Clinical trial NCT00663234: IMPAACT P1063: Safety and Effectiveness of Atorvastatin in HIV Infected Children and Adolescents With Hyperlipidemia
Official title: Phase I/II Safety and Efficacy Investigation of Atorvastatin for Treatment of PI-Associated Increased LDL Cholesterol in HIV-Infected Children and Adolescents
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: HIV Infections
Hyperlipidemia
Keywords: Treatment Experienced
Lead sponsor: International Maternal Pediatric Adolescent AIDS Clinical Trials Group
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2008-04-22
Enrollment: 28
Sex: ALL
Minimum age (years): 10
Maximum age (years): 23
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Treatment of HIV with combination antiretroviral regimens frequently results in the suppression of HIV viral load, significant immune recovery, and delayed disease progression. However, treatment with these regimens, particularly protease inhibitors (PIs), has been associated with significant increases in cholesterol and triglycerides in HIV-infected adults and children. The purpose of this study was to evaluate the safety and effectiveness of escalating doses of atorvastatin, a FDA-approved drug which lowers cholesterol and triglyceride levels, in HIV-infected children receiving stable antiretroviral regimens.

Detailed description: Antiretroviral regimens, particularly those containing PIs, often cause hyperlipidemia, which is an increase in the amount of fat (such as cholesterol and triglycerides) in the blood. These increases can lead to heart disease and pancreatitis. Although the mechanism by which PIs cause hyperlipidemia is not clearly understood, there are medications to combat this side effect. The primary purpose of this study was to evaluate the safety and effectiveness of escalating doses of atorvastatin, based on low-density lipoprotein cholesterol (LDL-C) levels, in HIV-infected children receiving stable antiretroviral therapy.

Participants were assigned to one of two groups based on age (10 to 14 years or 15 to 23 years) and were treated for a maximum of 48 weeks. The first six participants enrolled in the study were in the 15 to 23 year old age group. Once safety data through week 8 on these 6 participants was analyzed, the remaining participants were enrolled. All participants received atorvastatin in combination with a stable antiretroviral regimen. Each participant was followed independently according to a dose escalation algorithm for atorvastatin. Participants began dosing at 10 mg daily. If efficacy criteria were not met, dosing increased to 20 mg daily at week 8. Since dose escalations were done within subject, safety and efficacy rates were presented for the dose-escalation strategy overall and not for individual doses. Atorvastatin was provided by the study, but antiretrovirals were not.

Study visits occurred at study entry and weeks 4, 8, 12, 24, 36, and 48. Safety labs were collected at all study visits. Blood collection for lipid measurements occurred at weeks 4, 12, 24 and 48.

Eligibility criteria: Inclusion Criteria:

* A diagnosis of HIV-1 infection
* CD4 % of at least 15 at screening
* HIV-1 viral load of less than 10,000 copies/ml at screening
* On a stable antiretroviral therapy regimen for at least 6 months
* Tanner stage of 2 or higher
* At least two LDL-C measurements of 130 mg/dL or higher over the 6 months prior to screening and after documented attempts at modifying diet and other risk factors. More information on this criterion can be found in the protocol.
* Able to fast overnight for 8 hours
* Negative pregnancy test at screening
* Agree to use two appropriate forms of contraception (female participants). More information on this criterion can be found in the protocol.

Exclusion Criteria:

* Certain abnormal laboratory values
* Any laboratory or unresolved clinical toxicity of Grade 3 or higher
* Unlikely to remain on current antiretroviral therapy for at least six months after study entry
* Use of statin, fibrate, or niacin within 3 months prior to study entry
* Evidence of chronic ongoing myositis or history of myopathy or neuromuscular disorder
* Symptomatic peripheral neuropathy within 6 months prior to study entry
* Pharmacologic treatment for depression or other mental disorder excluding Attention Deficit Disorder within 30 days prior to study entry
* Presence of an active CDC Stage C opportunistic infection or serious bacterial infection requiring therapy within 2 weeks prior to screening.
* Chemotherapy for malignancy within 3 months prior to study entry
* Hepatitis B Surface Antigen positive
* Hepatitis C viremia
* Insulin-dependent diabetes mellitus
* Required treatment with an agent contraindicated with either atorvastatin or PIs. More information on this criterion can be found in the protocol.
* Pregnant or breastfeeding

