CompletedNCT01172535Updated Nov 5, 2021Results posted

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

A Phase 2/3 interventional study of Lopinavir/ritonavir in HIV, sponsored by National Institute of Allergy and Infectious Diseases (NIAID). Completed at 19 sites in 4 countries. Open to participants aged 4 Weeks and older. Per ClinicalTrials.gov, last updated 2021-11-05.

Sponsored by National Institute of Allergy and Infectious Diseases (NIAID) · Phase 2/3, Interventional, and Treatment

Phase: Phase 2/3
Study type: Interventional
Enrollment: 97
Allocation: Not applicable
Ages: 4 Weeks and older
Sex: All

Study 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.

Read the 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.

Conditions studied

Keywords

Lopinavir/ritonavir
Pediatric dosing
World Health Organization

In context

Lead sponsor

National Institute of Allergy and Infectious Diseases (NIAID) is the lead sponsor of 2,401 studies on the registry; 179 are open to participants now.

Of its 396 completed or terminated interventional studies of FDA-regulated products, 294 (74%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 4 Weeks and older
Sexes eligible: All
Accepts healthy volunteers: No

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

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

Phase: Phase 2 / Phase 3
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrollment: 97 participants (actual)

Study arms

Experimental
Lopinavir/ritonavir
Participants will receive lopinavir/ritonavir in addition to two nucleoside reverse transcriptase inhibitors (NRTIs) chosen by their doctors.
Drug: Lopinavir/ritonavir

Interventions

DrugLopinavir/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
Also known as: Kaletra, LPV/r

What researchers measure

Primary outcomes

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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: 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
Time frame: 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.
Time frame: Measured at study completion (week 24)

Secondary outcomes

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)
Time frame: 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
Time frame: Measured at entry and study completion (week 24)
Treatment Efficacy (CD4%)
Having CD4%≥25 at the week 24 visit.
Time frame: Measured at entry and study completion (week 24)

Results

Posted Dec 21, 2015

Participant flow

There were 97 participants enrolled from 19 clinical sites in four countries. There were 57 participants on the liquid formulation and 40 on tablet. Accrual took place from May 20, 2011 through June 19, 2013.

Participant flow — Overall Study
Milestone	Lopinavir/Ritonavir
Started	97
Completed	89
Not completed	8
Withdrew: Death	3
Withdrew: Withdrawal by subject	2
Withdrew: Lost to follow-up	1
Withdrew: Ineligible at study entry	1
Withdrew: Unwilling to adhere to study requirement	1

Outcome measures

PrimaryLopinovir/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

Time frame:: Measured at 4 weeks of treatment prior to the observed dose and at 2, 4, 6, 8, and 12 hours post-dose
Reported as:: Geometric mean · mcg*hr/mL

Lopinovir/Ritonavir Area Under the Concentration-time Curve (AUC0-24)
mcg*hr/mL	Lopinavir/Ritonavir
Lopinovir/Ritonavir Area Under the Concentration-time Curve (AUC0-24)	196 (177 to 217)

PrimaryMaximum Concentration of Lopinavir/Ritonavir (Cmax)

Maximum concentration of lopinavir/ritonavir, as determined by analysis of 12-hour pharmacokinetic sampling

Time frame:: Measured at 4 weeks of treatment prior to the observed dose and at 2, 4, 6, 8, and 12 hours post-dose
Reported as:: Geometric mean · mcg/mL

Maximum Concentration of Lopinavir/Ritonavir (Cmax)
mcg/mL	Lopinavir/Ritonavir
Maximum Concentration of Lopinavir/Ritonavir (Cmax)	11.25 (10.24 to 12.35)

PrimaryMinimum Concentration of Lopinavir/Ritonavir (Cmin)

Minimum concentration of lopinavir/ritonavir, as determined by analysis of 12-hour pharmacokinetic sampling

Time frame:: Measured at 4 weeks of treatment prior to the observed dose and at 2, 4, 6, 8, and 12 hours post-dose
Reported as:: Geometric mean · mcg/mL

Minimum Concentration of Lopinavir/Ritonavir (Cmin)
mcg/mL	Lopinavir/Ritonavir
Minimum Concentration of Lopinavir/Ritonavir (Cmin)	2.47 (1.52 to 4.02)

PrimaryClearance of Lopinavir/Ritonavir (CL/F)

Clearance of lopinavir/ritonavir, as determined by analysis of 12-hour pharmacokinetic sampling

Time frame:: Measured at 4 weeks of treatment prior to the observed dose and at 2, 4, 6, 8, and 12 hours post-dose
Reported as:: Geometric mean · L/h/kg

Clearance of Lopinavir/Ritonavir (CL/F)
L/h/kg	Lopinavir/Ritonavir
Clearance of Lopinavir/Ritonavir (CL/F)	0.15 (0.13 to 0.17)

PrimaryProportion 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)

Time frame:: Measured at 4 weeks of treatment prior to the observed dose and at 2, 4, 6, 8, and 12 hours post-dose
Reported as:: Number · proportion of participants

