A Dose Ranging Trial of GSK1349572 and 2 NRTI in HIV-1 Infected, Therapy Naive Subjects (ING112276)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Shionogi
GlaxoSmithKline
Information provided by (Responsible Party):
ViiV Healthcare
ClinicalTrials.gov Identifier:
NCT00951015
First received: July 30, 2009
Last updated: December 19, 2013
Last verified: October 2013
Results First Received: August 22, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Infection, Human Immunodeficiency Virus
Interventions: Drug: GSK1349572
Drug: efavirenz

  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
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Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Eligible participants (par.) were randomized (ran) to receive Dolutegravir (DTG) (3 dose groups) or Efavirenz for 96 weeks. At Week 96, par. ran. to any dose of DTG entered an open-label phase and continued to receive DTG at the selected dose of 50 milligrams. A total of 208 par. were ran., and 205 received at least one dose of study medication.

Reporting Groups
  Description
DTG 10 mg OD Participants received Dolutegravir (DTG) 10 milligrams (mg), DTG matching placebo, and Abacavir (ABC)/Lamivudine (3TC) 600 mg/300 mg or Tenofovir (TDF)/Emtricitabine (FTC) 300 mg/200 mg orally once daily (OD) for 96 weeks. Following Week 96, participants continued to receive DTG 50 mg OD.
DTG 25 mg OD Participants received DTG 25 mg, DTG matching placebo, and ABC/3TC 600 mg/300 mg or TDF/FTC 300 mg/200 mg orally OD for 96 weeks. Following Week 96, participants continued to receive DTG 50 mg OD.
DTG 50 mg OD Participants received DTG 50 mg and ABC/3TC 600 mg/300 mg or TDF/FTC 300 mg/200 mg orally OD for 96 weeks. Following Week 96, participants continued to receive DTG 50 mg OD.
EFV 600 mg OD Participants received Efavirenz (EFV) 600 mg and ABC/3TC 600 mg/300 mg or TDF/FTC 300 mg/200 mg orally OD for 96 weeks.

Participant Flow:   Overall Study
    DTG 10 mg OD     DTG 25 mg OD     DTG 50 mg OD     EFV 600 mg OD  
STARTED     53     51     51     50  
Ongoing     47     45     46     8  
COMPLETED     0     0     0     32  
NOT COMPLETED     53     51     51     18  
Adverse Event                 1                 1                 2                 5  
Lack of Efficacy                 1                 1                 0                 0  
Protocol Violation                 1                 1                 1                 0  
Protocol-Defined Stopping Criteria                 0                 0                 0                 1  
Lost to Follow-up                 0                 2                 1                 2  
Withdrawal by Subject                 3                 1                 1                 2  
Ongoing                 47                 45                 46                 8  



  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.
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Reporting Groups
  Description
DTG 10 mg OD Participants received Dolutegravir (DTG) 10 milligrams (mg), DTG matching placebo, and Abacavir (ABC)/Lamivudine (3TC) 600 mg/300 mg or Tenofovir (TDF)/Emtricitabine (FTC) 300 mg/200 mg orally once daily (OD) for 96 weeks. Following Week 96, participants continued to receive DTG 50 mg OD.
DTG 25 mg OD Participants received DTG 25 mg, DTG matching placebo, and ABC/3TC 600 mg/300 mg or TDF/FTC 300 mg/200 mg orally OD for 96 weeks. Following Week 96, participants continued to receive DTG 50 mg OD.
DTG 50 mg OD Participants received DTG 50 mg and ABC/3TC 600 mg/300 mg or TDF/FTC 300 mg/200 mg orally OD for 96 weeks. Following Week 96, participants continued to receive DTG 50 mg OD.
EFV 600 mg OD Participants received Efavirenz (EFV) 600 mg and ABC/3TC 600 mg/300 mg or TDF/FTC 300 mg/200 mg orally OD for 96 weeks.
Total Total of all reporting groups

