Clinical trial NCT04314193: Effectiveness of Methotrexate Versus Prednisone as First-line Therapy for Pulmonary Sarcoidosis
Official title: The PREDMETH Trial: Effectiveness of Methotrexate Versus Prednisone as First-line Therapy for Pulmonary Sarcoidosis - A Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Sarcoidosis, Pulmonary
Keywords: sarcoidosis
pulmonary
prednisone
methotrexate
Lead sponsor: Erasmus Medical Center
Sponsor class: OTHER
Collaborators: name: St. Antonius Hospital
name: Longfonds
First posted: 2020-03-19
Enrollment: 138
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, randomized, open-label, multi-center (17 hospitals in the Netherlands), single country, non-inferiority trial.

Randomization 1:1 to oral prednisone (start 40 mg daily, to be tapered to 10 mg daily) or oral methotrexate (15 mg weekly to be increased to 25 mg weekly) for 24 weeks. Thereafter continuation of trial for 18 months on regular treatment (investigator decision).
Primary purpose: TREATMENT

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 Evidence-based treatment recommendations are limited, outdated and largely based on expert opinion.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.

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

Primary outcomes:
measure: Forced Vital Capacity (FVC)
timeFrame: 24 weeks after inclusion
Secondary outcomes:
measure: Forced Vital Capacity (FVC)
timeFrame: 4 weeks
measure: Forced Vital Capacity (FVC)
timeFrame: 16 weeks
measure: Time to major pulmonary improvement measured by FVC
timeFrame: 24 weeks
measure: Change in FVC
timeFrame: 4 weeks
measure: Change in FVC
timeFrame: 16 weeks
measure: Change in FVC
timeFrame: 24 weeks
measure: Change in DLCO
timeFrame: 4 weeks
measure: Change in DLCO
timeFrame: 16 weeks
measure: Change in DLCO
timeFrame: 24 weeks
measure: Changes in Angiotensin-Converting Enzyme (ACE)
timeFrame: 2 years
measure: Between group changes in sACE levels during treatment
timeFrame: 2 years
measure: Changes in soluble interleukin-2 receptor (sIL-2R)
timeFrame: 2 years
measure: Between group changes in sIL-2R levels during treatment
timeFrame: 2 years
measure: Changes in extracellular vesicles during treatment
timeFrame: 2 years
measure: Between group changes in extracellular vesicles absolute numbers
timeFrame: 2 years
measure: Changes in protein expression levels in extracellular vesicles during treatment
timeFrame: 2 years
measure: Between group changes in protein expression levels in extracellular vesicles
timeFrame: 2 years
measure: Changes in T lymphocyte phenotypes during Treatment
timeFrame: 2 years
measure: Between group changes in T lymphocyte phenotypes
timeFrame: 2 years
measure: Changes in T lymphocyte absolute cell numbers
timeFrame: 2 years
measure: Between group changes in T lymphocyte absolute cell numbers
timeFrame: 2 years
measure: Changes in the distribution of T lymphocytes during treatment
timeFrame: 2 years
measure: Between group changes in the distribution of T lymphocytes
timeFrame: 2 years
measure: Changes in dendritic cell phenotypes during Treatment
timeFrame: 2 years
measure: Between group changes in dendritic cell phenotypes
timeFrame: 2 years
measure: Changes in dendritic cell absolute cell numbers
timeFrame: 2 years
measure: Between group changes in dendritic cell absolute cell numbers
timeFrame: 2 years
measure: Changes in the distribution of dendritic cells during treatment
timeFrame: 2 years
measure: Between group changes in the distribution of dendritic cells
timeFrame: 2 years
measure: Changes in monocyte subset phenotypes during Treatment
timeFrame: 2 years
measure: Between group changes in monocyte subset phenotypes
timeFrame: 2 years
measure: Changes in monocyte absolute cell numbers
timeFrame: 2 years
measure: Between group changes in monocyte absolute cell numbers
timeFrame: 2 years
measure: Changes in the distribution of monocytes during treatment
timeFrame: 2 years
measure: Between group changes in the distribution of monocytes
timeFrame: 2 years
measure: Correlation between biomarkers and clinical parameters
timeFrame: 2 years
measure: The King's Sarcoidosis Questionnaire (KSQ)
timeFrame: baseline
measure: The King's Sarcoidosis Questionnaire (KSQ)
timeFrame: baseline and 4 weeks after inclusion
measure: The King's Sarcoidosis Questionnaire (KSQ)
timeFrame: baseline and 16 weeks after inclusion
measure: The King's Sarcoidosis Questionnaire (KSQ)
timeFrame: baseline and 24 weeks after inclusion
measure: The King's Sarcoidosis Questionnaire (KSQ)
timeFrame: baseline and 1 year after inclusion
measure: The King's Sarcoidosis Questionnaire (KSQ)
timeFrame: baseline and 2 years after inclusion
measure: The Chronic Respiratory Questionnaire (CRQ)
timeFrame: baseline
measure: The Chronic Respiratory Questionnaire (CRQ)
timeFrame: baseline and 4 weeks after inclusion
measure: The Chronic Respiratory Questionnaire (CRQ)
timeFrame: baseline and 16 weeks after inclusion
measure: The Chronic Respiratory Questionnaire (CRQ)
timeFrame: baseline and 24 weeks after inclusion
measure: The Chronic Respiratory Questionnaire (CRQ)
timeFrame: baseline and 1 year after inclusion
measure: The Chronic Respiratory Questionnaire (CRQ)
timeFrame: baseline and 2 years after inclusion
measure: The global rating of change scale (GRC)
timeFrame: baseline
measure: The global rating of change scale (GRC)
timeFrame: baseline and 4 weeks after inclusion
measure: The global rating of change scale (GRC)
timeFrame: baseline and 16 weeks after inclusion
measure: The global rating of change scale (GRC)
timeFrame: baseline and 24 weeks after inclusion
measure: The global rating of change scale (GRC)
timeFrame: baseline and 1 year after inclusion
measure: The global rating of change scale (GRC)
timeFrame: baseline and 2 years after inclusion
measure: The EuroQol five dimensions 5-level questionnaire (EQ-5D-5L)
timeFrame: baseline
measure: The EuroQol five dimensions 5-level questionnaire (EQ-5D-5L)
timeFrame: baseline and 4 weeks after inclusion
measure: The EuroQol five dimensions 5-level questionnaire (EQ-5D-5L)
timeFrame: baseline and 16 weeks after inclusion
measure: The EuroQol five dimensions 5-level questionnaire (EQ-5D-5L)
timeFrame: baseline and 24 weeks after inclusion
measure: The EuroQol five dimensions 5-level questionnaire (EQ-5D-5L)
timeFrame: baseline and 1 year after inclusion
measure: The EuroQol five dimensions 5-level questionnaire (EQ-5D-5L)
timeFrame: baseline and 2 years after inclusion
measure: The Medical Research Council Dyspnea scale
timeFrame: Baseline
measure: The Medical Research Council Dyspnea scale
timeFrame: Baseline and 4 weeks after inclusion
measure: The Medical Research Council Dyspnea scale
timeFrame: Baseline and 16 weeks after inclusion
measure: The Medical Research Council Dyspnea scale
timeFrame: Baseline and 24 weeks after inclusion
measure: The Medical Research Council Dyspnea scale
timeFrame: Baseline and 1 year after inclusion
measure: The Medical Research Council Dyspnea scale
timeFrame: Baseline and 2 years after inclusion
measure: The fatigue assessment scale (FAS)
timeFrame: Baseline
measure: The fatigue assessment scale (FAS)
timeFrame: Baseline and 4 weeks after inclusion
measure: The fatigue assessment scale (FAS)
timeFrame: Baseline and 16 weeks after inclusion
measure: The fatigue assessment scale (FAS)
timeFrame: Baseline and 24 weeks after inclusion
measure: The fatigue assessment scale (FAS)
timeFrame: Baseline and 1 year after inclusion
measure: The fatigue assessment scale (FAS)
timeFrame: Baseline and 2 years after inclusion
measure: Number of patients who discontinue/switch medication
timeFrame: During 24 weeks
measure: Patient Experience and Satisfaction with Medication questionnaire
timeFrame: baseline
measure: Patient Experience and Satisfaction with Medication questionnaire
timeFrame: 4 weeks
measure: Patient Experience and Satisfaction with Medication questionnaire
timeFrame: 16 weeks
measure: Patient Experience and Satisfaction with Medication questionnaire
timeFrame: 24 weeks
measure: Patient Experience and Satisfaction with Medication questionnaire
timeFrame: 1 year
measure: Patient Experience and Satisfaction with Medication questionnaire
timeFrame: 2 years
Other outcomes:
Locations:
city: 's-Hertogenbosch
country: Netherlands
facility: Jeroen Bosch Ziekenhuis
city: Amsterdam
country: Netherlands
facility: Vrije Universiteit Medisch Centrum
city: Amsterdam
country: Netherlands
facility: Onze Lieve Vrouwe Gasthuis
city: Amsterdam
country: Netherlands
facility: Academisch Medisch Centrum
city: Arnhem
country: Netherlands
facility: Rijnstate Ziekenhuis
city: Breda
country: Netherlands
facility: Amphia hospital
city: Eindhoven
country: Netherlands
facility: Catharina Ziekenhuis
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Groningen
country: Netherlands
facility: Martini Ziekenhuis
city: Heerlen
country: Netherlands
facility: Zuyderland Medisch Centrum
city: Leeuwarden
country: Netherlands
facility: Medical Center Leeuwarden
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
city: Leidschendam
country: Netherlands
facility: Haaglanden Medisch Centrum
city: Nieuwegein
country: Netherlands
facility: Sint Antonius Ziekenhuis
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Venlo
country: Netherlands
facility: VieCuri Medical Center
city: Zwolle
country: Netherlands
facility: Isala Klinieken
Study officials:
affiliation: Erasmus Medical Center
name: Marlies Wijsenbeek, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: St. Antonius Hospital
name: Marcel Veltkamp, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.