A Pilot Study Assessing the Integrase Inhibitor GSK1349572 in HIV-infected Persons With Virus Resistant to Raltegravir

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
ViiV Healthcare
ClinicalTrials.gov Identifier:
NCT00950859
First received: July 23, 2009
Last updated: January 9, 2014
Last verified: November 2013
Results First Received: August 15, 2013  
Study Type: Interventional
Study Design: Allocation: Non-Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Single Group Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Infection, Human Immunodeficiency Virus
Interventions: Drug: GSK1349572 (Cohort I)
Drug: GSK1349572 (Cohort II)

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Participants recruited initially to Cohort I and subsequently to Cohort II. Recruitment to Cohort I was closed 9 months before recruitment to Cohort II was opened. Recruitment was not randomized.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Cohort I (DTG 50 mg OD) Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).
Cohort II (DTG 50 mg BID) Participants received DTG 50 mg twice a day (BID).

Participant Flow:   Overall Study
    Cohort I (DTG 50 mg OD)     Cohort II (DTG 50 mg BID)  
STARTED     27     24  
Ongoing     13     19  
COMPLETED     0     0  
NOT COMPLETED     27     24  
Adverse Event                 2                 2  
Insufficient Viral Load Response                 12                 2  
Protocol Violation                 0                 1  
Ongoing                 13                 19  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Cohort I (DTG 50 mg OD) Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).
Cohort II (DTG 50 mg BID) Participants received DTG 50 mg twice a day (BID).
Total Total of all reporting groups

Baseline Measures
    Cohort I (DTG 50 mg OD)     Cohort II (DTG 50 mg BID)     Total  
Number of Participants  
[units: participants]
  27     24     51  
Age, Customized  
[units: Years]
Median ( Full Range )
     
Years     48  
  ( 19 to 61 )  
  47  
  ( 33 to 68 )  
  47  
  ( 19 to 68 )  
Gender  
[units: Participants]
     
Female     2     6     8  
Male     25     18     43  
Race/Ethnicity, Customized  
[units: Participants]
     
African American/African Heritage     3     5     8  
White-Arabic/North African Heritage     1     1     2  
White-White/Caucasian/European Heritage     23     18     41  



  Outcome Measures
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1.  Primary:   Number of Participants Who Achieved HIV-1 RNA <400 Copies (c)/Milliliter (mL) or at Least 0.7 log10 c/mL Below Their Baseline Value at Day 11   [ Time Frame: Baseline (Day 1) and Day 11 ]

Measure Type Primary
Measure Title Number of Participants Who Achieved HIV-1 RNA <400 Copies (c)/Milliliter (mL) or at Least 0.7 log10 c/mL Below Their Baseline Value at Day 11
Measure Description The number of participants who acheived Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) <400 c/mL or at least 0.7 log10 c/mL below their Baseline value at Day 11 was assessed. The last observation was carried forward if a participant had missed the Day 11 visit. The Baseline observation was carried forward if a participant had discontinued the treatment before Day 11. Blood samples for assessment of HIV-1 RNA levels were collected at Baseline and Day 11.
Time Frame Baseline (Day 1) and Day 11  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-Treat Exposed (ITT-E) Population: all participants who received at least one dose of study medication and who had at least one post-Baseline measure of plasma HIV-1 RNA.

Reporting Groups
  Description
Cohort I (DTG 50 mg OD) Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).
Cohort II (DTG 50 mg BID) Participants received DTG 50 mg twice a day (BID).

Measured Values
    Cohort I (DTG 50 mg OD)     Cohort II (DTG 50 mg BID)  
Number of Participants Analyzed  
[units: participants]
  27     24  
Number of Participants Who Achieved HIV-1 RNA <400 Copies (c)/Milliliter (mL) or at Least 0.7 log10 c/mL Below Their Baseline Value at Day 11  
[units: Participants]
  21     23  


Statistical Analysis 1 for Number of Participants Who Achieved HIV-1 RNA <400 Copies (c)/Milliliter (mL) or at Least 0.7 log10 c/mL Below Their Baseline Value at Day 11
Groups [1] Cohort I (DTG 50 mg OD)
percentage of participants [2] 78
95% Confidence Interval ( 58 to 91 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant estimation information:
  The estimated value represents the percentage of participants with HIV-1 RNA <400 c/mL or at least 0.7 log10 c/mL below their Baseline value at Day 11.

Statistical Analysis 2 for Number of Participants Who Achieved HIV-1 RNA <400 Copies (c)/Milliliter (mL) or at Least 0.7 log10 c/mL Below Their Baseline Value at Day 11
Groups [1] Cohort II (DTG 50 mg BID)
percentage of participants [2] 96
95% Confidence Interval ( 79 to 100 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant estimation information:
  The estimated value represents the percentage of participants with HIV-1 RNA <400 c/mL or at least 0.7 log10 c/mL below their Baseline value at Day 11.



