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Safety and Effectiveness of Lopinavir/Ritonavir in Individuals Who Have Failed Prior HIV Therapy

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ClinicalTrials.gov Identifier: NCT00357552
Recruitment Status : Completed
First Posted : July 27, 2006
Results First Posted : September 25, 2012
Last Update Posted : March 20, 2018
Sponsor:
Collaborator:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
AIDS Clinical Trials Group

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition HIV Infections
Interventions Drug: Emtricitabine/Tenofovir disoproxil fumarate
Drug: Lopinavir/Ritonavir
Enrollment 123
Recruitment Details  
Pre-assignment Details  
Arm/Group Title LPV/r Monotherapy
Hide Arm/Group Description Participants will receive lopinavir/ritonavir twice daily for up to 104 weeks. Upon confirmation of virologic failure, emtricitabine (FTC)/tenofovir (TDF) once a day will be added to their regimen.
Period Title: Screening
Started 207 [1]
Completed 123 [2]
Not Completed 84
Reason Not Completed
Did not meet eligibility criteria             84
[1]
The number of participants who started this period, is the number of participants who screened.
[2]
The number of participants who completed this period, is the number of participants who enrolled.
Period Title: Weeks 0 to 24
Started 123
Completed 122 [1]
Not Completed 1
Reason Not Completed
Death             1
[1]
One subject died prior to week 24.
Period Title: Weeks 24 to 104
Started 122
Completed 117
Not Completed 5
Reason Not Completed
Death             3
Not able to get to clinic             2
Arm/Group Title LPV/r Monotherapy
Hide Arm/Group Description Participants will receive lopinavir/ritonavir twice daily for up to 104 weeks. Upon confirmation of virologic failure, emtricitabine (FTC)/tenofovir (TDF) once a day will be added to their regimen.
Overall Number of Baseline Participants 123
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 123 participants
<=18 years
0
   0.0%
Between 18 and 65 years
123
 100.0%
>=65 years
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 123 participants
39.4  (8.2)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 123 participants
Female
70
  56.9%
Male
53
  43.1%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 123 participants
South Africa 22
Thailand 24
India 12
Malawi 40
Tanzania 25
1.Primary Outcome
Title Percentage of Enrolled Participants With Virologic Success at Week 24 on LPV/r Monotherapy
Hide Description Virologic success at week 24 on LPV/r monotherapy was defined as remaining on LPV/r monotherapy at week 24 without prior virologic failure. Virologic failure was met with either of these two conditions: (i) failure to suppress HIV-1 RNA to < 400 copies/mL by week 24 or (ii) confirmed HIV-1 RNA >= 400 copies/mL after confirmed HIV-1 RNA < 400 copies/mL.
Time Frame From study entry to week 24
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All enrolled individuals.
Arm/Group Title LPV/r Monotherapy
Hide Arm/Group Description:
Participants will receive lopinavir/ritonavir twice daily for up to 104 weeks. Upon confirmation of virologic failure, emtricitabine (FTC)/tenofovir (TDF) once a day will be added to their regimen.
Overall Number of Participants Analyzed 123
Measure Type: Number
Number (90% Confidence Interval)
Unit of Measure: percentage of enrolled subjects
87
(81 to 92)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LPV/r Monotherapy
Comments The null hypothesis was that LPV/r monotherapy provides at least a 65% short-term virologic response. The target sample size was 120 subjects. Assuming an underlying true 24 week success rate of 76%, this sample size was chosen in order to provide at least 90% power to show that the true 24 week virologic success rate of LPV/r monotherapy in this population is greater than 65%.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Success of the strategy is assessed according to whether the lower bound of the exact 90% confidence interval of this proportion is greater than 65%.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method confidence interval
Comments Success was determined by whether the lower bound of the 90% exact confidence interval was greater than 65%.
Method of Estimation Estimation Parameter proportion
Estimated Value 87
Confidence Interval (2-Sided) 90%
81 to 92
Estimation Comments exact confidence interval
2.Primary Outcome
Title Probability of Grade 3 or 4 Sign or Symptom, or Laboratory Toxicity Over 24 Weeks on Study.
Hide Description Probability of Grade 3 or 4 sign or symptom, or laboratory toxicity over 24 weeks on study using Kaplan-Meier estimates of the cumulative probability of Grade 3 or 4 sign or symptom, or laboratory toxicity at week 24. Grading of adverse events (signs and symptoms and laboratory toxicities) was according to Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, December 2004.
Time Frame From study entry to week 24
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All enrolled individuals.
Arm/Group Title LPV/r Monotherapy
Hide Arm/Group Description:
Participants will receive lopinavir/ritonavir twice daily for up to 104 weeks. Upon confirmation of virologic failure, emtricitabine (FTC)/tenofovir (TDF) once a day will be added to their regimen.
Overall Number of Participants Analyzed 123
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: cumulative probability of grade 3 or 4
0.23
(0.16 to 0.31)
3.Secondary Outcome
Title Number of Screened Subjects With at Least One NNRTI, or NRTI-associated Resistance Mutation at A5230 Screening.
Hide Description Number of screened subjects with at least one NNRTI, or NRTI-associated resistance mutation. Resistance interpretations used the November 30, 2011 Stanford algorithm.
Time Frame Screening
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All screened individuals.
Arm/Group Title All Screened Subjects With Available Sequences
Hide Arm/Group Description:
All screened individuals, for whom a sequence could be obtained, regardless of whether they enrolled or not.
Overall Number of Participants Analyzed 207
Measure Type: Number
Unit of Measure: number of screened subjects
At least one NNRTI-associated mutation 201
At least one NRTI-associated mutation 197
4.Secondary Outcome
Title Time to Treatment Failure, Defined as the First Occurrence of Death, Disease Progression, or Virologic Failure.
