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Safety and Effectiveness of Raltegravir Plus Darunavir/Ritonavir in Treatment-Naive HIV-Infected Adults

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ClinicalTrials.gov Identifier: NCT00830804
Recruitment Status : Completed
First Posted : January 28, 2009
Results First Posted : October 10, 2011
Last Update Posted : November 8, 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-1 Infections
Interventions Drug: Raltegravir
Drug: Darunavir/Ritonavir
Enrollment 113
Recruitment Details Study participants were recruited from 22 U.S. sites from April 2009 to August 2009.
Pre-assignment Details Study participants were HIV-1-infected, antiretroviral(ARV)-naive men and women, 18 years and older with plasma HIV-1 RNA >= 5000 copies/ml. One enrolled participant never started study treatment.
Arm/Group Title RAL + DRV/RTV
Hide Arm/Group Description Raltegravir (400 mg BID) plus Darunavir/Ritonavir (800 mg/100 mg QD) for 52 weeks
Period Title: Overall Study
Started 112 [1]
Completed 97
Not Completed 15
Reason Not Completed
Lost to Follow-up             4
Death             1
Unable to get to clinic             7
Consent withdrawn             2
Unwilling to adhere to study requirement             1
[1]
113 subjects enrolled. One subject never started study treatment and was excluded in all analysis.
Arm/Group Title RAL+DRV/RTV
Hide Arm/Group Description Raltegravir (400 mg BID) plus Darunavir/Ritonavir (800 mg/100 mg QD) for 52 weeks
Overall Number of Baseline Participants 112
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous   [1] 
Median (Full Range)
Unit of measure:  Years
Number Analyzed 112 participants
36
(19 to 66)
[1]
Measure Description: Age (in years) of participants at study entry
Age, Customized   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 112 participants
18-29 33
30-39 38
40-49 25
50-59 12
60-69 4
[1]
Measure Description: Age (in years) of participants at study entry
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 112 participants
Female
14
  12.5%
Male
98
  87.5%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 112 participants
112
1.Primary Outcome
Title Proportion of Participants With Virologic Failure After Initiating RAL Plus DRV/RTV at or Prior to Week 24
Hide Description Virologic failure is defined as: at week 12, confirmed plasma HIV-1 RNA >= 1000 copies/ml or confirmed rebound from the week 4 value by >0.5 log10 copies/ml (for subjects with week 4 value <= 50 copies/ml, confirmed rebound to >50 copies/ml); at week 24 or later, confirmed value > 50 copies/ml. Viral load confirmation was scheduled 7-35 days after initial virologic failure. The proportion was estimated using Kaplan-Meier method. An adaptation of Greenwood's variance estimate was used in constructing the confidence interval.
Time Frame From start of study treatment to week 24
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants who started study treatment were included. The intent-to-treat approach was used, ignoring whether a participant was on or off treatment at the time of HIV-1 RNA measurement and censoring follow-up if a participant was lost-to-follow-up without previously meeting the definition of virologic failure.
Arm/Group Title RAL+DRV/RTV
Hide Arm/Group Description:
Raltegravir (400 mg BID) plus Darunavir/Ritonavir (800 mg/100 mg QD) for 52 weeks
Overall Number of Participants Analyzed 112
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Proportion of participants
0.16
(0.10 to 0.24)
2.Secondary Outcome
Title Proportion of Participants With Virologic Failure or Off Study Treatment Regimen or Death at or Prior to Week 24
Hide Description The proportion of participants with virologic failure (see primary outcome measure for definition) and/or premature treatment discontinuation/modification and/or death was estimated using Kaplan-Meier method. An adaptation of Greenwood's variance estimate was used in constructing the confidence interval.
Time Frame From start of study treatment to Week 24
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants who started study treatment were included in the analysis.
