Efficacy and Safety of Two Glucocorticoid Regimens in the Treatment of Sarcoidosis

Study Overview
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Brief Summary
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For pulmonary sarcoidosis, the initial dose recommended by the joint statement of the American Thoracic Society (ATS), European Respiratory Society (ERS), and The World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) is 20-40 mg per day.5 The exact dose and duration of treatment for sarcoidosis are unknown.4 We hypothesize that a higher dose of 40 mg per day as compared to a 20 mg/day dose of prednisone will be more effective in preventing post-treatment relapse by effective initial suppression of the granulomatous inflammation and reduction of the disease load. In this study, we compare the efficacy and safety of medium dose (40 mg/day prednisone) and low dose (20 mg/day prednisone) glucocorticoids in the treatment of acute sarcoidosis.

Detailed Description
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Glucocorticoids are the cornerstone of treatment of sarcoidosis and are used as the first-line agents in patients requiring immunosuppressive therapy.4 The optimal dose and duration of glucocorticoids is an unresolved issue. For pulmonary sarcoidosis, the initial dose recommended by the joint statement of the ATS/ERS/WASOG is 20-40 mg per day.5 The duration of treatment recommended is at least one year. However, mild disease of recent onset may respond to a shorter duration of treatment. Further, as most of the toxic effects of glucocorticoids are cumulative, the dose and duration of steroids need to be kept to a minimum to balance the benefit and risks of treatment. Two large studies performed about two decades ago used an initial dose of 30 mg and 20 mg respectively for treating acute sarcoidosis. While the British Thoracic Society employed steroid treatment (initial dose 30 mg/day) for one year, in the Finnish study, oral glucocorticoids (initial dose 20 mg/day) were administered for three months and were followed by inhaled budesonide.3,6 In a recent Delphi study of experts, 37% and 20% of the experts used an initial prednisone equivalent dose of 40 mg per day and 20 mg per day regardless of weight, respectively.7 About 23% used doses of 20 mg, 30 mg, or 40 mg per day depending on weight. However, consensus was reached that a dose higher than 40 mg per day is not required. Apart from the initial response to glucocorticoids in symptoms and lung function, the rate of relapse after cessation of treatment is an important outcome in the management of sarcoidosis. The exact dose and duration of treatment for sarcoidosis are unknown.4 We hypothesize that a higher dose of 40 mg per day as compared to a 20 mg/day dose of prednisone will be more effective in preventing post-treatment relapse by effective initial suppression of the granulomatous inflammation and reduction of the disease load. In this study, we compare the efficacy and safety of medium dose (40 mg/day prednisone) and low dose (20 mg/day prednisone) glucocorticoids in the treatment of acute sarcoidosis.

Official Title
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Efficacy and Safety of Two Glucocorticoid Regimens in the Treatment of Sarcoidosis: a Randomized Controlled Trial

Conditions
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Sarcoidosis

Intervention / Treatment
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* Drug: Low dose prednisolone
* Drug: Medium dose prednisolone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Computed tomography of the chest consistent with a diagnosis of sarcoidosis of the lung/mediastinal lymph nodes Diagnosis of sarcoidosis made on cytological or histological samples Having significant symptoms requiring immunosuppressive treatment and/or having reduced lung function (defined as forced vital capacity or forced expiratory volume in one second (FEV1) less than 80% predicted) or an extrathoracic manifestation of the disease requiring treatment with low-medium dose glucocorticoids Onset of symptoms within two years of study entry Exclusion Criteria: Pregnant or lactating women Subjects having any manifestation requiring high dose steroid treatment (this includes symptomatic neurosarcoidosis, life threatening cardiac sarcoidosis, vision threatening posterior uveitis or other forms of vision threatening ocular sarcoidosis) Having absolute contraindication for prednisone in a dose of 40 mg/day (this includes untreated glaucoma, uncontrolled diabetes mellitus, untreated infections, untreated severe psychiatric disorders) Unwilling to participate in the study Having received glucocorticoids (prednisolone equivalent >15 mg/day) for more than three weeks in the preceding two years

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low dose prednisolone<br>An initial dose of 20 mg/day will be administered for 8 weeks, followed by 15 mg/day for 8 weeks, 10 mg/day for 4 weeks, and 5 mg/day for 4 weeks, after which the drug will be tapered over 2 weeks and discontinued. | Drug: Low dose prednisolone<br>* An initial dose of 20 mg/day will be administered for 8 weeks, followed by 15 mg/day for 8 weeks, 10 mg/day for 4 weeks, and 5 mg/day for 4 weeks, after which the drug will be tapered over 2 weeks and discontinued.<br>|
| Active Comparator: Medium dose prednisolone<br>An initial dose of 40 mg/day will be administered for 4 weeks, followed by 30 mg/day for 4 weeks, 20 mg/day for 4 weeks, 15 mg/day for 4 weeks, 10 mg/day for 4 weeks, and 5 mg/day for 4 weeks, after which the drug will be tapered over 2 weeks and discontinued. | Drug: Medium dose prednisolone<br>* An initial dose of 40 mg/day will be administered for 4 weeks, followed by 30 mg/day for 4 weeks, 20 mg/day for 4 weeks, 15 mg/day for 4 weeks, 10 mg/day for 4 weeks, and 5 mg/day for 4 weeks, after which the drug will be tapered over 2 weeks and discontinued.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse or treatment failure | The proportion of subjects with a relapse or treatment failure in the two study groups (initial dose 40 mg/day versus 20 mg/day of prednisone) at the end of 18 months | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean time to relapse/treatment failure | The difference between the mean time to relapse/treatment failure in the study groups | 18 months | 
| Response | The proportion of subjects with worsening, stabilization, improvement or resolution of the disease in the study groups at the end of 18 months | 18 months | 
| Lung function early | The difference in the mean change in forced vital capacity between the study groups at the end of 6 months | 6 months | 
| Cumulative dose of prednisolone | The difference in the mean cumulative dose of prednisolone between the study groups at the end of 18 months | 18 months | 
| Adverse effects | The adverse effects of treatment (acne, weight gain, hyperglycemia, hypertension, adrenal insufficiency, osteoporosis and any other adverse effects related to prednisolone) between the study groups at the end of 18 months | 18 months | 
| Change in the sarcoidosis-related quality-of-life assessed by the score on the Sarcoidosis Health Questionnaire at treatment completion | The Sarcoidosis Health Questionnaire is a health-related quality-of-life questionnaire for patients with sarcoidosis. Higher scores reflect better quality-of-life | 6 months | 
| Change in the sarcoidosis-related quality-of-life assessed by the score on the Sarcoidosis Health Questionnaire at completion of follow-up | The Sarcoidosis Health Questionnaire is a health-related quality-of-life questionnaire for patients with sarcoidosis. Higher scores reflect better quality-of-life | 18 months | 
| Change in fatigue severity assessed by the score on the Fatigue Assessment Scale at treatment completion | The Fatigue Assessment Scale is a validated instrument for assessing sarcoidosis-related fatigue. Higher scores reflect more severe fatigue | 6 months | 
| Change in fatigue severity assessed by the score on the Fatigue Assessment Scale at completion of follow-up | The Fatigue Assessment Scale is a validated instrument for assessing sarcoidosis-related fatigue. Higher scores reflect more severe fatigue | 18 months | 
| Lung function late | The difference in the mean change in forced vital capacity between the study groups at the end of18 months | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pulmonary sarcoidosis, corticosteroids, glucocorticoids, relapse, interstitial lung disease, diffuse parenchymal lung disease, immunosuppression, mediastinal lymphadenopathy