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Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Laura Schanberg, Duke University Medical Center
ClinicalTrials.gov Identifier:
NCT00065806
First received: August 1, 2003
Last updated: July 15, 2013
Last verified: July 2013
  Purpose

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).

Condition Intervention Phase
Lupus Erythematosus, Systemic
Drug: Atorvastatin
Drug: Placebo atorvastatin
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Duke University:

Primary Outcome Measures:
  • Change in Mean-Mean Common Carotid IMT (CIMT) [ Time Frame: Change from baseline to 36 months ] [ Designated as safety issue: No ]
    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 Outcome Measures:
  • Change in Mean-Max CIMT [ Time Frame: Change from baseline to 36 months ] [ Designated as safety issue: No ]
    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 CIMT [ Time Frame: Change from baseline to 36 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: Change from baseline to 36 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: Change from baseline to 36 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: Change from baseline to 36 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: Change from baseline to 36 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: Change from baseline to 36 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: Change from baseline to 36 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: Change from baseline to 36 months ] [ Designated as safety issue: No ]
    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 Near Wall CIMT [ Time Frame: Change from baseline to 36 months ] [ Designated as safety issue: No ]
    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.

  • Change in Mean-Mean Near Wall CIMT [ Time Frame: Change from baseline to 36 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: Change from baseline to 36 months ] [ Designated as safety issue: No ]
  • Change in Total Cholesterol [ Time Frame: Change from baseline to 36 months ] [ Designated as safety issue: No ]
  • Change in HDL Cholesterol [ Time Frame: Change from baseline to 36 months ] [ Designated as safety issue: No ]
  • Change in LDL Cholesterol [ Time Frame: Change from baseline to 36 months ] [ Designated as safety issue: No ]
  • Change in Triglycerides [ Time Frame: Change from baseline to 36 months ] [ Designated as safety issue: No ]
  • Change in Lipoprotein A [ Time Frame: Change from baseline to 36 months ] [ Designated as safety issue: No ]
  • Change in Homocysteine [ Time Frame: Change from baseline to 36 months ] [ Designated as safety issue: No ]

Enrollment: 221
Study Start Date: September 2003
Study Completion Date: December 2009
Primary Completion Date: December 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
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.
Drug: 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.
Other Names:
  • Lipitor
  • Atorvastatin Calcium
Placebo Comparator: 2
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.
Drug: 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.

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

Ages Eligible for Study:   10 Years to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  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: NCT00065806

Locations
United States, North Carolina
Duke Medical Center / Duke Clinical Research Institute
Durham, North Carolina, United States, 27715
Sponsors and Collaborators
Laura Schanberg
Investigators
Principal Investigator: Laura E. Schanberg, MD Duke Medical Center
  More Information

No publications provided by Duke University

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Laura Schanberg, Associate Director, Professor, Duke University Medical Center
ClinicalTrials.gov Identifier: NCT00065806     History of Changes
Other Study ID Numbers: Pro00006680, NIAMS-090, N01 AR022265
Study First Received: August 1, 2003
Results First Received: February 11, 2013
Last Updated: July 15, 2013
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Duke University:
Pediatric lupus
Atherosclerosis
SLE
HMG CoA reductase inhibitor

Additional relevant MeSH terms:
Lupus Erythematosus, Systemic
Atherosclerosis
Arterial Occlusive Diseases
Arteriosclerosis
Autoimmune Diseases
Cardiovascular Diseases
Connective Tissue Diseases
Immune System Diseases
Vascular Diseases
Atorvastatin
Anticholesteremic Agents
Antimetabolites
Enzyme Inhibitors
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Hypolipidemic Agents
Lipid Regulating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 24, 2014