Study of the Efficacy of Nintedanib+Tocilizumab in Patients With Systemic Sclerosis and Interstitial Lung Disease (NINTOC-TU)

Multicentre Clinical Trial Evaluating the Safety and Efficacy of the Combination of Nintedanib+Tocilizumab Compared to Standard Treatment in Patients With Systemic Sclerosis and Interstitial Lung Disease. Analysis With Theranostic Approach

The study includes adult patients with systemic sclerosis (SSc) with interstitial lung disease (ILD) to evaluate the efficacy and safety of nintedanib plus tocilizumab combination therapy compared to standard therapy (methotrexate, mycophenolate mofetil) for 56 weeks.

Study Overview

• Status: Not yet recruiting
• Conditions: Systemic Sclerosis; Interstitial Lung Disease
• Intervention / Treatment: Drug: Tocilizumab; Drug: Nintedanib; Drug: Standard therapy

Detailed Description

Full title of the trial:

A multicentre clinical trial evaluating the safety and efficacy of the combination of nintedanib and tocilizumab compared to standard treatment in patients with systemic sclerosis and interstitial lung disease. Analysis with theranostic approach and assessment of cytokine activity, markers of inflammation and pulmonary fibrosis using computed tomography, positron emission tomography, and metabolome and transcriptome studies in selected patients. NINTOC-TU study.

• Study Type: Interventional
• Enrollment (Estimated): 86
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Maria Maślińska, PhD, MD; Phone Number: +48 226880632; Email: maria.maslinska@spartanska.pl

Study Locations

• Poland
  • Mazowieckie
    • Warsaw, Mazowieckie, Poland, 02-637
      • Centrum Wsparcia Badań Klinicznych
      • Contact: Justyna Kwiatkowska-Golańska; Phone Number: +48 22 6880632; Email: justyna.kwiatkowska-golanska@spartanska.pl
      • Principal Investigator: Maria Maślińska, PhD, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Men or women aged 18-74 at the date of signing the informed consent.
2. Written informed consent in accordance with the International Harmonization Guidelines Harmonized Tripartite: Guidelines for Good Clinical Practice (ICH-GCP) and local regulations signed before any study procedure.
3. 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 active disease [patients with limited and diffused SSc)] and with an overall disease duration of less than or equal to (≤ 72 months).
4. Patients with interstitial lung disease (ILD) confirmed by HRCT (min. 10% lung involvement).
5. Evaluation of skin induration with the modified Rodnan skin score (mRSS) from 10 to 45 units inclusive.
6. Patients treated with conventional drugs such as mycophenolate mofetil, methotrexate; should be on stable doses for ≥ 8 weeks before and including the screening visit (W0).
7. Patients may be treated with standard therapy, but no new therapy or withdrawal of therapy within 8 weeks before the first screening visit (W0).
8. Patients taking oral glucocorticosteroids (GCS) should be on a stable dose of ≤ 10 mg/day prednisone or equivalent for at least 8 weeks before the baseline visit.
9. 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:

1. Patients not fully capable of giving informed consent.
2. Pregnant or breastfeeding women.
3. Major surgery within 8 weeks before screening (W0A).
4. Rheumatic disease other than systemic sclerosis (systemic lupus erythematosus, rheumatoid arthritis, mixed connective tissue disease). Diagnosis of secondary Sjögren's syndrome is acceptable.
5. Active diverticulitis and severe enteritis.
6. Untreated lipid disorders (Initiation of treatment and modification of the lipid profile enable re-screening for examination after 8 weeks from the start of hypolipidemic treatment).
7. Immunization with a live or attenuated vaccine within 4 weeks before scheduled treatment.
8. Known hypersensitivity to human, humanized or murine monoclonal antibodies and hypersensitivity to peanut, soya.
9. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels greater than 1.5 times the upper limit of normal (ULN). If normalized, the patient may be considered for re-screening.
10. Bilirubin >1.5 x ULN.
11. Creatinine clearance <30 ml/min.
12. Significant pulmonary hypertension (PH).
13. Airway obstruction (forced expiratory volume before bronchodilation in 1 second (FEV1)/FVC <0.7) and other clinically significant pulmonary abnormalities.
14. Cardiovascular diseases with heart failure NYHA III/IV.
15. More than 4 digital ulcers or a history of severe digital necrosis requiring hospitalization or severe other digital ulcers.
16. 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.
17. History of stroke, or myocardial infarction within 6 months before screening.
18. Prior treatment with pirfenidone or nintedanib if a minimum of 6 months had not been completed before enrolling the patient in the NINTOC-TU study.
19. Plasmapheresis and/or plasma exchange within the last 12 weeks before 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.
20. Treatment with prednisone >10 mg/day, azathioprine, hydroxychloroquine, colchicine, D-penicillamine, sulfasalazine if within 8 weeks before W0. Cyclophosphamide within < 8 weeks of randomization visit (W 1). Rituximab within 6 months of visit (randomization W1).
21. Unstable (fluctuating) background therapy with mycophenolate mofetil or methotrexate in the last 8 weeks.
22. Patients with chronic liver disease (Child-Pugh A, B, C hepatic impairment).
23. Active or significant history of infection, including treatment with intravenous antibiotics within the last 4 weeks or oral antibiotics within 2 weeks before screening. Including active confirmed tuberculosis or latent tuberculosis without chemoprophylaxis following applicable local recommendations. Active infection with HBV, HCV, Herpes-Zoster virus in the last 12 months. Human Immunodeficiency Virus (HIV) infection.
24. 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.
25. Active or history of malignancy, except for excised/cured local basal cell or squamous cell carcinoma of the skin or cervical carcinoma in situ.
26. Active or past drug or alcohol abuse.
27. The inability to understand and comply with the requirements of the protocol (lack of compliance) excludes from participation in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: combined therapy Nintedanib + Tocilizumab with or without standard treatment + extended diagnostics; tocilizumab pre-filled syringe 162 mg subcutaneously once a week nintedanib tablets 150 mg twice a day or 2 x 100 mg a day	Drug: Tocilizumab; Tocilizumab 162 mg s.c./week; Drug: Nintedanib; Nintedanib - established doses of nintedanib for adults in the treatment of ILD, also SSc-ILD: 2 x 150 mg daily, in the event of e.g. increased liver enzyme levels, poorer treatment tolerance (e.g. diarrhea), the dose can be reduced to 2 x 100 mg; Drug: Standard therapy; mycophenolate mofetil stable dose from 1000 - 3000 mg daily tablet 500 mg or 250 mg regardless of the preparation (Mycofit, CellCept, Mycophenolate mofetil, Myfenax) or methotrexate 10-25 mg/week orally or subcutaneously as above, regardless of the preparation; Other Names: methotrexate; mycophenolate mofetil
