IMPAACT P1063: Safety and Effectiveness of Atorvastatin in HIV Infected Children and Adolescents With Hyperlipidemia

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
HIV Infections; Hyperlipidemia	Drug: Atorvastatin	Phase 1; Phase 2

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	28 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
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 Start Date :	August 2009
Actual Primary Completion Date :	December 2014
Actual Study Completion Date :	December 2014

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Age 10 to 14; Participants ages 10 to 14 years receiving oral atorvastatin for 48 weeks while on a stable antiretroviral regimen	Drug: Atorvastatin; 10 mg to 20 mg atorvastatin taken orally once daily. Dosage is dependent on efficacy criteria.; Other Name: Lipitor
Experimental: Age 15 to 23; Participants ages 15 to 23 years receiving oral atorvastatin for 48 weeks while on a stable antiretroviral regimen	Drug: Atorvastatin; 10 mg to 20 mg atorvastatin taken orally once daily. Dosage is dependent on efficacy criteria.; Other Name: Lipitor

Outcome Measures

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Primary Outcome Measures :

1. Percentage of Participants Experiencing at Least One Treatment-related Adverse Event (AE) [ Time Frame: Study entry to weeks 12, 24, and 48 ]
   AEs were graded by the clinicians according to the Division of AIDS (DAIDS) AE Grading Table (see references in the Protocol Section) as follows: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Potentially Life-Threatening, Grade 5=Death. Relationship to study treatment was determined by the core study team. The primary outcome measure includes any AE of grade 3 or higher and liver function tests (LFTs) of grade 2 or higher.
2. Percentage of Participants Experiencing at Least One Adverse Event (AE) [ Time Frame: Study entry to weeks 12, 24, and 48 ]
   AEs were graded by the clinicians according to the Division of AIDS (DAIDS) AE Grading Table (see references in the Protocol Section) as follows: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Potentially Life-Threatening, Grade 5=Death. The primary outcome measure includes any AE of grade 3 or higher and liver function tests (LFTs) of grade 2 or higher.
3. Percentage of Participants Who Met the LDL Cholesterol (LDL-C) Efficacy Criteria (Intention to Treat) [ Time Frame: Study entry and weeks 4, 12, 24, and 48 ]
   Efficacy was defined as having LDL-C of 110 mg/dL or less or at least 30% decline in LDL-C from baseline to the specified week.
4. Percentage of Participants Who Met the LDL Cholesterol (LDL-C) Efficacy Criteria (Data Available) [ Time Frame: Study entry and weeks 4, 12, 24, and 48 ]
   Efficacy was defined as having LDL-C of 110 mg/dL or less or at least 30% decline in LDL-C from baseline to the specified week.
5. Percentage of Participants Who Met the LDL Cholesterol (LDL-C) Efficacy Criteria (Per Protocol) [ Time Frame: Study entry and weeks 4, 12, 24, and 48 ]
   Efficacy was defined as having LDL-C of 110 mg/dL or less or at least 30% decline in LDL-C from baseline to the specified week.
6. Percentage of Participants Who Met the LDL Cholesterol (LDL-C) Efficacy Criteria and Did Not Experience a Primary Safety Endpoint Attributable to Study Drug [ Time Frame: Study entry and weeks 4, 12, 24, and 48 ]
   Efficacy was defined as having LDL-C of 110 mg/dL or less or at least 30% decline in LDL-C from baseline to the specified week.
7. Percentage of Participants Who Met the LDL Cholesterol (LDL-C) Efficacy Criteria by Age Group [ Time Frame: Study entry and weeks 4, 12, 24, and 48 ]
   Efficacy was defined as having LDL-C of 110 mg/dL or less or at least 30% decline in LDL-C from baseline to the specified week.
8. Percentage of Participants Who Met the LDL Cholesterol (LDL-C) Efficacy Criteria by NNRTI Treatment [ Time Frame: Study entry and weeks 4, 12, 24, and 48 ]
   Efficacy was defined as having LDL-C of 110 mg/dL or less or at least 30% decline in LDL-C from baseline to the specified week.
9. Percent Change in LDL Cholesterol (LDL-C) From Study Entry [ Time Frame: Study entry and weeks 4, 12, 24, and 48 ]
10. Percentage of Participants Experiencing at Least One Treatment-related Adverse Event (AE) by Age Group [ Time Frame: Study entry to weeks 12, 24, and 48 ]
    AEs were graded by the clinicians according to the Division of AIDS (DAIDS) AE Grading Table (see references in the Protocol Section) as follows: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Potentially Life-Threatening, Grade 5=Death. Relationship to study treatment was determined by the core study team. The primary outcome measure includes any AE of grade 3 or higher and liver function tests (LFTs) of grade 2 or higher.
11. Percentage of Participants Experiencing at Least One Adverse Event (AE) by Age Group [ Time Frame: Study entry to weeks 12, 24, and 48 ]
    AEs were graded by the clinicians according to the Division of AIDS (DAIDS) AE Grading Table (see references in the Protocol Section) as follows: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Potentially Life-Threatening, Grade 5=Death. The primary outcome measure includes any AE of grade 3 or higher and liver function tests (LFTs) of grade 2 or higher.

