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

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ClinicalTrials.gov Identifier: NCT01172535
Recruitment Status : Completed
First Posted : July 29, 2010
Results First Posted : December 21, 2015
Last Update Posted : December 21, 2015
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition HIV
Intervention Drug: Lopinavir/ritonavir
Enrollment 97
Recruitment Details 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.
Pre-assignment Details HIV-infected infants and children ≥3 to <25 kg had to be LPV/r-treatment naïve. Children ≥10 kg had to demonstrate ability and willingness to swallow tablets. Participants were stratified by weight and drug formulation (liquid vs. tablet).
Arm/Group Title Lopinavir/Ritonavir
Hide Arm/Group Description Participants receiving lopinavir/ritonavir, dosed according to World Health Organization (WHO) pediatric weight band dosing guidelines, in addition to two nucleoside reverse transcriptase inhibitors (NRTIs) chosen by their doctors.
Period Title: Overall Study
Started 97
Completed 89
Not Completed 8
Reason Not Completed
Death             3
Withdrawal by Subject             2
Lost to Follow-up             1
Ineligible at study entry             1
Unwilling to adhere to study requirement             1
Arm/Group Title Lopinavir/Ritonavir
Hide Arm/Group Description Participants receiving lopinavir/ritonavirr, dosed according to World Health Organization (WHO) pediatric weight band dosing guidelines, in addition to two nucleoside reverse transcriptase inhibitors (NRTIs) chosen by their doctors.
Overall Number of Baseline Participants 97
Hide Baseline Analysis Population Description
All participants enrolled in the study
Age, Continuous  
Median (Inter-Quartile Range)
Unit of measure:  Years
Number Analyzed 97 participants
2.5
(0.5 to 6.2)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 97 participants
Female
54
  55.7%
Male
43
  44.3%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 97 participants
Hispanic or Latino
31
  32.0%
Not Hispanic or Latino
42
  43.3%
Unknown or Not Reported
24
  24.7%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 97 participants
American Indian or Alaska Native
0
   0.0%
Asian
37
  38.1%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
39
  40.2%
White
7
   7.2%
More than one race
0
   0.0%
Unknown or Not Reported
14
  14.4%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 97 participants
United States 5
Brazil 32
South Africa 23
Thailand 37
HIV RNA (copies/mL) at study entry  
Median (Inter-Quartile Range)
Unit of measure:  Log copies/mL
Number Analyzed 97 participants
5.2
(4.6 to 5.7)
CD4% at study entry  
Median (Inter-Quartile Range)
Unit of measure:  Percentage of total lymphocytes
Number Analyzed 97 participants
24.2
(15.8 to 29.0)
1.Primary Outcome
Title Lopinovir/Ritonavir Area Under the Concentration-time Curve (AUC0-24)
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants having complete pharmacokinetics data at week 4
Arm/Group Title Lopinavir/Ritonavir
Hide Arm/Group Description:
Participants receiving lopinavir/ritonavir, dosed according to World Health Organization (WHO) pediatric weight band dosing guidelines, in addition to two nucleoside reverse transcriptase inhibitors (NRTIs) chosen by their doctors.
Overall Number of Participants Analyzed 81
Geometric Mean (90% Confidence Interval)
Unit of Measure: mcg*hr/mL
196
(177 to 217)
2.Primary Outcome
Title Maximum Concentration of Lopinavir/Ritonavir (Cmax)
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants having complete pharmacokinetics data at week 4
Arm/Group Title Lopinavir/Ritonavir
Hide Arm/Group Description:
Participants receiving lopinavir/ritonavir, dosed according to World Health Organization (WHO) pediatric weight band dosing guidelines, in addition to two nucleoside reverse transcriptase inhibitors (NRTIs) chosen by their doctors.
Overall Number of Participants Analyzed 81
Geometric Mean (90% Confidence Interval)
Unit of Measure: mcg/mL
11.25
(10.24 to 12.35)
3.Primary Outcome
Title Minimum Concentration of Lopinavir/Ritonavir (Cmin)
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants having complete pharmacokinetics data at week 4
Arm/Group Title Lopinavir/Ritonavir
Hide Arm/Group Description:
Participants receiving lopinavir/ritonavir, dosed according to World Health Organization (WHO) pediatric weight band dosing guidelines, in addition to two nucleoside reverse transcriptase inhibitors (NRTIs) chosen by their doctors.
Overall Number of Participants Analyzed 81
Geometric Mean (90% Confidence Interval)
Unit of Measure: mcg/mL
2.47
(1.52 to 4.02)
4.Primary Outcome
Title Clearance of Lopinavir/Ritonavir (CL/F)
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants having complete pharmacokinetics data at week 4
Arm/Group Title Lopinavir/Ritonavir
Hide Arm/Group Description:
Participants receiving lopinavir/ritonavir, dosed according to World Health Organization (WHO) pediatric weight band dosing guidelines, in addition to two nucleoside reverse transcriptase inhibitors (NRTIs) chosen by their doctors.
