Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

A Trial Comparing GSK1349572 50mg Plus Abacavir/Lamivudine Once Daily to Atripla (Also Called The SINGLE Trial)

This study has been completed.
Sponsor:
Collaborators:
Shionogi
GlaxoSmithKline
Information provided by (Responsible Party):
ViiV Healthcare
ClinicalTrials.gov Identifier:
NCT01263015
First received: December 16, 2010
Last updated: September 23, 2016
Last verified: September 2016
Results First Received: August 15, 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 I
Interventions: Drug: Dolutegravir
Drug: Atripla
Drug: Abacavir/Lamivudine
Drug: Abacavir/Lamivudine Placebo
Drug: Dolutegravir placebo
Drug: Atripla placebo

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Study consisted of 96 weeks double-blind phase, followed by a 48 week open-label phase.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
A total of 844 participants (par.) were randomized (1:1) to one of the two treatment arms. Of these, 833 par. received at least one dose of study medication. Of the 11 par. who were randomized but not treated with investigational product, 7 par. withdrew consent, 3 par. were randomized in error, and 1 par. was lost to follow-up.

Reporting Groups
  Description
DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily During double-blind phase, participants received a dolutegravir (DTG) 50 milligram (mg) tablet along with an Abacavir/Lamivudine (ABC/3TC) 600/300 mg tablet once daily (OD) orally, with placebo to match Efavirenz/Tenofovir disoproxil fumarate/Emtricitabine (EFV/TDF/FTC) 600/200/300 mg for 96 weeks.
EFV/TDF/FTC 600/200/300 mg Once Daily During double-blind phase, participants received EFV/TDF/FTC 600/200/300 mg OD, with placebo to match DTG 50 mg and ABC/3TC 600/300 mg for 96 weeks.

Participant Flow for 2 periods

Period 1:   Double-blind Phase: 96 Weeks Duration
    DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily   EFV/TDF/FTC 600/200/300 mg Once Daily
STARTED   414   419 
COMPLETED   342   310 
NOT COMPLETED   72   109 
Adverse Event                13                48 
Lack of Efficacy                18                14 
Protocol Violation                14                12 
Lost to Follow-up                17                18 
Withdrawal by Subject                9                15 
Physician Decision                1                2 

Period 2:   Open-label Phase: 48 Weeks Duration
    DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily   EFV/TDF/FTC 600/200/300 mg Once Daily
STARTED   341   309 
COMPLETED   317   278 
NOT COMPLETED   24   31 
Adverse Event                3                10 
Lack of Efficacy                7                2 
Protocol Violation                3                2 
Lost to Follow-up                8                8 
Physician Decision                0                2 
Withdrawal by Subject                3                7 



  Baseline Characteristics
  Hide Baseline Characteristics

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
DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily During double-blind phase, participants received a dolutegravir (DTG) 50 milligram (mg) tablet along with an Abacavir/Lamivudine (ABC/3TC) 600/300 mg tablet once daily (OD) orally, with placebo to match Efavirenz/Tenofovir disoproxil fumarate/Emtricitabine (EFV/TDF/FTC) 600/200/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive DTG 50 mg tablet along with ABC/3TC 600/300 mg tablet OD orally, for additional 48 weeks during open-label phase.
EFV/TDF/FTC 600/200/300 mg Once Daily During double-blind phase, participants received EFV/TDF/FTC 600/200/300 mg OD, with placebo to match DTG 50 mg and ABC/3TC 600/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive EFV/TDF/FTC 600/200/300 mg OD for additional 48 weeks during open-label phase.
Total Total of all reporting groups

Baseline Measures
   DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily   EFV/TDF/FTC 600/200/300 mg Once Daily   Total 
Overall Participants Analyzed 
[Units: Participants]
 414   419   833 
Age 
[Units: Years]
Mean (Standard Deviation)
 36.5  (10.74)   36.4  (10.43)   36.4  (10.58) 
Gender 
[Units: Participants]
     
Female   67   63   130 
Male   347   356   703 
Race/Ethnicity, Customized 
[Units: Participants]
     
African American (Af Am)/African Heritage (Af Ht)   98   99   197 
American Indian (AI) or Alaska Native (Nat)   13   17   30 
Asian   9   9   18 
White   284   285   569 
Af Am/Af Ht & AI or Alaska Native   0   1   1 
Af Am/Af Ht & Nat Hawaiian/other Pacific Islander   0   1   1 
Af Am/Af Ht & White   3   2   5 
American Indian or Alaska Native & White   6   4   10 
Asian & White   1   0   1 
Missing   0   1   1 


  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   Proportion of Subjects Responding Based on Plasma HIV-1 RNA <50 c/mL at Week 48   [ Time Frame: Week 48 ]

Measure Type Primary
Measure Title Proportion of Subjects Responding Based on Plasma HIV-1 RNA <50 c/mL at Week 48
Measure Description The percentage of participants with plasma HIV-1 RNA <50 c/mL at Week 48 was assessed. Plasma samples were collected for the quantitative assessment of HIV-1 RNA based on the Missing, Switch, or Discontinuation equals Failure (MSDF) algorithm,as codified by the Food and Drug Administration's Snapshot algorithm. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (due to missing data or discontinuation of investigationl product prior to the visit window) as non-responders, as well as participants who switched their concomitant antiretroviral therapy (ART) in certain scenarios. Since changes in ART were not permitted in this protocol, all such participants who changed ART were to be considered non-responders. Otherwise, virologic success or failure was to be determined by the last available HIV-1 RNA assessment while the participant was on treatment within the visit of interest window.
Time Frame Week 48  
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 randomized participants who received at least one dose of study medication

Reporting Groups
  Description
DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily During double-blind phase, participants received a dolutegravir (DTG) 50 milligram (mg) tablet along with an Abacavir/Lamivudine (ABC/3TC) 600/300 mg tablet once daily (OD) orally, with placebo to match Efavirenz/Tenofovir disoproxil fumarate/Emtricitabine (EFV/TDF/FTC) 600/200/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive DTG 50 mg tablet along with ABC/3TC 600/300 mg tablet OD orally, for additional 48 weeks during open-label phase.
EFV/TDF/FTC 600/200/300 mg Once Daily During double-blind phase, participants received EFV/TDF/FTC 600/200/300 mg OD, with placebo to match DTG 50 mg and ABC/3TC 600/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive EFV/TDF/FTC 600/200/300 mg OD for additional 48 weeks during open-label phase.

Measured Values
   DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily   EFV/TDF/FTC 600/200/300 mg Once Daily 
Participants Analyzed 
[Units: Participants]
 414   419 
Proportion of Subjects Responding Based on Plasma HIV-1 RNA <50 c/mL at Week 48 
[Units: Percentage of participants]
 88   81 


Statistical Analysis 1 for Proportion of Subjects Responding Based on Plasma HIV-1 RNA <50 c/mL at Week 48
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Wilcoxon (Mann-Whitney)
P Value [4] 0.003
Difference in percentage [5] 7.3
95% Confidence Interval 2.3 to 12.2
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Non-inferiority could be concluded if the lower bound of a two-sided 95% confidence interval for the difference (DTG + ABC/3TC minus EFV/TDF/FTC) in percentages between the two treatment arms was > -10%.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value is for the test of superiority.
[5] Other relevant estimation information:
  The estimated value reflects the percentage on DTG + ABC/3TC minus the percentage on EFV/TDF/FTC.



2.  Secondary:   Time to Viral Suppression (<50 c/mL)   [ Time Frame: From Baseline until Week 144) (average of 877.4 days for DTG; average of 788.8 study days for EFV/TDF/FTC) ]

Measure Type Secondary
Measure Title Time to Viral Suppression (<50 c/mL)
Measure Description Viral suppression is defined as the first viral load value<50 c/mL. The Kaplan-Meier method was used to estimate time to viral suppression, defined as the time from the first dose of study treatment until the first viral load value <50 c/mL was reached. Participants who withdrew for any reason without having suppressed prior to the analysis were censored.
Time Frame From Baseline until Week 144) (average of 877.4 days for DTG; average of 788.8 study days for EFV/TDF/FTC)  
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
DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily During double-blind phase, participants received a dolutegravir (DTG) 50 milligram (mg) tablet along with an Abacavir/Lamivudine (ABC/3TC) 600/300 mg tablet once daily (OD) orally, with placebo to match Efavirenz/Tenofovir disoproxil fumarate/Emtricitabine (EFV/TDF/FTC) 600/200/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive DTG 50 mg tablet along with ABC/3TC 600/300 mg tablet OD orally, for additional 48 weeks during open-label phase.
EFV/TDF/FTC 600/200/300 mg Once Daily During double-blind phase, participants received EFV/TDF/FTC 600/200/300 mg OD, with placebo to match DTG 50 mg and ABC/3TC 600/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive EFV/TDF/FTC 600/200/300 mg OD for additional 48 weeks during open-label phase.

Measured Values
   DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily   EFV/TDF/FTC 600/200/300 mg Once Daily 
Participants Analyzed 
[Units: Participants]
 414   419 
Time to Viral Suppression (<50 c/mL) 
[Units: Days]
Median (95% Confidence Interval)
 28 
 (28.0 to 29.0) 
 84 
 (83.0 to 84.0) 

No statistical analysis provided for Time to Viral Suppression (<50 c/mL)



3.  Secondary:   Percentage of Participants With Plasma Human Immunodeficiency Virus -1 (HIV-1) Ribonucleic Acid (RNA) <50 Copies/Milliliter (c/mL) at Week 96 and Week 144   [ Time Frame: Week 96 and Week 144 ]

