Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE)

Laura Schanberg

Status and phase: Completed; Phase 3

Conditions: Lupus Erythematosus, Systemic

Treatments: Drug: Atorvastatin; Drug: Placebo atorvastatin

Study type: Interventional

Funder types: Other

Identifiers

NCT00065806

NIAMS-090

Pro00006680

N01 AR022265

Details and patient eligibility

About

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).

Full 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.

Enrollment: 221 patients

Sex: All

Ages: 10 to 21 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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221 participants in 2 patient groups, including a placebo group

1

Experimental group

Description:

Patients will be treated with dietary intervention (AHA Therapeutic Lifestyle Changes [TLC] diet, [http://www.nhlbi.nih.gov/cgi-bin/chd/step2intro.cgi]), cardiovascular risk factor reduction counseling, hydroxychloroquine, low-dose aspirin, a multivitamin containing folate, plus atorvastatin at 10 mg or 20 mg depending on the patient's weight. Patients weighing more than 50 kg will receive 10 mg qd atorvastatin for the first month, which will be increased to 20 mg qd at the Day 30 visit and continue through month 36. Participants weighing less than 50kg will receive a maximum of 10 mg po qd for 36 months.

Treatment:

Drug: Atorvastatin

2

Placebo Comparator group

Description:

Patients will be treated with dietary intervention (AHA Therapeutic Lifestyle Changes [TLC] diet, [http://www.nhlbi.nih.gov/cgi-bin/chd/step2intro.cgi]), cardiovascular risk factor reduction counseling, hydroxychloroquine, low-dose aspirin, a multivitamin containing folate, plus placebo at 10 mg or 20 mg depending on the patient's weight. Patients weighing more than 50 kg will receive 10 mg qd placebo for the first month, which will be increased to 20 mg qd at the Day 30 visit and continue through month 36. Participants weighing less than 50kg will receive a maximum of 10 mg po qd for 36 months.

Treatment:

Drug: Placebo atorvastatin