Lovastatin for the Treatment of Mildly Active Rheumatoid Arthritis

Study Overview
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Brief Summary
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Rheumatoid arthritis (RA) is the most common inflammatory arthritis and a major health problem. The purpose of this study is to determine the safety and effectiveness of lovastatin for controlling inflammation in mildly active RA.

Detailed Description
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RA is characterized by persistent inflammation of peripheral joints, causing pain, stiffness, swelling, and warmth. The inflammation may cause progressive joint damage and destruction, resulting in deformity and loss of function. Both traditional and biologic disease-modifying antirheumatic drugs (DMARDs) have been prescribed for RA patients to control existing inflammatory symptoms and affect long-term prognosis. However, DMARD use is expensive, and the long-term safety of DMARDs is unknown. Lovastatin is an HMG-CoA reductase inhibitor (also known as a statin) used to lower levels of cholesterol and other fats in the blood. The purpose of this study is to examine the safety and efficacy of lovastatin in controlling inflammation in individuals with RA who have mildly active RA disease despite treatment. Participants will be randomly assigned to one of two study arms (Experimental or Placebo). There will be four study visits over 12 weeks. At each visit, a physical exam, vital signs measurement, medication history, a pregnancy test (if applicable), and blood collection will occur. Additional safety blood testing will occur at Week 2. Tender and swollen joint counts and a Physician Global Assessment will occur at study entry and Week 12. Participants will also be asked to complete self-assessments at study entry and Week 12.

Official Title
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A Double Blind, Placebo Controlled, Phase II, Randomized Study of Lovastatin Therapy in the Treatment of Mildly Active Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Lovastatin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of RA as defined by 1987 American College of Rheumatology (ACR) criteria Functional Class I, II, or III RA as defined by 1987 ACR criteria Serum C-reactive protein (CRP) measurement of greater than 5 mg/L Mildly active disease with at least one swollen and two tender joints, but no more than six swollen and eight tender joints If on corticosteroids, dose must be stable and 10 mg/day prednisone (or equivalent) or less for at least 4 weeks prior to study entry If on DMARD, dose must be stable for at least 4 weeks (methotrexate, leflunomide, azathioprine, etanercept, adalimumab, anakinra) or at least 3 months (hydroxychloroquine, gold, or abatacept) Willing to use acceptable means of contraception Exclusion Criteria: Serum creatinine level greater than 1.5 mg/dL Currently taking a statin or have taken a statin within 12 weeks of study entry History of an adverse reaction to a statin Active or recent infection within 4 weeks of study entry Myositis or an unexplained elevation in creatine phosphokinase (CPK) Joint replacement surgery within 60 days of study entry or plan to undergo joint replacement surgery during the course of the study Intra-articular cortisone injections within 4 weeks of study entry Chronic disorders other than RA affecting the joints, including systemic lupus erythematosus (SLE), psoriatic arthritis, gout, scleroderma, or known reactive arthritis (Reiter's syndrome) HIV infection Hepatitis B surface antigen positive Hepatitis C antibody positive Treatment with infliximab within 12 weeks of study entry Treatment with rituximab Treatment with medications known to be metabolized by the cytochrome P3A4 pathway. More information about this criterion can be found in the protocol. Require amiodarone or verapamil Investigational drug or treatment during the 4 weeks or seven half-lives prior to study entry History of alcohol abuse History of liver disease, current liver disease (e.g., hepatitis, cirrhosis), or abnormal liver function (AST or ALT greater than 2 times the upper limit of normal [ULN]) Any condition that, in the opinion of the investigator, may interfere with the study Pregnancy or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Lovastatin<br>Participants are randomized to take two 40 mg lovastatin tablets orally once daily for a total of 12 weeks in a blinded (masked) fashion. For toxicity, the dose could either be adjusted to one 40 mg lovastatin tablet or treatment could be discontinued. In addition to the active ingredient lovastatin, each tablet contained the following ingredients: microcrystalline cellulose, lactose monohydrate, magnesium stearate, and pregelatinized starch. Butylated hydroxyanisole (BHA) was added as a preservative and D&C Yellow #10, FD&C Blue #1, and Yellow #6 were added as dyes. | Drug: Lovastatin<br>* Two 40 mg lovastatin tablets orally once daily for a total of 12 weeks in a blinded (masked) fashion<br>* Other names: Mevinolin;|
| Placebo Comparator: Placebo<br>Participants are randomized to take two placebo tablets orally once daily for a total of 12 weeks in a blinded (masked) fashion. For toxicity, the dose could either be adjusted to one placebo tablet or treatment could be discontinued. The placebo tablets contained microcrystalline cellulose, NF (Avicel PH 102) and Supro AA Swedish Orange Opaque Capsule Shells, Color 4188. | Drug: Placebo<br>* Two placebo tablets orally once daily for a total of 12 weeks in a blinded (masked) fashion<br>* Other names: Inactive drug (pharmacologically);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Mean Change From Baseline in Log Transformed C - Reactive Protein (CRP) at Day 84 | Blood draw for CRP, an acute phase reactant used to identify the presence of nonspecific inflammation. Change=Day 84 value minus Baseline value. Normal serum CRP reference range in this study is 0-4 mg/L (log transformed: -4.2 to 1.4). Participants with measurements for designated time points were included in analysis. An increased CRP level indicates the presence of inflammation. Reduced CRP levels could mean a decrease in inflammation. | Baseline (Day 0), Day 84 (Wk 12) | 
| Change From Baseline in Alkaline Phosphatase, Alanine Aminotransferase (ALT), and Aspartate Aminotransferase (AST) at Day 84 | Blood samples were taken from participants at Baseline and Day 84. Participants with measurements for designated time points included in analysis. Change=Day 84 value minus Baseline value. A positive difference reflects an increased laboratory parameter value over time; a negative difference reflects a decreased laboratory parameter value over time. Normal laboratory values depend on a subject age, gender, and the specific laboratory methods that were used to determine the lab values. Reference: http://www.merckmanuals.com/professional/appendixes/normal_laboratory_values/blood_tests_normal_values.html | Baseline (Day 0), Day 84 (Wk 12) | 
| Change From Baseline in Total Bilirubin, Creatinine, BUN, Phosphorus, Calcium, and Glucose at Day 84 | Blood samples were taken from participants at Baseline and Day 84. Participants with measurements for designated time points included in analysis. Change=Day 84 value minus Baseline value. A positive difference reflects an increased laboratory parameter value over time; a negative difference reflects a decreased laboratory parameter value over time. Normal laboratory values depend on a subject age, gender, and the specific laboratory methods that were used to determine the lab values. Reference: http://www.merckmanuals.com/professional/appendixes/normal_laboratory_values/blood_tests_normal_values.html | Baseline (Day 0), Day 84 (Wk 12) | 
| Change From Baseline in Albumin, Total Protein, Hemoglobin, and Mean Corpuscular Hemoglobin Concentration (MCHC) at Day 84 | Blood samples were taken from participants at Baseline and Day 84. Participants with measurements for designated time points included in analysis. Change=Day 84 value minus Baseline value. A positive difference reflects an increased laboratory parameter value over time; a negative difference reflects a decreased laboratory parameter value over time. Normal laboratory values depend on a subject age, gender, and the specific laboratory methods that were used to determine the lab values. Reference: http://www.merckmanuals.com/professional/appendixes/normal_laboratory_values/blood_tests_normal_values.html | Baseline (Day 0), Day 84 (Wk 12) | 
| Change From Baseline in Potassium, Sodium, Chloride, and Total CO2 at Day 84 | Blood samples were taken from participants at Baseline and Day 84. Participants with measurements for designated time points included in analysis. Change=Day 84 value minus Baseline value. A positive difference reflects an increased laboratory parameter value over time; a negative difference reflects a decreased laboratory parameter value over time. Normal laboratory values depend on a subject age, gender, and the specific laboratory methods that were used to determine the lab values. Reference: http://www.merckmanuals.com/professional/appendixes/normal_laboratory_values/blood_tests_normal_values.html | Baseline (Day 0), Day 84 (Wk 12) | 
| Change From Baseline in CPK at Day 84 | Blood samples were taken from participants at Baseline and Day 84. Participants with measurements for designated time points included in analysis. Change=Day 84 value minus Baseline value. A positive difference reflects an increased laboratory parameter value over time; a negative difference reflects a decreased laboratory parameter value over time. Normal laboratory values depend on a subject age, gender, and the specific laboratory methods that were used to determine the lab values. Reference: http://www.merckmanuals.com/professional/appendixes/normal_laboratory_values/blood_tests_normal_values.html | Baseline (Day 0), Day 84 (Wk 12) | 
| Change From Baseline in Counts: White Blood Cells (WBC), Neutrophils, Bands, Lymphocytes, Monocytes, Eosinophils, Basophils, Platelets, and Reticulocytes at Day 84 | Blood samples were taken from participants at Baseline and Day 84. Participants with measurements for designated time points included in analysis. Change=Day 84 value minus Baseline value. A positive difference reflects an increased laboratory parameter value over time; a negative difference reflects a decreased laboratory parameter value over time. Normal laboratory values depend on a subject age, gender, and the specific laboratory methods that were used to determine the lab values. Reference: http://www.merckmanuals.com/professional/appendixes/normal_laboratory_values/blood_tests_normal_values.html | Baseline (Day 0), Day 84 (Wk 12) | 
| Change From Baseline in Hematocrit (Hct) at Day 84 | Blood samples were taken from participants at Baseline and Day 84. Participants with measurements for designated time points included in analysis. Change=Day 84 value minus Baseline value. A positive difference reflects an increased laboratory parameter value over time; a negative difference reflects a decreased laboratory parameter value over time. Normal laboratory values depend on a subject age, gender, and the specific laboratory methods that were used to determine the lab values. Reference: http://www.merckmanuals.com/professional/appendixes/normal_laboratory_values/blood_tests_normal_values.html | Baseline (Day 0), Day 84 (Wk 12) | 
| Change From Baseline in Red Cell Distribution Width (RDW) at Day 84 | Blood samples were taken from participants at Baseline and Day 84. Participants with measurements for designated time points included in analysis. Change=Day 84 value minus Baseline value. A positive difference reflects an increased laboratory parameter value over time; a negative difference reflects a decreased laboratory parameter value over time. Normal laboratory values depend on a subject age, gender, and the specific laboratory methods that were used to determine the lab values. Reference: http://www.merckmanuals.com/professional/appendixes/normal_laboratory_values/blood_tests_normal_values.html | Baseline (Day 0), Day 84 (Wk 12) | 
| Change From Baseline in Mean Corpuscular Hemoglobin (MCH) at Day 84 | Blood samples were taken from participants at Baseline and Day 84. Participants with measurements for designated time points included in analysis. Change=Day 84 value minus Baseline value. A positive difference reflects an increased laboratory parameter value over time; a negative difference reflects a decreased laboratory parameter value over time. Normal laboratory values depend on a subject age, gender, and the specific laboratory methods that were used to determine the lab values. Reference: http://www.merckmanuals.com/professional/appendixes/normal_laboratory_values/blood_tests_normal_values.html | Baseline (Day 0), Day 84 (Wk 12) | 
| Change From Baseline in Mean Corpuscular Volume (MCV) at Day 84 | Blood samples were taken from participants at Baseline and Day 84. Participants with measurements for designated time points included in analysis. Change=Day 84 value minus Baseline value. A positive difference reflects an increased laboratory parameter value over time; a negative difference reflects a decreased laboratory parameter value over time. Normal laboratory values depend on a subject age, gender, and the specific laboratory methods that were used to determine the lab values. Reference: http://www.merckmanuals.com/professional/appendixes/normal_laboratory_values/blood_tests_normal_values.html | Baseline (Day 0), Day 84 (Wk 12) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Mean Change From Baseline in the Disease Activity Score Using C-reactive Protein (DAS28-CRP) on Day 84 | The DAS28-CRP score is on a scale of 0 to 10 and indicates current activity of rheumatoid arthritis (>5.1=high disease activity; 3.2-<=5.1=moderate disease activity; <=3.2=low disease activity; <2.6=remission). The score uses a combination of four variables: 1) the number of tender joints (of the 28 that are measured); 2) the number of swollen joints (of the 28 that are measured); 3) serum C-reactive protein (CRP) lab value in mg/L , and 4) Patient Global Assessment of Disease Activity. Using a formula, the physician determines the score. Participants with measurements for designated time points included in analysis. | Baseline (Day 0) to Day 84 (Wk 12) | 
| Percentage of Participants Meeting ACR20 Response Criteria at Day 84 (ACR: American College of Rheumatology) | Patients were ACR20 Responders if they had: at least 20% improvement in both tender joint count (28 examined) and swollen joint count (28 examined), and 20% improvement in at least three of the following 5 remaining ACR core measures: • Patient's pain assessment (Visual Analogue Scale (VAS) 100 mm) • Patient's global assessment of disease activity (VAS 100 mm) • Physician's global assessment of disease activity (VAS 100 mm) • Patient self-assessed disability (Health Assessment Questionnaire (HAQ)) score • Acute phase reactant C-reactive protein. Participants with measurements for designated time points were included in analysis. | Day 84 (Wk 12) | 
| Adjusted Mean Change From Baseline in Serum IgM Rheumatoid Factor by ELISA (ELISA: Enzyme-linked Immunosorbent Assay) | Rheumatoid factor (RF) is an antibody often present in the blood of a person with rheumatoid arthritis. In this study, a positive value for RF was 0.5 IU/mL or greater; a negative value for RF was <0.5 IU/mL. Change= Day 84 value minus Baseline value. In general, presence of the antibody indicates aggressive rheumatoid arthritis and higher risk of joint damage. Participants with measurements for designated time points included in analysis. | Baseline (Day 0), Day 84 (Wk 12) | 
| Adjusted Mean Change From Baseline in Serum Anti-cyclic Citrullinated Peptide (Anti-CCP) by ELISA (ELISA: Enzyme-linked Immunosorbent Assay) | Anti-CCP antibodies are autoantibodies frequently detected in the serum of individuals with rheumatoid arthritis. In this study, a positive value for anti-CCP was 8 IU/mL or greater; a negative value for anti-CCP was <8 IU/mL. Change= subtraction of Day 0 from Day 84 anti-CCP value. In general, high levels of the antibody indicate an aggressive rheumatoid arthritis and a higher risk of joint damage. Participants with measurements for designated time points included in analysis. | Baseline ( Day 0), Day 84 (Wk 12) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Arthritis, Rheumatoid