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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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HIV

Intervention / Treatment
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* Drug: Lopinavir/ritonavir


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 4 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lopinavir/ritonavir<br>Participants will receive lopinavir/ritonavir in addition to two nucleoside reverse transcriptase inhibitors (NRTIs) chosen by their doctors. | Drug: Lopinavir/ritonavir<br>* 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<br>* Other names: LPV/r;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adherence | 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) | Measured at week 4, week 12, and study completion (week 24) | 
| Treatment Efficacy (HIV Viral Load) | Having HIV viral load <400 copies/mL at the week 24 visit | Measured at entry and study completion (week 24) | 
| Treatment Efficacy (CD4%) | Having CD4%≥25 at the week 24 visit. | Measured at entry and study completion (week 24) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lopinavir/ritonavir, Pediatric dosing, World Health Organization