Rheumatoid Arthritis
Conditions
Keywords
RA, Rheumatoid Arthritis
Brief summary
Rheumatoid arthritis (RA) is a form of arthritis that causes pain, swelling, stiffness, and loss of function in the joints. Over time, joint deformity, joint destruction, and loss of function can occur. Current treatment aims to improve symptoms, but there is no cure for the disease. Pioglitazone is drug that is effective in treating people with diabetes. This study will determine whether pioglitazone can also be used to effectively treat people with RA.
Detailed description
RA is an autoimmune disease that causes long-term inflammation of the joints and sometimes other body tissues, too. Recent studies have found that there is an increased prevalence of coronary artery atherosclerosis, metabolic syndrome, and insulin resistance among people with RA. Furthermore, insulin resistance, which can lead to hyperinsulinemia-too much insulin in the blood-has been associated with RA disease activity and the severity of coronary artery atherosclerosis. These correlations suggest that inflammation and hyperinsulinemia somehow interact and facilitate one another. Pioglitazone is a prescription drug that reduces insulin resistance and is currently used to treat people with diabetes. This study will determine whether pioglitazone can also be used to effectively treat people with RA. Specifically, the study will evaluate the effect of pioglitazone on inflammation, insulin resistance, and atherosclerosis. Participation in this study will last about 20 weeks. At an initial 1-hour screening, participants will undergo a physical examination, medical history review, blood sampling, and, if female, a urine pregnancy test. Eligible participants will then return for the first of six monthly study visits. At this first visit, participants will be randomly assigned to receive either pioglitazone or placebo, both of which will be taken daily for 8 weeks. This will be followed by a 4-week wash-out period, during which no study treatments will be taken. Then, at Week 12, participants will begin daily treatments of whatever they were not assigned to originally. This second treatment phase will also last for 8 weeks. All of the study visits will involve the same tests and procedures. The morning before each study visit, participants will collect their urine in a jug, which they will bring to the clinic. Participants will then undergo blood sampling, blood pressure measurements, and artery stiffness measurements. During the study visits at Weeks 4, 8, 16, and 20, participants will be asked to report on their symptoms, pain, and any adverse effects.
Interventions
DRUGPioglitazone
45 mg by mouth once a day for 8 weeks
DRUGPlacebo
By mouth once a day for 8 weeks
Sponsors
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Vanderbilt University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Meets the American College of Rheumatology (ACR) criteria for the diagnosis of rheumatoid arthritis (RA) * Stable disease activity, as evidenced by no change in immunomodulating or anti-inflammatory therapy in the 1 month before study entry * Moderate disease activity, as reflected by a minimum of three swollen and tender joints * If female of childbearing potential, willing to use effective method of contraception
Exclusion criteria
* Allergic to pioglitazone * Active cancer (other than skin cancer) * HIV infected * Currently receiving dialysis * Received an organ or bone marrow transplant * Heart failure * Severe edema, as judged by the principal investigator * Diabetes mellitus requiring drug therapy: levels of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than twice the upper limit of normal * Underwent major surgery in the 3 months before study entry * Severe comorbid condition that is likely to compromise survival or study participation * Currently receiving gemfibrozil or rifampin * Osteoporosis and not receiving osteoporosis medications * Unwillingness, or other inability, to cooperate with study procedures * Pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease Activity Score Based on 28-joint Disease Activity Score (DAS28) | Measured after 8 weeks of treatment | A measure of disease activity based upon tender joint count of 28 joints, swollen joint count of 28 joints, erythrocyte sedimentation rate, and global disease activity (GH) as reported by participant. Calculation is as follows: DAS28=0.56\*sqrt(t28) + 0.28\*sqrt(sw28) + 0.70\*Ln(ESR) + 0.014\*GH |