Active Comparator: standard treatment (reference group) + extended diagnostics; mycophenolate mofetil stable dose from 1000 - 3000 mg daily tablet 500 mg or 250 mg regardless of the preparation (Mycofit, CellCept, Mycophenolate mofetil, Myfenax) or methotrexate 10-25 mg/week orally or subcutaneously as above, regardless of the preparation	Drug: Standard therapy; mycophenolate mofetil stable dose from 1000 - 3000 mg daily tablet 500 mg or 250 mg regardless of the preparation (Mycofit, CellCept, Mycophenolate mofetil, Myfenax) or methotrexate 10-25 mg/week orally or subcutaneously as above, regardless of the preparation; Other Names: methotrexate; mycophenolate mofetil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The decrease in forced vital capacity (FVC) of the lungs	The decrease in forced vital capacity (FVC) of the lungs expressed in ml calculated after 56 weeks of treatment	56 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in percent lung involvement	Change in percent lung involvement assessed by computed tomography (HRCT%) from baseline to assessment in 56 weeks of study	56 weeks
Assessment of absolute changes in DLCO	Assessment of absolute changes in DLCO at week 56 compared to baseline (baseline)	56 weeks
Assessment of the absolute changes in predicted FVC%	Assessment of the the absolute changes in predicted FVC% at week 56 from baseline	56 weeks
Change in the Six-minute walk test (6MWT) result	Change in the Six-minute walk test (6MWT) result at week 56 compared to the baseline value	56 weeks
Change in the Health Assessment Questionnaire-Disability Index (HAQ-DI) score	Change in the Health Assessment Questionnaire-Disability Index (HAQ-DI) score at week 56 (from min. 0 to max.3). Scores of 0 to 1 are generally considered to represent mild to moderate difficulty, 1 to 2 moderate to severe disability, and 2 to 3 severe to very severe disability.	56 weeks
A change in the patient's global assessment of disease activity	A change in the patient's global assessment of disease activity (Patient's Global Assessment - PtGA), assessment at week 56 - PtGA scoring on Visual Analog Scale from optimal condition - 0 mm (min) to 100 mm (max) - the worse condition.	56 weeks
A change in the physician's global assessment of disease activity	A change in the physician's global assessment of disease activity (Physician's Global Assessment - PGA), assessment at week 56 - PGA scoring on Visual Analog Scale from optimal condition - 0 mm (min) to 100 mm (max) - the worse condition.	56 weeks
Assessment of the absolute changes from baseline in total scores in St. George's Respiratory Questionnaire (SGRQ)	Assessment of the absolute changes from baseline in total scores in St. George's Respiratory Questionnaire (SGRQ) at 56 weeks. St. George's Respiratory Questionnaire (SGRQ) ranges from 1 to 100, where 0 indicates best health and 100 indicates worst health.	56 weeks
Assessment of absolute changes compared to baseline values on the modified Rodnan skin Score (mRSS)	Assessment of absolute changes compared to baseline values on the modified Rodnan skin Score (mRSS) at week 56. mRSS is a semiquantitative score, ranging from 0 (normal) to 3 (severe), used to evaluate the skin thickness in 17 different cutaneous sites (for a total score from 0 (good) to 51 (the worst condition).	56 weeks
Percentage of participants with threshold improvement from baseline in modified Rodnan skin Score (mRSS)	Percentage of participants with threshold improvement from baseline in modified Rodnan skin Score (mRSS) at week 56. mRSS is a semiquantitative score, ranging from 0 (normal) to 3 (severe), used to evaluate the skin thickness in 17 different cutaneous sites (for a total score from 0 (good) to 51 (the worst condition).	56 weeks
Percentage of participants with modified Rodnan skin Score (mRSS) improvement greater than or equal to (>/=) 20%, 40%, or 60%	Percentage of participants with modified Rodnan skin Score (mRSS) improvement greater than or equal to (>/=) 20%, 40%, or 60% [time frame: baseline to week 56]. mRSS is a semiquantitative score, ranging from 0 (normal) to 3 (severe), used to evaluate the skin thickness in 17 different cutaneous sites (for a total score from 0 (good) to 51 (the worst condition).	Time frame: from baseline to week 56

