Hydroxychloroquine to Improve Insulin Sensitivity in Rheumatoid Arthritis - Full Text View

Purpose

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.

Condition	Intervention	Phase
Rheumatoid Arthritis Insulin Resistance	Drug: Hydroxychloroquine	Phase 3


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Crossover Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	Hydroxychloroquine to Improve Insulin Sensitivity in Rheumatoid Arthritis

Resource links provided by NLM:

Genetics Home Reference related topics: rheumatoid arthritis

MedlinePlus related topics: Arthritis Cholesterol Diabetes Medicines Rheumatoid Arthritis

Drug Information available for: Hydroxychloroquine Hydroxychloroquine sulfate Insulin

U.S. FDA Resources

Further study details as provided by Brigham and Women's Hospital:

Primary Outcome Measures:

Insulin Sensitivity Index [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
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:

HOMA-IR [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
HOMA-B = (360 x Insulin)/(Glucose - 63)
Total Cholesterol [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
mg/dL
LDL Cholesterol [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
mg/dL
HDL Cholesterol [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
mg/dL
Triglycerides [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
mg/dL


Enrollment:	30
Study Start Date:	June 2010
Study Completion Date:	June 2012
Primary Completion Date:	April 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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.	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
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

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.

Eligibility


Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

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: NCT01132118

Locations


United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115

Sponsors and Collaborators

Brigham and Women's Hospital

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

Investigators


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

More Information

Publications:

Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999 Sep;22(9):1462-70.

Reilly MP, Wolfe ML, Rhodes T, Girman C, Mehta N, Rader DJ. Measures of insulin resistance add incremental value to the clinical diagnosis of metabolic syndrome in association with coronary atherosclerosis. Circulation. 2004 Aug 17;110(7):803-9. Epub 2004 Aug 2.

Hanley AJ, Williams K, Stern MP, Haffner SM. Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study. Diabetes Care. 2002 Jul;25(7):1177-84.

Glaser K, Sung ML, O'Neill K, Belfast M, Hartman D, Carlson R, Kreft A, Kubrak D, Hsiao CL, Weichman B. Etodolac selectively inhibits human prostaglandin G/H synthase 2 (PGHS-2) versus human PGHS-1. Eur J Pharmacol. 1995 Jul 25;281(1):107-11.

Gabriel SE. The epidemiology of rheumatoid arthritis. Rheum Dis Clin North Am. 2001 May;27(2):269-81. Review.

Young A, Koduri G, Batley M, Kulinskaya E, Gough A, Norton S, Dixey J; Early Rheumatoid Arthritis Study (ERAS) group. Mortality in rheumatoid arthritis. Increased in the early course of disease, in ischaemic heart disease and in pulmonary fibrosis. Rheumatology (Oxford). 2007 Feb;46(2):350-7. Epub 2006 Aug 14.

Goodson N, Marks J, Lunt M, Symmons D. Cardiovascular admissions and mortality in an inception cohort of patients with rheumatoid arthritis with onset in the 1980s and 1990s. Ann Rheum Dis. 2005 Nov;64(11):1595-601. Epub 2005 Apr 20.

Solomon DH, Karlson EW, Rimm EB, Cannuscio CC, Mandl LA, Manson JE, Stampfer MJ, Curhan GC. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation. 2003 Mar 11;107(9):1303-7.

Maradit-Kremers H, Nicola PJ, Crowson CS, Ballman KV, Gabriel SE. Cardiovascular death in rheumatoid arthritis: a population-based study. Arthritis Rheum. 2005 Mar;52(3):722-32.

Solomon DH, Curhan GC, Rimm EB, Cannuscio CC, Karlson EW. Cardiovascular risk factors in women with and without rheumatoid arthritis. Arthritis Rheum. 2004 Nov;50(11):3444-9.

Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA. 2001 May 16;285(19):2481-5.

Dessein PH, Joffe BI. Insulin resistance and impaired beta cell function in rheumatoid arthritis. Arthritis Rheum. 2006 Sep;54(9):2765-75.

Chung CP, Oeser A, Solus JF, Gebretsadik T, Shintani A, Avalos I, Sokka T, Raggi P, Pincus T, Stein CM. Inflammation-associated insulin resistance: differential effects in rheumatoid arthritis and systemic lupus erythematosus define potential mechanisms. Arthritis Rheum. 2008 Jul;58(7):2105-12. doi: 10.1002/art.23600.

Quatraro A, Consoli G, Ceriello A, Giugliano D. Is there a role for chloroquine treatment in diabetes? A three case report. Diabete Metab. 1988 Sep-Oct;14(5):666-7.

Garcia-Webb P, Bonser AM. Insulin binding and degradation in isolated hepatocytes from streptozotocin injected rats. Biochem Biophys Res Commun. 1985 Apr 30;128(2):487-93.

Emami J, Pasutto FM, Mercer JR, Jamali F. Inhibition of insulin metabolism by hydroxychloroquine and its enantiomers in cytosolic fraction of liver homogenates from healthy and diabetic rats. Life Sci. 1999;64(5):325-35.

Quatraro A, Consoli G, Magno M, Caretta F, Nardozza A, Ceriello A, Giugliano D. Hydroxychloroquine in decompensated, treatment-refractory noninsulin-dependent diabetes mellitus. A new job for an old drug? Ann Intern Med. 1990 May 1;112(9):678-81.

Gerstein HC, Thorpe KE, Taylor DW, Haynes RB. The effectiveness of hydroxychloroquine in patients with type 2 diabetes mellitus who are refractory to sulfonylureas--a randomized trial. Diabetes Res Clin Pract. 2002 Mar;55(3):209-19.

Wasko MC, Hubert HB, Lingala VB, Elliott JR, Luggen ME, Fries JF, Ward MM. Hydroxychloroquine and risk of diabetes in patients with rheumatoid arthritis. JAMA. 2007 Jul 11;298(2):187-93.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Solomon DH, Garg R, Lu B, Todd DJ, Mercer E, Norton T, Massarotti E. Effect of hydroxychloroquine on insulin sensitivity and lipid parameters in rheumatoid arthritis patients without diabetes mellitus: a randomized, blinded crossover trial. Arthritis Care Res (Hoboken). 2014 Aug;66(8):1246-51.


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
Study First Received:	May 25, 2010
Results First Received:	August 8, 2014
Last Updated:	September 2, 2014
Health Authority:	United States: Institutional Review Board

Keywords provided by Brigham and Women's Hospital:


rheumatoid arthritis insulin resistance hydroxychloroquine cholesterol

Additional relevant MeSH terms:


Arthritis Arthritis, Rheumatoid Insulin Resistance Autoimmune Diseases Connective Tissue Diseases Glucose Metabolism Disorders Hyperinsulinism Immune System Diseases Joint Diseases Metabolic Diseases Musculoskeletal Diseases	Rheumatic Diseases Hydroxychloroquine Anti-Infective Agents Antimalarials Antiparasitic Agents Antiprotozoal Agents Antirheumatic Agents Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Therapeutic Uses

ClinicalTrials.gov processed this record on March 03, 2015

Hydroxychloroquine to Improve Insulin Sensitivity in Rheumatoid Arthritis (RA PLUS)