| Homeostasis Model Assessment (HOMA) for Insulin Sensitivity | Measured after 8 weeks of treatment | Homa is a measure of insulin sensitivity, using glucose measured in mmol/L and insulin measured in milliUnits per liter (mU/L) Calculated using the formula Glucose \* Insulin/22/5 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| C-reactive Protein (CRP) | Measured after 8 weeks of treatment | — |
| ESR | baseline and after 8 weeks on either placebo or pioglitazone | sed rate |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Baseline Characteristics of Participants participants who met American College of Rheumatology (ACR) criteria for rheumatoid arthritis (RA), age 18 or older, with moderate disease activity and no change in immunomodulating or anti-inflammatory therapy in past month | 34 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 2 |
| Overall Study | med change not allowed by protocol | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Baseline Characteristics of Participants |
|---|---|
| Age, Continuous | 51.0 years STANDARD_DEVIATION 14.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 29 Participants |
| Region of Enrollment United States | 34 participants |
| Sex: Female, Male Female | 28 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 34 | 6 / 34 |
| serious Total, serious adverse events | 0 / 34 | 2 / 34 |
Outcome results
Primary
Disease Activity Score Based on 28-joint Disease Activity Score (DAS28)
A measure of disease activity based upon tender joint count of 28 joints, swollen joint count of 28 joints, erythrocyte sedimentation rate, and global disease activity (GH) as reported by participant. Calculation is as follows: DAS28=0.56\*sqrt(t28) + 0.28\*sqrt(sw28) + 0.70\*Ln(ESR) + 0.014\*GH
Time frame: Measured after 8 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone Phase Baseline | Disease Activity Score Based on 28-joint Disease Activity Score (DAS28) | 4.40 units on a scale | Standard Deviation 1 |
| Pioglitazone Phase After 8 Weeks | Disease Activity Score Based on 28-joint Disease Activity Score (DAS28) | 4.03 units on a scale | Standard Deviation 1.15 |
| Placebo Phase Baseline | Disease Activity Score Based on 28-joint Disease Activity Score (DAS28) | 4.57 units on a scale | Standard Deviation 1.28 |
| Placebo Phase wk 8/20 | Disease Activity Score Based on 28-joint Disease Activity Score (DAS28) | 4.48 units on a scale | Standard Deviation 1.2 |
Primary
Homeostasis Model Assessment (HOMA) for Insulin Sensitivity
Homa is a measure of insulin sensitivity, using glucose measured in mmol/L and insulin measured in milliUnits per liter (mU/L) Calculated using the formula Glucose \* Insulin/22/5
Time frame: Measured after 8 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone Phase Baseline | Homeostasis Model Assessment (HOMA) for Insulin Sensitivity | 2.83 units on a scale | Standard Deviation 2.5 |
| Pioglitazone Phase After 8 Weeks | Homeostasis Model Assessment (HOMA) for Insulin Sensitivity | 2.44 units on a scale | Standard Deviation 2.08 |
| Placebo Phase Baseline | Homeostasis Model Assessment (HOMA) for Insulin Sensitivity | 2.38 units on a scale | Standard Deviation 1.75 |
| Placebo Phase wk 8/20 | Homeostasis Model Assessment (HOMA) for Insulin Sensitivity | 3.11 units on a scale | Standard Deviation 3.47 |
Secondary
C-reactive Protein (CRP)
Time frame: Measured after 8 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone Phase Baseline | C-reactive Protein (CRP) | 8.1 mg/dl | Standard Deviation 11.41 |
| Pioglitazone Phase After 8 Weeks | C-reactive Protein (CRP) | 5.02 mg/dl | Standard Deviation 7.64 |
| Placebo Phase Baseline | C-reactive Protein (CRP) | 7.7 mg/dl | Standard Deviation 13.6 |
| Placebo Phase wk 8/20 | C-reactive Protein (CRP) | 8.25 mg/dl | Standard Deviation 10.32 |
Secondary
ESR
sed rate
Time frame: baseline and after 8 weeks on either placebo or pioglitazone
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone Phase Baseline | ESR | 18.5 mm/hr | Standard Deviation 18.2 |
| Pioglitazone Phase After 8 Weeks | ESR | 17 mm/hr | Standard Deviation 17.06 |
| Placebo Phase Baseline | ESR | 19.5 mm/hr | Standard Deviation 20 |
| Placebo Phase wk 8/20 | ESR | 18.88 mm/hr | Standard Deviation 20.8 |