Clinical trial NCT00065806: Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE)
Official title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Test the Safety and Efficacy of Lipitor (Atorvastatin) in Reducing the Progression of Carotid IMT in Early Childhood SLE
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Lupus Erythematosus, Systemic
Keywords: Pediatric lupus
Atherosclerosis
SLE
HMG CoA reductase inhibitor
Lead sponsor: Duke University
Sponsor class: OTHER
First posted: 2003-08-04
Enrollment: 221
Sex: ALL
Minimum age (years): 10
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is:

1. To assess the efficacy of a lipid-lowering agent (atorvastatin) on the development of atherosclerosis that predisposes children with SLE to cardiovascular events in adulthood.
2. To assess the safety of intermediate-term (36 months) treatment of children and young adults with atorvastatin.
3. To further characterize the course of SLE in children and young adults, by establishing a cohort of pediatric SLE patients to be followed prospectively.
4. To establish a mechanism for conducting clinical trials in rare pediatric rheumatic diseases using the Children's Arthritis and Rheumatology Research Alliance (CARRA).

Detailed description: Children and adolescents with SLE represent 15% of all SLE patients. Children with SLE suffer high morbidity that affects many organ systems, reduces their quality of life, and shortens their lifespan. As more children with SLE survive into adulthood, atherosclerotic cardiovascular disease has emerged as a major concern. SLE is a significant risk factor for myocardial infarction and death in young premenopausal women with SLE, even after controlling for traditional cardiovascular risk factors. Acceleration of atherogenesis in SLE most likely reflects SLE-associated vascular immune and inflammatory changes.

Although limited, the data on cardiovascular and lipid abnormalities in children with SLE implicate atherosclerosis as an important cause of long-term morbidity and mortality. The 3-hydroxy-3-methlglutaryl-coenzyme A (HMG CoA) reductase inhibitors, or statins, reduce mortality and morbidity from atherosclerosis in adults and have intrinsic anti-inflammatory and immune modulatory properties. These anti-inflammatory and immune modulatory activities may have particular benefit in the prevention and treatment of atherosclerosis in SLE. This trial will evaluate atorvastatin in children with SLE in the largest cohort of pediatric SLE patients ever studied prospectively.

Children in this study will be randomized to receive either atorvastatin or a placebo. All children will be followed for 3 years, during which they will have 15 study visits. Study visits will generally last 2 hours and will include medical interview, medication review and pill count, physical examination, and blood and urine tests. Cardiovascular-specific outcome measures will include assessments of high sensitivity CRP; fasting lipid profile; homocysteine level; apolipoprotein A, B1, and Lp(a); carotid intima media thickness (IMT); and tensor diffusion/MRI.

Eligibility criteria: Inclusion Criteria:

* Meets American College of Rheumatology (ACR) revised diagnostic guidelines for SLE
* Weight of 25 kg (55 lbs) or more
* Outpatient
* Ability to complete self-report questionnaires in either English or Spanish
* Willingness to comply with recommended diet
* Acceptable methods of contraception

Exclusion Criteria:

* Drug-induced lupus
* Liver disease (ALT or aspartate aminotransferase greater than 2 X normal value)
* Myositis (CK greater than 3 X normal value)
* Inability to obtain adequate-quality IMT images
* Current use of oral or parenteral tacrolimus or cyclosporine
* Dialysis or serum creatinine reater than 2.5 mg/dL
* Active nephrotic syndrome (urinary protein greater than 3 g/24 h and serum albumin less than 2.3 g/dl)
* Total cholesterol greater than 350 mg/dL
* Xanthoma
* Familial hypercholesterolemia
* Pregnant or breastfeeding
* Use of estrogen-containing contraceptives (e.g., Lo-Ovral)
* Unable to adhere to study regimen
* Life-threatening non-SLE illness that would interfere with ability to complete the study
* Current drug or alcohol abuse
* Anticipated poor compliance
* Participation in another drug intervention study within 30 days of study enrollment