Measure Type Secondary
Measure Title Percentage of Participants With Plasma Human Immunodeficiency Virus -1 (HIV-1) Ribonucleic Acid (RNA) <50 Copies/Milliliter (c/mL) at Week 96 and Week 144
Measure Description The percentage of participants with plasma HIV-1 RNA <50 c/mL at Week 96 and Week 144 was assessed. Plasma samples were collected for the quantitative assessment of HIV-1 RNA based on the Missing, Switch, or Discontinuation equals Failure (MSDF) algorithm,as codified by the Food and Drug Administration's Snapshot algorithm. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (due to missing data or discontinuation of investigationl product prior to the visit window) as non-responders, as well as participants who switched their concomitant antiretroviral therapy (ART) in certain scenarios. Since changes in ART were not permitted in this protocol, all such participants who changed ART were to be considered non-responders. Otherwise, virologic success or failure was to be determined by the last available HIV-1 RNA assessment while the participant was on treatment within the visit of interest window.
Time Frame Week 96 and Week 144  
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 randomized participants who received at least one dose of study medication

Reporting Groups
  Description
DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily During double-blind phase, participants received a dolutegravir (DTG) 50 milligram (mg) tablet along with an Abacavir/Lamivudine (ABC/3TC) 600/300 mg tablet once daily (OD) orally, with placebo to match Efavirenz/Tenofovir disoproxil fumarate/Emtricitabine (EFV/TDF/FTC) 600/200/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive DTG 50 mg tablet along with ABC/3TC 600/300 mg tablet OD orally, for additional 48 weeks during open-label phase.
EFV/TDF/FTC 600/200/300 mg Once Daily During double-blind phase, participants received EFV/TDF/FTC 600/200/300 mg OD, with placebo to match DTG 50 mg and ABC/3TC 600/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive EFV/TDF/FTC 600/200/300 mg OD for additional 48 weeks during open-label phase.

Measured Values
   DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily   EFV/TDF/FTC 600/200/300 mg Once Daily 
Participants Analyzed 
[Units: Participants]
 414   419 
Percentage of Participants With Plasma Human Immunodeficiency Virus -1 (HIV-1) Ribonucleic Acid (RNA) <50 Copies/Milliliter (c/mL) at Week 96 and Week 144 
[Units: Percentage of participants]
   
Week 96   77   70 
Week 144   71   63 


Statistical Analysis 1 for Percentage of Participants With Plasma Human Immunodeficiency Virus -1 (HIV-1) Ribonucleic Acid (RNA) <50 Copies/Milliliter (c/mL) at Week 96 and Week 144
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Wilcoxon (Mann-Whitney)
P Value [4] 0.016
Difference in percentage [5] 7.1
95% Confidence Interval 1.2 to 13.1
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Non-inferiority could be concluded if the lower bound of a two-sided 95% confidence interval for the difference (DTG + ABC/3TC minus EFV/TDF/FTC) in percentages between the two treatment arms was > -10%.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value is for the test of superiority.
[5] Other relevant estimation information:
  Week 96:The estimated value reflects the percentage on DTG + ABC/3TC minus the percentage on EFV/TDF/FTC.

Statistical Analysis 2 for Percentage of Participants With Plasma Human Immunodeficiency Virus -1 (HIV-1) Ribonucleic Acid (RNA) <50 Copies/Milliliter (c/mL) at Week 96 and Week 144
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Wilcoxon (Mann-Whitney)
P Value [4] 0.010
Difference in percentage [5] 8.3
95% Confidence Interval 1.9 to 14.6
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Non-inferiority could be concluded if the lower bound of a two-sided 95% confidence interval for the difference (DTG + ABC/3TC minus EFV/TDF/FTC) in percentages between the two treatment arms was >-10%.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value is for the test of superiority.
[5] Other relevant estimation information:
  Week 144:Estimated value reflects the percentage on DTG + ABC/3TC minus the percentage on EFV/TDF/FTC.



4.  Secondary:   Number of Participants With a Confirmed Plasma HIV-1 RNA Level >=1000 c/mL at or After Week 16 and Before Week 24, or a Confirmed Plasma HIV-1 RNA Level >=200 c/mL at or After Week 24   [ Time Frame: From Baseline until Week 144) (average of 877.4 days for DTG; average of 788.8 study days for EFV/TDF/FTC) ]