Collaborators and Investigators

• Sponsor: National Institute of Geriatrics, Rheumatology and Rehabilitation, Poland
• Collaborators: Medical Research Agency, Poland
• Investigators: Principal Investigator: Maria Maślińska, PhD, MD, National Institute of Geriatrics,Rheumatology and Rehabilitation

Publications and helpful links

General Publications

• Kowal-Bielecka O, Fransen J, Avouac J, Becker M, Kulak A, Allanore Y, Distler O, Clements P, Cutolo M, Czirjak L, Damjanov N, Del Galdo F, Denton CP, Distler JHW, Foeldvari I, Figelstone K, Frerix M, Furst DE, Guiducci S, Hunzelmann N, Khanna D, Matucci-Cerinic M, Herrick AL, van den Hoogen F, van Laar JM, Riemekasten G, Silver R, Smith V, Sulli A, Tarner I, Tyndall A, Welling J, Wigley F, Valentini G, Walker UA, Zulian F, Muller-Ladner U; EUSTAR Coauthors. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2017 Aug;76(8):1327-1339. doi: 10.1136/annrheumdis-2016-209909. Epub 2016 Nov 9.
• Flaherty KR, Brown KK, Wells AU, Clerisme-Beaty E, Collard HR, Cottin V, Devaraj A, Inoue Y, Le Maulf F, Richeldi L, Schmidt H, Walsh S, Mezzanotte W, Schlenker-Herceg R. Design of the PF-ILD trial: a double-blind, randomised, placebo-controlled phase III trial of nintedanib in patients with progressive fibrosing interstitial lung disease. BMJ Open Respir Res. 2017 Sep 17;4(1):e000212. doi: 10.1136/bmjresp-2017-000212. eCollection 2017.
• Richeldi L, Cottin V, Flaherty KR, Kolb M, Inoue Y, Raghu G, Taniguchi H, Hansell DM, Nicholson AG, Le Maulf F, Stowasser S, Collard HR. Design of the INPULSIS trials: two phase 3 trials of nintedanib in patients with idiopathic pulmonary fibrosis. Respir Med. 2014 Jul;108(7):1023-30. doi: 10.1016/j.rmed.2014.04.011. Epub 2014 Apr 29.
• Inoue Y, Suda T, Kitamura H, Okamoto M, Azuma A, Inase N, Kuwana M, Makino S, Nishioka Y, Ogura T, Takizawa A, Ugai H, Stowasser S, Schlenker-Herceg R, Takeuchi T. Efficacy and safety of nintedanib in Japanese patients with progressive fibrosing interstitial lung diseases: Subgroup analysis of the randomised, double-blind, placebo-controlled, phase 3 INBUILD trial. Respir Med. 2021 Oct;187:106574. doi: 10.1016/j.rmed.2021.106574. Epub 2021 Aug 12.
• Cottin V, Richeldi L, Rosas I, Otaola M, Song JW, Tomassetti S, Wijsenbeek M, Schmitz M, Coeck C, Stowasser S, Schlenker-Herceg R, Kolb M; INBUILD Trial Investigators. Nintedanib and immunomodulatory therapies in progressive fibrosing interstitial lung diseases. Respir Res. 2021 Mar 16;22(1):84. doi: 10.1186/s12931-021-01668-1.
• Shima Y, Kawaguchi Y, Kuwana M. Add-on tocilizumab versus conventional treatment for systemic sclerosis, and cytokine analysis to identify an endotype to tocilizumab therapy. Mod Rheumatol. 2019 Jan;29(1):134-139. doi: 10.1080/14397595.2018.1452178. Epub 2018 Apr 9.
• Denton CP, De Lorenzis E, Roblin E, Goldman N, Alcacer-Pitarch B, Blamont E, Buch M, Carulli M, Cotton C, Del Galdo F, Derrett-Smith E, Douglas K, Farrington S, Fligelstone K, Gompels L, Griffiths B, Herrick A, Hughes M, Pain C, Pantano G, Pauling J, Prabu A, O'Donoghue N, Renzoni E, Royle J, Samaranayaka M, Spierings J, Tynan A, Warburton L, Ong V. Management of systemic sclerosis: British Society for Rheumatology guideline scope. Rheumatol Adv Pract. 2023 Mar 14;7(1):rkad022. doi: 10.1093/rap/rkad022. eCollection 2023.
• Khanna D, Lescoat A, Roofeh D, Bernstein EJ, Kazerooni EA, Roth MD, Martinez F, Flaherty KR, Denton CP. Systemic Sclerosis-Associated Interstitial Lung Disease: How to Incorporate Two Food and Drug Administration-Approved Therapies in Clinical Practice. Arthritis Rheumatol. 2022 Jan;74(1):13-27. doi: 10.1002/art.41933. Epub 2021 Nov 10.

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): December 30, 2027
• Study Completion (Estimated): March 30, 2028

Study Registration Dates

• First Submitted: February 29, 2024
• First Submitted That Met QC Criteria: February 29, 2024
• First Posted (Actual): March 6, 2024

Study Record Updates

• Last Update Posted (Actual): March 21, 2024
• Last Update Submitted That Met QC Criteria: March 19, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: combination therapy; systemic sclerosis; tocilizumab; ILD; nintedanib
• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Respiratory Tract Diseases; Connective Tissue Diseases; Sclerosis; Lung Diseases; Scleroderma, Systemic; Scleroderma, Diffuse; Lung Diseases, Interstitial; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anti-Bacterial Agents; Protein Kinase Inhibitors; Antibiotics, Antineoplastic; Reproductive Control Agents; Antitubercular Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Antibiotics, Antitubercular; Nintedanib; Methotrexate; Mycophenolic Acid
• Other Study ID Numbers: NIGRIR_004NINTOC-TU

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No