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

Phase I/II Safety and Efficacy Investigation of Atorvastatin for Treatment of PI-Associated Increased LDL Cholesterol in HIV-Infected Children and Adolescents

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.

Study Overview

Status

Terminated

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

28

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

10 years to 23 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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
10 mg to 20 mg atorvastatin taken orally once daily. Dosage is dependent on efficacy criteria.
Other Names:
  • Lipitor
Experimental: Age 15 to 23
Participants ages 15 to 23 years receiving oral atorvastatin for 48 weeks while on a stable antiretroviral regimen
10 mg to 20 mg atorvastatin taken orally once daily. Dosage is dependent on efficacy criteria.
Other Names:
  • Lipitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Study entry to weeks 12, 24, and 48
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.
Study entry to weeks 12, 24, and 48
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.
Study entry and weeks 4, 12, 24, and 48
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.
Study entry and weeks 4, 12, 24, and 48
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.
Study entry and weeks 4, 12, 24, and 48
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.
Study entry and weeks 4, 12, 24, and 48
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.
Study entry and weeks 4, 12, 24, and 48
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.
Study entry and weeks 4, 12, 24, and 48
Percent Change in LDL Cholesterol (LDL-C) From Study Entry
Time Frame: Study entry and weeks 4, 12, 24, and 48
Study entry and weeks 4, 12, 24, and 48
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.
Study entry to weeks 12, 24, and 48
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.
Study entry to weeks 12, 24, and 48

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percent Change in Fasting Total Cholesterol (TC) From Study Entry
Time Frame: Study entry and weeks 4, 12, 24, and 48
Study entry and weeks 4, 12, 24, and 48
Percent Change in Triglycerides (TG) From Study Entry
Time Frame: Study entry and weeks 4, 12, 24, and 48
Study entry and weeks 4, 12, 24, and 48
Percent Change in HDL-cholesterol (HDL-C) From Study Entry
Time Frame: Study entry and weeks 4, 12, 24, and 48
Study entry and weeks 4, 12, 24, and 48
Percent Change in Apolipoprotein A1 (Apo A-1) From Study Entry
Time Frame: Study entry and weeks 12, 24, and 48
Study entry and weeks 12, 24, and 48
Percent Change in Apolipoprotein B (Apo B) From Study Entry
Time Frame: Study entry and weeks 12, 24, and 48
Study entry and weeks 12, 24, and 48
Percent Change in High-sensitivity CRP (Hs-CRP) From Study Entry
Time Frame: Study entry and weeks 12, 24, and 48
Study entry and weeks 12, 24, and 48
Percent Change in Interleukin 6 (IL-6) From Study Entry
Time Frame: Study entry and weeks 12, 24, and 48
Study entry and weeks 12, 24, and 48
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.
Study entry and weeks 12, 24, and 48

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2009

Primary Completion (Actual)

December 1, 2014

Study Completion (Actual)

December 1, 2014

Study Registration Dates

First Submitted

April 21, 2008

First Submitted That Met QC Criteria

April 21, 2008

First Posted (Estimate)

April 22, 2008

Study Record Updates

Last Update Posted (Estimate)

April 6, 2016

Last Update Submitted That Met QC Criteria

March 8, 2016

Last Verified

March 1, 2016

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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