2.  Secondary:   Mean Change From Baseline in Plasma HIV-1 RNA at Day 6 to 8, Day 11, and Weeks 4, 12, 24, 48, 72, and 96   [ Time Frame: Baseline; Day 6 to 8; Day 11; Weeks 4, 12, 24, 48, 72, and 96 ]

Measure Type Secondary
Measure Title Mean Change From Baseline in Plasma HIV-1 RNA at Day 6 to 8, Day 11, and Weeks 4, 12, 24, 48, 72, and 96
Measure Description Mean change from Baseline in Plasma HIV-1 RNA was assessed on Day 6 to 8, Day 11, and Weeks 4, 12, 24, 48, 72, and 96 using data of the observed cases. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time Frame Baseline; Day 6 to 8; Day 11; Weeks 4, 12, 24, 48, 72, and 96  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT-E Population. Only those participants available at the indicated time points were analyzed.

Reporting Groups
  Description
Cohort I (DTG 50 mg OD) Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).
Cohort II (DTG 50 mg BID) Participants received DTG 50 mg twice a day (BID).

Measured Values
    Cohort I (DTG 50 mg OD)     Cohort II (DTG 50 mg BID)  
Number of Participants Analyzed  
[units: participants]
  27     24  
Mean Change From Baseline in Plasma HIV-1 RNA at Day 6 to 8, Day 11, and Weeks 4, 12, 24, 48, 72, and 96  
[units: Log10 copies/mL]
Mean ± Standard Deviation
   
Day 6 to 8, n=27, 24     -1.31  ± 0.71     -1.40  ± 0.43  
Day 11, n=27, 24     -1.45  ± 0.77     -1.76  ± 0.53  
Week 4, n=26, 24     -1.82  ± 1.03     -2.06  ± 0.78  
Week 12, n=22, 24     -1.94  ± 1.14     -2.30  ± 0.93  
Week 24, n=18, 22     -1.99  ± 1.08     -2.50  ± 0.81  
Week 48, n=15, 20     -2.02  ± 1.07     -2.63  ± 0.78  
Week 72, n=14, 0     -2.10  ± 1.03     NA  ± NA [1]
Week 96, n=13, 0     -2.06  ± 1.13     NA  ± NA [1]
[1] As of the data cut-off, Week 48 is the last time point which all participants in Cohort II would have had opportunity to reach if they had not discontinued prematurely. No data were available for analysis at this time point.

No statistical analysis provided for Mean Change From Baseline in Plasma HIV-1 RNA at Day 6 to 8, Day 11, and Weeks 4, 12, 24, 48, 72, and 96



3.  Secondary:   Number of Participants Who Achieved Plasma HIV-1 RNA <400 c/mL and <50 c/mL at Baseline and Weeks 4, 12, 24, 48, 72, and 96: TLOVR Analysis.   [ Time Frame: Baseline; Weeks 4, 12, 24, 48, 72, and 96 ]

Measure Type Secondary
Measure Title Number of Participants Who Achieved Plasma HIV-1 RNA <400 c/mL and <50 c/mL at Baseline and Weeks 4, 12, 24, 48, 72, and 96: TLOVR Analysis.
Measure Description The number of participants with plasma HIV-1 RNA <400 c/mL or <50 c/mL was assessed at Weeks 4, 12, 24, 48, 72, and 96 per the Food and Drug Administration's Time to Loss of Virological Response (TLOVR) algorithm. Using the TLOVR algorithm, participants are considered to have failed on therapy if they never achieved confirmed RNA levels below the threshold, if they had confirmed rebound of RNA above the threshold, if they made a non-permitted change in background regimen, or if they permanently discontinued investigational product for any reason.
Time Frame Baseline; Weeks 4, 12, 24, 48, 72, and 96  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT-E Population

Reporting Groups
  Description
Cohort I (DTG 50 mg OD) Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).
Cohort II (DTG 50 mg BID) Participants received DTG 50 mg twice a day (BID).

Measured Values
    Cohort I (DTG 50 mg OD)     Cohort II (DTG 50 mg BID)  
Number of Participants Analyzed  
[units: participants]
  27     24  
Number of Participants Who Achieved Plasma HIV-1 RNA <400 c/mL and <50 c/mL at Baseline and Weeks 4, 12, 24, 48, 72, and 96: TLOVR Analysis.  
[units: Participants]
   
Baseline, <50 c/mL     0     0  
Week 4, <50 c/mL     9     12  
Week 12, <50 c/mL     13     16  
Week 24, <50 c/mL     11     19  
Week 48, <50 c/mL     9     17  
Week 72, <50 c/mL     8     NA [1]
Week 96, <50 c/mL     7     NA [1]
Baseline, <400 c/mL     0     0  
Week 4, <400 c/mL     16     17  
Week 12, <400 c/mL     16     20  
Week 24, <400 c/mL     14     20  
Week 48, <400 c/mL     13     18  
Week 72, <400 c/mL     12     NA [2]
Week 96, <400 c/mL     10     NA [2]
[1] As of the data cut-off, Week 48 is the last time point which all participants in Cohort II would have had opportunity to reach if they had not discontinued prematurely. Only data to Week 48 were therefore analyzed using TLOVR.
[2] As of the data cut-off, Week 48 is the last time point which all participants in Cohort II would have had opportunity to reach if they had not discontinued prematurely. Only data to Week 48 were therefore analysed using TLOVR.

No statistical analysis provided for Number of Participants Who Achieved Plasma HIV-1 RNA <400 c/mL and <50 c/mL at Baseline and Weeks 4, 12, 24, 48, 72, and 96: TLOVR Analysis.



4.  Secondary:   Change From Baseline in CD4+ Cell Count at Day 11 and Weeks 4, 12, 24, 48, 72, and 96   [ Time Frame: Baseline; Day 11; Weeks 4, 12, 24, 48, 72, and 96 ]

Measure Type Secondary
Measure Title Change From Baseline in CD4+ Cell Count at Day 11 and Weeks 4, 12, 24, 48, 72, and 96
Measure Description Change from Baseline in CD4+ cell count was assessed at Day 11 and at Weeks 4, 12, 24, 48, 72, and 96. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time Frame Baseline; Day 11; Weeks 4, 12, 24, 48, 72, and 96  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT-E Population. Only those participants available at the indicated time points were analyzed.

Reporting Groups
  Description
Cohort I (DTG 50 mg OD) Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).
Cohort II (DTG 50 mg BID) Participants received DTG 50 mg twice a day (BID).

Measured Values
    Cohort I (DTG 50 mg OD)     Cohort II (DTG 50 mg BID)  
Number of Participants Analyzed  
[units: participants]
  27     24  
Change From Baseline in CD4+ Cell Count at Day 11 and Weeks 4, 12, 24, 48, 72, and 96  
[units: cells per cubic millimeter (mm^3)]
Median ( Full Range )
   
Baseline, n=27, 24     114  
  ( 44 to 227 )  
  202  
  ( 19 to 384 )  
Day 11, n=27, 24     34  
  ( 2 to 71 )  
  14  
  ( 0 to 69 )  
Week 4, n=27, 24     57  
  ( 33 to 108 )  
  35  
  ( 8 to 69 )  
Week 12, n= 22, 24     84  
  ( 26 to 124 )  
  57  
  ( 8 to 103 )  
Week 24, n=17, 22     78  
  ( 54 to 175 )  
  79  
  ( 17 to 147 )  
Week 48, n=15, 20     102  
  ( 29 to 160 )  
  106  
  ( 45 to 245 )  
Week 72, n=14, 0     163  
  ( 58 to 204 )  
  NA  
  ( NA to NA ) [1]
Week 96, n=13, 0     142  
  ( 75 to 202 )  
  NA  
  ( NA to NA ) [1]
[1] As of the data cut-off, Week 48 is the last time point which all participants in Cohort II would have had opportunity to reach if they had not discontinued prematurely. No data were available for analysis at this time point.

No statistical analysis provided for Change From Baseline in CD4+ Cell Count at Day 11 and Weeks 4, 12, 24, 48, 72, and 96



5.  Secondary:   Cmax, Cmin, and Ctau of DTG   [ Time Frame: Day 10 ]

Measure Type Secondary
Measure Title Cmax, Cmin, and Ctau of DTG
Measure Description The maximum plasma concentration (Cmax), minimum plasma concentration (Cmin), and concentration at the end of a dosing interval (Ctau) of DTG were assessed at Day 10. Blood samples for pharmacokinetic (PK) assessments were collected at pre-dose (within 15 minutes prior to dose) and 2, 3, 4, 8, and 24 hours post-dose on Day 10 for DTG 50 mg OD and pre-dose (within 15 minutes prior to dose) and 2, 3, 4 and 8 hours post morning dose and 12 hours post evening dose for DTG 50 mg BID.
Time Frame Day 10  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Pharmacokinetic (PK) Parameter Population: all participants who provided at least one evaluable PK concentration

Reporting Groups
  Description
Cohort I (DTG 50 mg OD) Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).
Cohort II (DTG 50 mg BID) Participants received DTG 50 mg twice a day (BID).

Measured Values
    Cohort I (DTG 50 mg OD)     Cohort II (DTG 50 mg BID)  
Number of Participants Analyzed  
[units: participants]
  25     23  
Cmax, Cmin, and Ctau of DTG  
[units: Micrograms per milliliter (µg/mL)]
Geometric Mean ( Geometric Coefficient of Variation )
   
Cmax     3.04  
  ( 38% )  
  5.41  
  ( 40% )  
Ctau     0.69  
  ( 91% )  
  2.72  
  ( 70% )  
Cmin     0.48  
  ( 136% )  
  2.61  
  ( 67% )  

No statistical analysis provided for Cmax, Cmin, and Ctau of DTG



6.  Secondary:   C0 Assessment of DTG   [ Time Frame: Day 10; Weeks 4 and 24 ]

Measure Type Secondary
Measure Title C0 Assessment of DTG
Measure Description The plasma DTG concentration immediately prior to dosing at steady state (C0) was assessed at Day 10, and Weeks 4 and 24. Blood samples for pharmacokinetic assessments were collected at pre-dose (within 15 minutes prior to dose).
Time Frame Day 10; Weeks 4 and 24  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Parameter Population

Reporting Groups
  Description
Cohort I (DTG 50 mg OD) Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).
Cohort II (DTG 50 mg BID) Participants received DTG 50 mg twice a day (BID).