Measure Type Secondary
Measure Title Number of Participants With a Confirmed Plasma HIV-1 RNA Level >=1000 c/mL at or After Week 16 and Before Week 24, or a Confirmed Plasma HIV-1 RNA Level >=200 c/mL at or After Week 24
Measure Description Data are presented as Kaplan Meier estimates of virologic failure (VF), defined as a confirmed plasma HIV-1 RNA level >=1000 c/mL at or after Week 16 and before Week 24, or a confirmed plasma HIV-1 RNA level >=200 c/mL at or after Week 24. A plasma HIV-1 RNA value was considered to be confirmed failure if a consecutive measurement satisfied the same failure criterion. The number of participants who experienced autoimmune deficiency syndrome (AIDS) Clinical Trials Group (ACTG) VFs was measured. For participants who withdrew from the study/were not documented to have reached confirmed VF at the cut off date of the Week 48 analysis, time to VF was to be censored at the planned visit week of the last measured plasma HIV-1 RNA sample. Data for participants who missed three consecutive scheduled plasma HIV-1 RNA measurements were to be censored at the planned visit week of the last assessment prior to the 3 consecutive missed visits.
Time Frame From Baseline until Week 144) (average of 877.4 days for DTG; average of 788.8 study days for EFV/TDF/FTC)  
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
DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily During double-blind phase, participants received a dolutegravir (DTG) 50 milligram (mg) tablet along with an Abacavir/Lamivudine (ABC/3TC) 600/300 mg tablet once daily (OD) orally, with placebo to match Efavirenz/Tenofovir disoproxil fumarate/Emtricitabine (EFV/TDF/FTC) 600/200/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive DTG 50 mg tablet along with ABC/3TC 600/300 mg tablet OD orally, for additional 48 weeks during open-label phase.
EFV/TDF/FTC 600/200/300 mg Once Daily During double-blind phase, participants received EFV/TDF/FTC 600/200/300 mg OD, with placebo to match DTG 50 mg and ABC/3TC 600/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive EFV/TDF/FTC 600/200/300 mg OD for additional 48 weeks during open-label phase.

Measured Values
   DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily   EFV/TDF/FTC 600/200/300 mg Once Daily 
Participants Analyzed 
[Units: Participants]
 414   419 
Number of Participants With a Confirmed Plasma HIV-1 RNA Level >=1000 c/mL at or After Week 16 and Before Week 24, or a Confirmed Plasma HIV-1 RNA Level >=200 c/mL at or After Week 24 
[Units: Participants]
   
ACTG virologic failures   11   8 
Censored participants   403   411 

No statistical analysis provided for Number of Participants With a Confirmed Plasma HIV-1 RNA Level >=1000 c/mL at or After Week 16 and Before Week 24, or a Confirmed Plasma HIV-1 RNA Level >=200 c/mL at or After Week 24



5.  Secondary:   Change From Baseline in Plasma HIV-1 RNA at Weeks 2, 4, 8, 12, 16, 24, 32, 40,48, 60, 72, 84, 96, 108, 120, 132 and 144   [ Time Frame: Baseline and at Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132 and 144 ]

Measure Type Secondary
Measure Title Change From Baseline in Plasma HIV-1 RNA at Weeks 2, 4, 8, 12, 16, 24, 32, 40,48, 60, 72, 84, 96, 108, 120, 132 and 144
Measure Description Blood samples were collected for the measurement of HIV-1 RNA in plasma. Changes from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants available at the indicated time points were assessed (represented by n=X, X in the category titles).
Time Frame Baseline and at Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132 and 144  
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
DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily During double-blind phase, participants received a dolutegravir (DTG) 50 milligram (mg) tablet along with an Abacavir/Lamivudine (ABC/3TC) 600/300 mg tablet once daily (OD) orally, with placebo to match Efavirenz/Tenofovir disoproxil fumarate/Emtricitabine (EFV/TDF/FTC) 600/200/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive DTG 50 mg tablet along with ABC/3TC 600/300 mg tablet OD orally, for additional 48 weeks during open-label phase.
EFV/TDF/FTC 600/200/300 mg Once Daily During double-blind phase, participants received EFV/TDF/FTC 600/200/300 mg OD, with placebo to match DTG 50 mg and ABC/3TC 600/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive EFV/TDF/FTC 600/200/300 mg OD for additional 48 weeks during open-label phase.

Measured Values
   DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily   EFV/TDF/FTC 600/200/300 mg Once Daily 
Participants Analyzed 
[Units: Participants]
 414   419 
Change From Baseline in Plasma HIV-1 RNA at Weeks 2, 4, 8, 12, 16, 24, 32, 40,48, 60, 72, 84, 96, 108, 120, 132 and 144 
[Units: Log10 copies/mL]
Mean (Standard Deviation)
   
Week 2, n=387, 376   -2.46  (0.49)   -1.96  (0.46) 
Week 4, n=404, 391   -2.88  (0.58)   -2.25  (0.52) 
Week 8, n=395, 386   -2.99  (0.64)   -2.60  (0.60) 
Week 12, n=394, 377   -3.01  (0.70)   -2.85  (0.63) 
Week 16, n=386, 366   -3.03  (0.66)   -2.98  (0.65) 
Week 24, n=389, 364   -3.05  (0.69)   -3.01  (0.76) 
Week 32, n=380, 355   -3.04  (0.70)   -3.05  (0.72) 
Week 40, n=370, 345   -3.05  (0.68)   -3.04  (0.70) 
Week 48, n=370, 343   -3.03  (0.69)   -3.04  (0.69) 
Week 60, n=360, 330   -3.03  (0.67)   -3.05  (0.69) 
Week 72, n=354, 320   -3.03  (0.70)   -3.06  (0.70) 
Week 84, n=353, 314   -3.02  (0.70)   -3.07  (0.68) 
Week 96, n=345, 310   -2.99  (0.73)   -3.06  (0.68) 
Week 108, n=340, 300   -3.01  (0.71)   -3.08  (0.67) 
Week 120, n=333, 289   -3.00  (0.77)   -3.07  (0.67) 
Week 132, n=323, 284   -3.03  (0.68)   -3.06  (0.67) 
Week 144, n=313,269   -3.02  (0.72)   -3.04  (0.69) 

