Comparison of the Effectiveness of Two Different Dosages of Cortisone Compared to Placebo in Rheumatoid Arthritis

Study Overview
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Brief Summary
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Although cortisone is widely used in the treatment of patients with early rheumatoid arthritis, the best dosage is not known. Therefore we will compare two standard prednisolon starting dosages and placebo in the treatment of patients with early active rheumatoid arthritis on the background of the established therapy with methotrexate. In total 450 patients will be included into the study. Two different treatment arms starting with 10 or 60 mg of prednisolone, and one placebo arm. Duration of intervention is 12 weeks. In parallel, all patients start medication with methotrexate, usual dosage 15 mg/week. Primary efficacy endpoint is progression of radiographic damage after one year compared to baseline. Safety monitoring is performed.

Detailed Description
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BACKGROUND: Although glucocorticoids (GCs) are widely used in the treatment of patients with early rheumatoid arthritis (RA), the best dosage for GCs, related to both, efficacy and safety, is not known. OBJECTIVE: To compare two standard p.o. GC starting dosages and the non-use of GCs in the treatment of patients with early active RA on the background of the established 'anchor' therapy with methotrexate (MTX). METHODS: Randomised double-blind placebo-controlled trial with two treatment arms (starting with 10 or 60 mg of p.o. prednisolone (P), tapered down to 5 mg P per day within 8 weeks) and one placebo arm, each arm comprising 150 patients. Duration of intervention is 12 weeks. In parallel, all patients start medication with MTX, usual dosage 15 mg/week. Primary efficacy endpoint is progression of radiographic damage after one year compared to baseline. Secondary endpoints are: percentage of patients in remission, changes of functional capacity etc. Safety monitoring is performed. The analysis is performed in three hierarchical steps. First step is an analysis of covariance to compare the group with an initial P dosage of 60 mg (V60) and the placebo group (Pl). In case of a statistical significant result (α = 0.05), a comparison of the group starting with 10 mg P (V10) and Pl will be done in a second step (α = 0.05). In case of superiority of V10 versus Pl, a third step will be a non-inferiority test for V10 versus V60 (α = 0.025).

Official Title
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Comparison of the Efficacy and Safety of Two Different Starting Dosages of Prednisolone in Early Active Rheumatoid Arthritis: a Randomized, Placebo Controlled Trial

Conditions
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Progression of Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Prednisolone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of rheumatoid arthritis based on expert opinion according to the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2009 criteria (Hawker 2009) disease duration < 3 years active disease: disease activity score (DAS) 28 erythrocyte sedimentation rate (ESR) (Prevoo et al 1995) > 4 plus ≥ 3 swollen joints Exclusion Criteria: Prior treatment with disease-modifying antirheumatic drugs (DMARDs) (except for hydroxychloroquine or sulfasalazine or methotrexate during the last four weeks before screening) Clinically relevant comorbidity: concurrent liver disease (ALT > 2 times upper limit of normal), active hepatitis B or C viral infection, renal disease (creatinine clearance < 30 ml/minute), clinically relevant haematological disease due to the judgement of the rheumatologist, uncontrolled diabetes mellitus, uncontrolled arterial hypertension, relevant immunodeficiency incl. HIV-infection, clinically significant pulmonary fibrosis, history of malignant melanoma, complicated or refractory gastrointestinal ulcers, presence or history of severe infections, uncontrolled increased intraocular pressure, pregnancy or planned pregnancy, non-compliance, age < 18 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prednisolone 10<br>Prednihexal (Prednisolon), daily oral tablet, 10 mg during week one to four, 7,5 mg during week five to eight. Finally 5 mg for four weeks. | Drug: Prednisolone<br>* To compare two standard p.o. GC starting dosages and the non-use of GCs in the treatment of patients with early active RA on the background of the established 'anchor' therapy with methotrexate (MTX).<br>* Other names: PredniHexal;|
| Experimental: Prednisolone 60<br>Prednihexal (Prednisolon), daily oral tablet, 60 mg during the first week, weekly tapering: 40 mg, 20mg, 15mg, 10mg, 7,5mg. 7,5mg continued for one more week. Finally 5 mg for four weeks | Drug: Prednisolone<br>* To compare two standard p.o. GC starting dosages and the non-use of GCs in the treatment of patients with early active RA on the background of the established 'anchor' therapy with methotrexate (MTX).<br>* Other names: PredniHexal;|
| Placebo Comparator: Placebo<br>daily oral tablet | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression of radiographic damage after one year as quantified by the van der Heijde modification of the Sharp score (SHS). Determined at baseline and after one year. | 15 sites in each hand and wrist and six joints in each foot are examined for joint space narrowing on a scale of 0 to 437: 0 indicates no narrowing, 1 represents minimal narrowing, 2 indicates loss of 50% of the joint space, 3 indicates loss of 75% of the joint space, and 4 represents complete loss of the joint space. The erosions are counted individually, usually at 16 sites in each hand and wrist and six sites in each foot, with a maximum score of 5 given for a destroyed hand or foot joint. For joints in the feet, the van der Heijde version of the Sharp scoring system has a maximum score of 10 for a destroyed joint | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients in remission | as defined by the DAS 28 score | 12 weeks, 24 weeks, 52 weeks | 
| Changes of functional capacity | as defined by the so called Hannover function questionnaire | Baseline, 12 weeks, 52 weeks | 
| Patient's assessment of disease activity | on a scale between 0 and 10 | Baseline, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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radiographic damage, rheumatoid arthritis