Methotrexate as Remission Maintenance Therapy After Remission-Induction With Tocilizumab and Glucocorticoids in Giant Cell Arteritis (MTXinGCA)

A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy of Methotrexate as Remission Maintenance Therapy After Remission-Induction Therapy With Tocilizumab and Glucocorticoids in Subjects With Giant Cell Arteritis

The standard treatment for Giant Cell arteritis (GCA) is Glucocorticoids(GC), even if GC-related adverse events are commonly occuring. Therefore, other practises for reducing relapses and cumulative GC-doses are needed. Currently, the Interleukin-6-inhibitor tocilizumab is used in combination with GC to achieve higher remission rates and lower cumulative GC-doses. The use of tocilizumab also has some disadvantages. One is the increased susceptibility to infections. On top of that, a long-term follow-up of the phase II study by Villiger et al. showed a 55% relapse-rate after discontinuation of intravenous tocilizumab after a median of five months.

Studies have also shown that methotrexate(MTX) in combination with GC was able to prevent relapses and reduce cumulative GC doses.

The aim of the study is to evaluate whether MTX is superior to placebo to prevent relapses in subjects with GCA after Remission-Induction Therapy with Glucocorticoids and Tocilizumab. Our hypothesis is that Methotrexate can maintain remission, once stable remission has been induced by GC and Tocilizumab and will prevent the occurrence of relapses.

Study Overview

• Status: Recruiting
• Conditions: Giant Cell Arteritis
• Intervention / Treatment: Drug: Methotrexate; Drug: Sodium chloride

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Valentin S. Schäfer, Dr. med.; Phone Number: +49 228 287-17000; Email: rheumatologie@ukbonn.de

Study Locations

• Germany
  • Bonn, Germany
    • Recruiting
    • Medical Clinic and Polyclinic III Internal medicine Oncology, Hematology University Hospital Bonn, Rheumatology and Clinical Immunology
    • Contact: Valentin S. Schäfer; Phone Number: +49 228 287-17000; Email: rheumatologie@ukbonn.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects male or female, aged ≥18 years
• Written informed consent of the capable subject for voluntary participation in the study.
• Diagnosis of GCA as confirmed by the investigator fulfilment (also in retrospect) of the proposed extended 1990 classification criteria for GCA .
• Previous treatment with glucocorticoids and tocilizumab for new or relapsing GCA
• GCA patients who have been treated with tocilizumab and in whom discontinuation of tocilizumab therapy has been decided by the treating rheumatologist, within standard treatment at the department of rheumatology are eligible.
• total tocilizumab therapy should have been at least 6 months before inclusion.
• Patients should be in stable remission (defined as the absence of signs or symptoms of GCA and normal C-Reactive Protein (<1mg/dl), off glucocorticoids for at least 1 months at screening.
• Willing and able to inject methotrexate or placebo subcutaneously at randomization
• Male and female subjects agreeing to conduct efficient contraception (unless they have no childbearing potential)

Exclusion Criteria:

• Severe renal (glomerular filtration rate <30/min) failure
• Conditions other than GCA requiring continuous or intermittent treatment with oral or parenteral Glucocorticoids unless the last exposure to Glucocorticoids was >1 months before screening
• Other inflammatory rheumatic diseases (e.g. rheumatoid arthritis)
• Current treatment with any other conventional, biologic or targeted synthetic DMARD except tocilizumab
• Elevation of transaminases above three times the norm
• Simultaneous participation in another clinical trial, or participation in a clinical trial taking an investigational product, up to 30 days prior to participation in this clinical trial.
• Pregnant or breast feeding women
• Contraindications for therapy with Methotrexate, as indicated in the summary of product characteristics

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Methotrexate; The patient will be treated for 12 months weekly with methotrexate. Methotrexate will be provided at a dose of 17.5mg as a pre-filled syringe for self-injection. A dose reduction to 15 mg/week in case of intolerance, elevated liver enzymes >3x upper limit of normal or to 10 mg/week if glomerular filtration rate <50/min will be possible. If glomerular filtration rate <30/min, termination of treatment.	Drug: Methotrexate; 17,5/15/10 mg Methotrexate subcutaneously
Placebo Comparator: Placebo; Patients receive sodium chloride as a placebo subcutaneously. It will be administered in the form of a pre-filled syringe for self-injection once a week for 12 months.	Drug: Sodium chloride; Sodium chloride subcutaneously

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Time to relapse during the 12 months treatment period	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative prednisone doses at months 6, 12 and 18		18 months
Number of relapses per patient during the 12 months treatment period		12 months
Time to first, second and third relapse after randomization		18 months
Percentage of patients with a relapse at month 6 and 18 after discontinuation of Tocilizumab		18 months
Health-related quality of life: Short Form-36	The possible score ranges from 0 to 100 points, where 0 points represent the greatest possible health limitation, while 100 points represent no health limitation at all	18 months
Self-reported fatigue : FACIT-Fatigue (Functional Assessment of Chronic Illness Therapy - Fatigue Scale)	The possible score ranges from 0 to 52 points. The higher this value, the better the quality of life.	18 months
Patient Global Assessment of disease activity (PGA)	The possible score ranges from 0 to 100 points, where 0 points represent the lowest disease activity and 100 the highest.	18 months
Patient Assessment of pain	The possible score ranges from 0 to 100 points, where 0 points represent the least pain intensity and 100 the most pain intensity	18 months
Investigator reported Evaluator Global Assessment of disease activity (EGA)	The possible score ranges from 0 to 100 points, where 0 points represent the lowest disease activity and 100 the highest.	18 months
Occurrence of symptoms and signs related to Giant cell arteritis		18 months
Number of vasculitic vessels and change of intima-media-values of temporal and axillary arteries		18 months
Prevalence of aortitis at baseline and month 12 and 18 in MRI		18 months
Proportion of subjects with increased Erythrocyte Sedimentation Rate (>20mm/h) and C-Reactive Protein levels (> 10mg/L)		18 months
Occurrence of adverse events and serious adverse events		12 months

Collaborators and Investigators

• Sponsor: University of Bonn
• Investigators: Principal Investigator: Valentin S. Schäfer, Dr. med., University Hospital of Bonn

Study record dates

Study Major Dates

• Study Start (Actual): November 23, 2022
• Primary Completion (Anticipated): November 1, 2025
• Study Completion (Anticipated): November 1, 2025

Study Registration Dates

• First Submitted: November 8, 2022
• First Submitted That Met QC Criteria: November 18, 2022
• First Posted (Actual): November 21, 2022

Study Record Updates

• Last Update Posted (Actual): December 21, 2022
• Last Update Submitted That Met QC Criteria: December 16, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Ultrasound; Methotrexate; Tocilizumab; Glucocorticoids; Vasculitis; Giant cell arteritis; Rheumatic disease; Remission maintenance
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Skin Diseases; Immune System Diseases; Autoimmune Diseases of the Nervous System; Autoimmune Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Muscular Diseases; Vasculitis; Skin Diseases, Vascular; Vasculitis, Central Nervous System; Polymyalgia Rheumatica; Giant Cell Arteritis; Arteritis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Methotrexate
• Other Study ID Numbers: MED3-201802; EU-CT No: 2022-501058-12-00 (Other Identifier: EU Clinical Trials Register); DRKS-ID: DRKS00030571 (Other Identifier: German Clinical Trials Register)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Sharing Time Frame: We plan to share data, if an adequate proposal is submitted

Drug and device information, study documents

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