Hydroxychloroquine to Improve Insulin Sensitivity in Rheumatoid Arthritis

NCT01132118 | Completed Phase 3 Results DMC

• 2 other identifiers: 2009P001926R21AR057924
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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.

Conditions

Rheumatoid Arthritis; Insulin Resistance

Keywords

rheumatoid arthritis; insulin resistance; hydroxychloroquine; cholesterol

Outcome Measures

Primary Outcomes (1)

• Insulin Sensitivity Index

  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)

  Baseline and Week 8

Secondary Outcomes (6)

• HOMA-IR

  Baseline and Week 8

• HOMA-B

  Baseline and Week 8

• Total Cholesterol

  Baseline and Week 8

• LDL Cholesterol

  Baseline and Week 8

• HDL Cholesterol

  Baseline and Week 8

Study Arms (2)

Placebo then HCQ

OTHER

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

HCQ then Placebo

OTHER

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

Interventions

Hydroxychloroquine 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.

Also known as: Plaquenil

HCQ then Placebo; Placebo then HCQ

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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)

Sponsors & Collaborators

• Brigham and Women's Hospital: lead
• National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS): collaborator

Study Sites (1)

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Related Publications (20)

• 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. doi: 10.2337/diacare.22.9.1462.

  PMID: 10480510 BACKGROUND

• 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. doi: 10.1161/01.CIR.0000138740.84883.9C. Epub 2004 Aug 2.

  PMID: 15289378 BACKGROUND

• 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. doi: 10.2337/diacare.25.7.1177.

  PMID: 12087016 BACKGROUND

• 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. doi: 10.1016/0014-2999(95)00302-2.

  PMID: 8566109 BACKGROUND

• Gabriel SE. The epidemiology of rheumatoid arthritis. Rheum Dis Clin North Am. 2001 May;27(2):269-81. doi: 10.1016/s0889-857x(05)70201-5.

  PMID: 11396092 BACKGROUND

• 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. doi: 10.1093/rheumatology/kel253. Epub 2006 Aug 14.

  PMID: 16908509 BACKGROUND

• 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. doi: 10.1136/ard.2004.034777. Epub 2005 Apr 20.

  PMID: 15843450 BACKGROUND

• 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. doi: 10.1161/01.cir.0000054612.26458.b2.

  PMID: 12628952 BACKGROUND

• 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. doi: 10.1002/art.20878.

  PMID: 15751097 BACKGROUND

• 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. doi: 10.1002/art.20636.

  PMID: 15529391 BACKGROUND

• 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. doi: 10.1001/jama.285.19.2481.

  PMID: 11368701 BACKGROUND

• Dessein PH, Joffe BI. Insulin resistance and impaired beta cell function in rheumatoid arthritis. Arthritis Rheum. 2006 Sep;54(9):2765-75. doi: 10.1002/art.22053.

  PMID: 16947779 BACKGROUND

• 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.

  PMID: 18576352 BACKGROUND

• 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. No abstract available.

  PMID: 3069509 BACKGROUND

• 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. doi: 10.1016/0006-291x(85)90073-7.

  PMID: 3888217 BACKGROUND

• 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. doi: 10.1016/s0024-3205(98)00568-2.

  PMID: 10072192 BACKGROUND

• 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. doi: 10.7326/0003-4819-112-9-678.

  PMID: 2110430 BACKGROUND

• 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. doi: 10.1016/s0168-8227(01)00325-4.

  PMID: 11850097 BACKGROUND

• 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. doi: 10.1001/jama.298.2.187.

  PMID: 17622600 BACKGROUND

• 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. doi: 10.1002/acr.22285.

  PMID: 24470436 DERIVED

MeSH Terms

Conditions

Arthritis, Rheumatoid; Insulin Resistance

Interventions

Hydroxychloroquine

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Daniel H. Solomon
• Organization: Brigham and Women's Hospital

dsolomon@partners.org

617-525-8127

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Clinical Sciences

Study Record Dates

• First Submitted: May 25, 2010
• First Posted: May 27, 2010
• Study Start: June 1, 2010
• Primary Completion: April 1, 2012
• Study Completion: June 1, 2012
• Last Updated: September 3, 2014
• Results First Posted: September 3, 2014

Record last verified: 2014-09

Locations

US (1)