Tofacitinib in the Treatment of Rheumatoid Arthritis-related Interstitial Lung Disease. (RAILDTo)

Safety and Tolerability of Tofacitinib in the Treatment of Rheumatoid Arthritis-related Interstitial Lung Disease (RAILDTo Trial).

Nowadays, no single drug is approved to treat rheumatoid arthritis-related interstitial lung disease (RA-ILD). The medical management of this clinical condition is empirical and controversial. There is preliminary data that tofacitinib may have a beneficial effect in treating RA-ILD. Tofacitinib may have a double role in treating RA-ILD: treat RA disease activity and an anti-fibrotic possible impact. Moreover, tofacitinib may be used as monotherapy for the treatment of rheumatoid arthritis (RA) This is a phase IIa clinical trial to evaluate the safety and tolerability of tofacitinib in RA-ILD patients.

Study Overview

• Status: Recruiting
• Conditions: Rheumatoid Arthritis; Interstitial Lung Disease
• Intervention / Treatment: Drug: Tofacitinib

Detailed Description

This is a phase 2 open-label study designed to evaluate the safety and tolerability of tofacitinib in RA-ILD patients. Patients who met the inclusion criteria of the study protocol will receive tofacitinib 5 mg BID for 12 months.

Objectives

Primary objectives:

1. To evaluate the safety and tolerability of tofacitinib 5 mg PO BID as monotherapy for managing RA-ILD in RA-ILD patients.
2. To evaluate the pulmonary function of patients treated with tofacitinib PO BID as monotherapy to manage RA-ILD in RA-ILD patients, at baseline, at three months of follow-up, at six months of follow-up, and one year of follow-up.
3. To estimate the efficacy of tofacitinib 5 mg PO BID as monotherapy for the management of RA-ILD, in RA-ILD patients, at three months of follow-up, at six months of follow-up, and at one year of follow-up, according to the ACR 20, 50, 70 response criteria, and the following disease activity scores index: DAS 28, CDAI and SDAI.

All the included patients will receive Tofacitinib in doses of 5 mg BID until the end of the protocol.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jorge Rojas-Serrano, MD, PhD; Phone Number: 5276 + 52 5554871700; Email: jrojas@iner.gob.mx
• Study Contact Backup: Name: Andrea Estrada-Garrido, MD; Phone Number: 5276 +52 5554871700; Email: estradagara@yahoo.com.mx

Study Locations

• Mexico
  • Tlalpan
    • Mexico City, Tlalpan, Mexico, 14080
      • Recruiting
      • Instituto Nacional de Enfermedades Respiratorias, Ismael Cosío Villegas
      • Contact: Jorge Rojas-Serrano, MD, PhD; Phone Number: 5276 + 52 5554871700; Email: jrojas@iner.gob.mx
      • Contact: Andrea Estrada-Garrido, MD; Phone Number: 5276 +52 5554871700; Email: estradagara@yahoo.com.mx
      • Sub-Investigator: Mayra Mejia, MD
      • Sub-Investigator: Heidegger Mateos-Toledo, MD
      • Sub-Investigator: Andrea Estrada-Garrido, MD
      • Sub-Investigator: Ramces Falfán-Valencia, PhD
      • Sub-Investigator: Angel E. Vega-Sánchez, MD
      • Sub-Investigator: Norma A. Téllez-Navarrete, MD, MsC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients must fulfill ACR/EULAR 2010 RA classification criteria.
2. Patients must have an interstitial lung disease confirmed by a high-resolution computed tomography scan or a surgical lung biopsy. Nonspecific interstitial pneumonia, usual interstitial pneumonia, lymphocytic pneumonia, and organized pneumonia, either by HRCT or surgical biopsy, will be included.
3. Patients must be 18 years of age or older.
4. There is no evidence of active, latent, or inadequately treated infection with Mycobacterium tuberculosis (TB).
5. Patients must discontinue using the non-permitted medications: leflunomide, azathioprine, cyclosporine, tacrolimus, cyclophosphamide, and any biologic disease-modifying drug (bDMDARDs) such as anti-TNF therapy, rituximab, tocilizumab, etc. Patients must have a stable prednisone dose of ≤ 10 mg/ PO/day for at least three months.
6. All patients must have stable doses of prednisone during the last three months of follow-up, and the prednisone dose must be ≤ 10 mg/day. Patients without a prednisone history in the previous three months may also be included in the protocol.

Exclusion Criteria:

1. Seropositivity for the following infections: HIV, HBV, and HCV.
2. Absolute neutrophil count ≤ 1,200/L
3. Absolute platelet count ≤ 100,000 /L
4. Severe renal damage with GFR < 30 ml/min based on CKD-EPI formula.
5. AST or ALT greater than 1.5 times the upper limit of normal AST and ALT levels
6. Severe hepatic, hematologic, gastrointestinal, cardiac, and neurological disease may put the patient´s life at risk regardless of ILD severity.
7. Severe active infections at baseline evaluation, such as pneumonia, urinary tract infections, meningitis.