Baseline Measures
    DTG 10 mg OD     DTG 25 mg OD     DTG 50 mg OD     EFV 600 mg OD     Total  
Number of Participants  
[units: participants]
  53     51     51     50     205  
Age  
[units: Years]
Mean ± Standard Deviation
  34.2  ± 9.25     37.0  ± 9.79     37.0  ± 8.89     40.7  ± 11.19     37.2  ± 10.00  
Gender  
[units: Participants]
         
Female     11     5     6     6     28  
Male     42     46     45     44     177  
Race/Ethnicity, Customized  
[units: participants]
         
African American/African Heritage (HER)     7     6     8     4     25  
American Indian or Alaska Native     1     3     4     2     10  
Japanese/East Asian HER/South East Asian HER     0     0     0     1     1  
Native Hawaiian or other Pacific Islander     3     0     0     0     3  
White     41     42     38     43     164  
African American/African HER & White     0     0     1     0     1  
Asian & White     1     0     0     0     1  



  Outcome Measures
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1.  Primary:   Number of Participants With Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) <50 Copies/Milliliter (c/mL) at Week 16   [ Time Frame: Week 16 ]

2.  Secondary:   Viral Change Over the Initial 2 Weeks of Treatment   [ Time Frame: Baseline and Week 2 ]

3.  Secondary:   Change From Baseline in HIV-1 RNA at the Indicated Time Points   [ Time Frame: Baseline (Day 1), Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 32, Week 40, Week 48, Week 60, Week 72, Week 84, and Week 96 ]

4.  Secondary:   Change From Baseline in Cluster of Differentiation 4+ (CD4+) Cell Counts at the Indicated Time Points   [ Time Frame: Baseline (Day 1), Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 32, Week 40, Week 48, Week 60, Week 72, Week 84, and Week 96 ]

5.  Secondary:   Number of Participants With New HIV-associated Conditions of the Indicated Class   [ Time Frame: From Baseline up to Week 96 ]

6.  Secondary:   Number of Participants With the Indicated Type of HIV-1 Disease Progression (AIDS or Death)   [ Time Frame: From Baseline up to Week 96 ]

7.  Secondary:   Number of Participants With Plasma HIV-1 RNA <50 c/mL   [ Time Frame: Baseline (Day 1), Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 32, Week 40, Week 48, Week 60, Week 72, Week 84, and Week 96 ]

8.  Secondary:   Number of Participants With Plasma HIV-1 RNA <400 c/mL   [ Time Frame: Baseline (Day 1), Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 32, Week 40, Week 48, Week 60, Week 72, Week 84, and Week 96 ]

9.  Secondary:   Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Events (SAE)   [ Time Frame: From Baseline up to Week 96/Early Withdrawal ]

10.  Secondary:   Number of Participants With the Indicated Grade 1 to Grade 4 Treatment-emergent Clinical Chemistry and Hematology Toxicities   [ Time Frame: From Baseline up to Week 96/Early Withdrawal ]

11.  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 up to Week 96/Early Withdrawal ]

12.  Secondary:   Number of Participants With the Indicated Treatment-emergent Major Mutations of Other Classes Detected at the Time of Protocol-defined Virologic Failure (PDVF), as a Measure of Genotypic Resistance   [ Time Frame: From Baseline up to Week 96/Early Withdrawal ]

13.  Secondary:   Number of Participants With the Indicated Fold Increase in DTG FC (Fold Change in IC50 Relative to Wild-type Virus) at the Time of PDVF, as a Measure of Post-Baseline Phenotypic Resistance   [ Time Frame: From Baseline up to Week 96/Early Withdrawal ]

14.  Secondary:   Plasma DTG Concentration   [ Time Frame: Week 2, Week 12, and Week 24 ]

15.  Secondary:   AUC(0-tau) of DTG   [ Time Frame: pre-dose and 2, 3, 4, 8, and 24 hours post-dose at Week 2 ]

16.  Secondary:   Cmax, Cmin, and Ctau of DTG   [ Time Frame: pre-dose and 2, 3, 4, 8, and 24 hours post-dose at Week 2 ]

17.  Secondary:   C0 and C0 Avg of DTG   [ Time Frame: Week 2, Week 12, and Week 24 ]

18.  Secondary:   Time to Maximal Drug Concentration (Tmax) of DTG   [ Time Frame: pre-dose and 2, 3, 4, 8, and 24 hours post-dose at Week 2 ]