Arm/Group Title RAL+DRV/RTV
Hide Arm/Group Description:
Raltegravir (400 mg BID) plus Darunavir/Ritonavir (800 mg/100 mg QD) for 52 weeks
Overall Number of Participants Analyzed 112
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Proportion of participants
0.21
(0.14 to 0.29)
3.Secondary Outcome
Title Change in Plasma HIV-1 RNA From Baseline to Week 1
Hide Description Results report the week 1 change from baseline (week 1 - baseline) in HIV-1 RNA. Baseline HIV-1 RNA was computed as the mean of the log10 HIV-1 RNA values at pre-entry and study entry.
Time Frame Baseline and week 1
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analyis was based on an intent-to-treat approach, ignoring whether a participant was on or off study treatment at the time the sample for HIV-1 RNA was obtained.
Arm/Group Title RAL+DRV/RTV
Hide Arm/Group Description:
Raltegravir (400 mg BID) plus Darunavir/Ritonavir (800 mg/100 mg QD) for 52 weeks
Overall Number of Participants Analyzed 112
Median (Inter-Quartile Range)
Unit of Measure: log10 copies/ml
-1.67
(-1.93 to -1.42)
4.Secondary Outcome
Title Proportion of Participants With Plasma HIV-1 RNA < 50 Copies/ml or <200 Copies/ml at Week 24
Hide Description Results report the percentage of participants with plasma HIV-1 RNA < 50 copies/ml or <200 copies/ml at week 24.
Time Frame From start of study treatment to week 24
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants who started study treatment were included. An intent-to-treat approach was used ignoring participants who were off-study or with missing HIV-1 RNA at week 24.
Arm/Group Title RAL+DRV/RTV
Hide Arm/Group Description:
Raltegravir (400 mg BID) plus Darunavir/Ritonavir (800 mg/100 mg QD) for 52 weeks
Overall Number of Participants Analyzed 107
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: proportion of participants
With HIV-1 RNA < 50 copies/ml
0.79
(0.70 to 0.86)
With HIV-1 RNA < 200 copies/ml
0.93
(0.87 to 0.97)
5.Secondary Outcome
Title Proportion of Participants With Plasma HIV-1 RNA <50 Copies/ml or <200 Copies/ml at Week 48
Hide Description Results report the percentage of participants with plasma HIV-1 RNA <50 copies/ml or <200 copies/ml at week 48.
Time Frame From start of study treatment to week 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants who started study treatment were included. An intent-to-treat approach was used ignoring participants who were off study treatment or with missing HIV-1 RNA at week 48.
Arm/Group Title RAL+DRV/RTV
Hide Arm/Group Description:
Raltegravir (400 mg BID) plus Darunavir/Ritonavir (800 mg/100 mg QD) for 52 weeks
Overall Number of Participants Analyzed 100
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: proportion of participants
With HIV-1 RNA < 50 copies/ml
0.71
(0.61 to 0.79)
With HIV-1 RNA < 200 copies/ml
0.86
(0.78 to 0.92)
6.Secondary Outcome
Title Proportion of Participants Who Experienced Signs/Symptoms or Laboratory Toxicities Grade 3 or Higher, or of Any Grade Which Led to a Permanent Change or Discontinuation of Study Treatment
Hide Description Signs, symptoms and laboratory values were graded according to the Division of AIDS Adverse Event Grading System. Results report the percentage of participants who had grade 3 or higher events, or events of any grade which led to a permanent change or discontinuation of study treatment, which occurred any time from start of treatment to end of treatment.
Time Frame From start of study treatment to week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants who started study treatment were included in the analysis.
Arm/Group Title RAL+DRV/RTV
Hide Arm/Group Description:
Raltegravir (400 mg BID) plus Darunavir/Ritonavir (800 mg/100 mg QD) for 52 weeks
Overall Number of Participants Analyzed 112
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: proportion of participants
0.20
(0.13 to 0.28)
7.Secondary Outcome
Title Number of Participants With Pretreatment Drug Resistance
Hide Description Results report the number of participants who had resistance to non-nucleoside reverse transciptase inhibitors (NNRTI), nucleoside reverse transciptase inhibitors (NRTI) and protease inbitors (PI) based on genotypic resistance testing done prior to participant's entry into the study. Participants are classified into one (and only one category) based on the maximum number of drug class resistance seen for the participant.
