Hydroxychloroquine to Improve Insulin Sensitivity in Rheumatoid Arthritis

NCT ID: NCT01132118

Last Updated: 2014-09-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-06-30
• Study Completion Date: 2012-06-30

Brief Summary

The purpose of this study is to determine whether hydroxychloroquine (HCQ) reduces insulin resistance in non-diabetic subjects with rheumatoid arthritis (RA). The investigators will conduct a double-blind randomized crossover trial in subjects with RA to test the hypothesis that HCQ improves insulin sensitivity. The investigators will also use data from the trial to identify determinants of insulin resistance in RA. The investigators hypothesize that RA will be associated with an increased risk of insulin resistance and that independent risk factors for increased insulin resistance in RA include higher BMI, elevated acute phase reactants, greater fat to muscle ratio, and less physical activity.

Detailed Description

Our ability to better control the pain and disability of rheumatoid arthritis (RA) now focuses attention on reducing the impact of RA-associated comorbidities. The most common cause of death in RA is cardiovascular (CV) disease, and the risk of myocardial infarction and stroke are approximately doubled in RA. The determinants of CV risk in RA include traditional CV risk factors as well as aspects of the inflammatory process defining RA. It is likely that RA-associated inflammation accelerates atherosclerosis through direct effects on the endothelium as well as indirect effects on insulin metabolism. Several studies report an increased prevalence of insulin resistance among persons with RA. However, it is not clear whether the inflammation of RA causes insulin resistance. Corticosteroids and abnormalities in the hypothalamic-pituitary axis may also contribute to abnormal glucose metabolism. Little information is available to guide management of a pre-diabetic insulin resistance state in RA.

Hydroxychloroquine (HCQ), a commonly used medicine early in RA, may play a role in improving insulin resistance. Several previous trials demonstrated the ability of HCQ to reduce blood glucose levels in diabetics, and a large epidemiologic study found that subjects with RA using HCQ were less likely to develop diabetes. In animal models, anti-malarials lower blood glucose through slowing insulin metabolism.

With CV disease a major comorbidity in RA and insulin resistance possibly a major determinant of CV risk, intervention studies need to begin to translate prior work into clinical therapeutics.

Relevance: If this study demonstrates a beneficial effect of HCQ on insulin resistance among the randomized subjects, this would provide strong evidence that HCQ has benefits beyond RA and SLE disease activity. Currently, HCQ is stopped in many patients as they "step-up" to more aggressive DMARD treatments, or HCQ may never be tried in some patients who present with RA carrying with poor prognosis. If HCQ improves insulin sensitivity, there may be rationale for continuing HCQ chronically in patients with RA. As well, a larger clinical endpoint study would be strongly considered.

Conditions

Rheumatoid Arthritis; Insulin Resistance

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Placebo then HCQ

This arm of the study will contain half the study population after randomization. The participants in this arm will receive hydroxychloroquine for 8 weeks and then crossover to a placebo for 8 weeks. Study staff will be blinded to which order they are taking the hydroxychloroquine and placebo in.

Group Type: OTHER

Hydroxychloroquine

Intervention Type: DRUG

Hydroxychloroquine comes in 200 mg tablets and is taken orally. The dose provided will be based upon a calculation of 6.5 mg/kg (subject's weight), which is the dose range commonly used to treat rheumatoid arthritis and lupus. Dosages will be rounded to the nearest 100 mg.

HCQ then Placebo

This arm of the study will contain half the study population after randomization. The participants in this arm will receive hydroxychloroquine for 8 weeks and then crossover to a placebo for 8 weeks. Study staff will be blinded to which order they are taking the hydroxychloroquine and placebo in.

Group Type: OTHER

Hydroxychloroquine

Intervention Type: DRUG

Hydroxychloroquine comes in 200 mg tablets and is taken orally. The dose provided will be based upon a calculation of 6.5 mg/kg (subject's weight), which is the dose range commonly used to treat rheumatoid arthritis and lupus. Dosages will be rounded to the nearest 100 mg.

Interventions

Hydroxychloroquine

Hydroxychloroquine comes in 200 mg tablets and is taken orally. The dose provided will be based upon a calculation of 6.5 mg/kg (subject's weight), which is the dose range commonly used to treat rheumatoid arthritis and lupus. Dosages will be rounded to the nearest 100 mg.

Intervention Type: DRUG

Other Intervention Names

Plaquenil

Eligibility Criteria

Inclusion Criteria

• Age 18 or older
• Able to provide informed consent and comply with study visits
• Hemoglobin ≥ 10 g/dL (within last two months)
• WBC ≥ 4 K/uL (within last two months)
• Platelet count ≥ 150 ≤ 450 K/uL (within last two months)
• (GFR) Creatinine clearance ≥ 70 ml/min (MDRD) (within last two months)
• SGOT, SGPT ≤ 1.5 times upper limits of normal (within last two months)
• Normal eye exam within 12 months of study entry (copy of letter from subject's ophthalmologist or optometrist stating that the subject has no evidence of macular pathology)
• Diagnosis of rheumatoid arthritis

Exclusion Criteria

• History of any neuromuscular disease including muscular dystrophy, metabolic myopathies, peripheral neuropathy, multiple sclerosis, and other myopathies or myositides
• History of diabetes or fasting plasma glucose of 126 mg/dl or greater
• History of any untoward reaction to antimalarials
• Uncontrolled hypertension (>140/90)
• History of any ophthalmologic disease except for glaucoma or cataracts
• Planned elective surgery during the study period
• Digoxin therapy
• Treatment with corticosteroids (> 5 mg) for any disorder
• History of psoriasis
• Any chronic disease that in the opinion of the investigator warrants exclusion (e.g. inflammatory bowel disease, malignancy other than basal cell carcinoma, chronic liver disease)
• History of chronic intestinal disorders (Crohn's disease, ulcerative colitis, celiac sprue, collagenous colitis, eosinophilic enteritis)
• Creatinine clearance ≤ 60 ml/min (MDRD) (within last two months)
• Hemoglobin ≤ 10 g/dL (within last two months)
• WBC ≤ 4 K/uL (within last two months)
• Platelet count ≤ 150 ≥ 450 K/uL (within last two months)
• SGOT, SGPT ≥ 1.5 times upper limits of normal (within last two months)
• Women who are pregnant or breastfeeding

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

NIH

Sponsor Role: collaborator

Brigham and Women's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Daniel H. Solomon, M.D.,MPH

Director of Clinical Sciences

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Daniel H Solomon, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

Brigham and Women's Hospital

Elena M Massarotti, MD

Role: PRINCIPAL_INVESTIGATOR

Brigham and Women's Hospital

Rajesh K Garg, MD

Role: PRINCIPAL_INVESTIGATOR

Brigham and Women's Hospital

Locations

Brigham and Women's Hospital

Boston, Massachusetts, United States

Countries

United States

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Other Identifiers

R21AR057924

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2009P001926

Identifier Type: -

Identifier Source: org_study_id