A Phase II/III Trial of Lopinavir/Ritonavir Dosed According to the WHO Pediatric Weight Band Dosing Guidelines

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT01172535
First received: July 28, 2010
Last updated: November 16, 2015
Last verified: November 2015
  Purpose
Treatment of children and infants with HIV requires modification of medication dosing according to a child's specific weight. For lopinavir/ritonavir (LPV/r), a second line treatment option that is increasingly necessary due to infant drug resistance, this dosing is often complicated and impractical in busy clinical settings. To address this, the World Health Organization (WHO) has released a simplified dosing table based on infant weight bands. This study will evaluate the absorption, safety, and tolerance of LPV/r in infants when dosed according to the new WHO guidelines.

Condition Intervention Phase
HIV
Drug: Lopinavir/ritonavir
Phase 2
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II/III Trial of Lopinavir/Ritonavir Dosed According to the WHO Pediatric Weight Band Dosing Guidelines

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Lopinovir/Ritonavir Area Under the Concentration-time Curve (AUC0-24) [ Time Frame: Measured at 4 weeks of treatment prior to the observed dose and at 2, 4, 6, 8, and 12 hours post-dose ] [ Designated as safety issue: No ]
    Area under the curve over 24 hours (AUC0-24), as determined by a non-compartmental analysis of 12-hour pharmacokinetic sampling for lopinavir/ritonavir

  • Maximum Concentration of Lopinavir/Ritonavir (Cmax) [ Time Frame: Measured at 4 weeks of treatment prior to the observed dose and at 2, 4, 6, 8, and 12 hours post-dose ] [ Designated as safety issue: No ]
    Maximum concentration of lopinavir/ritonavir, as determined by analysis of 12-hour pharmacokinetic sampling

  • Minimum Concentration of Lopinavir/Ritonavir (Cmin) [ Time Frame: Measured at 4 weeks of treatment prior to the observed dose and at 2, 4, 6, 8, and 12 hours post-dose ] [ Designated as safety issue: No ]
    Minimum concentration of lopinavir/ritonavir, as determined by analysis of 12-hour pharmacokinetic sampling

  • Clearance of Lopinavir/Ritonavir (CL/F) [ Time Frame: Measured at 4 weeks of treatment prior to the observed dose and at 2, 4, 6, 8, and 12 hours post-dose ] [ Designated as safety issue: No ]
    Clearance of lopinavir/ritonavir, as determined by analysis of 12-hour pharmacokinetic sampling

  • Proportion of Participants With an AUC of Less Than 10% of Adults [ Time Frame: Measured at 4 weeks of treatment prior to the observed dose and at 2, 4, 6, 8, and 12 hours post-dose ] [ Designated as safety issue: No ]
    Proportion of participants with an AUC less that 10% of adults (AUC0-24 <104 mcg*hr/mL)

  • Number of Participants Experiencing Adverse Events of Grade 3 or 4 [ Time Frame: Measured at study visits through end of study (weeks 2, 4, 12, 24) ] [ Designated as safety issue: Yes ]
    Adverse events were graded by the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, dated December, 2004, Clarification August 2009, which is available on the RSC web site (http://rsc.tech-res.com/safetyandpharmacovigilance/). Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = potentially life-threatening, Grade 5 = death

  • Proportion of Participants Tolerating LPV/r [ Time Frame: Measured at study completion (week 24) ] [ Designated as safety issue: No ]
    Participants were considered to have tolerated medication if they did not stop treatment before the 24 week PK visit for any reason other than completing treatment or death not related to treatment.


Secondary Outcome Measures:
  • Adherence [ Time Frame: Measured at week 4, week 12, and study completion (week 24) ] [ Designated as safety issue: No ]
    Adherence, defined as proportion of doses taken (note: proportion could be greater than 1.0 for reasons such as tablets having to be taken twice due to first one being spit out or imprecise measurement of liquid doses)

  • Treatment Efficacy (HIV Viral Load) [ Time Frame: Measured at entry and study completion (week 24) ] [ Designated as safety issue: No ]
    Having HIV viral load <400 copies/mL at the week 24 visit

  • Treatment Efficacy (CD4%) [ Time Frame: Measured at entry and study completion (week 24) ] [ Designated as safety issue: No ]
    Having CD4%≥25 at the week 24 visit.


Enrollment: 97
Study Start Date: November 2010
Study Completion Date: December 2013
Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Lopinavir/ritonavir
Participants will receive lopinavir/ritonavir in addition to two nucleoside reverse transcriptase inhibitors (NRTIs) chosen by their doctors.
Drug: Lopinavir/ritonavir
Heat-stable tablets of 100 mg lopinavir, 25 mg ritonavir, or liquid formulation of 80 mg lopinavir, 20 mg ritonavir, dosed according to World Health Organization (WHO) pediatric weight band dosing guidelines
Other Names:
  • Kaletra
  • LPV/r

Detailed Description:

Because of previous exposure to nevirapine or other non-nucleoside reverse transcriptase inhibitors (NNRTIs), either by direct treatment or through their mothers in pregnancy, infants must often receive an alternate antiretroviral regimen that includes LPV/r. Dosing of LPV/r is currently based on a child's specific weight, and calculations of proper dosages are often too complicated to be practical in busy clinics, particularly those in limited resource settings. In order to simplify medication delivery and reduce prescribing errors, the WHO has released a dosing schedule for LPV/r based on groupings of infants and children by weight. This study will evaluate the pharmacokinetics, safety, and tolerance of LPV/r dosed according to these guidelines. The following strata were used to guide accrual:

Number of Participants to be Enrolled by Weight Band:

3-4.9 kg: 11 liquid

5-6.9 kg: 11 liquid

7-9.9 kg: 17 liquid

10-16.9 kg: 11 liquid, 22 tablet

17-19.9 kg: 11 tablet

20-24.9 kg: 11 tablet

Participation in this study will last 6 months. Infant participants and their caretakers will need to attend study visits at entry and Weeks 2, 4, 12, and 24. At entry, participants will be given LPV/r either in liquid or tablet form, depending on whether they can swallow pills. Dosing will be calculated using the WHO schedule. At all study visits, participants will undergo a physical exam and caretakers will be asked about how well the child is taking the study medications. In addition, at Weeks 4, 12, and 24, blood samples will be taken from the participant to determine health and levels of the medication in the body. The visit on Week 4 will also require pharmacokinetic testing, which means the child will need to be monitored at the hospital for 12 hours and complete six additional blood drawls. All other study visits will last 1 to 2 hours.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Weight equal to or greater than 3 kg, but less than 25 kg, at the time of enrollment
  • Confirmed diagnosis of HIV-1 infection
  • Lopinavir/ritonavir (LPV/r)-treatment naïve and LPV/r-treatment eligible as defined by country-specific guidelines or the WHO pediatric treatment guidelines and confirmed by investigator
  • Willingness to take two nucleoside reverse transcriptase inhibitos (NRTIs), in accordance with appropriate national or international treatment guidelines
  • Demonstrated ability and willingness to swallow tablets for children larger than 10 kg. This can be assessed before inclusion (for example, a test trial with similar size solid tablet such as tic-tac).
  • Participants in the weight band between 10 and 16.9 kg that are unable to swallow tablets will receive liquid formulation
  • Parent or legal guardian able and willing to provide written informed consent

Exclusion Criteria:

  • Planned concurrent use of non-nucleoside reverse transcriptase inhibitors (NNRTIs), integrase inhibitors, or an entry inhibitor
  • Planned concurrent protease inhibitor (PI) use, other than LPV/r
  • Prior treatment with LPV/r. Prior treatment with other PIs is allowed.
  • Results of certain laboratory tests indicating adverse events of Grade 3 or greater
  • Results of a lipase test indicating adverse event of Grade 2 or greater or clinical evidence of pancreatitis within 30 days prior to study entry
  • Tuberculosis co-treatment with rifampicin-containing regimen
  • Treatment with any enzyme-inducing antiepileptic drugs, such as henobarbital, phenytoin or carbamazepine
  • Clinical condition requiring the use of a prohibited medication (see protocol for more details)
  • Clinically unstable child requiring acute treatment for a serious opportunistic infection
  • Chemotherapy for active malignancy
  • Any clinically significant diseases (other than HIV-1 infection) or clinically significant findings during the screening medical history or physical examination that, in the investigator's opinion, would compromise participation in this study
  • Treatment with experimental drugs for any indication within 30 days prior to study entry
  • Known history of cardiac conduction abnormality and/or underlying structural heart disease, including congenital long QT
  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: NCT01172535

Locations
United States, California
University of California, UC San Diego CRS
La Jolla,, California, United States, 92093-0672
United States, Colorado
Univ. of Colorado Denver NICHD CRS
Aurora, Colorado, United States, 80045
United States, Massachusetts
Boston Medical Center Ped. HIV Program NICHD CRS
Boston, Massachusetts, United States, 02118
Brazil
SOM Federal University Minas Gerais Brazil NICHD CRS
Belo Horizonte, Minas Gerais, Brazil, 30130-100
Hosp. Santa Casa Porto Alegre Brazil NICHD CRS
Porto Alegre, Rio Grande do Sul, Brazil, 90020-090
Hospital Federal dos Servidores do Estado NICHD CRS
Rio de Janeiro, Brazil, 20221-903
Instituto de Puericultura e Pediatria Martagao Gesteira - UFRJ NICHD CRS
Rio de Janeiro, Brazil, 21941-612
Hosp. Geral De Nova Igaucu Brazil NICHD CRS
Rio de Janeiro, Brazil, 26030
Inst de Infectologia Emilio Ribas Sao Paulo Brazil NICHD CRS
Sao Paulo, Brazil, 01246-900
Univ. of Sao Paulo Brazil NICHD CRS
Sao Paulo, Brazil, 14049-900
South Africa
Shandukani CRS
Johannesburg, Gauteng, South Africa, 2001
Family Clinical Research Unit (FAM-CRU) CRS
Tygerberg, Western Cape Province, South Africa, 7505
Thailand
Siriraj Hospital Mahidol University CRS
Bangkok, Bangkoknoi, Thailand, 10700
Bhumibol Adulyadej Hosp. CRS
Saimai, Bangkok, Thailand, 10220
Prapokklao Hosp. CRS
Chantaburi, Thailand, 22000
Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
Chiang Mai, Thailand, 50200
Chiangrai Prachanukroh Hospital CRS
Chiangrai, Thailand, 57000
Chonburi Hosp. CRS
Chonburi, Thailand, 2000
Phayao Provincial Hosp. CRS
Phayao, Thailand, 56000
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
Study Chair: Jorge A. Pinto, MD Federal University of Minas Gerais
  More Information

No publications provided

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT01172535     History of Changes
Obsolete Identifiers: NCT01338038
Other Study ID Numbers: P1083  10787  IMPAACT P1083 
Study First Received: July 28, 2010
Results First Received: November 16, 2015
Last Updated: November 16, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Lopinavir/ritonavir
Pediatric dosing
World Health Organization

Additional relevant MeSH terms:
Lopinavir
Ritonavir
Anti-HIV Agents
Anti-Infective Agents
Anti-Retroviral Agents
Antiviral Agents
Enzyme Inhibitors
HIV Protease Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protease Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on February 08, 2016