Overall Number of Participants Analyzed 81
Geometric Mean (90% Confidence Interval)
Unit of Measure: L/h/kg
0.15
(0.13 to 0.17)
5.Primary Outcome
Title Proportion of Participants With an AUC of Less Than 10% of Adults
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants with complete pharmacokinetics data at week 4
Arm/Group Title Lopinavir/Ritonavir
Hide Arm/Group Description:
Participants receiving lopinavir/ritonavir, dosed according to World Health Organization (WHO) pediatric weight band dosing guidelines, in addition to two nucleoside reverse transcriptase inhibitors (NRTIs) chosen by their doctors.
Overall Number of Participants Analyzed 81
Measure Type: Number
Number (90% Confidence Interval)
Unit of Measure: proportion of participants
0.15
(0.09 to 0.23)
6.Primary Outcome
Title Number of Participants Experiencing Adverse Events of Grade 3 or 4
Hide Description 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)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants
Arm/Group Title Lopinavir/Ritonavir
Hide Arm/Group Description:
Participants receiving lopinavir/ritonavir, dosed according to World Health Organization (WHO) pediatric weight band dosing guidelines, in addition to two nucleoside reverse transcriptase inhibitors (NRTIs) chosen by their doctors.
Overall Number of Participants Analyzed 97
Measure Type: Number
Unit of Measure: participants
32
7.Primary Outcome
Title Proportion of Participants Tolerating LPV/r
Hide Description 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)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants
Arm/Group Title Lopinavir/Ritonavir
Hide Arm/Group Description:
Participants receiving lopinavir/ritonavir, dosed according to World Health Organization (WHO) pediatric weight band dosing guidelines, in addition to two nucleoside reverse transcriptase inhibitors (NRTIs) chosen by their doctors.
Overall Number of Participants Analyzed 97
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: proportion of participants
0.93
(0.86 to 0.97)
8.Secondary Outcome
Title Adherence
Hide Description 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)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants bringing medication to be measured at the study visit
Arm/Group Title Week 4 Week 12 Week 24
Hide Arm/Group Description:
Participants bringing medication to be measured at study week 4
Participants bringing medication to be measured at study week 12
Participants bringing medication to be measured at study week 24
Overall Number of Participants Analyzed 62 59 59
Median (Inter-Quartile Range)
Unit of Measure: Proportion of expected doses taken
1.00
(0.97 to 1.10)
0.99
(0.88 to 1.01)
1.00
(0.91 to 1.01)
9.Secondary Outcome
Title Treatment Efficacy (HIV Viral Load)
Hide Description Having HIV viral load <400 copies/mL at the week 24 visit
Time Frame Measured at entry and study completion (week 24)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants with data from both study entry and the week 24 study visit
Arm/Group Title Lopinavir/Ritonavir
Hide Arm/Group Description:
Participants receiving lopinavir/ritonavir, dosed according to World Health Organization (WHO) pediatric weight band dosing guidelines, in addition to two nucleoside reverse transcriptase inhibitors (NRTIs) chosen by their doctors.
Overall Number of Participants Analyzed 79
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: proportion of participants
0.72
(0.61 to 0.82)
10.Secondary Outcome
Title Treatment Efficacy (CD4%)
Hide Description Having CD4%≥25 at the week 24 visit.
Time Frame Measured at entry and study completion (week 24)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants with data from both study entry and the week 24 study visit
Arm/Group Title Lopinavir/Ritonavir
Hide Arm/Group Description:
Participants receiving lopinavir/ritonavir, dosed according to World Health Organization (WHO) pediatric weight band dosing guidelines, in addition to two nucleoside reverse transcriptase inhibitors (NRTIs) chosen by their doctors.
Overall Number of Participants Analyzed 83
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: proportion of participants
0.71
(0.60 to 0.81)
Time Frame From entry until off-study (week 24)
Adverse Event Reporting Description Expedited adverse event (AE) reporting followed Intensive Division of AIDS (DAIDS) Reporting Level, which included Aes resulting in death, significant disabilities, requiring hospitalization, and ≥grade 3 Aes defined by the “DAIDS Table for Grading the Severity of Adult and Pediatric Aes”, V1.0, 12/2004.
 
Arm/Group Title LPV/r
Hide Arm/Group Description Participants receiving lopinavir/ritonavir, dosed according to World Health Organization (WHO) pediatric weight band dosing guidelines, in addition to two nucleoside reverse transcriptase inhibitors (NRTIs) chosen by their doctors.
All-Cause Mortality
LPV/r
Affected / at Risk (%)
Total   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
LPV/r
Affected / at Risk (%)
Total   20/97 (20.62%) 
Blood and lymphatic system disorders   
Neutropenia  1  1/97 (1.03%) 
Cardiac disorders   
Cardiomyopathy  1  1/97 (1.03%) 
General disorders   
Drowning  1  1/97 (1.03%) 
Infections and infestations   
Bronchitis  1  1/97 (1.03%) 
Gastroenteritis  1  2/97 (2.06%) 
Herpes zoster  1  1/97 (1.03%) 
Immune reconstitution inflammatory syndrome associated tuberculosis  1  1/97 (1.03%) 
Influenza  1  1/97 (1.03%) 
Measles  1  2/97 (2.06%) 
Pneumonia  1  6/97 (6.19%) 
Pneumonia bacterial  1  1/97 (1.03%) 
Pneumonia respiratory syncytial viral  1  1/97 (1.03%) 
Investigations   
Amylase increased  1  3/97 (3.09%) 
Metabolism and nutrition disorders   
Hyperamylasaemia  1  1/97 (1.03%) 
Hyperkalaemia  1  1/97 (1.03%) 
Hypokalaemia  1  1/97 (1.03%) 
Skin and subcutaneous tissue disorders   
Rash  1  1/97 (1.03%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
LPV/r
Affected / at Risk (%)
Total   96/97 (98.97%) 
Blood and lymphatic system disorders   
Lymphadenopathy  1  8/97 (8.25%) 
Eye disorders   
Conjunctival pallor  1  5/97 (5.15%) 
Eye discharge  1  8/97 (8.25%) 
Gastrointestinal disorders   
Diarrhoea  1  33/97 (34.02%) 
Vomiting  1  30/97 (30.93%) 
General disorders   
Pyrexia  1  42/97 (43.30%) 
Hepatobiliary disorders   
Hepatomegaly  1  9/97 (9.28%) 
Immune system disorders   
Immune reconstitution inflammatory syndrome  1  5/97 (5.15%) 
Infections and infestations   
Bronchitis  1  6/97 (6.19%) 
Gastroenteritis  1  13/97 (13.40%) 
Impetigo  1  7/97 (7.22%) 
Oral candidiasis  1  6/97 (6.19%) 
Pharyngitis  1  6/97 (6.19%) 
Pneumonia bacterial  1  7/97 (7.22%) 
Investigations   
Alanine aminotransferase abnormal  1  5/97 (5.15%) 
Alanine aminotransferase increased  1  18/97 (18.56%) 
Amylase abnormal  1  39/97 (40.21%) 
Aspartate aminotransferase increased  1  18/97 (18.56%) 
Blood bicarbonate decreased  1  54/97 (55.67%) 
Blood calcium decreased  1  11/97 (11.34%) 
Blood calcium increased  1  25/97 (25.77%) 
Blood cholesterol increased  1  19/97 (19.59%) 
Blood glucose decreased  1  19/97 (19.59%) 
Blood glucose increased  1  9/97 (9.28%) 
Blood magnesium decreased  1  10/97 (10.31%) 
Blood phosphorus decreased  1  8/97 (8.25%) 
Blood potassium decreased  1  7/97 (7.22%) 
Blood potassium increased  1  14/97 (14.43%) 
Blood sodium decreased  1  58/97 (59.79%) 
Breath sounds abnormal  1  7/97 (7.22%) 
Haemoglobin decreased  1  40/97 (41.24%) 
Neutrophil count decreased  1  25/97 (25.77%) 
Platelet count decreased  1  7/97 (7.22%) 
Metabolism and nutrition disorders   
Decreased appetite  1  5/97 (5.15%) 
Respiratory, thoracic and mediastinal disorders   
Cough  1  48/97 (49.48%) 
Dyspnoea  1  8/97 (8.25%) 
Nasal congestion  1  10/97 (10.31%) 
Oropharyngeal pain  1  5/97 (5.15%) 
Productive cough  1  12/97 (12.37%) 
Rales  1  7/97 (7.22%) 
Rhinorrhoea  1  43/97 (44.33%) 
Rhonchi  1  11/97 (11.34%) 
Use of accessory respiratory muscles  1  6/97 (6.19%) 
Wheezing  1  7/97 (7.22%) 
Skin and subcutaneous tissue disorders   
Dry skin  1  6/97 (6.19%) 
Papule  1  13/97 (13.40%) 
Rash  1  18/97 (18.56%) 
Skin exfoliation  1  6/97 (6.19%) 
Skin lesion  1  6/97 (6.19%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
In accordance with the Clinical Trials Agreement between NIAID (DAIDS) and company collaborators, NIAID (DAIDS) provides companies with a copy of any abstract, press release, or manuscript prior to submission for publication with sufficient time for company review and comment. The publication/other disclosure can be delayed for up to 30 additional business days for manuscripts and seven (7) business days for abstracts, to preserve U.S. or foreign patent or other intellectual property rights
Results Point of Contact
Name/Title: Melissa Allen, Director, IMPAACT Operations Center
Organization: Family Health International (FHI 360)
Phone: (919) 405-1429
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 ( Registry Identifier: DAIDS ES )
IMPAACT P1083
First Submitted: July 28, 2010
First Posted: July 29, 2010
Results First Submitted: November 16, 2015
Results First Posted: December 21, 2015
Last Update Posted: December 21, 2015