Hide Description 25th percentile in weeks from study entry to treatment failure, defined as the first occurrence of death, disease progression, or virologic failure. Virologic failure was defined as HIV-1 >= 400 copies/mL after week 24 or 2 consecutive HIV-1 RNA >= 400 copies/mL after week 16 following suppression on LPV/r monotherapy.
Time Frame Study entry to Week 104
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants enrolled.
Arm/Group Title LPV/r Monotherapy
Hide Arm/Group Description:
Participants will receive lopinavir/ritonavir twice daily for up to 104 weeks. Upon confirmation of virologic failure, emtricitabine (FTC)/tenofovir (TDF) once a day will be added to their regimen.
Overall Number of Participants Analyzed 123
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: weeks
48.0
(40.0 to 80.0)
5.Secondary Outcome
Title Number of Participants With Study-targeted Diagnoses and Clinical Events
Hide Description Cardiac disorders, Infections and infestations, Metabolism and nutrition disorders, Neoplasms benign, malignant and unspecified (including cysts and polyps), Pregnancy, puerperium and perinatal conditions, Vascular disorders, were specified a priori as study-targeted events by the study chair.
Time Frame Study entry to week 104
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants enrolled.
Arm/Group Title LPV/r Monotherapy
Hide Arm/Group Description:
Participants will receive lopinavir/ritonavir twice daily for up to 104 weeks. Upon confirmation of virologic failure, emtricitabine (FTC)/tenofovir (TDF) once a day will be added to their regimen.
Overall Number of Participants Analyzed 123
Measure Type: Number
Unit of Measure: participants
39
6.Secondary Outcome
Title Number of Subjects With at Least One New PI-associated Resistance Mutation at Time of Virologic Failure.
Hide Description Number of subjects with at least one new PI-associated resistance mutation at time of virologic failure. Resistance interpretations used the May 6, 2009 Stanford algorithm.
Time Frame At time of virologic failure
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
16 subjects met the criteria for endpoint failure; 15 subjects were virologic failures and 1 subject intensified prior to virologic failure. Of the 15 subjects with virologic failure, 11 had sequence data, and sequencing failed for 4.
Arm/Group Title Virologic Failures by Week 24.
Hide Arm/Group Description:
Subjects who met virologic failure criteria by week 24, for whom a sequence could be obtained.
Overall Number of Participants Analyzed 11
Measure Type: Number
Unit of Measure: participants
2
7.Secondary Outcome
Title Percentage of Subjects Reporting Not Skipping Medications in the Last Month.
Hide Description The percentage of subjects reporting never missing medications in the last month.
Time Frame Study entry and weeks 2, 4, 8, 12, 16, 20, and 24
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants enrolled.
Arm/Group Title LPV/r Monotherapy
Hide Arm/Group Description:
Participants will receive lopinavir/ritonavir twice daily for up to 104 weeks. Upon confirmation of virologic failure, emtricitabine (FTC)/tenofovir (TDF) once a day will be added to their regimen. The study is ongoing. Results from entry to week 24 are posted. They will be updated upon completion of study duration of 104 weeks.
Overall Number of Participants Analyzed 123
Measure Type: Number
Unit of Measure: percentage of subjects with data
week 2 (N=120) 90
week 4 (N=121) 86.8
week 8 (N=123) 87.8
week 12 (N=123) 86.2
week 16 (N=122) 86.1
week 20 (N=120) 90.9
week 24 (N=122) 89.4
8.Secondary Outcome
Title Time to First New Grade 3 or 4 Sign or Symptom or Laboratory Toxicity Following LPV/r Intensification
Hide Description 25th percentile in weeks from study entry to first new grade 3 or 4 sign or symptom or laboratory toxicity following LPV/r intensification. Grading of adverse events (signs and symptoms and laboratory toxicities) was according to Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, December 2004.
Time Frame From LPV/r intensification to week 104
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants enrolled.
Arm/Group Title LPV/r Monotherapy
Hide Arm/Group Description:
Participants will receive lopinavir/ritonavir twice daily for up to 104 weeks. Upon confirmation of virologic failure, emtricitabine (FTC)/tenofovir (TDF) once a day will be added to their regimen.
Overall Number of Participants Analyzed 123
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: weeks
26.0
(13.1 to 53.3)
9.Secondary Outcome
Title Level of HIV-1 RNA as Ascertained From Paired DBS and Plasma
Hide Description Proportion of DBS samples with HIV-1 RNA level <= 400 copies/mL, proportion of plasma samples with HIV-1 RNA level <= 400 copies/mL and proportion of paired DBS and plasma samples that are concordant (both <= 400 copies/mL or both > 400 copies/mL). Results are pooled over 4 different storage temperature conditions (-80C, -20C, 4C and room temperature).
Time Frame At study entry and weeks 24 and 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants with DBS samples available at study entry, week 24 or 48, with corresponding plasma HIV-1 RNA levels.
Arm/Group Title LPV/r Monotherapy
Hide Arm/Group Description:
Participants will receive lopinavir/ritonavir twice daily for up to 104 weeks. Upon confirmation of virologic failure, emtricitabine (FTC)/tenofovir (TDF) once a day will be added to their regimen.
Overall Number of Participants Analyzed 45
Overall Number of Units Analyzed
Type of Units Analyzed: Paired DBS and plasma samples
140
Measure Type: Number
Unit of Measure: proportion of samples
study entry DBS <= 400 cp/mL 0.17
study entry plasma <= 400 cp/mL 0.00
study entry DBS & plasma concordance 0.83
week 24 DBS <= 400 cp/mL 0.82
week 24 plasma <= 400 cp/mL 0.80
week 24 DBS & plasma concordance 0.80
week 48 DBS <= 400 cp/mL 0.94
week 48 plasma <= 400 cp/mL 0.91
week 48 DBS & plasma concordance 0.97
10.Secondary Outcome
Title HIV-1 Viral Sequence as Ascertained From Paired DBS and Plasma
Hide Description HIV-1 viral sequencing as ascertained from paired DBS and plasma
Time Frame At study entry and virologic failure
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
HIV-1 viral sequence testing in DBS was not performed
Arm/Group Title LPV/r Monotherapy
Hide Arm/Group Description:

Participants will receive lopinavir/ritonavir twice daily for up to 104 weeks. Upon confirmation of virologic failure, emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) once a day will be added to their regimen.

Emtricitabine/Tenofovir disoproxil fumarate: Once daily

Lopinavir/Ritonavir: Twice daily

Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
11.Secondary Outcome
Title Proportion of Participants With Plasma HIV-1 RNA Levels < 400 Copies/mL From Baseline to Week 104
Hide Description [Not Specified]
Time Frame At Weeks 0, 12, 16, 20, 24, 32, 40, 48, 56, 68, 80, 92, 104
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants enrolled.
Arm/Group Title LPV/r Monotherapy
Hide Arm/Group Description:
Participants will receive lopinavir/ritonavir twice daily for up to 104 weeks. Upon confirmation of virologic failure, emtricitabine (FTC)/tenofovir (TDF) once a day will be added to their regimen.
Overall Number of Participants Analyzed 123
Measure Type: Number
Unit of Measure: proportion of participants
week 0 (N=123) 0.02
week 12 (N=122) 0.75
week 16 (N=121) 0.87
week 20 (N=115) 0.84
week 24 (N=122) 0.84
week 32 (N=121) 0.83
week 40 (N=118) 0.84
week 48 (N=118) 0.87
week 56 (N=120) 0.86
week 68 (N=116) 0.91
week 80 (N=117) 0.85
week 92 (N=116) 0.87
week 104 (N=117) 0.89
12.Secondary Outcome
Title Change in CD4+ Cell Counts From Study Entry to Week 104
Hide Description [Not Specified]
Time Frame Study entry and week 104
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants enrolled.
Arm/Group Title LPV/r Monotherapy
Hide Arm/Group Description:
Participants will receive lopinavir/ritonavir twice daily for up to 104 weeks. Upon confirmation of virologic failure, emtricitabine (FTC)/tenofovir (TDF) once a day will be added to their regimen.
Overall Number of Participants Analyzed 123
Median (Inter-Quartile Range)
Unit of Measure: cells/mm^3
213
(111 to 326)
Time Frame From study entry up to 104 weeks.
Adverse Event Reporting Description The protocol required reporting of all signs, symptoms and laboratory abnormalities >= grade 3 and any that led to a study treatment change, regardless of grade. The "DAIDS Table for Grading the Severity of Adult and Pediatric Aes", V1.0, 12/2004 was used.
 