No statistical analysis provided for Change From Baseline in Plasma HIV-1 RNA at Weeks 2, 4, 8, 12, 16, 24, 32, 40,48, 60, 72, 84, 96, 108, 120, 132 and 144



6.  Secondary:   Change From Baseline in CD4+ Cell Counts at Week 144   [ Time Frame: Baseline and Week 144 ]

Measure Type Secondary
Measure Title Change From Baseline in CD4+ Cell Counts at Week 144
Measure Description Cluster of differentiation (CD4) lymphocyte cells (also called T-cells or T-helper cells) are the primary targets of HIV. The CD4 count and the CD4 percentage mark the degree of immunocompromise. The CD4 count is used to stage the patient's disease, determine the risk of opportunistic illnesses, assess prognosis, and guide decisions about when to start antiretroviral therapy. Change from Baseline was calculated as the Week 144 value minus the Baseline value. The least squares mean is the estimated mean change from Baseline in CD4+ cell counts at Week 144 calculated from a repeated measures model including the following covariates: treatment, visit, Baseline plasma HIV-1 RNA, Baseline CD4+ cell count, treatment*visit interaction, Baseline HIV-1 RNA*visit interaction, and Baseline CD4+ cell count*visit interaction. No assumptions were made about the correlations between a participant's readings of CD4+, i.e., the correlation matrix for within-participant errors is unstructured.
Time Frame Baseline and Week 144  
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
DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily During double-blind phase, participants received a dolutegravir (DTG) 50 milligram (mg) tablet along with an Abacavir/Lamivudine (ABC/3TC) 600/300 mg tablet once daily (OD) orally, with placebo to match Efavirenz/Tenofovir disoproxil fumarate/Emtricitabine (EFV/TDF/FTC) 600/200/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive DTG 50 mg tablet along with ABC/3TC 600/300 mg tablet OD orally, for additional 48 weeks during open-label phase.
EFV/TDF/FTC 600/200/300 mg Once Daily During double-blind phase, participants received EFV/TDF/FTC 600/200/300 mg OD, with placebo to match DTG 50 mg and ABC/3TC 600/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive EFV/TDF/FTC 600/200/300 mg OD for additional 48 weeks during open-label phase.

Measured Values
   DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily   EFV/TDF/FTC 600/200/300 mg Once Daily 
Participants Analyzed 
[Units: Participants]
 414   419 
Change From Baseline in CD4+ Cell Counts at Week 144 
[Units: Cells per millimeters cubed (cells/mm^3)]
Least Squares Mean (Standard Deviation)
 378.48  (10.99)   331.57  (11.59) 


Statistical Analysis 1 for Change From Baseline in CD4+ Cell Counts at Week 144
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Repeated Measure Mixed Model
P Value [4] 0.003
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Adjusted mean is the estimated mean change from baseline (BL) in CD4 + Cell Count at Week 144 in each arm calculated from a repeated measures model including the following covariates: treatment, visit, BL plasma HIV-1 RNA, BL CD4 cell count, treatment*visit interaction, BL HIV-1 RNA*visit interaction and BL CD4 cell count*visit interaction. No assumptions were made about the correlations between a par.’s readings of CD4 i.e. the correlation matrix for within-subject errors is unstructured.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value is for the test of superiority.



7.  Secondary:   Change From Baseline in CD4+ Cell Counts at Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132 and 144   [ Time Frame: Baseline and Week 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132 and 144 ]

Measure Type Secondary
Measure Title Change From Baseline in CD4+ Cell Counts at Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132 and 144
Measure Description CD4 lymphocyte cells (also called T-cells or T-helper cells) are the primary targets of HIV. The CD4 count and the CD4 percentage mark the degree of immunocompromise. The CD4 count is used to stage the patient's disease, determine the risk of opportunistic illnesses, assess prognosis, and guide decisions about when to start antiretroviral therapy. Change from Baseline was calculated as the value at Indicated visit minus the Baseline value. Only those participants available at the indicated time points were assessed (represented by n=X, X in the category titles).
Time Frame Baseline and Week 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132 and 144  
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
DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily During double-blind phase, participants received a dolutegravir (DTG) 50 milligram (mg) tablet along with an Abacavir/Lamivudine (ABC/3TC) 600/300 mg tablet once daily (OD) orally, with placebo to match Efavirenz/Tenofovir disoproxil fumarate/Emtricitabine (EFV/TDF/FTC) 600/200/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive DTG 50 mg tablet along with ABC/3TC 600/300 mg tablet OD orally, for additional 48 weeks during open-label phase.
EFV/TDF/FTC 600/200/300 mg Once Daily During double-blind phase, participants received EFV/TDF/FTC 600/200/300 mg OD, with placebo to match DTG 50 mg and ABC/3TC 600/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive EFV/TDF/FTC 600/200/300 mg OD for additional 48 weeks during open-label phase.