Measured Values
    Cohort I (DTG 50 mg OD)     Cohort II (DTG 50 mg BID)  
Number of Participants Analyzed  
[units: participants]
  25     23  
C0 Assessment of DTG  
[units: µg/mL]
Geometric Mean ( Geometric Coefficient of Variation )
   
C0, Day 10     0.51  
  ( 139% )  
  3.20  
  ( 69% )  
C0, Week 4     0.57  
  ( 100% )  
  2.55  
  ( 63% )  
C0, Week 24     0.38  
  ( 114% )  
  2.38  
  ( 69% )  

No statistical analysis provided for C0 Assessment of DTG



7.  Secondary:   Tmax of DTG   [ Time Frame: Day 10 ]

Measure Type Secondary
Measure Title Tmax of DTG
Measure Description The tmax is defined as the time of occurrence of the maximum plasma concentration (Cmax). The tmax was assessed at Day 10. Blood samples for pharmacokinetic assessments were collected at pre-dose (within 15 minutes prior to dose) and 2, 3, 4, 8, and 24 hours post-dose on Day 10 for DTG 50 mg OD and pre-dose (within 15 minutes prior to dose) and 2, 3, 4 and 8 hours post morning dose and 12 hours post evening dose for DTG 50 mg BID.
Time Frame Day 10  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Parameter Population

Reporting Groups
  Description
Cohort I (DTG 50 mg OD) Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).
Cohort II (DTG 50 mg BID) Participants received DTG 50 mg twice a day (BID).

Measured Values
    Cohort I (DTG 50 mg OD)     Cohort II (DTG 50 mg BID)  
Number of Participants Analyzed  
[units: participants]
  25     23  
Tmax of DTG  
[units: Hours]
Median ( Full Range )
  2.97  
  ( 1.97 to 7.92 )  
  2.00  
  ( 0.00 to 7.87 )  

No statistical analysis provided for Tmax of DTG



8.  Secondary:   AUC0-24 Assessment of DTG   [ Time Frame: Day 10 ]

Measure Type Secondary
Measure Title AUC0-24 Assessment of DTG
Measure Description AUC is defined as the area under the DTG concentration-time curve as a measure of drug exposure. AUC(0-24) is defined as the area under the concentration-time curve from time zero (pre-dose) to 24 hours. AUC0-24 of DTG was assessed at Day 10. Blood samples for pharmacokinetic assessments were collected at pre-dose (within 15 minutes prior to dose) and 2, 3, 4, 8, and 24 hours post-dose on Day 10 for DTG 50 mg OD and pre-dose (within 15 minutes prior to dose) and 2, 3, 4 and 8 hours post morning dose and 12 hours post evening dose for DTG 50 mg BID.
Time Frame Day 10  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Parameter Population

Reporting Groups
  Description
Cohort I (DTG 50 mg OD) Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).
Cohort II (DTG 50 mg BID) Participants received DTG 50 mg twice a day (BID).

Measured Values
    Cohort I (DTG 50 mg OD)     Cohort II (DTG 50 mg BID)  
Number of Participants Analyzed  
[units: participants]
  25     23  
AUC0-24 Assessment of DTG  
[units: Micrograms*hour per milliliter (µg*hr/mL]
Geometric Mean ( Geometric Coefficient of Variation )
  36.46  
  ( 53% )  
  93.36  
  ( 50% )  

No statistical analysis provided for AUC0-24 Assessment of DTG



9.  Secondary:   Number of Participants With the Indicated HIV-1 Associated Conditions, Excluding Recurrences   [ Time Frame: From the day of the first dose of study drug to the data cut-off (median 86 weeks for Cohort I, median 49 weeks for Cohort II ]

Measure Type Secondary
Measure Title Number of Participants With the Indicated HIV-1 Associated Conditions, Excluding Recurrences
Measure Description The number of participants with post-Baseline emergent HIV-1 disease progression (Acquired immunodeficiency syndrome (AIDS) or death) was assessed per the Centers for Disease Control and Prevention (CDC) 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. The CDC classifies HIV infection as Category A (participants with asymptomatic HIV infection, acute HIV infection with accompanying illness, or persistent generalized lymphadenopathy), Category B (participants with symptomatic non-AIDS condition, i.e., conditions that are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection), and Category C (includes AIDS indicator conditions as defined by diagnostic or presumptive measures).
Time Frame From the day of the first dose of study drug to the data cut-off (median 86 weeks for Cohort I, median 49 weeks for Cohort II  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT-E Population

Reporting Groups
  Description
Cohort I (DTG 50 mg OD) Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).
Cohort II (DTG 50 mg BID) Participants received DTG 50 mg twice a day (BID).

Measured Values
    Cohort I (DTG 50 mg OD)     Cohort II (DTG 50 mg BID)  
Number of Participants Analyzed  
[units: participants]
  27     24  
Number of Participants With the Indicated HIV-1 Associated Conditions, Excluding Recurrences  
[units: Participants]
   
Category B, Candidiasis, oropharyngeal     1     1  
Category C, Herpes simplex     1     0  
Category C, Lymphoma, immunoblast     1     0  
Death, Brain mass     1     0  
Death, Completed suicide     0     1  
Death, Febrile bone marrow aplasia     1     0  
Death, Immunoblastic lymphoma     1     0  

No statistical analysis provided for Number of Participants With the Indicated HIV-1 Associated Conditions, Excluding Recurrences



10.  Secondary:   Number of Participants With HIV-1 Associated Disease Progression With the Indicated Shifts to CDC Class C or Death   [ Time Frame: From the day of the first dose of study drug to the data cut-off (median 86 weeks for Cohort I, median 49 weeks for Cohort II ]

Measure Type Secondary
Measure Title Number of Participants With HIV-1 Associated Disease Progression With the Indicated Shifts to CDC Class C or Death
Measure Description The number of participants with HIV-1 disease progression (AIDS or death) was assessed per the Centers for Disease Control and Prevention (CDC) 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. The CDC classifies HIV infection as Category A (participants with asymptomatic HIV infection, acute HIV infection with accompanying illness, or persistent generalized lymphadenopathy), Category B (participants with symptomatic non-AIDS condition, i.e., conditions that are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection), and Category C (includes AIDS indicator conditions as defined by diagnostic or presumptive measures).
Time Frame From the day of the first dose of study drug to the data cut-off (median 86 weeks for Cohort I, median 49 weeks for Cohort II  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT-E Population.

Reporting Groups
  Description
Cohort I (DTG 50 mg OD) Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).
Cohort II (DTG 50 mg BID) Participants received DTG 50 mg twice a day (BID).

Measured Values
    Cohort I (DTG 50 mg OD)     Cohort II (DTG 50 mg BID)  
Number of Participants Analyzed  
[units: participants]
  27     24  
Number of Participants With HIV-1 Associated Disease Progression With the Indicated Shifts to CDC Class C or Death  
[units: Participants]
   
From CDC class A to CDC class C     0     0  
From CDC class B to CDC class C     0     0  
From CDC class C to new CDC class C     1     0  
From CDC Class A, B, or C to death     2     1  

No statistical analysis provided for Number of Participants With HIV-1 Associated Disease Progression With the Indicated Shifts to CDC Class C or Death



11.  Secondary:   Number of Participants (Cumulative) With Protocol-defined Virological Failure (PDVF) at Day 11 and Weeks 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 84, and 96   [ Time Frame: Day 11; Weeks 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 84 and 96 ]

Measure Type Secondary
Measure Title Number of Participants (Cumulative) With Protocol-defined Virological Failure (PDVF) at Day 11 and Weeks 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 84, and 96
Measure Description PDVF is defined in relation to Baseline plasma HIV-1 RNA levels: at Day 11, a decrease of <0.7 log10 c/mL unless <400 c/mL; at Weeks 8 to <16, a decrease of <1.0 log10 c/mL unless <400 c/mL or an increase of >= 1.0 log10 c/mL from nadir; and at or after Week 16, ≥400 c/mL. PDVF at Day 11 was based on a single plasma HIV-1 RNA evaluation and did not require confirmation. Confirmation testing was required for visits at or after Week 8. For the combination treatment phase, all HIV-1 RNA samples that meet a criterion for suspected PDVF must be confirmed by a second measurement performed at least 1 week but not more than 4 weeks apart from the date of the original sample.
Time Frame Day 11; Weeks 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 84 and 96  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT-E Population

Reporting Groups
  Description
Cohort I (DTG 50 mg OD) Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).
Cohort II (DTG 50 mg BID) Participants received DTG 50 mg twice a day (BID).

Measured Values
    Cohort I (DTG 50 mg OD)     Cohort II (DTG 50 mg BID)  
Number of Participants Analyzed  
[units: participants]
  27     24  
Number of Participants (Cumulative) With Protocol-defined Virological Failure (PDVF) at Day 11 and Weeks 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 84, and 96  
[units: Participants]
   
Day 11     6     1  
Week 8     7     3  
Week 12     9     3  
Week 16     10     5  
Week 20     10     5  
Week 24     12     5  
Week 32     12     5  
Week 40     12     5  
Week 48     13     5  
Week 60     13     NA [1]
Week 72     14     NA [2]
Week 84     15     NA [2]
Week 96     16     NA [2]
[1] As of the data cut-off, Week 48 is the last time point which all participants in Cohort II would have had opportunity to reach if they had not discontinued prematurely. There were no confirmed PDVFs in Cohort II to data cut-off after Week 48.
[2] No data were available for analysis from Cohort II at this time point.

No statistical analysis provided for Number of Participants (Cumulative) With Protocol-defined Virological Failure (PDVF) at Day 11 and Weeks 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 84, and 96



12.  Secondary:   Number of Participants With the Indicated Genotypic Resistance at Baseline   [ Time Frame: Baseline ]

Measure Type Secondary
Measure Title Number of Participants With the Indicated Genotypic Resistance at Baseline
Measure Description At Baseline, the integrase genotypic results were used to document resistance to raltegravir (RAL) and for the allocation of participants to one of two genotypic groups according to their RAL signature mutations to ensure a broad range of sensitivity to DTG. These results were not used to pre-define subgroup for analysis.
Time Frame Baseline  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT-E Population

Reporting Groups
  Description
Cohort I (DTG 50 mg OD) Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).
Cohort II (DTG 50 mg BID) Participants received DTG 50 mg twice a day (BID).

Measured Values
    Cohort I (DTG 50 mg OD)     Cohort II (DTG 50 mg BID)  
Number of Participants Analyzed  
[units: participants]
  27     24  
Number of Participants With the Indicated Genotypic Resistance at Baseline  
[units: Participants]
   
Q148 + 2     3     2  
Q 148 + 1     4     8  
Mixture     2     1  
Y143     12     6  
N155     4     6  
Other     2     1  

No statistical analysis provided for Number of Participants With the Indicated Genotypic Resistance at Baseline



13.  Secondary:   Median Fold Change in Sensitivity to DTG by the Baseline (Day 1) IN Mutational Group   [ Time Frame: Baseline (Day 1) ]

Measure Type Secondary
Measure Title Median Fold Change in Sensitivity to DTG by the Baseline (Day 1) IN Mutational Group
Measure Description Summary of median fold change in sensitivity to DTG by Integrase (IN) mutational group was assessed. The IN mutational group comprises of the following mutations: Q148 +2, Q148 +1, mixture (participants with virus containing more than one Y143, Q148 or N155 mutation at Day 1), Y143, N155, other (participants with virus having no mutations at codons 143, 148, or 155 at Day 1). Fold change (FC) is the fold change in 50% Inhibitory Concentration (IC50) relative to the wild-type control virus.
Time Frame Baseline (Day 1)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT-E Population

Reporting Groups
  Description
Cohort I (DTG 50 mg OD) Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).
Cohort II (DTG 50 mg BID) Participants received DTG 50 mg twice a day (BID).

Measured Values
    Cohort I (DTG 50 mg OD)     Cohort II (DTG 50 mg BID)  
Number of Participants Analyzed  
[units: participants]
  27     24  
Median Fold Change in Sensitivity to DTG by the Baseline (Day 1) IN Mutational Group  
[units: DTG fold change in sensitivity]
Mean ( Full Range )
   
Q148 + 2, n=3, 2     21  
  ( 14 to 35 )  
  4  
  ( 2.1 to 6.0 )  
Q148 + 1, n=4, 8     5.5  
  ( 3.3 to 25 )  
  5.5  
  ( 4.1 to 8.2 )  
Mixture, n=2, 1     7.8  
  ( 6.5 to 9.1 )  
  9.48  
  ( 9.48 to 9.48 )  
Y143, n=12, 6     1.1  
  ( 0.6 to 1.4 )  
  1.2  
  ( 0.92 to 1.8 )  
N155, n=4, 6     1.8  
  ( 1.5 to 5.1 )  
  2.3  
  ( 1.3 to 4.0 )  
Other, n=2, 1     1.2  
  ( 0.9 to 1.5 )  
  0.87  
  ( 0.87 to 0.87 )  

No statistical analysis provided for Median Fold Change in Sensitivity to DTG by the Baseline (Day 1) IN Mutational Group



14.  Secondary:   Number of Participants With the Indicated Treatment-emergent Integrase (IN) Mutations Detected at the Time of Protocol-defined Virologic Failure (PDVF) as a Measure of Genotypic Resistance   [ Time Frame: From Baseline (Day 1) to the data cut-off (median 86 weeks for Cohort I, median 49 weeks for Cohort II) ]

Measure Type Secondary
Measure Title Number of Participants With the Indicated Treatment-emergent Integrase (IN) Mutations Detected at the Time of Protocol-defined Virologic Failure (PDVF) as a Measure of Genotypic Resistance
Measure Description An analysis of changes at specific amino acids in the IN coding region associated with resistance to raltegravir, elvitegravir, or DTG was performed at Day 1 and at the time of PDVF. PDVF is defined in relation to Baseline plasma HIV-1 RNA levels: at Day 11, a decrease of <0.7 log10 c/mL unless <400 c/mL; at Weeks 8 to <16, a decrease of <1.0 log10 c/mL unless <400 c/mL or an increase of >= 1.0 log10 c/mL from nadir; and at or after Week 16, ≥400 c/mL. PDVF at Day 11 was based on a single plasma HIV-1 RNA evaluation and did not require confirmation. Confirmation testing was required for visits at or after Week 8. For the combination treatment phase, all HIV-1 RNA samples that meet a criterion for suspected PDVF must be confirmed by a second measurement performed at least 1 week but not more than 4 weeks apart from the date of the original sample.
Time Frame From Baseline (Day 1) to the data cut-off (median 86 weeks for Cohort I, median 49 weeks for Cohort II)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
On-treatment Genotypic Resistance Population: all ITT-E participants who met the criteria for protocol-defined virological failure (PDVF)

Reporting Groups
  Description
Cohort I (DTG 50 mg OD) Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).
Cohort II (DTG 50 mg BID) Participants received DTG 50 mg twice a day (BID).

