Efficacy and Safety Comparison of Etanercept and Methotrexate in Inducing Steroid-Free Remission in Giant Cell Arteritis Patients
- Trial ID
- 2023-506623-29-01
- Protocol
- ABM/EFFECTA/2023
- Sponsor
- Agencja Badań Medycznych
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this randomized trial is to compare the effectiveness of treatment with **etanercept** (ETN) versus **methotrexate** (MTX) in the induction of sustained steroid-free remission in patients with **giant cell arteritis** (GCA). This is clinically relevant as achieving sustained remission without the use of steroids can significantly reduce the risk of steroid-related adverse effects, improving patient outcomes and quality of life.
Secondary objectives include:
- Comparing the effectiveness of ETN versus MTX in the prevention of deaths in the course of GCA.
- Comparing the effectiveness of ETN versus MTX in the prevention of severe ischemic complications of GCA.
- Comparing the effectiveness of ETN versus MTX in the maintenance of steroid-free remission in patients with GCA.
- Comparing the effectiveness of ETN versus MTX in the induction of GCA remission.
- Assessing the steroid-sparing effect of ETN versus MTX in patients with GCA.
- Comparing the effectiveness of ETN versus MTX in the prevention of GCA relapses.
- Assessing the influence of treatment with ETN versus MTX on the quality of life of GCA patients.
- Comparing the safety of treatment with ETN versus MTX in patients with GCA.
Participants
The clinical trial focuses on patients diagnosed with **giant cell arteritis** (GCA), aiming to evaluate the effectiveness of etanercept versus methotrexate in achieving sustained steroid-free remission. The study population includes both male and female participants aged 50 years and older, as per the 2022 American College of Rheumatology/EULAR classification criteria for GCA. Participants are required to have active GCA, characterized by symptoms or signs attributed to the condition and elevated inflammatory markers. The trial includes individuals with new onset, refractory, or relapsing GCA. The sponsor has not provided information regarding the total number of participants. The trial population was selected based on specific inclusion criteria, including the requirement for written informed consent and adherence to contraception guidelines for participants of child-bearing potential. The study involves a vulnerable population, and lifestyle factors such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **etanercept** and **methotrexate** in patients with **giant cell arteritis** (GCA). This is a randomized, double-blind, controlled trial with a primary objective to compare the effectiveness of these treatments in achieving sustained steroid-free remission. The trial is expected to commence on April 15, 2024, and conclude by November 30, 2028, with a total duration of approximately 4.5 years. Participants will be involved in the study for up to 104 weeks from randomization.
The trial will include several key visits: an initial screening visit, regular follow-up visits, and an end-of-study visit. The screening visit will confirm eligibility based on criteria such as age (≥50 years), diagnosis of GCA, and active disease status. Follow-up visits will occur at weeks 24, 52, 78, and 104 to assess remission status, monitor adverse events, and adjust treatment as necessary. The end-of-study visit will evaluate the primary endpoint, which is the percentage of sustained steroid-free GCA remission at week 52, and secondary endpoints, including mortality rate and incidence of severe ischemic complications.
Participants will be randomly assigned to receive either etanercept or methotrexate, with the treatment regimen including a tapering schedule for **prednisone**. The maximum treatment period for methotrexate is 78 weeks, while prednisone and other systemic corticosteroids are limited to 26 weeks. Conditions for early termination from the study include non-compliance with the protocol, withdrawal of consent, or occurrence of serious adverse events. The trial will adhere to rigorous ethical standards, ensuring informed consent and the use of effective contraception for participants of child-bearing potential during and after the study period.
Treatment
The clinical trial involves the administration of several medications, each with specific roles and administration protocols. **Etanercept** is utilized as a test medication in this study. It is provided in the form of a solution for injection in a pre-filled syringe. The active substance, etanercept, is administered subcutaneously with a maximum daily dose of 50 mg and a total maximum dose of 3900 mg over a treatment period of up to 78 weeks. This medication is used off-label in the context of this trial.
