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

Phase 4

Active, not recruiting

• Conditions: Sarcoidosis, Pulmonary
• Interventions: Drug: Methotrexate; Drug: Prednisolone

• Registration Number: NCT04314193
• Lead Sponsor: Erasmus Medical Center

Brief Summary

This is a prospective, randomized, non-blinded, multi-center, non-inferiority trial designed to compare effectiveness and side-effects of methotrexate versus prednisolone 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 Evidence-based treatment recommendations are limited, outdated and largely based on expert opinion.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.

Study Timeline

• Study First Submitted: 2020-02-24
• Study First Submitted QC: 2020-03-16
• Study First Posted: 2020-03-19
• Study Start: 2020-06-01
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-08
• Last Update Posted: 2024-03-12
• Primary Completion: 2024-07
• Study Completion: 2026-07

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 138

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 decline/≥10% DLCO decline in the past year. For pulmonary functions tests GLI reference values are used.

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
methotrexate	Methotrexate	-
prednisolone	Prednisolone	-

Primary Outcome Measures

Name	Time	Method
Forced Vital Capacity (FVC)	24 weeks after inclusion	Change in hospital-measured FVC between baseline and 24 weeks

Secondary Outcome Measures

Name	Time	Method
Change in FVC	24 weeks	The percentage of patients with a 5 and 10% improvement or decline in FVC at 24 weeks.
Change in DLCO	24 weeks	The percentage of patients with a 10% or \> 10% improvement or decline in DLCO at 24 weeks.
Changes in Angiotensin-Converting Enzyme (ACE)	2 years	Differences in serum levels of sACE (U/ml) in serum of sarcoidosis patients before, during and after treatment
Between group changes in extracellular vesicles absolute numbers	2 years	Differences in absolute numbers of extracellular vesicles in serum of sarcoidosis patients on prednisolone versus methotrexate
Between group changes in protein expression levels in extracellular vesicles	2 years	Differences in protein expression in extracellular vesicles in serum of sarcoidosis patients on prednisolone versus methotrexate
Between group changes in the distribution of T lymphocytes	2 years	Differences in the frequencies of T-cells (%) in peripheral blood of sarcoidosis patients on prednisolone versus methotrexate
Changes in dendritic cell phenotypes during Treatment	2 years	Flow cytometry analysis will be used to determine how the frequencies and distribution of different cell subtypes change during treatment. Different phenotypes can be identified through expression of a number of cell surface markers, expression is measured in MFI (mean fluorescence intensity).; Differences in phenotype of dendritic cells (MFI) in peripheral blood of sarcoidosis patients before, during and after treatment
Between group changes in dendritic cell absolute cell numbers	2 years	Differences in the absolute numbers of dendritic cells (cells/ml) in peripheral blood of sarcoidosis patients on prednisolone versus methotrexate
Between group changes in monocyte absolute cell numbers	2 years	Differences in the absolute numbers of monocytes (cells/ml) in peripheral blood of sarcoidosis patients on prednisolone versus methotrexate
The fatigue assessment scale (FAS)	Baseline and 2 years after inclusion	The fatigue assessment scale (FAS) is a 10-item self-administered questionnaire about fatigue in patients with sarcoidosis. The score ranges from 5-50 points, with a score of ≥ 22 points as cut-off for fatigue. The MCID is 4 points or a 10% lower score.
Forced Vital Capacity (FVC)	16 weeks	Change in hospital-measured FVC between baseline and 16 weeks.
Between group changes in T lymphocyte phenotypes	2 years	Flow cytometry analysis will be used to determine how the frequencies and distribution of different cell subtypes change during treatment. Different phenotypes can be identified through expression of a number of cell surface markers, expression is measured in MFI (mean fluorescence intensity).; Differences in phenotype of T-cells (MFI) in peripheral blood of sarcoidosis patients on prednisolone versus methotrexate
Between group changes in monocyte subset phenotypes	2 years	Flow cytometry analysis will be used to determine how the frequencies and distribution of different cell subtypes change during treatment. Different phenotypes can be identified through expression of a number of cell surface markers, expression is measured in MFI (mean fluorescence intensity).; Differences expression of monocyte specific cell surface markers on monocytes (MFI) in peripheral blood of sarcoidosis patients on prednisolone versus methotrexate
Changes in monocyte absolute cell numbers	2 years	Differences in the absolute numbers of monocytes (cells/ml) in peripheral blood of sarcoidosis patients before, during and after treatment
Patient Experience and Satisfaction with Medication questionnaire	2 years	Correlation between patient expectations with medication and consecutive experiences measured with the PESaM questionnaire which assess patient expectations at baseline in an 11-item questionnaire and patient experiences and side-effects with medication after 12 weeks in a 26-item questionnaire on a 0-4 Likert scale. For each question it is different whether a higher score represents better or worse outcomes.
Time to major pulmonary improvement measured by FVC	24 weeks	Time to major pulmonary improvement measured by home-measured FVC, whereby major pulmonary improvement is defined as 80% of the maximum percent predicted FVC reached anywhere during the first 24 weeks of treatment.
Between group changes in sIL-2R levels during treatment	2 years	Differences in serum levels of sIL-2R (U/ml) in serum of sarcoidosis patients on prednisolone versus methotrexate
Changes in extracellular vesicles during treatment	2 years	Differences in absolute numbers of extracellular vesicles in serum of sarcoidosis patients before, during and after treatment
