EvER-ILD 2: Evaluation of Efficacy and safety of Rituximab in patients with progressive Interstitial Lung Disease (ILD) with inflammatory component: 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]

Trial duration

16 Jan 2023 → ongoing

Decision date (initial)

2022-10-10

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

DGOS

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

The main objective of the EvER-ILD2 study is to evaluate the efficacy on lung function at 6 months of one course rituximab (2 infusions) comparatively to one course of placebo (2 infusions) in a broad range of progressive ILD patients with inflammatory component.

Secondary objectives 7

1. - To evaluate the efficacy of rituximab treatment at 6 months versus placebo on: • progression-free survival (PFS) • patient’s quality of life • patients' consumption of corticosteroids • several functional, radiographic and biological parameters
2. - To evaluate the safety of rituximab compared to placebo throughout the study period.
3. - To evaluate adverse events on patients with anti-fibrosants at the inclusion versus patients without anti-fibrosants.
4. - To describe the evolution of SARS-COV2 antibodies from baseline to 6 months in the two randomization groups.
5. - To describe the pharmacokinetics of rituximab and the pharmacokinetic-pharmacodynamic relationship in these diseases.
6. - To identify variables associated with the clinical response and, if possible, adverse effects of rituximab.
7. - To establish a collection of serum samples to allow for further studies of potential new markers of treatment response in ILD patients.

Conditions and MedDRA coding

Interstitial lung disease

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Patients ≥ 18 years old
2. Who meet at least one of the following criteria for worsening ILD within 24 months: a) a relative decline in the FVC of >= 10% of the predicted value b) a relative decrease in the FVC of >=5 to 10% of the predicted value AND i) worsening respiratory symptoms OR ii) an increased extent of ILD on high-resolution CT OR iii) a relative decrease in the DLCO of >= 15% of the predicted value. c) worsening of respiratory symptoms AND an increased extent of ILD on high-resolution CT
3. AND presence of an inflammatory component defined by: a) a previous histological pattern with lymphocyte infiltrations distant from pulmonary fibrosis to suggest an inflammatory component on pulmonary sample (for example: interstitial lymphoid aggregates with germinal centers, diffuse lympho-plasmocytic infiltrations, granulomas, giant cells or centrilobular inflammation…) b) OR a previous alveolar lymphocytosis > 20% on BALF
4. Subjects covered by the French social security system
5. Written informed consent obtained from subject
6. Ability for subject to comply with the requirements of the study.

Exclusion criteria 15

1. Known diagnosis of significant respiratory disorders (asthma, tuberculosis, aspergillosis, cystic fibrosis, IPF, CTD-ILD, sarcoidosis, desquamative interstitial pneumonia, pulmonary hypertension (PAMp > 30mmHg)) or a significant severe heart failure
2. 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, including severe cardiomyopathy or severe heart failure
3. Patient who cannot walk more than 100 meters at 6-minutes walk test
4. HRCT profile of definite usual interstitial pneumonia (UIP)
5. Histological model of definite UIP
6. Initiation of a new therapy or with interruption/modification of therapy dosage within 6 weeks prior to visit 1
7. Patient who has already received a rituximab-based treatment line
8. Known hypersensitivity to rituximab, to murine proteins or other excipients or sulfonamide antibiotics
9. Treatment with monoclonal antibodies (such as, but not limited to, etanercept, adalimumab, efalizumab, infliximab, golimumab, certolizumab, tocilizumab) within 6 months (if 5 half-lives ≤ 6 months) prior to inclusion
10. Patients on a lung transplant list
11. Pregnant or breastfeeding women, or women of childbearing age not using a reliable method of contraception during the study and for 12 months following the end of the study treatment
12. 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
13. Patients with incomplete anti-SarsCoV2 vaccine regimen (according to current recommendations) or patient who has not receive treatment with therapeutic antibodies anti-SARSCov2 (ex: tixagévimab/cilgavimab)
14. Patient under judicial protection, deprivation of liberty
15. 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 mL) from baseline to 6 months.

Secondary endpoints 13

1. Change from baseline in FVC (in % of predicted) to 6 months
2. Progression free survival (PFS) at 6 months, 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) the need for new immunosuppressive therapy or/and anti-fibrotic therapies (excluding corticosteroids), or d) inclusion on a lung transplant list, or e) death.
3. Changes from baseline to 6 months in the King’s Brief Interstitial Lung Disease (K-BILD) questionnaire and L-PF symptom and impact questionnaire
4. Difference in cumulative doses of corticosteroids at 6 months
5. Changes from baseline to 6 months in % of predicted diffusing capacity for carbon monoxide (DLCO)
6. Changes from baseline to 6 months in the 6-minute walk test
7. Change from baseline to 6 months in accelerometer-assessed physical activity
8. Changes from baseline to 6 months of biological markers related to B-cell depletion: CD19 lymphocytes and gammaglobulins,
9. Changes from baseline to 6 months of serology by ELISA of 15 environmental antigens.
10. Changes from baseline to 6 months in high-resolution computed tomography (HRCT) of chest images
11. All adverse events, especially serious infectious adverse events, occurring during the six-month treatment period
12. Pharmacokinetic parameters of rituximab: volume of distribution, rituximab clearance and half-life
13. Change from baseline to 6 months of SARS COV 2 antibodies

Investigational products

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

Test 1

Comparator 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

49 Boulevard Beranger

City

Tours

Postcode

37000

Country

France

Scientific contact point

Organisation

Centre Hospitalier Regional Universitaire De Tours

Contact name

Pr. MARCHAND ADAM

Public contact point

Organisation

Centre Hospitalier Regional Universitaire De Tours

Contact name

Pr. MARCHAND ADAM

Locations

1 EU/EEA country · 29 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

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