Arm/Group Title LPV/r
Hide Arm/Group Description Participants will receive lopinavir/ritonavir twice daily for up to 104 weeks. Upon confirmation of virologic failure, emtricitabine (FTC)/tenofovir (TDF) once a day will be added to their regimen.
All-Cause Mortality
LPV/r
Affected / at Risk (%)
Total   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
LPV/r
Affected / at Risk (%)
Total   20/123 (16.26%) 
Cardiac disorders   
Acute myocardial infarction  1  1/123 (0.81%) 
Gastrointestinal disorders   
Diarrhoea  1  1/123 (0.81%) 
General disorders   
Death  1  1/123 (0.81%) 
Infections and infestations   
Gastroenteritis  1  2/123 (1.63%) 
Pneumonia bacterial  1  1/123 (0.81%) 
Investigations   
Blood cholesterol increased  1  1/123 (0.81%) 
Blood phosphorus decreased  1  1/123 (0.81%) 
Blood triglycerides increased  1  2/123 (1.63%) 
Low density lipoprotein increased  1  1/123 (0.81%) 
Metabolism and nutrition disorders   
Dyslipidaemia  1  1/123 (0.81%) 
Hyperglycaemia  1  4/123 (3.25%) 
Hyperlipidaemia  1  2/123 (1.63%) 
Hypertriglyceridaemia  1  1/123 (0.81%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Cervix carcinoma  1  1/123 (0.81%) 
Nervous system disorders   
Headache  1  1/123 (0.81%) 
Pregnancy, puerperium and perinatal conditions   
Abortion spontaneous  1  1/123 (0.81%) 
Surgical and medical procedures   
Diabetes mellitus management  1  1/123 (0.81%) 
Vascular disorders   
Deep vein thrombosis  1  1/123 (0.81%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.0
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   122/123 (99.19%) 
Gastrointestinal disorders   
Abdominal pain  1  8/123 (6.50%) 
Diarrhoea  1  13/123 (10.57%) 
Nausea  1  7/123 (5.69%) 
Vomiting  1  12/123 (9.76%) 
General disorders   
Chest pain  1  13/123 (10.57%) 
Pain  1  9/123 (7.32%) 
Pyrexia  1  27/123 (21.95%) 
Infections and infestations   
Malaria  1  11/123 (8.94%) 
Nasopharyngitis  1  8/123 (6.50%) 
Pneumonia bacterial  1  9/123 (7.32%) 
Upper respiratory tract infection  1  22/123 (17.89%) 
Urinary tract infection  1  7/123 (5.69%) 
Investigations   
Alanine aminotransferase increased  1  22/123 (17.89%) 
Aspartate aminotransferase increased  1  18/123 (14.63%) 
Blood albumin decreased  1  22/123 (17.89%) 
Blood alkaline phosphatase increased  1  10/123 (8.13%) 
Blood bicarbonate decreased  1  24/123 (19.51%) 
Blood bilirubin increased  1  7/123 (5.69%) 
Blood cholesterol increased  1  76/123 (61.79%) 
Blood glucose decreased  1  9/123 (7.32%) 
Blood glucose increased  1  31/123 (25.20%) 
Blood phosphorus decreased  1  39/123 (31.71%) 
Blood potassium decreased  1  18/123 (14.63%) 
Blood sodium decreased  1  62/123 (50.41%) 
Blood triglycerides increased  1  22/123 (17.89%) 
Haemoglobin decreased  1  15/123 (12.20%) 
Low density lipoprotein increased  1  54/123 (43.90%) 
Neutrophil count decreased  1  38/123 (30.89%) 
Platelet count decreased  1  10/123 (8.13%) 
White blood cell count decreased  1  19/123 (15.45%) 
Nervous system disorders   
Headache  1  21/123 (17.07%) 
Respiratory, thoracic and mediastinal disorders   
Cough  1  34/123 (27.64%) 
Oropharyngeal pain  1  13/123 (10.57%) 
Rhinorrhoea  1  7/123 (5.69%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.0
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 five (5) business days for abstracts, to preserve U.S. or foreign patent or other intellectual property rights.
Results Point of Contact
Name/Title: ACTG Clinicaltrials.gov Coordinator
Organization: ACTG Network Coordinating Center, Social and Scientific Systems, Inc.
Phone: (301) 628-3313
Responsible Party: AIDS Clinical Trials Group
ClinicalTrials.gov Identifier: NCT00357552     History of Changes
Other Study ID Numbers: ACTG A5230
1U01AI068636 ( U.S. NIH Grant/Contract )
First Submitted: July 25, 2006
First Posted: July 27, 2006
Results First Submitted: May 23, 2012
Results First Posted: September 25, 2012
Last Update Posted: March 20, 2018