Changes in T lymphocyte absolute cell numbers	2 years	Differences in the absolute numbers of T-cells (cells/ml) in peripheral blood of sarcoidosis patients before, during and after treatment
Changes in monocyte subset phenotypes during Treatment	2 years	Flow cytometry analysis will be used to determine how the frequencies and distribution of different cell subtypes change during treatment. Different phenotypes can be identified through expression of a number of cell surface markers, expression is measured in MFI (mean fluorescence intensity).; Differences in expression of monocyte specific cell surface markers on monocytes (MFI) in peripheral blood of sarcoidosis patients before, during and after treatment
Correlation between biomarkers and clinical parameters	2 years	The differences in percentage of biomarkers is compared with the differences in change of FVC and DLCOc.; Biomarkers are measured in peripheral blood and include: * monocytes, measured by flow cytometry (MFI); * Th-cells, measured by flow cytometry (MFI); * dendritic cells, measured by flow cytometry (MFI); * Proteins, measured by ELISA (ng/ml); * Serum biomarkers (U/l)
The King's Sarcoidosis Questionnaire (KSQ)	baseline and 2 years after inclusion	The King's Sarcoidosis Questionnaire (KSQ) assesses health status in patients with sarcoidosis. It comprises 29 items in 5 subdomains: general health status, lung, medication, skin and eyes. All scores range from 0 to 100, higher scores signifying beter health status. It takes about 3-5 minutes to complete.
The EuroQol five dimensions 5-level questionnaire (EQ-5D-5L)	baseline and 2 years after inclusion	Patients will complete the EQ-5D-5L questionnaire, a standardized instrument to measure health outcomes in two components: health description and valuation. It comprises five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression on a 5-point scale. From these 5 answers an index value is derived between 0 and 1, with a higher value corresponding with a better QoL. In the valuation part the patients' general health status is evaluated using a VAS-score from 0 to 100, with a higher score representing a better QoL.
Between group changes in sACE levels during treatment	2 years	Differences in serum levels of sACE (U/ml) in serum of sarcoidosis patients on prednisolone versus methotrexate
Changes in protein expression levels in extracellular vesicles during treatment	2 years	Differences in protein expression in extracellular vesicles in serum of sarcoidosis patients before, during and after treatment
Changes in T lymphocyte phenotypes during Treatment	2 years	Flow cytometry analysis will be used to determine how the frequencies and distribution of different cell subtypes change during treatment. Different phenotypes can be identified through expression of a number of cell surface markers, expression is measured in MFI (mean fluorescence intensity).; Differences in phenotype of T-cells (MFI) in peripheral blood of sarcoidosis patients before, during and after treatment.
Between group changes in dendritic cell phenotypes	2 years	Flow cytometry analysis will be used to determine how the frequencies and distribution of different cell subtypes change during treatment. Different phenotypes can be identified through expression of a number of cell surface markers, expression is measured in MFI (mean fluorescence intensity).; Differences in phenotype of dendritic cells (MFI) in peripheral blood of sarcoidosis patients on prednisolone versus methotrexate
Changes in dendritic cell absolute cell numbers	2 years	Differences in the absolute numbers of dendritic cells (cells/ml) in peripheral blood of sarcoidosis patients before, during and after treatment
Changes in the distribution of dendritic cells during treatment	2 years	Differences in the frequencies of dendritic cells (%) in peripheral blood of sarcoidosis patients before, during and after treatment
Changes in the distribution of monocytes during treatment	2 years	Differences in the frequencies of monocytes in peripheral blood of sarcoidosis patients before, during and after treatment
The Medical Research Council Dyspnea scale	Baseline and 2 years after inclusion	The Medical Research Council Dyspnea scale consists of one question measuring dyspnea on a scale from 0-5.
Number of patients who discontinue/switch medication	During 24 weeks	Every week patients register whether they missed pills (and the amount of pills wasted). Discontinuation or switch of medication is registered both by patients and researchers.
Changes in soluble interleukin-2 receptor (sIL-2R)	2 years	Differences in serum levels of sIL-2R (U/ml) in serum of sarcoidosis patients before, during and after treatment
Between group changes in T lymphocyte absolute cell numbers	2 years	Differences in the absolute numbers of T-cells (cells/ml) in peripheral blood of sarcoidosis patients on prednisolone versus methotrexate
Changes in the distribution of T lymphocytes during treatment	2 years	Differences in the frequencies of T-cells (%) in peripheral blood of sarcoidosis patients before, during and after treatment
Between group changes in the distribution of dendritic cells	2 years	Differences in the frequencies of dendritic cells (%) in peripheral blood of sarcoidosis patients on prednisolone versus methotrexate
Between group changes in the distribution of monocytes	2 years	Differences in the frequencies of monocytes in peripheral blood of sarcoidosis patients on prednisolone versus methotrexate
The Chronic Respiratory Questionnaire (CRQ)	baseline and 2 years after inclusion	The Chronic Respiratory Questionnaire (CRQ) is a 20-item self-reported validated questionnaire for HRQOL in patients with chronic respiratory disease. Scores range from 0 - 100 and higher scores signifying beter health quality.The minimal clinically important difference (MCID) is 0,5 points per item. It takes about 3-5 minutes to complete.
The global rating of change scale (GRC)	baseline and 2 years after inclusion	The global rating of change scale (GRC) is a measure in which patients are asked to rate if their QOL is improved or deteriorated over a certain period of time on a scale from -7 to +7. It consists of one questions and takes \<1 minute to complete.

