Lovastatin for the Treatment of Mildly Active Rheumatoid Arthritis

Rheumatoid Arthritis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00302952
• Other study ID #: DAIT ARA02
• Status: Terminated
• Phase: Phase 2
• Start date: November 6, 2007
• Est. completion date: April 30, 2012

Study information

• Verified date: August 2022
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 64
• Est. completion date: April 30, 2012
• Est. primary completion date: April 30, 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• Lovastatin
Two 40 mg lovastatin tablets orally once daily for a total of 12 weeks in a blinded (masked) fashion
• Placebo
Two placebo tablets orally once daily for a total of 12 weeks in a blinded (masked) fashion

Locations

Country	Name	City	State
United States	University of Colorado	Aurora	Colorado
United States	University of Alabama	Birmingham	Alabama
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Carolina Bone and Joint	Charlotte	North Carolina
United States	University of Chicago Medical Center	Chicago	Illinois
United States	Baylor Research Institute	Dallas	Texas
United States	Altoona Center for Clinical Research	Duncansville	Pennsylvania
United States	Duke University Medical Center	Durham	North Carolina
United States	Justus J. Fiechtner, MD, PLLC	Lansing	Michigan
United States	Feinstein Institute for Medical Research NS-LIJ Health System	Manhasset	New York
United States	Oklahoma Medical Research Foundation	Oklahoma City	Oklahoma
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	University of Rochester	Rochester	New York
United States	University of Utah	Salt Lake City	Utah
United States	University of California, San Francisco	San Francisco	California

Sponsors (2)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Autoimmunity Centers of Excellence

Country where clinical trial is conducted

United States, 

References & Publications (3)

Abud-Mendoza C, de la Fuente H, Cuevas-Orta E, Baranda L, Cruz-Rizo J, González-Amaro R. Therapy with statins in patients with refractory rheumatic diseases: a preliminary study. Lupus. 2003;12(8):607-11. — View Citation

Aranow C, Cush J, Bolster MB, Striebich CC, Dall'era M, Mackay M, Olech E, Frech T, Box J, Keating R, Wasko MC, St Clair W, Kivitz A, Huang W, Ricketts P, Welch B, Callahan S, Spychala M, Boyle K, York K, Keyes-Elstein L, Goldmuntz E, Diamond B, Davidson — View Citation

McCarey DW, McInnes IB, Madhok R, Hampson R, Scherbakov O, Ford I, Capell HA, Sattar N. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet. 2004 Jun 19;363(9426):2015-21. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)

External Links

•   Autoimmunity Centers of Excellence (ACE)
•   Division of Allergy, Immunology, and Transplantation (DAIT)
•   National Institute of Allergy and Infectious Diseases (NIAID)