 weeks
timeFrame: At 96 weeks
measure: Change from baseline in health assessment questionnaire modified for scleroderma at 48 weeks
timeFrame: At 48 weeks
measure: Change from baseline in health assessment questionnaire modified for scleroderma at 96 weeks
timeFrame: At 96 weeks
measure: Change from baseline in 36-items short form survey (SF-36) at 48 weeks
timeFrame: At 48 weeks
measure: Change from baseline in 36-items short form survey (SF-36) at 96 weeks
timeFrame: At 96 weeks
measure: Change from baseline in EuroQoL five dimensions (EQ-5D-5L) at 48 weeks
timeFrame: At 48 weeks
measure: Change from baseline in EuroQoL five dimensions (EQ-5D-5L) at 96 weeks
timeFrame: At 96 weeks
measure: Change from baseline in patient global assessment at 48 weeks
timeFrame: At 48 weeks
measure: Change from baseline in patient global assessment at 96 weeks
timeFrame: At 96 weeks
measure: Change from baseline in physician global assessment at 48 weeks
timeFrame: At 48 weeks
measure: Change from baseline in physician global assessment at 96 weeks
timeFrame: At 96 weeks
measure: Change from baseline in 6-minute walk oxygen saturation at 48 weeks
timeFrame: At 48 weeks
measure: Change from baseline in 6-minute walk oxygen desaturation at 96 weeks
timeFrame: At 96 weeks
measure: Change from baseline in modified Rodnan skin score (mRSS) at 48 weeks
timeFrame: At 48 weeks
measure: Change from baseline in modified Rodnan skin score (mRSS) at 96 weeks
timeFrame: At 96 weeks
measure: Change from baseline in nailfold capillary density at 48 weeks
timeFrame: At 48 weeks
measure: Change from baseline in nailfold capillary density at 96 weeks
timeFrame: At 96 weeks
measure: Change from baseline in nailfold capillaroscopy abnormalities and patterns at 48 weeks
timeFrame: At 48 weeks
measure: Change from baseline in nailfold capillaroscopy abnormalities and patterns at 96 weeks
timeFrame: At 96 weeks
measure: Change from baseline in quantitative SSc autoantibody titers at 48 weeks
timeFrame: At 48 weeks
measure: Change from baseline in quantitative SSc autoantibody titers at 96 weeks
timeFrame: At 96 weeks
measure: Change from baseline in Krebs von Lungen 6 (KL-6) titers at 48 weeks
timeFrame: At 48 weeks
measure: Change from baseline in Krebs von Lungen 6 (KL-6) titers at 96 weeks
timeFrame: At 96 weeks
Locations:
city: Montreal
country: Canada
facility: Centre hospitalier de l'Université de Montréal (CHUM)
state: Quebec
city: Montreal
country: Canada
facility: Jewish General Hospital - CIUSSS-COMTL
state: Quebec
city: Quebec City
country: Canada
facility: Institut Universitaire de Cardiologie et Pneumologie de Québec
state: Quebec
Study officials:
affiliation: Centre hospitalier de l'Université de Montréal (CHUM)
name: Sabrina Hoa, MD
role: PRINCIPAL_INVESTIGATOR
References: