Lovastatin for the Treatment of Mildly Active Rheumatoid Arthritis

This study has been completed.
Sponsor:
Collaborator:
Autoimmunity Centers of Excellence
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00302952
First received: March 13, 2006
Last updated: February 12, 2014
Last verified: February 2014
  Purpose

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.


Condition Intervention Phase
Rheumatoid Arthritis
Drug: Lovastatin
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver)
Primary Purpose: Treatment
Official Title: A Double Blind, Placebo Controlled, Phase II, Randomized Study of Lovastatin Therapy in the Treatment of Mildly Active Rheumatoid Arthritis

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Adjusted Mean Change From Baseline in Log Transformed C - Reactive Protein (CRP) at Day 84 [ Time Frame: Baseline (Day 0), Day 84 (Wk 12) ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Alkaline Phosphatase, Alanine Aminotransferase (ALT), and Aspartate Aminotransferase (AST) at Day 84 [ Time Frame: Baseline (Day 0), Day 84 (Wk 12) ] [ Designated as safety issue: Yes ]
    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

  • Change From Baseline in Total Bilirubin, Creatinine, BUN, Phosphorus, Calcium, and Glucose at Day 84 [ Time Frame: Baseline (Day 0), Day 84 (Wk 12) ] [ Designated as safety issue: Yes ]
    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

  • Change From Baseline in Albumin, Total Protein, Hemoglobin, and Mean Corpuscular Hemoglobin Concentration (MCHC) at Day 84 [ Time Frame: Baseline (Day 0), Day 84 (Wk 12) ] [ Designated as safety issue: Yes ]
    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

  • Change From Baseline in Potassium, Sodium, Chloride, and Total CO2 at Day 84 [ Time Frame: Baseline (Day 0), Day 84 (Wk 12) ] [ Designated as safety issue: Yes ]
    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

  • Change From Baseline in CPK at Day 84 [ Time Frame: Baseline (Day 0), Day 84 (Wk 12) ] [ Designated as safety issue: Yes ]
    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

  • Change From Baseline in Counts: White Blood Cells (WBC), Neutrophils, Bands, Lymphocytes, Monocytes, Eosinophils, Basophils, Platelets, and Reticulocytes at Day 84 [ Time Frame: Baseline (Day 0), Day 84 (Wk 12) ] [ Designated as safety issue: Yes ]
    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

  • Change From Baseline in Hematocrit (Hct) at Day 84 [ Time Frame: Baseline (Day 0), Day 84 (Wk 12) ] [ Designated as safety issue: Yes ]
    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

  • Change From Baseline in Red Cell Distribution Width (RDW) at Day 84 [ Time Frame: Baseline (Day 0), Day 84 (Wk 12) ] [ Designated as safety issue: Yes ]
    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

  • Change From Baseline in Mean Corpuscular Hemoglobin (MCH) at Day 84 [ Time Frame: Baseline (Day 0), Day 84 (Wk 12) ] [ Designated as safety issue: Yes ]
    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

  • Change From Baseline in Mean Corpuscular Volume (MCV) at Day 84 [ Time Frame: Baseline (Day 0), Day 84 (Wk 12) ] [ Designated as safety issue: Yes ]
    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


Secondary Outcome Measures:
  • Adjusted Mean Change From Baseline in the Disease Activity Score Using C-reactive Protein (DAS28-CRP) on Day 84 [ Time Frame: Baseline (Day 0) to Day 84 (Wk 12) ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants Meeting ACR20 Response Criteria at Day 84 (ACR: American College of Rheumatology) [ Time Frame: Day 84 (Wk 12) ] [ Designated as safety issue: No ]
    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.

  • Adjusted Mean Change From Baseline in Serum IgM Rheumatoid Factor by ELISA (ELISA: Enzyme-linked Immunosorbent Assay) [ Time Frame: Baseline (Day 0), Day 84 (Wk 12) ] [ Designated as safety issue: No ]
    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.

  • Adjusted Mean Change From Baseline in Serum Anti-cyclic Citrullinated Peptide (Anti-CCP) by ELISA (ELISA: Enzyme-linked Immunosorbent Assay) [ Time Frame: Baseline ( Day 0), Day 84 (Wk 12) ] [ Designated as safety issue: No ]
    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.


Enrollment: 64
Study Start Date: August 2006
Study Completion Date: April 2012
Primary Completion Date: April 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Lovastatin
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
Two 40 mg lovastatin tablets orally once daily for a total of 12 weeks in a blinded (masked) fashion
Other Names:
  • Altoprev
  • Mevacor
  • Mevinolin
Placebo Comparator: Placebo
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
Two placebo tablets orally once daily for a total of 12 weeks in a blinded (masked) fashion
Other Name: Inactive drug (pharmacologically)

Detailed 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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00302952

Locations
United States, Alabama
University of Alabama
Birmingham, Alabama, United States, 35294
United States, California
University of California, San Francisco
San Francisco, California, United States, 94143
United States, Colorado
University of Colorado
Aurora, Colorado, United States, 80095
United States, Illinois
University of Chicago Medical Center
Chicago, Illinois, United States, 60637
United States, Michigan
Justus J. Fiechtner, MD, PLLC
Lansing, Michigan, United States, 48910
United States, New York
Feinstein Institute for Medical Research NS-LIJ Health System
Manhasset, New York, United States, 11030
University of Rochester
Rochester, New York, United States, 14642
United States, North Carolina
Carolina Bone and Joint
Charlotte, North Carolina, United States, 29425
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Oklahoma
Oklahoma Medical Research Foundation
Oklahoma City, Oklahoma, United States, 73104
United States, Pennsylvania
Altoona Center for Clinical Research
Duncansville, Pennsylvania, United States, 16635
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States, 15261
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29425
United States, Texas
Baylor Research Institute
Dallas, Texas, United States, 75231
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84132
Sponsors and Collaborators
Autoimmunity Centers of Excellence
Investigators
Study Chair: Cynthia Aranow, MD Feinstein Institute for Medical Research NS-LIJ Health System
Study Chair: Betty Diamond, MD Feinstein Institute for Medical Research NS-LIJ Health System
  More Information

Publications:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00302952     History of Changes
Other Study ID Numbers: DAIT ARA02
Study First Received: March 13, 2006
Results First Received: December 18, 2013
Last Updated: February 12, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Arthritis, Rheumatoid

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Lovastatin
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Enzyme Inhibitors
Lipid Regulating Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 28, 2014