Time Frame At screening
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants who started study treatment were included in the analysis.
Arm/Group Title RAL + DRV/RTV
Hide Arm/Group Description:
Raltegravir (400 mg BID) plus Darunavir/Ritonavir (800 mg/100 mg QD) for 52 weeks
Overall Number of Participants Analyzed 112
Measure Type: Number
Unit of Measure: participants
With NNRTI mutations only 9
With NRTI mutations only 8
With Both NNRTI and NRTI mutations 1
With PI mutations only 2
With PI, NNRTI and NRTI mutations 1
No Resistance Detected 91
8.Secondary Outcome
Title Number of Participants With Integrase Drug Resistance at Virologic Failure
Hide Description Results report the number of participants who had integrase resistance mutation(s) detected at the time of virologic failure.
Time Frame From 12 weeks after starting study treatment to week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Only those participants who had virologic failure (see primary outcome measure for definition) and who had successful integrase genotyping at failure were included in the analysis.
Arm/Group Title RAL+DRV/RTV
Hide Arm/Group Description:
Raltegravir (400 mg BID) plus Darunavir/Ritonavir (800 mg/100 mg QD) for 52 weeks
Overall Number of Participants Analyzed 25
Measure Type: Number
Unit of Measure: participants
5
9.Secondary Outcome
Title Number of Participants With Protease Drug Resistance at Virologic Failure
Hide Description Results report the number of participants who had protease resistance mutation(s) detected at the time of virologic failure.
Time Frame From 12 weeks after starting study treatment to week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Only those participants who had virologic failure (see primary outcome measure for definition) and who had successful protease genotyping at failure were included in the analysis.
Arm/Group Title RAL+DRV/RTV
Hide Arm/Group Description:
Raltegravir (400 mg BID) plus Darunavir/Ritonavir (800 mg/100 mg QD) for 52 weeks
Overall Number of Participants Analyzed 23
Measure Type: Number
Unit of Measure: participants
0
10.Secondary Outcome
Title Number of Participants With Perfect Overall Adherence by Self Report
Hide Description At each study visit, adherence was measured in terms of the number of missed doses each participant had over a 4-day recall for each drug. Adherence for all study visit weeks were combined for an overall measure of adherence. Participants who had zero missed doses on all weeks in all drugs while on study were classified as having an overall "perfect" adherence.
Time Frame From one week after starting study treatment to week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants who started study treatment were included in the analysis.
Arm/Group Title RAL + DRV/RTV
Hide Arm/Group Description:
Raltegravir (400 mg BID) plus Darunavir/Ritonavir (800 mg/100 mg QD) for 52 weeks
Overall Number of Participants Analyzed 112
Measure Type: Number
Unit of Measure: participants
95
11.Secondary Outcome
Title Changes in Fasting Total Cholesterol, High-density Lipoprotein and Triglyceride at Week 24
Hide Description Results report the week 24 change from week 0 (week 24 - week 0) fasting total cholesterol, high-density lipoprotein and triglyceride.
Time Frame From start of study treatment through week 24
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Only those participants who started study treatment and who had fasting lipid measurements at week 24 and week 0 were included in the analysis.
Arm/Group Title RAL + DRV/RTV
Hide Arm/Group Description:
Raltegravir (400 mg BID) plus Darunavir/Ritonavir (800 mg/100 mg QD) for 52 weeks
Overall Number of Participants Analyzed 94
Median (Inter-Quartile Range)
Unit of Measure: mg/dL
Fasting Total Cholesterol
31.5
(12 to 46)
Fasting High-density Lipoprotein
6.5
(1 to 15)
Fasting Triglyceride
24.5
(-6 to 64)
12.Secondary Outcome
Title Change in Fasting Low-density Lipoprotein at Week 24
Hide Description Results report the week 24 change from week 0 (week 24 - week 0) fasting low-density lipoprotein (LDL). For participants whose calculated fasting LDL and direct fasting LDL were both reported, only the calculated fasting LDL was used. Direct fasting LDL was reported when the participant had high fasting triglyceride.