Measured Values
   DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily   EFV/TDF/FTC 600/200/300 mg Once Daily 
Participants Analyzed 
[Units: Participants]
 414   419 
Change From Baseline in CD4+ Cell Counts at Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132 and 144 
[Units: Cells per millimeters cubed (cells/mm^3)]
Mean (Standard Deviation)
   
Week 4, n=404,390   117.6  (114.51)   80.9  (112.43) 
Week 8, n=396,382   164.6  (129.98)   124.4  (124.50) 
Week 12, n=394,378   187.5  (157.46)   153.0  (131.91) 
Week 16, n=386,366   214.7  (173.35)   174.1  (132.02) 
Week 24, n=388,361   216.9  (162.89)   177.8  (147.72) 
Week 32, n=380,353   250.5  (172.06)   208.1  (152.13) 
Week 40, n=364,347   265.5  (187.81)   216.2  (158.49) 
Week 48, n=368,344   267.5  (192.30)   209.5  (164.37) 
Week 60, n=359,330   271.3  (188.05)   235.3  (171.98) 
Week 72, n=354,319   306.1  (202.02)   269.6  (180.04) 
Week 84, n=352,314   315.2  (197.92)   272.1  (172.28) 
Week 96, n=343,309   322.6  (205.35)   286.0  (195.70) 
Week 108, n=339,300   349.3  (218.76)   298.9  (188.41) 
Week 120, n=332,287   347.0  (234.96)   311.0  (198.79) 
Week 132, n=323,283   377.9  (205.78)   327.2  (175.31) 
Week 144, n=313,270   379.5  (221.17)   333.3  (189.25) 

No statistical analysis provided for Change From Baseline in CD4+ Cell Counts at Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132 and 144



8.  Secondary:   Number of Participants With the Indicated Post-baseline HIV-associated Conditions and Progression, Excluding Recurrences at Week 144   [ Time Frame: From Baseline until Week 144 ]

Measure Type Secondary
Measure Title Number of Participants With the Indicated Post-baseline HIV-associated Conditions and Progression, Excluding Recurrences at Week 144
Measure Description Clinical disease progression (CDP) was assessed according to the Centers for Disease Control and Prevention (CDC) HIV-1 classification system. Category (CAT) A: one or more of the following conditions (CON), without any CON listed in Categories B and C: asymptomatic HIV infection, persistent generalized lymphadenopathy, acute (primary) HIV infection with accompanying illness or history of acute HIV infection. CAT B: symptomatic CON that are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or that are considered by physicians to have a clinical course or to require management that is complicated by HIV infection; and not included among CON listed in clinical CAT C. CAT C: the clinical CON listed in the AIDS surveillance case definition. Indicators of CDP were defined as: CDC CAT A at Baseline (BS) to a CDC CAT C event (EV); CDC CAT B at BS to a CDC CAT C EV; CDC CAT C at BS to a new CDC CAT C EV; or CDC CAT A, B, or C at BS to death.
Time Frame From Baseline until Week 144  
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
DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily During double-blind phase, participants received a dolutegravir (DTG) 50 milligram (mg) tablet along with an Abacavir/Lamivudine (ABC/3TC) 600/300 mg tablet once daily (OD) orally, with placebo to match Efavirenz/Tenofovir disoproxil fumarate/Emtricitabine (EFV/TDF/FTC) 600/200/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive DTG 50 mg tablet along with ABC/3TC 600/300 mg tablet OD orally, for additional 48 weeks during open-label phase.
EFV/TDF/FTC 600/200/300 mg Once Daily During double-blind phase, participants received EFV/TDF/FTC 600/200/300 mg OD, with placebo to match DTG 50 mg and ABC/3TC 600/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive EFV/TDF/FTC 600/200/300 mg OD for additional 48 weeks during open-label phase.