8 History of drug abuse or alcoholism. 9. History of any malignancy 10. Patients with an FVC < 40% of what is expected will be excluded from the study.

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Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tofacitinib Arm; Tofacitinib in doses of 5 mg BID, in RA-ILD patients at stable doses of prednisone ≤ 10 mg/day during the last three months.	Drug: Tofacitinib; Tofacitinib in doses of 5 mg BID, in RA-ILD patients at stable doses of prednisone ≤ 10 mg/day during the last three months. Patients who met the inclusion criteria of the study protocol will received tofacitinib 5 mg BID for 12 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and severity of adverse events	Adverse event: Any untoward medical occurrence in a subject being included in the trial, in which the event may not necessarily have a causal relationship with the treatment. Examples of adverse events are as follows: abnormal test findings, clinically significant symptoms and signs, hypersensitivity reactions, and progression or worsening of RA or RA-ILD.	52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Forced Vital Capacity (liters)	Forced vital capacity (FVC) on spirometry, the data will be presented as percentages of predicted values, according to sex, age, height, and weight.	52 weeks
Carbon monoxide diffusing capacity (DLCO) (mil/min/mmHg)	The data will be presented as percentages of predicted values, according to sex, age, height, and weight.	52 weeks
6 minutes walk test	walked metters in 6 minutes	52 weeks
Rheumatoid arthritis disease activity according to the simplified disease activity (SDAI) index.	The SDAI index consists of the algebraic sum of the following items: tender joint count, swollen joint count, c-reactive protein, rheumatoid arthritis activity according to the patient, disease activity according to the attending physician.	52 weeks
Rheumatoid arthritis disease activity according to the Disease Activity Score Index (DAS28)	The DAS28 score is calculated with the tender joint count, swollen joint count, eritrosedimentation rate, patients' global health assesment aacording with the following formula DAS28 = ( 0.56 * sqr(TJC)) + (0.28 * sqr(SJC)) + ( 0.7 * ln(VSG)) + (0.014 * GH)	52 weeks

Collaborators and Investigators

• Sponsor: National Institute of Respiratory Diseases, Mexico
• Investigators: Principal Investigator: Jorge Rojas-Serrano, MD, PhD, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosío Villegas

Publications and helpful links

General Publications

• Vacchi C, Manfredi A, Cassone G, Cerri S, Della Casa G, Andrisani D, Salvarani C, Sebastiani M. Tofacitinib for the Treatment of Severe Interstitial Lung Disease Related to Rheumatoid Arthritis. Case Rep Med. 2021 Apr 22;2021:6652845. doi: 10.1155/2021/6652845. eCollection 2021.
• Citera G, Mysler E, Madariaga H, Cardiel MH, Castaneda O, Fischer A, Richette P, Chartrand S, Park JK, Strengholt S, Rivas JL, Thorat AV, Girard T, Kwok K, Wang L, Ponce de Leon D. Incidence Rates of Interstitial Lung Disease Events in Tofacitinib-Treated Rheumatoid Arthritis Patients: Post Hoc Analysis From 21 Clinical Trials. J Clin Rheumatol. 2021 Dec 1;27(8):e482-e490. doi: 10.1097/RHU.0000000000001552.
• Harigai M. Growing evidence of the safety of JAK inhibitors in patients with rheumatoid arthritis. Rheumatology (Oxford). 2019 Feb 1;58(Suppl 1):i34-i42. doi: 10.1093/rheumatology/key287.

Study record dates

Study Major Dates

• Study Start (Actual): August 8, 2022
• Primary Completion (Anticipated): March 2, 2024
• Study Completion (Anticipated): March 2, 2025

Study Registration Dates

• First Submitted: January 17, 2022
• First Submitted That Met QC Criteria: February 8, 2022
• First Posted (Actual): February 18, 2022

Study Record Updates

• Last Update Posted (Actual): April 27, 2023
• Last Update Submitted That Met QC Criteria: April 26, 2023
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Rheumatoid Arthritis; Tofacitinib; Interstitial Lung Disease; Usual interstitial pneumonia; Rheumatoid Arthritis-related interstitial lung disease
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Lung Diseases; Lung Diseases, Interstitial; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Tofacitinib
• Other Study ID Numbers: C17-21

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We will share data, including data dictionaries and analytic code, after presenting the results of the study in a congress or the final publication of the clinical trial. The data will be shared only if a formal research proposal and our local IRB approves this.
• IPD Sharing Time Frame: The data will be available after presenting the study results at an international congress or the final publication of the study.
• IPD Sharing Access Criteria: A formal research proposal, including a research protocol, should be presented to the PI of the study to share the data. The research proposal has to be approved by our local IRB.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes