Sarcoidosis, Pulmonary
Conditions
Keywords
sarcoidosis, pulmonary, prednisone, methotrexate
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 Evidence-based treatment recommendations are limited, outdated and largely based on expert opinion.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.
Interventions
DRUGMethotrexate
Oral methotrexate (15 mg weekly to be increased to 25 mg weekly) for 24 weeks.
DRUGPrednisone
Oral prednisone (start 40 mg daily, to be tapered to 10 mg daily) for 24 weeks.
Sponsors
St. Antonius Hospital
Longfonds
Erasmus Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
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).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Forced Vital Capacity (FVC) | 24 weeks after inclusion | Change in hospital-measured FVC between baseline and 24 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. This will be determined on the home spirometry data. |
| Change in FVC | 4 weeks | The percentage of patients with a 5 and 10% improvement or decline in FVC at 4 weeks. |
| Change in DLCO | 4 weeks | The percentage of patients with a 10% or \> 10% improvement or decline in DLCO at 4 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 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 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 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 |
| 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 |
| 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 |
| 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 |
| 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 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 |
| 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 |
| 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 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 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 |
| Forced Vital Capacity (FVC) | 4 weeks | Change in hospital-measured FVC between baseline and 4 weeks. |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 | 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 Chronic Respiratory Questionnaire (CRQ) | baseline | 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 | 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. |
| The EuroQol five dimensions 5-level questionnaire (EQ-5D-5L) | baseline | 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. |
| The Medical Research Council Dyspnea scale | Baseline | The Medical Research Council Dyspnea scale consists of one question measuring dyspnea on a scale from 0-5. |
| The fatigue assessment scale (FAS) | Baseline | 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. |
| 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. |
| Patient Experience and Satisfaction with Medication questionnaire | baseline | 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. |
| 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 |
Countries
Netherlands
Outcome results
None listed