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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
University of Arkansas
ClinicalTrials.gov Identifier:
NCT01537315
First received: February 10, 2012
Last updated: June 19, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Kidney Failure, Chronic
Cardiovascular Disease
Arteriosclerosis
Drug: Hydroxychloroquine
Other: Placebo comparator
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Hydroxychloroquine in Cardiovascular Disease in Patients With Chronic Kidney Disease: A Proof of Concept Study

Resource links provided by NLM:


Further study details as provided by University of Arkansas:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Enrollment: 10
Study Start Date: February 2012
Study Completion Date: September 2013
Primary Completion Date: September 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Matching Placebo
Patients with CVD and CKD will be randomized to either hydroxychloroquine (HCQ) or placebo in a 3:1 ratio (approximately 39 to HCQ and 13 to placebo)
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
Experimental: Hydroxychloroquine
Patients with CVD and CKD will be randomized to either hydroxychloroquine (HCQ) or placebo in a 3:1 ratio (approximately 39 to HCQ and 13 to placebo)
Drug: Hydroxychloroquine
200 mg capsule daily for 10 +/- 4 days, then 200 mg twice daily till end of study (duration approximately 6 months)
Other Name: Plaquenil

Detailed Description:

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.University of Arkansas for Medical Sciences (UAMS) has filed an Investigational New Drug (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).

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  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: NCT01537315

Locations
United States, Arkansas
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States, 72205
Central Arkansas Veterans Healthcare System
Little Rock, Arkansas, United States, 72205
United States, Florida
University of Florida
Gainesville, Florida, United States, 32610-0224
Sponsors and Collaborators
University of Arkansas
Investigators
Principal Investigator: Dumitru Rotaru, MD University of Arkansas
  More Information

No publications provided

Responsible Party: University of Arkansas
ClinicalTrials.gov Identifier: NCT01537315     History of Changes
Other Study ID Numbers: 132036
Study First Received: February 10, 2012
Last Updated: June 19, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by University of Arkansas:
Kidney Failure, Chronic
Cardiovascular Disease
Arteriosclerosis

Additional relevant MeSH terms:
Cardiovascular Diseases
Kidney Diseases
Renal Insufficiency, Chronic
Renal Insufficiency
Arteriosclerosis
Atherosclerosis
Kidney Failure, Chronic
Urologic Diseases
Arterial Occlusive Diseases
Vascular Diseases
Hydroxychloroquine
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antirheumatic Agents

ClinicalTrials.gov processed this record on October 01, 2014