Measured Values
   DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily   EFV/TDF/FTC 600/200/300 mg Once Daily 
Participants Analyzed 
[Units: Participants]
 414   419 
Number of Participants With the Indicated Post-baseline HIV-associated Conditions and Progression, Excluding Recurrences at Week 144 
[Units: Participants]
   
Week 144, Any category condition   17   24 
Week 144, Any Category B condition   12   17 
Week 144, Any Category C condition   5   6 
Week 144, Any death   0   2 
Week 144, Progression from CAT A to CAT C   4   4 
Week 144, Progression from CAT C to new CAT C   1   2 
Week 144, Progression from CAT A, B, or C to death   0   2 

No statistical analysis provided for Number of Participants With the Indicated Post-baseline HIV-associated Conditions and Progression, Excluding Recurrences at Week 144



9.  Secondary:   Number of Participants With the Indicated Grade 1 to 4 Clinical and Hematology Toxicities at Week144   [ Time Frame: From Baseline until Week 144 ]

Measure Type Secondary
Measure Title Number of Participants With the Indicated Grade 1 to 4 Clinical and Hematology Toxicities at Week144
Measure Description All Grade 1 to 4 post-Baseline-emergent chemistry toxicities included alanine aminotransferase (ALT), albumin, alkaline phosphatase (ALP), asparate aminotransferase (AST), carbon dioxide (CO2) content/bicarbonate, cholesterol, creatine kinase (CK), creatinine, hyperglycemia, hyperkalemia, hypernatremia, hypoglycemia, hypokalemia, hyponatremia, low density lipoprotein (LDL) cholesterol calculation, lipase, phosphorus inorganic, total bilirubin, and triglycerides. All Grade 1 to 4 post-Baseline-emergent hematology toxities included hemoglobin, platelet count, total neutrophils, and white blood cell count. The Division of AIDS (DAIDS) defined toxicity grades as follows: Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, potentially life threatening; Grade 5, death.
Time Frame From Baseline until Week 144  
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 who received at least one dose of investigational product

Reporting Groups
  Description
DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily During double-blind phase, participants received a dolutegravir (DTG) 50 milligram (mg) tablet along with an Abacavir/Lamivudine (ABC/3TC) 600/300 mg tablet once daily (OD) orally, with placebo to match Efavirenz/Tenofovir disoproxil fumarate/Emtricitabine (EFV/TDF/FTC) 600/200/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive DTG 50 mg tablet along with ABC/3TC 600/300 mg tablet OD orally, for additional 48 weeks during open-label phase.
EFV/TDF/FTC 600/200/300 mg Once Daily During double-blind phase, participants received EFV/TDF/FTC 600/200/300 mg OD, with placebo to match DTG 50 mg and ABC/3TC 600/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive EFV/TDF/FTC 600/200/300 mg OD for additional 48 weeks during open-label phase.

Measured Values
   DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily   EFV/TDF/FTC 600/200/300 mg Once Daily 
Participants Analyzed 
[Units: Participants]
 414   419 
Number of Participants With the Indicated Grade 1 to 4 Clinical and Hematology Toxicities at Week144 
[Units: Participants]
   
Week 144, ALT   62   81 
Week 144, Albumin   0   1 
Week 144, ALP   17   53 
Week 144, AST   77   85 
Week 144, CO2 content/bicarbonate   135   134 
Week 144, Cholesterol   156   140 
Week 144, CK   91   79 
Week 144, Creatinine   17   6 
Week 144, Hyperglycaemia   121   105 
Week 144, Hyperkalemia   4   12 
Week 144, Hypernatremia   11   9 
Week 144, Hypoglycaemia   24   21 
Week 144, Hypokalemia   38   21 
Week 144, Hyponatremia   63   86 
Week 144, LDL cholesterol calculation   124   111 
Week 144, Lipase   111   110 
Week 144, Phosphorus, inorganic   109   134 
Week 144, Total bilirubin   22   4 
Week 144, Triglycerides   11   11 
Week 144, Hemoglobin   7   11 
Week 144, Platelet count   20   19 
Week 144, Total neutrophils   70   80 
Week 144, White Blood Cell count   9   18 

No statistical analysis provided for Number of Participants With the Indicated Grade 1 to 4 Clinical and Hematology Toxicities at Week144



10.  Secondary:   Number of Participants With the Indicated Genotypic Resistance With Virological Failure (VF) Through 144   [ Time Frame: Through Week 144 ]

Measure Type Secondary
Measure Title Number of Participants With the Indicated Genotypic Resistance With Virological Failure (VF) Through 144
Measure Description Whole blood samples were collected from participants to provide plasma for storage samples for potential viral genotypic and phenotypic analyses. Participants with confirmed virological failure (confirmed HIV-1 RNA >=50 copies/mL throughout the study and/or confirmed HIV-1 RNA >=200 copies/mL at Week 144) had plasma samples tested for HIV-1 RT genotype and HIV-1 integrase genotype from Baseline samples and from samples collected at the time of virological failure. Genotype testing was conducted at Day 1 and at the time of suspected protocol-defined virological failure (PDVF). A genotyping assessment was made of change across all amino acids within the integrase (IN)-encoding region, with particular attention paid to specific amino acid changes associated with the development of resistance to RAL, ELV, or DTG.
Time Frame Through Week 144  
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 Population: all participants in the ITT-E Population with available on-treatment genotypic resistance data at the time of PDVF

Reporting Groups
  Description
DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily During double-blind phase, participants received a dolutegravir (DTG) 50 milligram (mg) tablet along with an Abacavir/Lamivudine (ABC/3TC) 600/300 mg tablet once daily (OD) orally, with placebo to match Efavirenz/Tenofovir disoproxil fumarate/Emtricitabine (EFV/TDF/FTC) 600/200/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive DTG 50 mg tablet along with ABC/3TC 600/300 mg tablet OD orally, for additional 48 weeks during open-label phase.
EFV/TDF/FTC 600/200/300 mg Once Daily During double-blind phase, participants received EFV/TDF/FTC 600/200/300 mg OD, with placebo to match DTG 50 mg and ABC/3TC 600/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive EFV/TDF/FTC 600/200/300 mg OD for additional 48 weeks during open-label phase.