19.  Secondary:   Relationship Between the Change From Baseline in Plasma HIV-1 RNA at Week 2 and the Indicated Plasma DTG PK Parameters   [ Time Frame: Week 2 ]

20.  Secondary:   Relationship Between the Change From Baseline in CD4+ Cell Counts at Week 96 and the Indicated Plasma DTG PK Parameters   [ Time Frame: Week 96 ]

21.  Secondary:   Relationship Between the Indicated Safety Parameters at Week 96 and the Indicated Plasma DTG PK Parameters   [ Time Frame: Week 96 ]
  Hide Outcome Measure 21

Measure Type Secondary
Measure Title Relationship Between the Indicated Safety Parameters at Week 96 and the Indicated Plasma DTG PK Parameters
Measure Description Relationships between log-transformed plasma DTG PK parameters (AUC[0-tau], Cmax, C0, C0avg, Ctau, and Cmin) and safety parameters (AE occurrence, maximum AE intensity, alanine aminotransferase [ALT], change from Baseline [CFB] in ALT, total bilirubin, CFB in total bilirubin, creatine kinase, CFB in creatine kinase, triglycerides, CFB in triglycerides, lipase, CFB in lipase, total cholesterol [TC], CFB in TC) was assessed using Pearson’s correlation analyses. The Pearson's correlation coefficient is a measure of the correlation between safety parameters and plasma DTG PK parameters and ranges from -1 to 1. A value of 0 indicates no statistical association; a value close to -1 or 1 indicates a higher association. The presence of >=1 AE was used for AE occurrence. The most severe AE grade/intensity was used for maximum AE intensity. Maximum laboratory values per participant were used for safety parameters. CFB was calculated as the post-Baseline value minus the value at Baseline.
Time Frame Week 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.
PK/PD Analysis Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the PK/PD Analysis Population.

Reporting Groups
  Description
Overall DTG All participants who received DTG in any DTG treatment group (DTG 10 mg OD, DTG 25 mg OD, and DTG 50 mg OD)

Measured Values
    Overall DTG  
Number of Participants Analyzed  
[units: participants]
  142  
Relationship Between the Indicated Safety Parameters at Week 96 and the Indicated Plasma DTG PK Parameters  
[units: Pearson's correlation coefficient]
 
