Effectiveness of Methotrexate Versus Prednisone as First-line Therapy for Pulmonary Sarcoidosis

NCT ID: NCT04314193

Last Updated: 2025-03-26

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 138 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-06-01
• Study Completion Date: 2026-07-31

Brief Summary

This is a prospective, randomized, non-blinded, multi-center, non-inferiority trial designed to compare effectiveness and side-effects of methotrexate versus prednisone as first-line therapy for pulmonary sarcoidosis.

Detailed Description

Sarcoidosis is a multisystem, granulomatous disorder, most commonly affecting the lungs. Symptom burden is high, and quality of life (QoL) and social participation are negatively affected. In patients with pulmonary sarcoidosis, treatment is recommended in case of significant symptoms and/or impaired or deteriorating lung function. Evidence-based treatment recommendations are limited, outdated and largely based on expert opinion.

Prednisone is currently the first-choice therapy in pulmonary sarcoidosis and leads to short-term improvement of lung function. Unfortunately, prednisone has major side-effects and is associated with impaired QoL. Methotrexate is presently considered second-line therapy, and appears to have fewer side-effects. The investigators hypothesize that first-line treatment with methotrexate is as effective as prednisone, with fewer side-effects and better QoL.

Conditions

Sarcoidosis, Pulmonary

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

methotrexate

Group Type: EXPERIMENTAL

Methotrexate

Intervention Type: DRUG

Oral methotrexate (15 mg weekly to be increased to 25 mg weekly) for 24 weeks.

prednisone

Group Type: ACTIVE_COMPARATOR

Prednisone

Intervention Type: DRUG

Oral prednisone (start 40 mg daily, to be tapered to 10 mg daily) for 24 weeks.

Interventions

Methotrexate

Oral methotrexate (15 mg weekly to be increased to 25 mg weekly) for 24 weeks.

Intervention Type: DRUG

Prednisone

Oral prednisone (start 40 mg daily, to be tapered to 10 mg daily) for 24 weeks.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Diagnosis of sarcoidosis according to the ATS/ERS/WASOG criteria, in case of absent histology a diagnosis of sarcoidosis can also be established in a multidisciplinary team meeting in a sarcoidosis expert center based on a highly suggestive clinical and radiological picture.
• Age ≥18 years.
• A pulmonary indication for treatment and parenchymal involvement on X-ray or CT-scan conducted within three months before inclusion (determined by the treating physician and conform current guidelines).
• A forced vital capacity (FVC) of ≤90% of predicted, or a diffusion capacity of the lung for carbon monoxide (DLCO) ≤70% of predicted, or ≥5% FVC absolute decline/≥10% DLCO absolute decline in the past year. For pulmonary functions tests GLI reference values are used.

Exclusion Criteria

• Any condition or circumstance that, in the opinion of the investigator, may make a subject unlikely or unable to complete the study or comply with study procedures.
• Previous immunosuppressive treatment for sarcoidosis
• Use of systemic immunosuppressive therapy within the preceding three months for another disease than sarcoidosis
• Pregnant, breastfeeding, or planning to become pregnant or breastfeed during the study treatment or within 90 days after the last dose in the randomized study phase. For males; planning to pro-create during the study or within 90 days after the last dose of the randomized study phase.
• Primary systemic treatment indication being an extra pulmonary location of sarcoidosis (e.g. cardiac of neurological)
• Contra-indication for methotrexate or corticosteroids:

• severely impaired renal function (creatinine clearance <30 ml/min)
• impaired hepatic function (serum bilirubin-value >5 mg/dl or 85,5 micromole/l)
• bone marrow insufficiency with severe leukopenia, thrombocytopenia, or anaemia
• severe acute or chronic infections, such as tuberculosis, HIV, parasitic infections or other immunodeficiency syndromes
• mouth, stomach or duodenal ulcers

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

St. Antonius Hospital

OTHER

Sponsor Role: collaborator

Longfonds

UNKNOWN

Sponsor Role: collaborator

Erasmus Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Marlies Wijsenbeek

Principal investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Marlies Wijsenbeek, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Erasmus Medical Center

Marcel Veltkamp, MD PhD

Role: PRINCIPAL_INVESTIGATOR

St. Antonius Hospital

Locations

Jeroen Bosch Ziekenhuis

's-Hertogenbosch, , Netherlands

Vrije Universiteit Medisch Centrum

Amsterdam, , Netherlands

Onze Lieve Vrouwe Gasthuis

Amsterdam, , Netherlands

Academisch Medisch Centrum

Amsterdam, , Netherlands

Rijnstate Ziekenhuis

Arnhem, , Netherlands

Amphia hospital

Breda, , Netherlands

Catharina Ziekenhuis

Eindhoven, , Netherlands

Medisch Spectrum Twente

Enschede, , Netherlands

Martini Ziekenhuis

Groningen, , Netherlands

Zuyderland Medisch Centrum

Heerlen, , Netherlands

Medical Center Leeuwarden

Leeuwarden, , Netherlands

Leids Universitair Medisch Centrum

Leiden, , Netherlands

Haaglanden Medisch Centrum

Leidschendam, , Netherlands

Sint Antonius Ziekenhuis

Nieuwegein, , Netherlands

Erasmus MC

Rotterdam, , Netherlands

VieCuri Medical Center

Venlo, , Netherlands

Isala Klinieken

Zwolle, , Netherlands

Countries

Netherlands

References

Kahlmann V, Janssen Bonas M, Moor CC, Grutters JC, Mostard RLM, van Rijswijk HNAJ, van der Maten J, Marges ER, Moonen LAA, Overbeek MJ, Koopman B, Loth DW, Nossent EJ, Wagenaar M, Kramer H, Wielders PLML, Bonta PI, Walen S, Bogaarts BAHA, Kerstens R, Overgaauw M, Veltkamp M, Wijsenbeek MS; PREDMETH Collaborators. First-Line Treatment of Pulmonary Sarcoidosis with Prednisone or Methotrexate. N Engl J Med. 2025 Jul 17;393(3):231-242. doi: 10.1056/NEJMoa2501443. Epub 2025 May 18.

Reference Type: DERIVED

PMID: 40387020 (View on PubMed)

Kahlmann V, Janssen Bonas M, Moor CC, van Moorsel CHM, Kool M, Kraaijvanger R, Grutters JC, Overgaauw M, Veltkamp M, Wijsenbeek MS; Collaborating investigators. Design of a randomized controlled trial to evaluate effectiveness of methotrexate versus prednisone as first-line treatment for pulmonary sarcoidosis: the PREDMETH study. BMC Pulm Med. 2020 Oct 19;20(1):271. doi: 10.1186/s12890-020-01290-9.

Reference Type: DERIVED

PMID: 33076885 (View on PubMed)

Other Identifiers

NL71782.078.19

Identifier Type: -

Identifier Source: org_study_id