Measured Values
    Cohort I (DTG 50 mg OD)     Cohort II (DTG 50 mg BID)  
Number of Participants Analyzed  
[units: participants]
  16     5  
Number of Participants With the Indicated Treatment-emergent Integrase (IN) Mutations Detected at the Time of Protocol-defined Virologic Failure (PDVF) as a Measure of Genotypic Resistance  
[units: Participants]
   
Any     6     3  
E138     2     2  
N155     2     2  
T97     2     2  
E92     0     2  
G140     2     0  
L74     2     0  
Q148     2     0  
T124     0     1  

No statistical analysis provided for Number of Participants With the Indicated Treatment-emergent Integrase (IN) Mutations Detected at the Time of Protocol-defined Virologic Failure (PDVF) as a Measure of Genotypic Resistance



15.  Secondary:   Number of Participants With the Indicated Fold Increase in DTG FC (Fold Change in IC50 Relative to Wild-type Virus) Between Baseline and the Time of PDVF, as a Measure of Post-Baseline Phenotypic Resistance   [ Time Frame: From Baseline (Day 1) to the data cut-off (median 86 weeks for Cohort I, median 49 weeks for Cohort II) ]

Measure Type Secondary
Measure Title Number of Participants With the Indicated Fold Increase in DTG FC (Fold Change in IC50 Relative to Wild-type Virus) Between Baseline and the Time of PDVF, as a Measure of Post-Baseline Phenotypic Resistance
Measure Description The FC in IC50 (50% inhibitory concentration) for DTG relative to wild-type virus was determined for virus isolated at Baseline and at the time of PDVF. The number of participants with the indicated change (ratio) in the two values at the time of PDVF is presented. PDVF is defined in relation to Baseline plasma HIV-1 RNA levels: at Day 11, a decrease of <0.7 log10 c/mL unless <400 c/mL; at Weeks 8 to <16, a decrease of <1.0 log10 c/mL unless <400 c/mL or an increase of >= 1.0 log10 c/mL from nadir; and at or after Week 16, ≥400 c/mL. PDVF at Day 11 was based on a single plasma HIV-1 RNA evaluation and did not require confirmation. Confirmation testing was required for visits at or after Week 8. For the combination treatment phase, all HIV-1 RNA samples that meet a criterion for suspected PDVF must be confirmed by a second measurement performed at least 1 week but not more than 4 weeks apart from the date of the original sample.
Time Frame From Baseline (Day 1) to the data cut-off (median 86 weeks for Cohort I, median 49 weeks for Cohort II)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PDVF Genotypic Resistance Populations: all participants in the ITT-E Population with available on-treatment genotypic resistance data at the time of PDVF failure. Only participants with Baseline IN mutations with PDVF who had paired Baseline and time of virological failure samples were considered for analysis.

Reporting Groups
  Description
Cohort I (DTG 50 mg OD) Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).
Cohort II (DTG 50 mg BID) Participants received DTG 50 mg twice a day (BID).

Measured Values
    Cohort I (DTG 50 mg OD)     Cohort II (DTG 50 mg BID)  
Number of Participants Analyzed  
[units: participants]
  15     5  
Number of Participants With the Indicated Fold Increase in DTG FC (Fold Change in IC50 Relative to Wild-type Virus) Between Baseline and the Time of PDVF, as a Measure of Post-Baseline Phenotypic Resistance  
[units: Participants]
   
<1 fold     3     0  
1-<2 fold     4     2  
2-<4 fold     1     0  
4-<8 fold     1     1  
>=8 fold     6     2  

No statistical analysis provided for Number of Participants With the Indicated Fold Increase in DTG FC (Fold Change in IC50 Relative to Wild-type Virus) Between Baseline and the Time of PDVF, as a Measure of Post-Baseline Phenotypic Resistance



16.  Secondary:   Number of Participants With the Indicated Grade 3 and Grade 4 Clinical Chemistry Toxicities   [ Time Frame: From the day of the first dose of study drug to the data cut-off (median 86 weeks for Cohort I, median 49 weeks for Cohort II) ]

Measure Type Secondary
Measure Title Number of Participants With the Indicated Grade 3 and Grade 4 Clinical Chemistry Toxicities
Measure Description Hematology and clinical chemistry data were summarized according to Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, dated December 2004. Grade 1, Mild; Grade 2, Moderate; Grade 3, Severe; Grade 4, Potentially life-threatening. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. The Grade 3 and Grade 4 clinical chemistry toxicities included: Albumin, Alkaline Phosphatase, Amylase, Aspartate Amino Transferase, Carbon dioxide content/Bicarbonate, Creatinine, Creatinine Clearance, Hypercalcemia, Hyperglycaemia, Hyperkalemia, Hypernatremia, Hypocalcemia, Hypoglycaemia, Hypokalemia, Hyponatremia, LDL Cholesterol, Magnesium, Phosphorus inorganic, and Total Bilirubin.
Time Frame From the day of the first dose of study drug to the data cut-off (median 86 weeks for Cohort I, median 49 weeks for Cohort II)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety Population: all participants that took at least one dose of DTG

Reporting Groups
  Description
Cohort I (DTG 50 mg OD) Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).
Cohort II (DTG 50 mg BID) Participants received DTG 50 mg twice a day (BID).

