Hydroxychloroquine to Improve Insulin Sensitivity in Rheumatoid Arthritis

Phase 3

Completed

Conditions: Rheumatoid Arthritis
Insulin Resistance

Interventions: Drug: Hydroxychloroquine

Registration Number: NCT01132118

Lead Sponsor: Brigham and Women's Hospital

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 30

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo then HCQ	Hydroxychloroquine	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.
HCQ then Placebo	Hydroxychloroquine	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.

Primary Outcome Measures

Name	Time	Method
Insulin Sensitivity Index	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)

Secondary Outcome Measures

Name	Time	Method
HOMA-IR	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	Baseline and Week 8	HOMA-B = (360 x Insulin)/(Glucose - 63)
Total Cholesterol	Baseline and Week 8	mg/dL
LDL Cholesterol	Baseline and Week 8	mg/dL
Triglycerides	Baseline and Week 8	mg/dL
HDL Cholesterol	Baseline and Week 8	mg/dL