Proportion of Participants With an AUC of Less Than 10% of Adults
proportion of participants	Lopinavir/Ritonavir
Proportion of Participants With an AUC of Less Than 10% of Adults	0.15 (0.09 to 0.23)

SecondaryAdherence

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)

Time frame:: Measured at week 4, week 12, and study completion (week 24)
Reported as:: Median · Proportion of expected doses taken

Adherence
Proportion of expected doses taken	Week 4	Week 12	Week 24
Adherence	1.00 (0.97 to 1.10)	0.99 (0.88 to 1.01)	1.00 (0.91 to 1.01)

SecondaryTreatment Efficacy (HIV Viral Load)

Having HIV viral load \<400 copies/mL at the week 24 visit

Time frame:: Measured at entry and study completion (week 24)
Reported as:: Number · proportion of participants

Treatment Efficacy (HIV Viral Load)
proportion of participants	Lopinavir/Ritonavir
Treatment Efficacy (HIV Viral Load)	0.72 (0.61 to 0.82)

SecondaryTreatment Efficacy (CD4%)

Having CD4%≥25 at the week 24 visit.

Time frame:: Measured at entry and study completion (week 24)
Reported as:: Number · proportion of participants

Treatment Efficacy (CD4%)
proportion of participants	Lopinavir/Ritonavir
Treatment Efficacy (CD4%)	0.71 (0.60 to 0.81)

PrimaryNumber 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

Time frame:: Measured at study visits through end of study (weeks 2, 4, 12, 24)
Reported as:: Number · participants

Number of Participants Experiencing Adverse Events of Grade 3 or 4
participants	Lopinavir/Ritonavir
Number of Participants Experiencing Adverse Events of Grade 3 or 4	32

PrimaryProportion 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.

Time frame:: Measured at study completion (week 24)
Reported as:: Number · proportion of participants

Proportion of Participants Tolerating LPV/r
proportion of participants	Lopinavir/Ritonavir
Proportion of Participants Tolerating LPV/r	0.93 (0.86 to 0.97)

Adverse events

Collected over From entry until off-study (week 24). Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
LPV/r	—	20/97 (20.6%)	96/97 (99%)

Most frequent serious events

Showing 10 of 17

Most frequent serious events
Event	LPV/r
PneumoniaInfections and infestations	6/97
Amylase increasedInvestigations	3/97
GastroenteritisInfections and infestations	2/97
MeaslesInfections and infestations	2/97
NeutropeniaBlood and lymphatic system disorders	1/97
CardiomyopathyCardiac disorders	1/97
DrowningGeneral disorders	1/97
BronchitisInfections and infestations	1/97
Herpes zosterInfections and infestations	1/97
Immune reconstitution inflammatory syndrome associated tuberculosisInfections and infestations	1/97

Most frequent other events

Showing 10 of 49

Most frequent other events
Event	LPV/r
Blood sodium decreasedInvestigations	58/97
Blood bicarbonate decreasedInvestigations	54/97
CoughRespiratory, thoracic and mediastinal disorders	48/97
RhinorrhoeaRespiratory, thoracic and mediastinal disorders	43/97
PyrexiaGeneral disorders	42/97
Haemoglobin decreasedInvestigations	40/97
Amylase abnormalInvestigations	39/97
DiarrhoeaGastrointestinal disorders	33/97
VomitingGastrointestinal disorders	30/97
Blood calcium increasedInvestigations	25/97

Baseline characteristics

All participants enrolled in the study

Age, Continuous
Age, Continuous(years)	Lopinavir/Ritonavir
Median	2.5 (0.5 to 6.2)

Sex: Female, Male
Sex: Female, Male(Participants)	Lopinavir/Ritonavir
Female	54
Male	43

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	Lopinavir/Ritonavir
Hispanic or Latino	31
Not Hispanic or Latino	42
Unknown or Not Reported	24

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Lopinavir/Ritonavir
American Indian or Alaska Native	0
Asian	37
Native Hawaiian or Other Pacific Islander	0
Black or African American	39
White	7
More than one race	0
Unknown or Not Reported	14

Region of Enrollment
Region of Enrollment(participants)	Lopinavir/Ritonavir
United States	5
Brazil	32
South Africa	23
Thailand	37

HIV RNA (copies/mL) at study entry
HIV RNA (copies/mL) at study entry(log copies/mL)	Lopinavir/Ritonavir
Median	5.2 (4.6 to 5.7)

CD4% at study entry
CD4% at study entry(percentage of total lymphocytes)	Lopinavir/Ritonavir
Median	24.2 (15.8 to 29.0)

Study locations

19 sites

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

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Nov 5, 2021, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT01172535
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Responsible party: Sponsor
First posted: Jul 29, 2010
Start date: Nov 2010
Primary completion: Dec 2013
Completion: Dec 2013
Results posted: Dec 21, 2015
Last update: Nov 5, 2021

Study contacts

Jorge A. Pinto, MD

study chair · Federal University of Minas Gerais

Oversight

Data monitoring committee: Yes

View the source record on ClinicalTrials.gov ↗

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