Clinical trial NCT01172535: A Phase II/III Trial of Lopinavir/Ritonavir Dosed According to the WHO Pediatric Weight Band Dosing Guidelines
Official title: A Phase II/III Trial of Lopinavir/Ritonavir Dosed According to the WHO Pediatric Weight Band Dosing Guidelines
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: HIV
Keywords: Lopinavir/ritonavir
Pediatric dosing
World Health Organization
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2010-07-29
Enrollment: 97
Sex: ALL
Minimum age (years): 4
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Lopinovir/Ritonavir Area Under the Concentration-time Curve (AUC0-24)
timeFrame: Measured at 4 weeks of treatment prior to the observed dose and at 2, 4, 6, 8, and 12 hours post-dose
measure: Maximum Concentration of Lopinavir/Ritonavir (Cmax)
timeFrame: Measured at 4 weeks of treatment prior to the observed dose and at 2, 4, 6, 8, and 12 hours post-dose
measure: Minimum Concentration of Lopinavir/Ritonavir (Cmin)
timeFrame: Measured at 4 weeks of treatment prior to the observed dose and at 2, 4, 6, 8, and 12 hours post-dose
measure: Clearance of Lopinavir/Ritonavir (CL/F)
timeFrame: Measured at 4 weeks of treatment prior to the observed dose and at 2, 4, 6, 8, and 12 hours post-dose
measure: Proportion of Participants With an AUC of Less Than 10% of Adults
timeFrame: Measured at 4 weeks of treatment prior to the observed dose and at 2, 4, 6, 8, and 12 hours post-dose
measure: Number of Participants Experiencing Adverse Events of Grade 3 or 4
timeFrame: Measured at study visits through end of study (weeks 2, 4, 12, 24)
measure: Proportion of Participants Tolerating LPV/r
timeFrame: Measured at study completion (week 24)
Secondary outcomes:
measure: Adherence
timeFrame: Measured at week 4, week 12, and study completion (week 24)
measure: Treatment Efficacy (HIV Viral Load)
timeFrame: Measured at entry and study completion (week 24)
measure: Treatment Efficacy (CD4%)
timeFrame: Measured at entry and study completion (week 24)
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California, UC San Diego CRS
state: California
city: Aurora
country: United States
facility: Univ. of Colorado Denver NICHD CRS
state: Colorado
city: Boston
country: United States
facility: Boston Medical Center Ped. HIV Program NICHD CRS
state: Massachusetts
city: Belo Horizonte
country: Brazil
facility: SOM Federal University Minas Gerais Brazil NICHD CRS
state: Minas Gerais
city: Porto Alegre
country: Brazil
facility: Hosp. Santa Casa Porto Alegre Brazil NICHD CRS
state: Rio Grande Do Sul
city: Rio de Janeiro
country: Brazil
facility: Hospital Federal dos Servidores do Estado NICHD CRS
city: Rio de Janeiro
country: Brazil
facility: Instituto de Puericultura e Pediatria Martagao Gesteira - UFRJ NICHD CRS
city: Rio de Janeiro
country: Brazil
facility: Hosp. Geral De Nova Igaucu Brazil NICHD CRS
city: Sao Paulo
country: Brazil
facility: Inst de Infectologia Emilio Ribas Sao Paulo Brazil NICHD CRS
city: Sao Paulo
country: Brazil
facility: Univ. of Sao Paulo Brazil NICHD CRS
city: Johannesburg
country: South Africa
facility: Shandukani CRS
state: Gauteng
city: Tygerberg
country: South Africa
facility: Family Clinical Research Unit (FAM-CRU) CRS
state: Western Cape Province
city: Bangkok
country: Thailand
facility: Siriraj Hospital Mahidol University CRS
state: Bangkoknoi
city: Saimai
country: Thailand
facility: Bhumibol Adulyadej Hosp. CRS
state: Bangkok
city: Chantaburi
country: Thailand
facility: Prapokklao Hosp. CRS
city: Chiang Mai
country: Thailand
facility: Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
city: Chiangrai
country: Thailand
facility: Chiangrai Prachanukroh Hospital CRS
city: Chonburi
country: Thailand
facility: Chonburi Hosp. CRS
city: Phayao
country: Thailand
facility: Phayao Provincial Hosp. CRS
Study officials:
affiliation: Federal University of Minas Gerais
name: Jorge A. Pinto, MD
role: STUDY_CHAIR
References: