Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE)

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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00065806

Enrollment

221

Registered

2003-08-04

Start date

2003-09-30

Completion date

2009-12-31

Last updated

2013-08-15

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Lupus Erythematosus, Systemic

Keywords

Pediatric lupus, Atherosclerosis, SLE, HMG CoA reductase inhibitor

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.

Interventions

DRUGAtorvastatin

Participants weighing more 50 kg will receive 10 mg of atorvastatin po qd as a starting dose, which will be increased to 20 mg po qd at the Day 30 visit and continue through month 36. Participants weighing less than 50 kg will receive a maximum of 10 mg po qd for 36 months.

DRUGPlacebo atorvastatin

Participants weighing more 50 kg will receive 10 mg of placebo po qd as a starting dose, which will be increased to 20 mg po qd at the Day 30 visit and continue through month 36. Participants weighing less than 50 kg will receive a maximum of 10 mg po qd for 36 months.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Caregiver)

Eligibility

Sex/Gender

ALL

Age

10 Years to 21 Years

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

Design outcomes

Primary

Measure	Time frame	Description
Change in Mean-Mean Common Carotid IMT (CIMT)	Change from baseline to 36 months	For the common carotid arterial segment, mean CIMT values were averaged across angles by side and wall to produce 4 summary variables (right common near wall mean, right common far wall mean, left common near wall mean and left common far wall mean). These summary variables were then averaged to estimate a single mean-mean common CIMT for each participant visit.

Secondary

Measure	Time frame	Description
Change in Mean-Mean CIMT	Change from baseline to 36 months	For each side, segment and wall, mean CIMT values were averaged over the 4 angles of interrogation to produce 12 summary variables (right common near wall mean, right common far wall mean, right bifurcation near wall mean, right bifurcation far wall mean, right internal near wall mean, right internal far wall mean, left common near wall mean, left common far wall mean, left bifurcation near wall mean, left bifurcation far wall mean, left internal near wall mean and left internal far wall mean). These 12 summary variables were then averaged to estimate a single mean-mean CIMT for each participant visit.
Change in Mean-Max Common CIMT	Change from baseline to 36 months	For each side and wall of the common carotid arterial segment, the maximum CIMT over the 4 angles of interrogation was selected to produce 4 summary variables (right common near wall max, right common far wall max, left common near wall max and left common far wall max). These summary variables were then averaged to estimate a single mean-max common CIMT for each participant visit.
Change in Mean-Max Internal CIMT	Change from baseline to 36 months	For each side and wall of the internal carotid arterial segment, the maximum CIMT over the 4 angles of interrogation was selected to produce 4 summary variables (right internal near wall max, right internal far wall max, left internal near wall max and left internal far wall max). These summary variables were then averaged to estimate a single mean-max internal CIMT for each participant visit.
Change in Mean-Mean Internal CIMT	Change from baseline to 36 months	For the internal carotid arterial segment, mean CIMT values were averaged across angles by side and wall to produce 4 summary variables (right internal near wall mean, right internal far wall mean, left internal near wall mean and left internal far wall mean). These summary variables were then averaged to estimate a single mean-mean internal CIMT for each participant visit.
Change in Mean-Max Bifurcation CIMT	Change from baseline to 36 months	For each side and wall of the bifurcation arterial segment, the maximum CIMT over the 4 angles of interrogation was selected to produce 4 summary variables (right bifurcation near wall max, right bifurcation far wall max, left bifurcation near wall max and left bifurcation far wall max). These summary variables were then averaged to estimate a single mean-max bifurcation CIMT for each participant visit.
Change in Mean-Mean Bifurcation CIMT	Change from baseline to 36 months	For the bifurcation arterial segment, mean CIMT values were averaged across angles by side and wall to produce 4 summary variables (right bifurcation near wall mean, right bifurcation far wall mean, left bifurcation near wall mean and left bifurcation far wall mean). These summary variables were then averaged to estimate a single mean-mean bifurcation CIMT for each participant visit.
Change in Mean-Max Far Wall CIMT	Change from baseline to 36 months	For the far wall measurements for each side and segment, the maximum CIMT over the 4 angles of interrogation was selected to produce 6 summary variables (right common far wall max, right bifurcation far wall max, right internal far wall max, left common far wall max, left bifurcation far wall max, and left internal far wall max). These 6 summary variables were then averaged to estimate a single mean-max far wall CIMT for each participant visit.
Change in Mean-Mean Far Wall CIMT	Change from baseline to 36 months	For the far wall measurements for each side and segment, mean CIMT values were averaged over the 4 angles of interrogation to produce 6 summary variables (right common far wall mean, right bifurcation far wall mean, right internal far wall mean, left common far wall mean, left bifurcation far wall mean and left internal far wall mean). These 6 summary variables were then averaged to estimate a single mean-mean far wall CIMT for each participant visit.
Change in Mean-Max CIMT	Change from baseline to 36 months	For each side, segment and wall, the maximum CIMT over the 4 angles of interrogation was selected to produce 12 summary variables (right common near wall max, right common far wall max, right bifurcation near wall max, right bifurcation far wall max, right internal near wall max, right internal far wall max, left common near wall max, left common far wall max, left bifurcation near wall max, left bifurcation far wall max, left internal near wall max and left internal far wall max). These 12 summary variables were then averaged to estimate a single mean-max CIMT for each participant visit.
Change in Mean-Mean Near Wall CIMT	Change from baseline to 36 months	For the near wall measurements for each side and segment, mean CIMT values were averaged over the 4 angles of interrogation to produce 6 summary variables (right common near wall mean, right bifurcation near wall mean, right internal near wall mean, left common near wall mean, left bifurcation wall mean and left internal far wall mean). These 6 summary variables were then averaged to estimate a single mean-mean far wall CIMT for each participant visit.
Change in Natural Log of mg/L for hsCRP	Change from baseline to 36 months	—
Change in Total Cholesterol	Change from baseline to 36 months	—
Change in HDL Cholesterol	Change from baseline to 36 months	—
Change in LDL Cholesterol	Change from baseline to 36 months	—
Change in Triglycerides	Change from baseline to 36 months	—
Change in Lipoprotein A	Change from baseline to 36 months	—
Change in Homocysteine	Change from baseline to 36 months	—
Change in Mean-Max Near Wall CIMT	Change from baseline to 36 months	For the near wall measurements for each side and segment, the maximum CIMT over the 4 angles of interrogation was selected to produce 6 summary variables (right common near wall max, right bifurcation near wall max, right internal near wall max, left common near wall max, left bifurcation near wall max, and left internal near wall max). These 6 summary variables were then averaged to estimate a single mean-max near wall CIMT for each participant visit.