AUC(0-tau) versus AE occurrence, n=45     0.114  
AUC(0-tau) versus maximum AE intensity, n=45     0.171  
AUC(0-tau) versus ALT, n=45     -0.196  
AUC(0-tau) versus CFB in ALT, n=45     -0.201  
AUC(0-tau) versus total bilirubin, n=45     0.364  
AUC(0-tau) versus CFB in total bilirubin, n=45     0.147  
AUC(0-tau) versus creatine kinase, n=45     -0.168  
AUC(0-tau) versus CFB in creatine kinase, n=45     -0.145  
AUC(0-tau) vs Triglycerides, n=45     0.104  
AUC(0-tau) versus CFB in triglycerides, n=45     0.216  
AUC(0-tau) versus lipase, n=45     -0.066  
AUC(0-tau) versus CFB in lipase, n=45     0.092  
AUC(0-tau) versus total cholesterol, n=45     -0.097  
AUC(0-tau) versus CFB in total cholesterol, n=45     -0.153  
Cmax versus AE occurrence, n=45     0.061  
Cmax versus maximum AE intensity, n=45     0.110  
Cmax versus ALT, n=45     -0.135  
Cmax versus CFB in ALT, n=45     -0.135  
Cmax versus total bilirubin, n=45     0.265  
Cmax versus CFB in total bilirubin, n=45     0.033  
Cmax versus creatine kinase, n=45     -0.188  
Cmax versus CFB in creatine kinase, n=45     -0.161  
Cmax versus triglycerides, n=45     0.134  
Cmax versus CFB in triglycerides, n=45     0.244  
Cmax versus lipase, n=45     -0.034  
Cmax versus CFB in lipase, n=45     0.115  
Cmax versus total cholesterol, n=45     -0.101  
Cmax versus CFB in total cholesterol, n=45     -0.192  
C0 versus AE occurrence, n=133     -0.080  
C0 versus maximum AE intensity, n=133     -0.003  
C0 versus ALT, n=133     -0.196  
C0 versus CFB in ALT, n=133     -0.237  
C0 versus total bilirubin, n=133     0.298  
C0 versus CFB in total bilirubin, n=133     0.120  
C0 versus creatine kinase, n=133     -0.094  
C0 versus CFB in creatine kinase, n=133     -0.093  
C0 versus triglycerides, n=133     -0.058  
C0 versus CFB in triglycerides, n=133     -0.012  
C0 versus lipase, n=133     -0.187  
C0 versus CFB in lipase, n=133     -0.137  
C0 versus total cholesterol, n=133     -0.179  
C0 versus CFB in total cholesterol, n=133     -0.125  
C0avg versus AE occurrence, n=140     -0.028  
C0avg versus maximum AE intensity, n=140     0.036  
C0avg versus ALT, n=140     -0.166  
C0avg versus CFB in ALT, n=140     -0.177  
C0avg versus total bilirubin, n=140     0.319  
C0avg versus CFB in total bilirubin, n=140     0.109  
C0avg versus creatine kinase, n=140     -0.114  
C0avg versus CFB in creatine kinase, n=140     -0.110  
C0avg versus triglycerides, n=140     0.057  
C0avg versus CFB in triglycerides, n=140     0.092  
C0avg versus lipase, n=140     -0.164  
C0avg versus CFB in lipase, n=140     -0.120  
C0avg versus total cholesterol, n=140     -0.170  
C0avg versus CFB in total cholesterol, n=140     -0.083  
Ctau versus AE occurrence, n=45     0.190  
Ctau versus maximum AE intensity, n=45     0.205  
Ctau versus ALT, n=45     -0.281  
Ctau versus CFB in ALT, n=45     -0.285  
Ctau versus total bilirubin, n=45     0.446  
Ctau versus CFB in total bilirubin, n=45     0.237  
Ctau versus creatine kinase, n=45     -0.143  
Ctau versus CFB in creatine kinase, n=45     -0.125  
Ctau versus triglycerides, n=45     0.061  
Ctau versus CFB in triglycerides, n=45     0.172  
Ctau versus lipase, n=45     -0.131  
Ctau versus CFB in lipase, n=45     0.056  
Ctau versus total cholesterol, n=45     -0.039  
Ctau versus CFB in total cholesterol, n=45     -0.108  
Cmin versus AE occurrence, n=45     0.156  
Cmin versus maximum AE intensity, n=45     0.193  
Cmin versus ALT, n=45     -0.236  
Cmin versus CFB in ALT, n=45     -0.253  
Cmin versus total bilirubin, n=45     0.430  
Cmin versus CFB in total bilirubin, n=45     0.171  
Cmin versus creatine kinase, n=45     -0.132  
Cmin versus CFB in creatine kinase, n=45     -0.124  
Cmin versus triglycerides, n=45     -0.042  
Cmin versus CFB in triglycerides, n=45     0.057  
Cmin versus lipase, n=45     -0.135  
Cmin versus CFB in lipase, n=45     0.032  
Cmin versus total cholesterol, n=45     -0.194  
Cmin versus CFB in total cholesterol, n=45     -0.208  

No statistical analysis provided for Relationship Between the Indicated Safety Parameters at Week 96 and the Indicated Plasma DTG PK Parameters



22.  Secondary:   Relationship Between Gastrointestinal System Organ Class AEs of Special Interest at Week 96 and the Indicated Plasma DTG PK Parameters   [ Time Frame: Week 96 ]

23.  Other Pre-specified:   Change From Baseline in Cluster of Differentiation 8+ (CD8+) Cell Counts at the Indicated Time Points   [ Time Frame: Baseline (Day 1), Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 32, Week 40, Week 48, Week 60, Week 72, Week 84, and Week 96 ]


  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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