Trial Locations

Locations (18)

Jeroen Bosch Ziekenhuis; 🇳🇱 's-Hertogenbosch, Netherlands

Onze Lieve Vrouwe Gasthuis; 🇳🇱 Amsterdam, Netherlands

Isala Klinieken; 🇳🇱 Zwolle, Netherlands

Vrije Universiteit Medisch Centrum; 🇳🇱 Amsterdam, Netherlands

Catharina Ziekenhuis; 🇳🇱 Eindhoven, Netherlands

Martini Ziekenhuis; 🇳🇱 Groningen, Netherlands

Sint Antonius Ziekenhuis; 🇳🇱 Nieuwegein, Netherlands

Medisch Spectrum Twente; 🇳🇱 Enschede, Netherlands

Leids Universitair Medisch Centrum; 🇳🇱 Leiden, Netherlands

VieCuri Medical Center; 🇳🇱 Venlo, Netherlands

Academisch Medisch Centrum; 🇳🇱 Amsterdam, Netherlands

Haaglanden Medisch Centrum; 🇳🇱 Leidschendam, Netherlands

Canisius Wilhelmina Ziekenhuis; 🇳🇱 Nijmegen, Netherlands

Rijnstate Ziekenhuis; 🇳🇱 Arnhem, Netherlands

Erasmus MC; 🇳🇱 Rotterdam, Netherlands

Amphia hospital; 🇳🇱 Breda, Netherlands

Zuyderland Medisch Centrum; 🇳🇱 Heerlen, Netherlands

Medical Center Leeuwarden; 🇳🇱 Leeuwarden, Netherlands