Hydroxychloroquine to Improve Insulin Sensitivity in Rheumatoid Arthritis (RA PLUS)
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ClinicalTrials.gov Identifier: NCT01132118 |
Recruitment Status
:
Completed
First Posted
: May 27, 2010
Results First Posted
: September 3, 2014
Last Update Posted
: September 3, 2014
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Condition or disease | Intervention/treatment | Phase |
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Rheumatoid Arthritis Insulin Resistance | Drug: Hydroxychloroquine | Phase 3 |
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.
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 30 participants |
Allocation: | Randomized |
Intervention Model: | Crossover Assignment |
Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
Primary Purpose: | Treatment |
Official Title: | Hydroxychloroquine to Improve Insulin Sensitivity in Rheumatoid Arthritis |
Study Start Date : | June 2010 |
Actual Primary Completion Date : | April 2012 |
Actual Study Completion Date : | June 2012 |

Arm | Intervention/treatment |
---|---|
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.
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Drug: 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.
Other Name: Plaquenil
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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.
|
Drug: 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.
Other Name: Plaquenil
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- Insulin Sensitivity Index [ Time Frame: Baseline and Week 8 ]
We will examine the effect of HCQ on the Matsuda Insulin Sensitivity Index (ISI) during the active treatment phase compared with placebo phase.
ISI is based on insulin and glucose levels in a fasting state during an oral glucose tolerance test (OGTT) and is calculated as follows:
ISI (Matsuda) = 10000/√ G0 X I0 X Gmean X Imean
G0 - fasting plasma glucose (mg/dL) I0 - fasting plasma insulin (mIU/L) Gmean - mean plasma glucose during OGTT (mg/dL) Imean - mean plasma insulin during OGTT (mIU/L)
- HOMA-IR [ Time Frame: Baseline and Week 8 ]
We will examine the effect of HCQ on HOMA-IR during the active treatment phase compared with placebo phase.
HOMA-IR = (Glucose x insulin)/405
- HOMA-B [ Time Frame: Baseline and Week 8 ]HOMA-B = (360 x Insulin)/(Glucose - 63)
- Total Cholesterol [ Time Frame: Baseline and Week 8 ]mg/dL
- LDL Cholesterol [ Time Frame: Baseline and Week 8 ]mg/dL
- HDL Cholesterol [ Time Frame: Baseline and Week 8 ]mg/dL
- Triglycerides [ Time Frame: Baseline and Week 8 ]mg/dL

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Ages Eligible for Study: | 18 Years and older (Adult, Senior) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
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

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01132118
United States, Massachusetts | |
Brigham and Women's Hospital | |
Boston, Massachusetts, United States, 02115 |
Principal Investigator: | Daniel H Solomon, MD, MPH | Brigham and Women's Hospital | |
Principal Investigator: | Elena M Massarotti, MD | Brigham and Women's Hospital | |
Principal Investigator: | Rajesh K Garg, MD | Brigham and Women's Hospital |
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: | Daniel H. Solomon, M.D.,MPH, Director of Clinical Sciences, Brigham and Women's Hospital |
ClinicalTrials.gov Identifier: | NCT01132118 History of Changes |
Other Study ID Numbers: |
2009P001926 R21AR057924 ( U.S. NIH Grant/Contract ) |
First Posted: | May 27, 2010 Key Record Dates |
Results First Posted: | September 3, 2014 |
Last Update Posted: | September 3, 2014 |
Last Verified: | September 2014 |
Keywords provided by Daniel H. Solomon, M.D.,MPH, Brigham and Women's Hospital:
rheumatoid arthritis insulin resistance hydroxychloroquine cholesterol |
Additional relevant MeSH terms:
Arthritis Arthritis, Rheumatoid Insulin Resistance Joint Diseases Musculoskeletal Diseases Rheumatic Diseases Connective Tissue Diseases Autoimmune Diseases Immune System Diseases Hyperinsulinism Glucose Metabolism Disorders Metabolic Diseases |
Insulin Hydroxychloroquine Hypoglycemic Agents Physiological Effects of Drugs Antimalarials Antiprotozoal Agents Antiparasitic Agents Anti-Infective Agents Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Antirheumatic Agents |