Measured Values
    Cohort I (DTG 50 mg OD)     Cohort II (DTG 50 mg BID)  
Number of Participants Analyzed  
[units: participants]
  27     24  
Number of Participants With the Indicated Grade 3 and Grade 4 Clinical Chemistry Toxicities  
[units: Participants]
   
Albumin, Grade 3     0     0  
Albumin, Grade 4     0     0  
Alkaline Phosphatase, Grade 3     0     0  
Alkaline Phosphatase, Grade 4     0     0  
Amylase, Grade 3     1     1  
Amylase, Grade 4     1     0  
Aspartate Amino Transferase, Grade 3     0     0  
Aspartate Amino Transferase, Grade 4     0     0  
Carbon dioxide content/Bicarbonate, Grade 3     0     0  
Carbon dioxide content/Bicarbonate, Grade 4     0     0  
Creatinine, Grade 3     0     0  
Creatinine, Grade 4     0     0  
Creatinine Clearance, estimated, Grade 3     0     0  
Creatinine Clearance, estimated, Grade 4     0     0  
Hypercalcemia, Grade 3     0     0  
Hypercalcemia, Grade 4     0     0  
Hyperglycaemia, Grade 3     0     0  
Hyperglycaemia, Grade 4     0     0  
Hyperkalemia, Grade 3     0     0  
Hyperkalemia, Grade 4     0     0  
Hypernatremia, Grade 3     1     0  
Hypernatremia, Grade 4     0     0  
Hypocalcemia, Grade 3     0     0  
Hypocalcemia, Grade 4     0     0  
Hypoglycaemia, Grade 3     0     0  
Hypoglycaemia, Grade 4     0     0  
Hypokalemia, Grade 3     0     0  
Hypokalemia, Grade 4     0     0  
Hyponatremia, Grade 3     0     0  
Hyponatremia, Grade 4     0     0  
LDL Cholesterol, Grade 3     2     1  
LDL Cholesterol, Grade 4     0     0  
Magnesium, Grade 3     0     0  
Magnesium, Grade 4     0     0  
Phosphorus inorganic, Grade 3     3     1  
Phosphorus inorganic, Grade 4     0     0  
Total Bilirubin, Grade 3     0     1  
Total Bilirubin, Grade 4     0     1  

No statistical analysis provided for Number of Participants With the Indicated Grade 3 and Grade 4 Clinical Chemistry Toxicities



17.  Secondary:   Number of Participants With the Indicated Grade 3 and Grade 4 Hematological Toxicities   [ Time Frame: From Baseline (Day 1) to the data cut-off (median 86 weeks for Cohort I, median 49 weeks for Cohort II) ]

Measure Type Secondary
Measure Title Number of Participants With the Indicated Grade 3 and Grade 4 Hematological Toxicities
Measure Description Hematology and clinical chemistry data were summarized according to Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, dated December 2004. Grade 1, Mild; Grade 2, Moderate; Grade 3, Severe; Grade 4, Potentially life-threatening. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. The Grade 3 and Grade 4 hematological toxicities included: Hemoglobin, Platelet Count, Total Neutrophils, and White Blood Cell count.
Time Frame From Baseline (Day 1) to the data cut-off (median 86 weeks for Cohort I, median 49 weeks for Cohort II)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety Population: all participants that took at least one dose of DTG

Reporting Groups
  Description
Cohort I (DTG 50 mg OD) Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).
Cohort II (DTG 50 mg BID) Participants received DTG 50 mg twice a day (BID).

Measured Values
    Cohort I (DTG 50 mg OD)     Cohort II (DTG 50 mg BID)  
Number of Participants Analyzed  
[units: participants]
  27     24  
Number of Participants With the Indicated Grade 3 and Grade 4 Hematological Toxicities  
[units: Participants]
   
Hemoglobin, Grade 3     0     1  
Hemoglobin, Grade 4     0     0  
Platelet count, Grade 3     0     0  
Platelet count, Grade 4     0     0  
Total Neutrophils, Grade 3     0     0  
Total Neutrophils, Grade 4     0     1  
White Blood Cell count, Grade 3     2     1  
White Blood Cell, Grade 4     1     1  

No statistical analysis provided for Number of Participants With the Indicated Grade 3 and Grade 4 Hematological Toxicities




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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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.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: GSK Response Center
Organization: ViiV Healthcare
phone: 866-435-7343


Publications:
Eron JJ, Clotet B, Durant J, et al. Safety and efficacy of dolutegravir (DTG) in HIV-1 treatment-experienced subjects with raltegravir-resistant virus: 24-week results of the VIKING study. J Infect Dis. 2013;207(5):740-8.


Responsible Party: ViiV Healthcare
ClinicalTrials.gov Identifier: NCT00950859     History of Changes
Other Study ID Numbers: 112961
Study First Received: July 23, 2009
Results First Received: August 15, 2013
Last Updated: January 9, 2014
Health Authority: United States: Food and Drug Administration