**Methotrexate** is employed as both a test and auxiliary medication. It is available as a solution for injection and is administered subcutaneously. The maximum daily dose is 25 mg, with a total maximum dose of 1930 mg over a treatment period of up to 78 weeks. Methotrexate acts as a folic acid antagonist and is classified as an antimetabolite, belonging to cytotoxic compounds. Its use in this trial is also off-label.
**Prednisone** is used as an auxiliary medication in the form of tablets. It is administered orally with a maximum daily dose of 60 mg and a total maximum dose of 2632 mg over a treatment period of up to 26 weeks. Prednisone is categorized under systemic corticosteroids.
**Methylprednisolone** is another auxiliary medication provided in tablet form. It is administered orally with a maximum daily dose of 48 mg and a total maximum dose of 2106 mg over a treatment period of up to 26 weeks. Similar to prednisone, methylprednisolone is classified as a systemic corticosteroid.
**Folic Acid** is used as an auxiliary medication in tablet form, administered orally. The maximum daily dose is 15 mg, with a total maximum dose of 1170 mg over a treatment period of up to 78 weeks. Folic acid serves as an antidote, reducing the side effects associated with methotrexate administration.
Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy and safety of these medications in the context of treating giant cell arteritis.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints related to the treatment of **giant cell arteritis (GCA)**. The primary endpoint is the percentage of sustained steroid-free GCA remission at week 52 from randomization. This is defined by the absence of symptoms and signs attributable to GCA, normalization of inflammatory markers (erythrocyte sedimentation rate [ESR] < 30 mm/1 hour and C-reactive protein [CRP] < 10 mg/L), and adherence to the protocol-defined prednisone taper regimen.
Secondary endpoints include a variety of measures: mortality rate in the course of GCA at 52 and 104 weeks, percentage of severe ischemic complications at 52 and 104 weeks, and percentage of sustained steroid-free GCA remission at week 104. Additional secondary endpoints involve the percentage of GCA remission at various timepoints (24, 52, 78, and 104 weeks), cumulative prednisone dose, time to GCA relapse, and the occurrence of major and minor GCA relapses. Quality of life changes will be measured using the SF-36 v.2 questionnaire at specified intervals, and the occurrence of serious and non-serious adverse events will be monitored throughout the trial duration.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient’s written informed consent to participate in the study
- Age ≥ 50 years.
- Diagnosis of GCA according to 2022 American College of Rheumatology/EULAR classification criteria for GCA or, in the case of involvement of only extracranial arteries, patients with a diagnosis of GCA based on medium or large-sized arterities that occurred at the age of ≥ 50 years and was confirmed by imaging, i.e. ultrasound, CT, MRI, conventional angiography or PET-CT, at the time of screening or in the past.
- New onset, refractory or relapsing GCA.
- Active GCA, defined as the presence of symptoms or signs attributed to GCA and not related to prior damage and elevated inflammatory markers, i.e. ESR ≥ 30 mm/1 hour or CRP ≥ 10 mg/L attributed to active GCA at screening or within 8 weeks prior to screening.
- Women of child-bearing potential and men who are sexually active with a woman of child-bearing potential must agree to the use of contraception with an adequate level of effectiveness during treatment with methotrexate/etanercept and for at least 6 months after its completion.
Exclusion Criteria
- Presence of ischemia of organ important for the patient’s survival (e.g. central nervous system, heart, lungs, kidneys, alimentary tract) in the course of GCA.
- Presence or history of other chronic autoimmune rheumatic disease that could interfere with the evaluation of the results of the following study, including: systemic lupus erythematosus, rheumatoid arthritis, or other systemic connective tissue disease, other than GCA systemic vasculitis.
- Oral mucous ulcers.
- Active stomach or duodenal ulcer.
- Presence or history of demyelinating syndrome
- History of major organ transplant (kidneys, lungs, heart, liver).
- Major surgery within 3 months prior to screening or major surgery planned during the study period.
- Hypersensitivity to methotrexate, etanercept or any other excipients of the methotrexate or etanercept.
- Acute, recurrent or chronic infection (e.g. tuberculosis, HIV infection) for which, in the Investigator’s opinion, participating in the study would expose patient to an unacceptable risk.
- Moderate or severe heart failure (New York Heart Association class III or IV), unstable ischemic heart disease, a stroke or myocardial infarction within 6 months prior to screening, or other cardiovascular disease that, in the Investigator’s opinion, would expose the patient to an unacceptable risk in case of participation in the study.
- Severe liver dysfunction
- Severe renal impairment
- Bone marrow hypoplasia
- Other severe disease (including, but not limited to, respiratory, nervous, endocrine, digestive, urinary tract disease) for which, in the Investigator’s opinion, participating in the study would expose patient to an unacceptable risk.
- A malignancy within 5 years prior to screening, except for: a. A completely resected cervical carcinoma in situ with no signs of recurrence within 12 months prior to screening; b. A completely cured basal cell skin carcinoma with no signs of recurrence within 12 months prior to screening.
- The following abnormalities in laboratory tests at screening: a. WBC < 3 G/L; b. NEU < 1 G/L; c. HGB < 9 g/dL; d. PLT < 100 G/L; e. ALT > 2 x ULN; f. AST > 2 x ULN; g. Total bilirubin >1,5 x ULN; h. eGFR < 50ml/min/1,73 m2; i. positive HBsAg; j. positive anti-HBc (total); k. positive anti-HCV; l. positive anti-HIV; m. positive or equivocal Quantiferon-TB Gold test.
- Positive result of a pregnancy test performed in women of child-bearing potential at screening or Visit 1.
- Previous use of the following treatment: a. Within 2 weeks prior to randomization: oral corticosteroids (CS) >60 mg/day prednisone or equivalent, parenteral CS; b. Within 12 weeks prior to randomization: methotrexate, leflunomide, sulfasalazine, chloroquine, hydroxychloroquine, azathioprine, cyclosporine A, mycophenolate mofetil, TNFα inhibitors, anakinra, abatacept, IL-17 blockers; c. Within 6 months prior to randomization: immunoglobulins, plasmapheresis, cyclophosphamide or other alkylating agents; d. Within 12 months prior to randomization: anti-CD20 antibodies; e. Oral or parenteral CS used chronically for reasons other than GCA.
- Abuse or addiction to drugs, alcohol or psychoactive substances.
- Live/attenuated vaccinations within 3 months prior to screening or planned administration of live vaccination during the study period.
- Use of other investigational drugs within 12 weeks or 5 half-lives, whichever is longer, prior to screening.
- Pregnancy or planned pregnancy during the study.
- Breastfeeding or planned breastfeeding during the study.
- Lack of patient cooperation
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Poland | Recruiting | 15 Apr 2024 | 88 |
Sites & Investigators
Research 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 |
|---|---|---|---|---|---|---|
METHOTREXATE | Comparator | — | SUBCUTANEOUS | 25 | 78 | SUB08856MIG |
METHOTREXATE | Test | — | SUBCUTANEOUS | 25 | 78 | SUB08856MIG |
FOLIC ACID | Other | — | ORAL | 15 | 78 | SUB07774MIG |
FOLIC ACID | Other | — | ORAL | 15 | 78 | SUB07774MIG |
METHOTREXATE | Test | — | SUBCUTANEOUS | 25 | 78 | SUB08856MIG |
METHOTREXATE | Comparator | — | SUBCUTANEOUS | 25 | 78 | SUB08856MIG |
METHOTREXATE | Test | — | SUBCUTANEOUS | 25 | 78 | SUB08856MIG |
PREDNISONE | Other | — | ORAL | 60 | 26 | SUB10020MIG |
METHOTREXATE | Comparator | — | SUBCUTANEOUS | 25 | 78 | SUB08856MIG |
PREDNISONE | Other | — | ORAL | 60 | 26 | SUB10020MIG |