Countries

United States

Participant flow

Participants by arm

Arm	Count
1 Atorvastatin 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. Atorvastatin : Participants weighing more 50 kg will receive 10 mg of atorvastatin po qd as a starting dose, which will be increased to 20 mg po qd at the Day 30 visit and continue through month 36. Participants weighing less than 50 kg will receive a maximum of 10 mg po qd for 36 months.	113
2 Placebo 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. Placebo atorvastatin : Participants weighing more 50 kg will receive 10 mg of placebo po qd as a starting dose, which will be increased to 20 mg po qd at the Day 30 visit and continue through month 36. Participants weighing less than 50 kg will receive a maximum of 10 mg po qd for 36 months.	108
Total	221

Baseline characteristics

Characteristic	1 Atorvastatin	2 Placebo	Total
Age, Categorical <=18 years	87 Participants	87 Participants	174 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	26 Participants	21 Participants	47 Participants
Age Continuous	15.7 years STANDARD_DEVIATION 2.8	15.8 years STANDARD_DEVIATION 2.5	15.7 years STANDARD_DEVIATION 2.6
Sex: Female, Male Female	95 Participants	89 Participants	184 Participants
Sex: Female, Male Male	18 Participants	19 Participants	37 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	94 / 113	95 / 108
serious Total, serious adverse events	34 / 113	40 / 108

Outcome results

Primary

Change in Mean-Mean Common Carotid IMT (CIMT)

For the common carotid arterial segment, mean CIMT values were averaged across angles by side and wall to produce 4 summary variables (right common near wall mean, right common far wall mean, left common near wall mean and left common far wall mean). These summary variables were then averaged to estimate a single mean-mean common CIMT for each participant visit.