Secondary Outcome Measures :

1. Percent Change in Fasting Total Cholesterol (TC) From Study Entry [ Time Frame: Study entry and weeks 4, 12, 24, and 48 ]
2. Percent Change in Triglycerides (TG) From Study Entry [ Time Frame: Study entry and weeks 4, 12, 24, and 48 ]
3. Percent Change in HDL-cholesterol (HDL-C) From Study Entry [ Time Frame: Study entry and weeks 4, 12, 24, and 48 ]
4. Percent Change in Apolipoprotein A1 (Apo A-1) From Study Entry [ Time Frame: Study entry and weeks 12, 24, and 48 ]
5. Percent Change in Apolipoprotein B (Apo B) From Study Entry [ Time Frame: Study entry and weeks 12, 24, and 48 ]
6. Percent Change in High-sensitivity CRP (Hs-CRP) From Study Entry [ Time Frame: Study entry and weeks 12, 24, and 48 ]
7. Percent Change in Interleukin 6 (IL-6) From Study Entry [ Time Frame: Study entry and weeks 12, 24, and 48 ]
8. Percentage of Participants With Undetectable Plasma HIV-1 RNA [ Time Frame: Study entry and weeks 12, 24, and 48 ]
   Undetectable is defined as plasma HIV-1 RNA below the lower limit of quantification of the assay used.

Eligibility Criteria

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Ages Eligible for Study:	10 Years to 23 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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

Contacts and Locations

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Locations

United States, Colorado
Univ. of Colorado Denver NICHD CRS (5052)
Aurora, Colorado, United States, 80045
United States, Florida
Univ. of Miami Ped. Perinatal HIV/AIDS CRS (4201)
Miami, Florida, United States, 33136
University of South Florida Tampa (5018)
Tampa, Florida, United States, 33620
United States, Illinois
Chicago Children's CRS (4001)
Chicago, Illinois, United States, 60614
United States, Louisiana
Tulane University (5095)
New Orleans, Louisiana, United States, 70112
United States, Massachusetts
Boston Medical Center Ped. HIV Program NICHD CRS (5011)
Boston, Massachusetts, United States, 02118
United States, New York
Bronx-Lebanon Hospital IMPAACT CRS (6901)
Bronx, New York, United States, 10457
New York University NY (5012)
New York, New York, United States, 10016
Metropolitan Hospital (5003)
New York, New York, United States, 10029
United States, Tennessee
St. Jude/UTHSC CRS (6501)
Memphis, Tennessee, United States, 38105
United States, Texas
Texas Children's Hosp. CRS (3801)
Houston, Texas, United States, 77030

Sponsors and Collaborators

International Maternal Pediatric Adolescent AIDS Clinical Trials Group

National Institute of Allergy and Infectious Diseases (NIAID)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

Study Chair:	Ann Melvin, MD	Seattle Children's Hospital
Study Chair:	Marilyn Crain, MD, MPH	University of Alabama at Birmingham

More Information

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Publications:

Kamin D, Hadigan C. Hyperlipidemia in children with HIV infection: an emerging problem. Expert Rev Cardiovasc Ther. 2003 May;1(1):143-50. Review.

Penzak SR, Chuck SK. Management of protease inhibitor-associated hyperlipidemia. Am J Cardiovasc Drugs. 2002;2(2):91-106. Review.

Solórzano Santos F, Gochicoa Rangel LG, Palacios Saucedo G, Vázquez 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.

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)

Responsible Party:	International Maternal Pediatric Adolescent AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:	NCT00663234 History of Changes
Other Study ID Numbers:	IMPAACT P1063; U01AI068632 ( U.S. NIH Grant/Contract ); 10167
First Posted:	April 22, 2008
Results First Posted:	April 6, 2016
Last Update Posted:	April 6, 2016
Last Verified:	March 2016

Keywords provided by International Maternal Pediatric Adolescent AIDS Clinical Trials Group:

Treatment Experienced

Additional relevant MeSH terms:

HIV Infections; Hyperlipidemias; Hyperlipoproteinemias; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Immunologic Deficiency Syndromes; Immune System Diseases	Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Atorvastatin Calcium; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors