Evaluation of Nintedanib and Tocilizumab Combination Therapy Versus Standard Treatment in Systemic Sclerosis-Associated Interstitial Lung Disease
- Trial ID
- 2024-517005-85-00
- Protocol
- NIGRIR_004NINTOC-TU
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this multicentre clinical trial is to evaluate the **efficacy** and **safety** of the combination therapy of nintedanib and tocilizumab compared to standard therapy, which includes methotrexate and mycophenolate mofetil, over a period of 56 weeks. This study targets patients with systemic sclerosis and interstitial lung disease, specifically those with at least 10% lung involvement as assessed by high-resolution computed tomography. The clinical relevance of this objective lies in potentially improving treatment outcomes for patients with these conditions, which are characterized by significant morbidity and limited therapeutic options.
Secondary objectives include the modification of the diagnostic pathway through the use of positron emission tomography (PET) examination, as well as transcriptome, genome, and metabolome tests. Additionally, the study will analyze fibrosis markers in lung tissue obtained via bronchoscopy and bronchoalveolar lavage (BAL), as well as in serum. These markers include TGF-β, VEGF, IFN-γ, KL-6, SP-D, CCL-2, CCL-18, CA15-3, CXCL-1, Ang1, and Ang2, which are part of the immune panel. These secondary objectives aim to enhance the understanding of disease mechanisms and improve diagnostic accuracy.
Participants
The clinical trial involves participants diagnosed with **systemic sclerosis** with interstitial lung disease (ILD), characterized by at least 10% lung involvement as assessed by high-resolution computed tomography (HRCT). The study population includes both male and female subjects aged between 18 and 74 years. Participants are required to have a documented diagnosis of systemic sclerosis according to the criteria of the American College of Rheumatology (ACR) and The European Alliance of Associations for Rheumatology (EULAR), with an overall disease duration of 72 months or less. The trial includes individuals with a modified Rodnan skin score (mRSS) ranging from 10 to 45 units. Participants must be on stable doses of conventional drugs such as mycophenolate mofetil or methotrexate for at least 8 weeks prior to the baseline visit. Those taking oral corticosteroids should maintain a stable dose of 10 mg/day prednisone or equivalent for at least 8 weeks before the baseline visit. The trial population was selected based on these criteria, and participants of childbearing potential are required to use effective contraception throughout the study. The sponsor has not provided information regarding the total number of participants.
Plans and Procedures
The clinical trial is designed to evaluate the **efficacy** and safety of a combination therapy involving **nintedanib** and **tocilizumab** compared to standard treatment in patients with systemic sclerosis and interstitial lung disease. This is a multicenter, randomized, double-blind, controlled trial with a duration of 56 weeks. The trial aims to assess the primary endpoint of a decrease in forced vital capacity (FVC) of the lungs, expressed in milliliters, after 56 weeks of treatment. Secondary endpoints include changes in lung involvement as assessed by high-resolution computed tomography (HRCT), changes in diffusing capacity of the lungs for carbon monoxide (DLCO), and various patient-reported outcomes.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, documented diagnosis of systemic sclerosis, and confirmed interstitial lung disease with at least 10% lung involvement. Following the screening, participants will be randomized to receive either the combination therapy or standard treatment. Follow-up visits will occur at regular intervals to monitor safety, efficacy, and any adverse events. The end-of-study visit will occur at week 56, where final assessments will be conducted.
The expected length of participant involvement is approximately 56 weeks, with conditions for early termination including significant adverse events, withdrawal of consent, or non-compliance with study procedures. Participants are required to maintain stable doses of any concurrent medications, such as mycophenolate mofetil or methotrexate, for at least eight weeks prior to the baseline visit. The trial will adhere to the International Harmonization Guidelines for Good Clinical Practice (ICH-GCP) and local regulations, ensuring the integrity and reliability of the data collected.
Treatment
The clinical trial involves the administration of **tocilizumab**, marketed as RoActemra, which is provided as a 162 mg **solution for injection** in a pre-filled syringe. This medication is administered via **subcutaneous use**. The maximum daily dose is 162 mg, and the treatment period extends up to 56 weeks. Tocilizumab is a protein-based therapeutic agent, specifically classified under the ATC code L04AC07. The product is manufactured by Roche Registration GmbH and is not a paediatric formulation.
Another experimental medication used in the trial is **nintedanib**, marketed as Ofev, available in two dosages: 100 mg and 150 mg **soft capsules**. Nintedanib is administered orally, with a maximum daily dose of 200 mg for the 100 mg capsules and 300 mg for the 150 mg capsules. The treatment duration is also set for 56 weeks. Nintedanib is a chemically synthesized compound, classified under the ATC code L01EX09. The product is manufactured by Boehringer Ingelheim International GmbH and is not formulated for paediatric use.
The trial also includes standard-of-care therapies, which may involve the use of methotrexate or mycophenolate mofetil, as comparator treatments. These non-experimental treatments are administered according to standard medical guidelines for patients with systemic sclerosis and interstitial lung disease. Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints over a 56-week period. The primary endpoint is the decrease in forced vital capacity (FVC) of the lungs, expressed in milliliters, calculated after 56 weeks of treatment. Secondary endpoints include changes from baseline in percent lung involvement as assessed by high-resolution computed tomography (HRCT%), evaluation of absolute changes in diffusing capacity of the lungs for carbon monoxide (DLCO) at week 56, and changes in FVC% at 56 weeks. Additional secondary endpoints involve changes from baseline in the 6-minute walk test (6MWT) at week 56, the Health Assessment Questionnaire-Disability Index (HAQ-DI) score, and the Patient's Global Assessment (PtGA) of disease activity by both the patient and physician at week 56.
Further assessments include the evaluation of absolute changes from baseline in the total score of the St. George's Respiratory Questionnaire (SGRQ) and the Modified Rodnan Skin Induration Score (mRSS) at week 56. The percentage of participants with threshold mRSS improvement from baseline at week 56 will also be evaluated, with specific attention to improvements greater than or equal to 20%, 40%, or 60%. These efficacy parameters will be measured using validated scales and imaging techniques, ensuring a comprehensive evaluation of the treatment's impact on patients with systemic sclerosis and interstitial lung disease. The trial will employ a combination of computed tomography, positron emission tomography, and metabolome and transcriptome studies in selected patients to assess cytokine activity, markers of inflammation, and pulmonary fibrosis.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Men or women aged 18-74 at the date of signing the informed consent.
- Written informed consent in accordance with the International Harmonization Guidelines Harmonized Tripartite Guidelines for Good Clinical Practice (ICH-GCP) and local regulations signed prior to any study procedure.
- Documented diagnosis of systemic sclerosis according to the criteria of the American College of Rheumatology (ACR) and The European Alliance of Associations for Rheumatology (former name - European League Against Rheumatism) - EULAR, meeting the criteria of an active disease [patients with limited and generalized TUu)] and with an overall disease duration of less than or equal to (≤ 72 months)..
- Patients with interstitial lung disease (ILD) confirmed by HRCT (min. 10% lung involvement).
- Evaluation of skin induration with the modified Rodnan scale (mRSS) from 10 to 45 units inclusive.
- Patients treated with conventional drugs such as mycophenolate mofetil, methotrexate; should be on stable doses for ≥ 8 weeks prior to and including the baseline visit (W0).
- Patients may be treated with standard therapy, but no new therapy or withdrawal of therapy within 8 weeks prior to the first screening visit (W0).
- Patients taking oral corticosteroids (GCS) should be on a stable dose of ≤ 10 mg/day prednisone or equivalent for at least 8 weeks prior to the baseline visit.
- Patients of childbearing potential should agree to abstain from sexual activity or use a highly effective method of contraception throughout the study and for at least 3 months after the last dose of medicinal products.
Exclusion Criteria
- Patients not fully capable of giving informed consent.
- Pregnant or breastfeeding women.
- Major surgery within 8 weeks prior to screening (W0A).
- Rheumatic disease other than systemic sclerosis (systemic lupus erythematosus, rheumatoid arthritis, mixed connective tissue disease), diagnosis of secondary Sjögren's syndrome is acceptable.
- Active diverticulitis and severe enteritis.
- Untreated lipid disorders (initiation of treatment and modification of the lipid profile enables re-screening for examination, rescreaning, after 8 weeks from the start of hypolipidemic treatment).
- Immunization with a live or attenuated vaccine within 4 weeks prior to scheduled treatment.