Primary outcomes:
measure: Change in Mean-Mean Common Carotid IMT (CIMT)
timeFrame: Change from baseline to 36 months
Secondary outcomes:
measure: Change in Mean-Max CIMT
timeFrame: Change from baseline to 36 months
measure: Change in Mean-Mean CIMT
timeFrame: Change from baseline to 36 months
measure: Change in Mean-Max Common CIMT
timeFrame: Change from baseline to 36 months
measure: Change in Mean-Max Internal CIMT
timeFrame: Change from baseline to 36 months
measure: Change in Mean-Mean Internal CIMT
timeFrame: Change from baseline to 36 months
measure: Change in Mean-Max Bifurcation CIMT
timeFrame: Change from baseline to 36 months
measure: Change in Mean-Mean Bifurcation CIMT
timeFrame: Change from baseline to 36 months
measure: Change in Mean-Max Far Wall CIMT
timeFrame: Change from baseline to 36 months
measure: Change in Mean-Mean Far Wall CIMT
timeFrame: Change from baseline to 36 months
measure: Change in Mean-Max Near Wall CIMT
timeFrame: Change from baseline to 36 months
measure: Change in Mean-Mean Near Wall CIMT
timeFrame: Change from baseline to 36 months
measure: Change in Natural Log of mg/L for hsCRP
timeFrame: Change from baseline to 36 months
measure: Change in Total Cholesterol
timeFrame: Change from baseline to 36 months
measure: Change in HDL Cholesterol
timeFrame: Change from baseline to 36 months
measure: Change in LDL Cholesterol
timeFrame: Change from baseline to 36 months
measure: Change in Triglycerides
timeFrame: Change from baseline to 36 months
measure: Change in Lipoprotein A
timeFrame: Change from baseline to 36 months
measure: Change in Homocysteine
timeFrame: Change from baseline to 36 months
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke Medical Center / Duke Clinical Research Institute
state: North Carolina
Study officials:
affiliation: Duke Medical Center
name: Laura E. Schanberg, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gurion R, Tangpricha V, Yow E, Schanberg LE, McComsey GA, Robinson AB; Atherosclerosis Prevention in Pediatric Lupus Erythematosus Investigators. Avascular necrosis in pediatric systemic lupus erythematosus: a brief report and review of the literature. Pediatr Rheumatol Online J. 2015 Apr 23;13:13. doi: 10.1186/s12969-015-0008-x.
citation: Robinson AB, Tangpricha V, Yow E, Gurion R, Schanberg LE, McComsey GA; APPLE Investigators. Vitamin D status is a determinant of atorvastatin effect on carotid intima medial thickening progression rate in children with lupus: an Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) substudy. Lupus Sci Med. 2014 Sep 10;1(1):e000037. doi: 10.1136/lupus-2014-000037. eCollection 2014.
citation: Robinson AB, Tangpricha V, Yow E, Gurion R, McComsey GA, Schanberg LE; APPLE Investigators. Vitamin D deficiency is common and associated with increased C-reactive protein in children and young adults with lupus: an Atherosclerosis Prevention in Pediatric Lupus Erythematosus substudy. Lupus Sci Med. 2014 Apr 30;1(1):e000011. doi: 10.1136/lupus-2014-000011. eCollection 2014.
citation: Ardoin SP, Schanberg LE, Sandborg CI, Barnhart HX, Evans GW, Yow E, Mieszkalski KL, Ilowite NT, Eberhard A, Imundo LF, Kimura Y, Levy D, von Scheven E, Silverman E, Bowyer SL, Punaro L, Singer NG, Sherry DD, McCurdy DK, Klein-Gitelman M, Wallace C, Silver RM, Wagner-Weiner L, Higgins GC, Brunner HI, Jung L, Soep JB, Reed AM, Thompson SD; APPLE investigators. Secondary analysis of APPLE study suggests atorvastatin may reduce atherosclerosis progression in pubertal lupus patients with higher C reactive protein. Ann Rheum Dis. 2014 Mar;73(3):557-66. doi: 10.1136/annrheumdis-2012-202315. Epub 2013 Feb 22.
citation: Schanberg LE, Sandborg C, Barnhart HX, Ardoin SP, Yow E, Evans GW, Mieszkalski KL, Ilowite NT, Eberhard A, Imundo LF, Kimura Y, von Scheven E, Silverman E, Bowyer SL, Punaro M, Singer NG, Sherry DD, McCurdy D, Klein-Gitelman M, Wallace C, Silver R, Wagner-Weiner L, Higgins GC, Brunner HI, Jung L, Soep JB, Reed AM, Provenzale J, Thompson SD; Atherosclerosis Prevention in Pediatric Lupus Erythematosus Investigators. Use of atorvastatin in systemic lupus erythematosus in children and adolescents. Arthritis Rheum. 2012 Jan;64(1):285-96. doi: 10.1002/art.30645.
citation: Schanberg LE, Sandborg C, Barnhart HX, Ardoin SP, Yow E, Evans GW, Mieszkalski KL, Ilowite NT, Eberhard A, Levy DM, Kimura Y, von Scheven E, Silverman E, Bowyer SL, Punaro L, Singer NG, Sherry DD, McCurdy D, Klein-Gitelman M, Wallace C, Silver R, Wagner-Weiner L, Higgins GC, Brunner HI, Jung L, Soep JB, Reed A; Atherosclerosis Prevention in Pediatric Lupus Erythematosus Investigators. Premature atherosclerosis in pediatric systemic lupus erythematosus: risk factors for increased carotid intima-media thickness in the atherosclerosis prevention in pediatric lupus erythematosus cohort. Arthritis Rheum. 2009 May;60(5):1496-507. doi: 10.1002/art.24469.