Hydroxychloroquine in Cardiovascular Disease in Patients With Chronic Kidney Disease: A Proof of Concept Study

• Change from baseline in aortic stiffness at 6 months [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  Aortic stiffness will be measured using aortic pulse wave velocity which is a non-invasive method, much like a doppler or ultrasound.
• Change from baseline in endothelial injury and/or dysfunction in 6 months as measured by sVCAM-1 [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Change from baseline in inflammatory markers such as IL-6, hs-CRP and oxidative stress at 6 months [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  These markers are measured by ELISA assays from serum.
• Change from baseline in other markers of CVD such as cardiac troponin-T at 6 months [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Progression of chronic kidney disease measured by a decline from baseline glomerular filtration rate at 6 months [ Time Frame: 6 months ] [ Designated as safety issue: No ]

• Change in baseline relevant cardiac markers of injury at 6 months [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  Markers to be measured are Asymmetrical Dimethylarginine, HDL, LDL, N-Terminal proBNP.
• Change in baseline systolic blood pressure and pulse pressure at 6 months [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Primary non-fatal cardiovascular events such as MI or stroke at 6 months [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Cardiovascular mortality: Primary cause of death due to acute cardiac events including MI, stroke, sudden cardiac death and CHF at 6 months. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Change in baseline proteinuria at 6 months. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Change from baseline need for ESA or change in dose at 6 months [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Initiation of dialysis within 6 months of baseline [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• All-cause mortality including incidence of sepsis including any mortality related to sepsis within 6 months of baseline. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Change in baseline renal function as measured by MDRD eGFR and cystatin C at 6 months. [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Presence of multiple traditional and nontraditional risk factors of atherosclerosis and cardiovascular disease (CVD) including inflammation in patients with chronic kidney disease (CKD) contribute to high CVD morbidity and mortality in this patient population. Additionally, the traditional approaches towards the therapy of CVD have little impact on CV mortality in these patients. Hydroxychloroquine (HCQ) used as anti-inflammatory in rheumatological disorders, has multiple beneficial properties relevant to the process of vascular disease. The effects of HCQ on atherosclerosis (AS) and vascular disease in CKD is not known yet. Thus, the study hypothesis is that HCQ treatment in individuals with CKD will provide clinically significant benefit in the management of CVD and will provide biological and functional atherosclerotic benefits.

This pilot study has been designed to look at the impact of hydroxychloroquine (HCQ) in the clinical model of accelerated atherosclerosis (AS) in the CKD population. This intervention is designed to have an impact on the initiation and progression of AS by reducing systemic inflammation, improving or restoring vascular endothelial function, and by improving the milieu of metabolic syndrome and insulin resistance.

The current study is a proof of concept study for the expansion of the use of HCQ for a new indication for the treatment of AS and CVD in patients with CKD. UAMS has filed an IND for a new indication on 4/28/11. The FDA responded that this study is exempt from an IND.

This "Proof-of-Concept" randomized double blinded placebo controlled study will evaluate the nature and extent of HCQ effects, and if found significantly beneficial, it will be used to guide the development of a large, multicenter, randomized control trial of HCQ to examine the hard clinical end points of CVD and mortality in patients with advanced CKD. The investigators propose to enroll 62 subjects to achieve the effects of HCQ in 52 individuals (39 HCQ group and 13 placebo group).

• Kidney Failure, Chronic
• Cardiovascular Disease
• Arteriosclerosis

• Drug: Hydroxychloroquine
  200 mg capsule daily for 10 +/- 4 days, then 200 mg twice daily till end of study (duration approx. 6 months)
  Other Name: Plaquenil
• Other: Placebo comparator
  matching capsule 200 mg daily for 10 +/- 4 days and thereafter 200 mg twice a day for duration of study, approximately 6 months

• Placebo Comparator: Matching Placebo
  Patients with CVD and CKD will be randomized to either hydroxychloroquine (HCQ) or placebo in a 3:1 ratio (approx. 39 to HCQ and 13 to placebo)
  Intervention: Other: Placebo comparator
• Experimental: Hydroxychloroquine
  Patients with CVD and CKD will be randomized to either hydroxychloroquine (HCQ) or placebo in a 3:1 ratio (approx. 39 to HCQ and 13 to placebo)
  Intervention: Drug: Hydroxychloroquine

Inclusion Criteria:

• Measured stage IV proteinuric CKD with an estimated MDRD GFR (eGFR) of 18 to 35 ml/min.
• Current or history of documented proteinuria of more than or equal to 300 mg/dL in 24 hours or a spot urine protein to creatinine ratio of greater than 0.3 ug/mg.
• Not on dialysis.
• Ages 18 to 80 years, both sexes, all races and ethnicities

Exclusion Criteria:

• G6PD deficiency or known hypersensitivity to 4-aminoquinoline compounds (such as chloroquine or hydroxychloroquine).
• Abnormal liver functions; AST and ALT more than 2.5 times the normal or INR without being anti-coagulated greater than 1.4.
• Known chronic active infections like HIV, Hepatitis B or Hepatitis C positive, chronic osteomyelitis etc.
• Recent serious infection including Pneumonia requiring hospitalization, meningitis, septicemia in the 2 months prior to screening.
• Active or recently treated (< 1 year in remission) malignancy or systemic inflammatory diseases (Patients with localized squamous cell carcinoma of the skin are eligible).
• Pregnancy, breastfeeding or planning to become pregnant during the course of the study.
• Use of systemic corticosteroids or other immunosuppression within last 3 months (acute course of steroid for a gouty arthritis or chronic obstructive pulmonary disease (COPD) is eligible if > 1 month ago).
• History of prolonged QTc interval > 450.
• Inability to attend or comply with treatment or follow-up scheduling.
• Life expectancy less than 6 months or uncontrolled congestive heart failure (CHF) (defined as more than 2 admissions in prior 6 months).
• Any other condition the PI determines may put the research subject in jeopardy during the course of the study.