Primary outcomes:
measure: Percentage of Participants Experiencing at Least One Treatment-related Adverse Event (AE)
timeFrame: Study entry to weeks 12, 24, and 48
measure: Percentage of Participants Experiencing at Least One Adverse Event (AE)
timeFrame: Study entry to weeks 12, 24, and 48
measure: Percentage of Participants Who Met the LDL Cholesterol (LDL-C) Efficacy Criteria (Intention to Treat)
timeFrame: Study entry and weeks 4, 12, 24, and 48
measure: Percentage of Participants Who Met the LDL Cholesterol (LDL-C) Efficacy Criteria (Data Available)
timeFrame: Study entry and weeks 4, 12, 24, and 48
measure: Percentage of Participants Who Met the LDL Cholesterol (LDL-C) Efficacy Criteria (Per Protocol)
timeFrame: Study entry and weeks 4, 12, 24, and 48
measure: Percentage of Participants Who Met the LDL Cholesterol (LDL-C) Efficacy Criteria and Did Not Experience a Primary Safety Endpoint Attributable to Study Drug
timeFrame: Study entry and weeks 4, 12, 24, and 48
measure: Percentage of Participants Who Met the LDL Cholesterol (LDL-C) Efficacy Criteria by Age Group
timeFrame: Study entry and weeks 4, 12, 24, and 48
measure: Percentage of Participants Who Met the LDL Cholesterol (LDL-C) Efficacy Criteria by NNRTI Treatment
timeFrame: Study entry and weeks 4, 12, 24, and 48
measure: Percent Change in LDL Cholesterol (LDL-C) From Study Entry
timeFrame: Study entry and weeks 4, 12, 24, and 48
measure: Percentage of Participants Experiencing at Least One Treatment-related Adverse Event (AE) by Age Group
timeFrame: Study entry to weeks 12, 24, and 48
measure: Percentage of Participants Experiencing at Least One Adverse Event (AE) by Age Group
timeFrame: Study entry to weeks 12, 24, and 48
Secondary outcomes:
measure: Percent Change in Fasting Total Cholesterol (TC) From Study Entry
timeFrame: Study entry and weeks 4, 12, 24, and 48
measure: Percent Change in Triglycerides (TG) From Study Entry
timeFrame: Study entry and weeks 4, 12, 24, and 48
measure: Percent Change in HDL-cholesterol (HDL-C) From Study Entry
timeFrame: Study entry and weeks 4, 12, 24, and 48
measure: Percent Change in Apolipoprotein A1 (Apo A-1) From Study Entry
timeFrame: Study entry and weeks 12, 24, and 48
measure: Percent Change in Apolipoprotein B (Apo B) From Study Entry
timeFrame: Study entry and weeks 12, 24, and 48
measure: Percent Change in High-sensitivity CRP (Hs-CRP) From Study Entry
timeFrame: Study entry and weeks 12, 24, and 48
measure: Percent Change in Interleukin 6 (IL-6) From Study Entry
timeFrame: Study entry and weeks 12, 24, and 48
measure: Percentage of Participants With Undetectable Plasma HIV-1 RNA
timeFrame: Study entry and weeks 12, 24, and 48
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Univ. of Colorado Denver NICHD CRS (5052)
state: Colorado
city: Miami
country: United States
facility: Univ. of Miami Ped. Perinatal HIV/AIDS CRS (4201)
state: Florida
city: Tampa
country: United States
facility: University of South Florida Tampa (5018)
state: Florida
city: Chicago
country: United States
facility: Chicago Children's CRS (4001)
state: Illinois
city: New Orleans
country: United States
facility: Tulane University (5095)
state: Louisiana
city: Boston
country: United States
facility: Boston Medical Center Ped. HIV Program NICHD CRS (5011)
state: Massachusetts
city: Bronx
country: United States
facility: Bronx-Lebanon Hospital IMPAACT CRS (6901)
state: New York
city: New York
country: United States
facility: New York University NY (5012)
state: New York
city: New York
country: United States
facility: Metropolitan Hospital (5003)
state: New York
city: Memphis
country: United States
facility: St. Jude/UTHSC CRS (6501)
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Hosp. CRS (3801)
state: Texas
Study officials:
affiliation: Seattle Children's Hospital
name: Ann Melvin, MD
role: STUDY_CHAIR
affiliation: University of Alabama at Birmingham
name: Marilyn Crain, MD, MPH
role: STUDY_CHAIR
References:
citation: Kamin D, Hadigan C. Hyperlipidemia in children with HIV infection: an emerging problem. Expert Rev Cardiovasc Ther. 2003 May;1(1):143-50. doi: 10.1586/14779072.1.1.143.
citation: Penzak SR, Chuck SK. Management of protease inhibitor-associated hyperlipidemia. Am J Cardiovasc Drugs. 2002;2(2):91-106. doi: 10.2165/00129784-200202020-00003.
citation: Solorzano Santos F, Gochicoa Rangel LG, Palacios Saucedo G, Vazquez Rosales G, Miranda Novales MG. Hypertriglyceridemia and hypercholesterolemia in human immunodeficiency virus-1-infected children treated with protease inhibitors. Arch Med Res. 2006 Jan;37(1):129-32. doi: 10.1016/j.arcmed.2005.05.013.
citation: The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, August 2009)