- Known hypersensitivity to human, humanized or murine monoclonal antibodies and hypersensitivity to peanut, soya.
- Aspartate aminotransferase (AST), alanine aminotransferase (ALT) >1.5 x ULN, if normalized, patient may be considered for re-screening.
- Bilirubin >1.5 x ULN.
- Creatinine clearance <30 ml/min.
- Significant pulmonary hypertension (PH).
- Airway obstruction (forced expiratory volume before bronchodilation in 1 second (FEV1)/FVC <0.7) and other clinically significant pulmonary abnormalities.
- Cardiovascular diseases with heart failure NYHA III/IV.
- More than 4 digital ulcers or a history of severe digital necrosis requiring hospitalization or severe other digital ulcers.
- Bleeding risk (such as bleeding tendency, fibrinolysis, full dose of anticoagulants, high dose of antiplatelet therapy, history of central nervous system (CNS) bleeding events in the last year. (INR) >2, prothrombin time (PT) and partial thromboplastin (PTT) > 1.5 x ULN) and history of a thrombotic event within the last year, history of thrombosis still requiring full therapeutic anticoagulant therapy, fibrinolysis or high-dose antiplatelet therapy > 150 mg ASA per day.
- History of stroke, myocardial infarction within 6 months prior to screening.
- Prior treatment with pirfenidone and nintedanib if a minimum of 6 months had not been completed prior to enrolling the patient in the NINTOC-TU study.
- Plasmapheresis and/or plasma exchange within the last 12 weeks prior to screening and use of immunoglobulins within the last 12 weeks and treatment with tocilizumab, treatments targeting B cell depletion, biologics (e.g. tumor necrosis factor antagonists), tyrosine kinase inhibitors, current treatment with alkylating agents (chlorambucil), autologous bone marrow transplantation, thalidomide, antithymocyte globulin, extracorporeal photopheresis.
- Treatment with prednisone >10 mg/day, azathioprine, hydroxychloroquine, colchicine, D-penicillamine, sulfasalazine if within 8 weeks prior to W0. Cyclophosphamide within < 8 weeks of randomization visit (W 1). Rituximab within 6 months of visit (randomization W1).
- Unstable (fluctuating) background therapy with mycophenolate mofetil or methotrexate in the last 8 weeks.
- Patients with chronic liver disease (Child Pugh A, B, C hepatic impairment).
- Active or significant history of infection, including treatment with intravenous antibiotics within the last 4 weeks or oral antibiotics within 2 weeks prior to screening. Including active confirmed tuberculosis or latent tuberculosis without chemoprophylaxis in accordance with applicable local recommendations. Active infection with HBV, HCV, Herpes-Zoster virus in the last 12 months. Human Immunodeficiency Virus (HIV) infection.
- A positive result of the SARS-CoV-2 PCR test during the "0" visit is an exclusion criterion, while a history of infection more than 4 weeks before the screening tests and confirmed by a negative SARS-CoV-2 PCR test is not an exclusion criterion.
- Active or history of malignancy, except for excised/cured local basal cell or squamous cell carcinoma of the skin or cervical carcinoma in situ.
- Active or past drug or alcohol abuse.
- The inability to understand and comply with the requirements of the protocol (lack of compliance) excludes from participation in the study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Poland | Not Recruiting | 31 Mar 2023 | 86 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
RoActemra 162 mg solution for injection in pre-filled syringe. | Test | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | SUBCUTANEOUS USE | 162 | 56 | PRD1576593 |
Ofev 100 mg soft capsules | Test | SOFT CAPSULES | ORAL USE | 200 | 56 | PRD2386460 |
RoActemra 162 mg solution for injection in pre-filled syringe. | Test | SOLUTION FOR INJECTION IN PRE-FILLED | SUBCUTANEOUS USE | 162 | 56 | PRD1753369 |
Ofev 150 mg soft capsules | Test | SOFT CAPSULES | ORAL USE | 300 | 56 | PRD2388630 |
Ofev 150 mg soft capsules | Test | SOFT CAPSULES | ORAL USE | 300 | 56 | PRD2388631 |
Ofev 100 mg soft capsules | Test | SOFT CAPSULES | ORAL USE | 200 | 56 | PRD2386479 |