Time Frame From start of study treatment through week 24
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Only those participants who started study treatment and who had fasting lipid measurements at week 24 and week 0 were included in the analysis.
Arm/Group Title RAL + DRV/RTV
Hide Arm/Group Description:
Raltegravir (400 mg BID) plus Darunavir/Ritonavir (800 mg/100 mg QD) for 52 weeks
Overall Number of Participants Analyzed 82
Median (Inter-Quartile Range)
Unit of Measure: mg/dL
16.0
(5 to 36)
13.Secondary Outcome
Title Changes in Fasting Total Cholesterol, High-density Lipoprotein and Triglyceride at Week 48
Hide Description Results report the week 48 change from week 0 (week 48 - week 0) fasting total cholesterol, high-density lipoprotein and triglyceride.
Time Frame From start of study treatment through week 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Only those participants who started study treatment and who had fasting lipid measurements at week 48 and week 0 were included in the analysis.
Arm/Group Title RAL + DRV/RTV
Hide Arm/Group Description:
Raltegravir (400 mg BID) plus Darunavir/Ritonavir (800 mg/100 mg QD) for 52 weeks
Overall Number of Participants Analyzed 85
Median (Inter-Quartile Range)
Unit of Measure: mg/dL
Fasting Total Cholesterol
30
(10 to 59)
Fasting High-density Lipoprotein
9
(2 to 17)
Fasting Triglyceride
23
(-31 to 81)
14.Secondary Outcome
Title Change in Fasting Low-density Lipoprotein at Week 48
Hide Description Results report the week 48 change from week 0 (week 48 - week 0) fasting low-density lipoprotein (LDL). For participants whose calculated fasting LDL and direct fasting LDL were both reported, only the calculated fasting LDL was used. Direct fasting LDL was reported when the participant had high fasting triglyceride.
Time Frame From start of study treatment through week 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Only those participants who started study treatment and who had fasting lipid measurements at week 48 and week 0 were included in the analysis.
Arm/Group Title RAL + DRV/RTV
Hide Arm/Group Description:
Raltegravir (400 mg BID) plus Darunavir/Ritonavir (800 mg/100 mg QD) for 52 weeks
Overall Number of Participants Analyzed 70
Median (Inter-Quartile Range)
Unit of Measure: mg/dL
17
(2 to 33)
15.Secondary Outcome
Title Change in CD4 Count at Week 48
Hide Description Results report the week 48 change from baseline (week 48 - baseline) in CD4 count. Baseline CD4 count was computed as the mean of CD4 count values at pre-entry and study entry.
Time Frame From start of study treatment through week 48
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Only those participants who started study treatment and who have values at baseline and at week 48 were included in the analysis.
Arm/Group Title RAL + DRV/RTV
Hide Arm/Group Description:
Raltegravir (400 mg BID) plus Darunavir/Ritonavir (800 mg/100 mg QD) for 52 weeks
Overall Number of Participants Analyzed 100
Median (Inter-Quartile Range)
Unit of Measure: cells/mm3
200
(114 to 318)
16.Secondary Outcome
Title Plasma Trough Concentration of Raltegravir
Hide Description Plasma trough concentrations (ng/ml) of Raltegravir (RAL) below the detection limit (10 ng/ml) were replaced by half the corresponding lower limit of quantitation. Geometric mean of trough concentrations obtained within the prescribed trough time (within 9-15 hours after the last RAL dose) was computed for each participant. For participants who experienced virologic failure (see primary outcome measure definition), only those concentrations on or before virologic failure confirmation were used in the geometric mean computation.
Time Frame From start of study treatment to week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants who started study treatment and who have at least one RAL plasma trough concentration obtained within 9-15 hours after the last RAL dose were included in the analysis.
Arm/Group Title RAL+DRV/RTV
Hide Arm/Group Description:
Raltegravir (400 mg BID) plus Darunavir/Ritonavir (800 mg/100 mg QD) for 52 weeks
Overall Number of Participants Analyzed 103
Median (Inter-Quartile Range)
Unit of Measure: ng/ml
117
(52 to 250)
17.Secondary Outcome
Title Plasma Trough Concentration of Darunavir
Hide Description Plasma trough concentrations (ng/ml) of Darunavir (DRV) below the detection limit (50 ng/ml) were replaced by half the corresponding lower limit of quantitation. Geometric mean of trough concentrations obtained within the prescribed trough time (within 20-28 hours after the last DRV dose) was computed for each participant. For participants who experienced virologic failure (see primary outcome measure definition), only those concentrations on or before virologic failure confirmation were used in the geometric mean computation.
Time Frame From start of study treatment to week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants who started study treatment and who have at least one DRV plasma trough concentration obtained within 20-28 hours after the last DRV dose were included in the analysis.
Arm/Group Title RAL+DRV/RTV
Hide Arm/Group Description:
Raltegravir (400 mg BID) plus Darunavir/Ritonavir (800 mg/100 mg QD) for 52 weeks
Overall Number of Participants Analyzed 83
Median (Inter-Quartile Range)
Unit of Measure: ng/ml
1218
(789 to 1809)
Time Frame From start of study treatment to week 52
Adverse Event Reporting Description Expedited adverse event (AE) reporting followed Intensive Division of AIDS (DAIDS) Reporting Level, which included AEs resulting in death, congenital anomalies, fetal losses, 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 RAL+DRV/RTV
Hide Arm/Group Description Raltegravir (400 mg BID) plus Darunavir/Ritonavir (800 mg/100 mg QD) for 52 weeks
All-Cause Mortality
RAL+DRV/RTV
Affected / at Risk (%)
Total   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
RAL+DRV/RTV
Affected / at Risk (%)
Total   13/112 (11.61%) 
Gastrointestinal disorders   
Diarrhoea  1  1/112 (0.89%) 
Jejunal perforation  1  1/112 (0.89%) 
General disorders   
Injection site reaction  1  1/112 (0.89%) 
Infections and infestations   
Bronchitis  1  1/112 (0.89%) 
Perirectal abscess  1  1/112 (0.89%) 
Pneumonia  1  2/112 (1.79%) 
Injury, poisoning and procedural complications   
Alcohol poisoning  1  1/112 (0.89%) 
Metabolism and nutrition disorders   
Diabetes mellitus  1  1/112 (0.89%) 
Nervous system disorders   
Convulsion  1  1/112 (0.89%) 
Syncope  1  1/112 (0.89%) 
Psychiatric disorders   
Substance abuse  1  1/112 (0.89%) 
Suicide attempt  1  1/112 (0.89%) 
Renal and urinary disorders   
Renal failure acute  1  1/112 (0.89%) 
Skin and subcutaneous tissue disorders   
Henoch-Schonlein purpura  1  1/112 (0.89%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 13.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
RAL+DRV/RTV
Affected / at Risk (%)
Total   78/112 (69.64%) 
Gastrointestinal disorders   
Nausea  1  6/112 (5.36%) 
Investigations   
Alanine aminotransferase increased  1  11/112 (9.82%) 
Aspartate aminotransferase increased  1  15/112 (13.39%) 
Blood cholesterol  1  45/112 (40.18%) 
Blood glucose abnormal  1  8/112 (7.14%) 
Blood sodium decreased  1  6/112 (5.36%) 
Blood uric acid increased  1  9/112 (8.04%) 
Low density lipoprotein abnormal  1  34/112 (30.36%) 
Neutrophil count decreased  1  14/112 (12.50%) 
White blood cell count decreased  1  8/112 (7.14%) 
Psychiatric disorders   
Depression  1  7/112 (6.25%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 14.0
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 Trial 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: NCT00830804     History of Changes
Other Study ID Numbers: ACTG A5262
1U01AI068636 ( U.S. NIH Grant/Contract )
First Submitted: January 26, 2009
First Posted: January 28, 2009
Results First Submitted: September 7, 2011
Results First Posted: October 10, 2011
Last Update Posted: November 8, 2018