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

Phase 2

Completed

Conditions: HIV

Interventions: Drug: Lopinavir/ritonavir

Registration Number: NCT01172535

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 97

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Lopinavir/ritonavir	Lopinavir/ritonavir	Participants will receive lopinavir/ritonavir in addition to two nucleoside reverse transcriptase inhibitors (NRTIs) chosen by their doctors.

Primary Outcome Measures

Name	Time	Method
Maximum Concentration of Lopinavir/Ritonavir (Cmax)	Measured at 4 weeks of treatment prior to the observed dose and at 2, 4, 6, 8, and 12 hours post-dose	Maximum concentration of lopinavir/ritonavir, as determined by analysis of 12-hour pharmacokinetic sampling
Lopinovir/Ritonavir Area Under the Concentration-time Curve (AUC0-24)	Measured at 4 weeks of treatment prior to the observed dose and at 2, 4, 6, 8, and 12 hours post-dose	Area under the curve over 24 hours (AUC0-24), as determined by a non-compartmental analysis of 12-hour pharmacokinetic sampling for lopinavir/ritonavir
Clearance of Lopinavir/Ritonavir (CL/F)	Measured at 4 weeks of treatment prior to the observed dose and at 2, 4, 6, 8, and 12 hours post-dose	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	Measured at 4 weeks of treatment prior to the observed dose and at 2, 4, 6, 8, and 12 hours post-dose	Proportion of participants with an AUC less that 10% of adults (AUC0-24 \<104 mcg\*hr/mL)
Minimum Concentration of Lopinavir/Ritonavir (Cmin)	Measured at 4 weeks of treatment prior to the observed dose and at 2, 4, 6, 8, and 12 hours post-dose	Minimum concentration of lopinavir/ritonavir, as determined by analysis of 12-hour pharmacokinetic sampling
Proportion of Participants Tolerating LPV/r	Measured at study completion (week 24)	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.
Number of Participants Experiencing Adverse Events of Grade 3 or 4	Measured at study visits through end of study (weeks 2, 4, 12, 24)	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

Secondary Outcome Measures

Name	Time	Method
Treatment Efficacy (HIV Viral Load)	Measured at entry and study completion (week 24)	Having HIV viral load \<400 copies/mL at the week 24 visit
Adherence	Measured at week 4, week 12, and study completion (week 24)	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 (CD4%)	Measured at entry and study completion (week 24)	Having CD4%≥25 at the week 24 visit.

Trial Locations

Locations (19): University of California, UC San Diego CRS
🇺🇸
La Jolla, California, United States
Boston Medical Center Ped. HIV Program NICHD CRS
🇺🇸
Boston, Massachusetts, United States
Hosp. Santa Casa Porto Alegre Brazil NICHD CRS
🇧🇷
Porto Alegre, Rio Grande Do Sul, Brazil
Hosp. Geral De Nova Igaucu Brazil NICHD CRS
🇧🇷
Rio de Janeiro, Brazil
Shandukani CRS
🇿🇦
Johannesburg, Gauteng, South Africa
Family Clinical Research Unit (FAM-CRU) CRS
🇿🇦
Tygerberg, Western Cape Province, South Africa
Bhumibol Adulyadej Hosp. CRS
🇹🇭
Saimai, Bangkok, Thailand
Siriraj Hospital Mahidol University CRS
🇹🇭
Bangkok, Bangkoknoi, Thailand
Prapokklao Hosp. CRS
🇹🇭
Chantaburi, Thailand
Chiangrai Prachanukroh Hospital CRS
🇹🇭
Chiangrai, Thailand
Phayao Provincial Hosp. CRS
🇹🇭
Phayao, Thailand
Univ. of Colorado Denver NICHD CRS
🇺🇸
Aurora, Colorado, United States
SOM Federal University Minas Gerais Brazil NICHD CRS
🇧🇷
Belo Horizonte, Minas Gerais, Brazil
Univ. of Sao Paulo Brazil NICHD CRS
🇧🇷
Sao Paulo, Brazil
Inst de Infectologia Emilio Ribas Sao Paulo Brazil NICHD CRS
🇧🇷
Sao Paulo, Brazil
Hospital Federal dos Servidores do Estado NICHD CRS
🇧🇷
Rio de Janeiro, Brazil
Instituto de Puericultura e Pediatria Martagao Gesteira - UFRJ NICHD CRS
🇧🇷
Rio de Janeiro, Brazil
Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
🇹🇭
Chiang Mai, Thailand
Chonburi Hosp. CRS
🇹🇭
Chonburi, Thailand