EvER-ILD 3 : Evaluation of Efficacy and safety of Rituximab and mycophenolate mofetil combination in patients with Interstitial Lung Disease related to systemic sclerosis: a multicentre double-blind placebo-controlled randomized trial.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Regional Universitaire De Tours

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08], Diseases [C] - Immune System Diseases [C20]

Trial duration

8 Jan 2025 → ongoing

Decision date (initial)

2024-10-01

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

The main objective of the EvER-ILD3 study is to evaluate the efficacy on lung function after 24 weeks of rituximab + MMF combination comparatively to placebo + MMF combination in patients with SSc-ILD severe at the initial assessment or at high risk of progression

Secondary objectives 6

1. - To evaluate the efficacy of rituximab + MMF treatment versus placebo + MMF after 24 and 48 weeks on: • Modified Rodnan skin score (mRSS) • progression-free survival (PFS) • patient’s quality of life • patients' consumption of corticosteroids • several functional, radiographic and biological parameters • physical activity
2. - To evaluate the safety of rituximab compared to placebo throughout the study period.
3. - To evaluate adverse events in patients with antifibrotic drugs at inclusion versus patients without antifibrotic drugs.
4. - To describe the pharmacokinetics of rituximab and the pharmacokinetic-pharmacodynamic relationship in this disease.
5. - To identify variables associated with the clinical response and, if possible, with adverse effects of rituximab.
6. - To establish a collection of serum samples to allow for further studies of potential new markers of treatment response in patients with SSc-ILD.

Conditions and MedDRA coding

Intersitial lung disease related to systemic sclerosis

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. 1) Male and female 18 years and older who meet the American College of Rheumatology/EUropean League Against Rheumatism collaborative initiative (ACR/EULAR) classification criteria 2013 for systemic scleroderma.
2. 2) Who are eligible for a treatment with MMF (up to 1500 mg twice daily if tolerated) for the management of SSc-ILD adapted from the French PNDS (revised may 2022) [9]: - Severe ILD at the baseline assessment i. with an extensive ILD on HRCT ≥20% according to Goh classification [10] ii. or with forced vital capacity of the predicted value (% FVC) ≤ 70%. - or ILD regardless of HRCT extension and at high risk of progression (age > 60 years, male gender, early cutaneous diffuse SSc (≤ 5 years), Afro-American or Afro-Caribbean ethnicity, anti-SCL70/Topoisomerase I autoantibody, or biological inflammation with CRP >= 5 mg/L). - or ILD regardless of HRCT extension and with progression criteria in the past 6-24 months before the initial assessment (based on INBUILD study): i. relative decline in the forced vital capacity of the predicted value (% FVC) >=10% ii. or relative decline in FVC of 5-10% associated with a relative decline in DLCO >= 15% iii. or relative decline in FVC of 5-10% associated with worsening of dyspnea or extension of ILD lesion on HRCT iv. or worsening of dyspnea with extension of HRCT opacities
3. 3) Person affiliated to a French social security system or equivalent
4. 4) Written informed consent obtained from participant with a specific check box on the Consent form of the study, understanding the risk for men and women treated with mycophenolate mofetil. And additional written consent on the care and contraception agreement form for women of childbearing potential because of use of mycophenolate
5. 5) Ability for subject to comply with the requirements of the study.

Exclusion criteria 15

1. 6) Known diagnosis of significant respiratory disorders (asthma, tuberculosis, aspergillosis, cystic fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, smoking-related ILD), severe cardiomyopathy or a known severe heart failure as considered by the investigator
2. 7) Known diagnosis of group 1 precapillary pulmonary hypertension (mean pulmonary artery pressure (mPAP) > 20 mmHg and pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg and pulmonary vascular resistance > 2 UWood and FVC ≥ 70% theoretical) or group 3 severe precapillary pulmonary hypertension (mPAP > 20 mmHg and PAWP ≤ 15 mmHg and pulmonary vascular resistance > 5 UWood, whatever the FVC)
3. 8) Concomitant medical or surgical disease, clinically significant as considered by the investigator, serious or unstable, acute or chronically progressive, or any condition that could affect the safety of the patient, in the opinion of the investigator
4. 9) Patient who cannot walk more than 100 meters
5. 10) Known MMF intolerance
6. 11) Initiation of a new therapy for SSc-ILD or with interruption / modification of therapy dosage within 4 weeks prior to baseline assessment
7. 12) Patient having already received a rituximab or MMF-based treatment line for SSc-ILD
8. 13) Known hypersensitivity to rituximab, to murine proteins, other excipients or sulphonamide antibiotics.
9. 14) Concomitant immunosuppressive treatments: >15 mg/day corticosteroids, azathioprine, cyclophosphamide, methotrexate, cyclosporine, tacrolimus, JAK inhibitors within 4 weeks prior to inclusion
10. 15) Treatment with monoclonal antibodies (such as, but not limited to, etanercept, adalimumab, efalizumab, infliximab, golimumab, certolizumab, tocilizumab) within 6 months prior to inclusion
11. 16) Patients on a lung transplant list
12. 17) Persons covered by articles L1121-5 to L1121-8 of the CSP (corresponding to all protected persons: pregnant women, parturients, nursing mothers, persons deprived of their liberty by judicial or administrative decision, minors, and persons subject to a legal protection measure: guardianship or trusteeship). Also, women of child-bearing potential (including female partners of sexually active men treated with mycophenolate) not using two reliable contraceptive methods and men not using a contraceptive method (condom), or women and men having a pregnancy project during the year following randomization
13. 18) Patients at high risk of infectious complications: Human Immunodeficiency Virus (HIV) positive or other known immunodeficiency syndromes, hepatitis B and C (HBV, HCV), COVID (within 3 month) or other known viral infection, infection requiring anti-infective treatment within 4 weeks of inclusion
14. 19) Patients with incomplete anti-SARS-CoV-2 vaccine regimen (according to current recommendations) and in this case, patient who has not receive treatment with anti SARS CoV2 therapeutic antibodies (ex : tixagévimab/cilgavimab).
15. 20) Concomitant participation in other interventional research with an investigational drug or medical device.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary outcome is the change in Forced Vital Capacity (FVC) (in % predicted) from baseline to week 24 with measures at baseline, week 12 and week 24.

Secondary endpoints 14

1. 1) Change in % of predicted FVC (% FVC) from baseline to week 48
2. 2) Change in FVC (mL) from baseline to weeks 24 and 48
3. 3) Change from baseline to weeks 24 and 48 in modified Rodnan skin score (mRSS)
4. 4) Progression free survival (PFS) to weeks 24 and 48, defined as the time to (first event considered): a) a first acute exacerbation, or b) a relative decline in the FVC of ≥ 10% of the predicted value, or c) inclusion on a lung transplant list, or d) inclusion for a therapeutic intensification by autologous haematological stem cell transplantation (AHSCT), or e) death.
5. 5) Overall survival (OS)
6. 6) Changes from baseline to weeks 24 and 48 in the EULAR ScleroID questionnaire, King’s Brief Interstitial Lung Disease (K-BILD) questionnaire and LF-P symptom and impact questionnaire
7. 7) Cumulative doses of corticosteroids at week 24 and 48
8. 8) Changes from baseline to weeks 24 and 48 in % of predicted diffusing capacity for carbon monoxide (DLCO)
9. 9) Changes from baseline to weeks 24 and 48 in the 6-minute walk test
10. 10) Change from baseline to week 24 in accelerometer-assessed physical activity
11. 11) Changes from baseline to week 48 in high-resolution computed tomography (HRCT) of chest images
12. 12) Changes from baseline to week 48 of biological markers related to B-cell depletion: CD19 B-cells and gamma globulins
13. 13) All adverse events, especially serious infectious adverse events, occurring during the 48 weeks treatment period
14. 14) Pharmacokinetic parameters of rituximab: volume of distribution, rituximab clearance and half-life

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Regional Universitaire De Tours

Sponsor organisation

Centre Hospitalier Regional Universitaire De Tours

Address

2 Boulevard Tonnelle

City

Tours Cedex 9

Postcode

37044

Country

France

Scientific contact point

Organisation

Centre Hospitalier Regional Universitaire De Tours

Contact name

Sylvain MARCHAND-ADAM

Public contact point

Organisation

Centre Hospitalier Regional Universitaire De Tours

Contact name

Sylvain MARCHAND-ADAM

Locations

1 EU/EEA country · 26 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

1 submissions — initial application plus substantial / non-substantial modifications