Measured Values
   DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily   EFV/TDF/FTC 600/200/300 mg Once Daily 
Participants Analyzed 
[Units: Participants]
 26   16 
Number of Participants With the Indicated Genotypic Resistance With Virological Failure (VF) Through 144 
[Units: Participants]
   
Week 144, RT mutation K65K/R   0   1 
Week 144, RT mutation K101E   0   1 
Week 144, RT mutation K103K/N   0   2 
Week 144, RT mutation K103N   0   2 
Week 144, RT mutation G190G/A   0   2 

No statistical analysis provided for Number of Participants With the Indicated Genotypic Resistance With Virological Failure (VF) Through 144



11.  Secondary:   Change From Baseline in the Symptom Bother Score (SBS) at Week 4 Through Week 48   [ Time Frame: Baseline and Week 4 through 48 ]

Measure Type Secondary
Measure Title Change From Baseline in the Symptom Bother Score (SBS) at Week 4 Through Week 48
Measure Description The Symptom Distress Module (SDM) is a 20-item, self-reported questionnaire measuring the presence/perceived distress linked to symptoms associated with HIV/its treatments. Developed with support from the AIDS Clinical Trials Group of the U.S. National Institute of Allergy and Infectious Diseases, it has demonstrated construct validity and has shown strong associations with physical/mental health summary scores and with disease severity. The SDM consists of 2 main scores: symptom count and the SBS, ranging from 0 (best) to 80 (worst) and based on the degree of bother that each symptom present posed. The SBS was calculated by adding the 20 individual bother item scores, which were calculated as: 0, “I do not have this symptom”; 1, "It doesn’t bother me”; 2, “It bothers me a little”; 3, “It bothers me”; 4, "It bothers me a lot." Estimates are calculated from an analysis of covariance (ANCOVA) model adjusting for age, sex, race, Baseline (BL) viral load, BL CD4+ cell count, and BL SBS.
Time Frame Baseline and Week 4 through 48  
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. Participants with missing bother item scores at Week 4 had their last observation carried forward (LOCF). Only those participants contributing to the model (i.e., without missing response variables after LOCF or covariates) were analyzed.

Reporting Groups
  Description
DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily During double-blind phase, participants received a dolutegravir (DTG) 50 milligram (mg) tablet along with an Abacavir/Lamivudine (ABC/3TC) 600/300 mg tablet once daily (OD) orally, with placebo to match Efavirenz/Tenofovir disoproxil fumarate/Emtricitabine (EFV/TDF/FTC) 600/200/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive DTG 50 mg tablet along with ABC/3TC 600/300 mg tablet OD orally, for additional 48 weeks during open-label phase.
EFV/TDF/FTC 600/200/300 mg Once Daily During double-blind phase, participants received EFV/TDF/FTC 600/200/300 mg OD, with placebo to match DTG 50 mg and ABC/3TC 600/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive EFV/TDF/FTC 600/200/300 mg OD for additional 48 weeks during open-label phase.

Measured Values
   DTG 50 mg Plus ABC/3TC 600/300 mg Once Daily   EFV/TDF/FTC 600/200/300 mg Once Daily 
Participants Analyzed 
[Units: Participants]
 394   393 
Change From Baseline in the Symptom Bother Score (SBS) at Week 4 Through Week 48 
[Units: Scores on a scale]
Least Squares Mean (Standard Error)
 -1.818  (0.3849)   -1.246  (0.3854) 

No statistical analysis provided for Change From Baseline in the Symptom Bother Score (SBS) at Week 4 Through Week 48




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

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
No text entered.


  More Information
  Hide More Information

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: GlaxoSmithKline
phone: 866-435-7343


Publications:
Brinson C, Walmsley S, Arasteh K, et al. Dolutegravir treatment response and safety by key subgroups in treatment naive HIV-infected individuals. Published at: Conference on Retroviruses and Opportunistic Infections - 20th Annual; March 3-6, 2013; Atlanta, GA.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: ViiV Healthcare
ClinicalTrials.gov Identifier: NCT01263015     History of Changes
Other Study ID Numbers: 114467
Study First Received: December 16, 2010
Results First Received: August 15, 2013
Last Updated: September 23, 2016
Health Authority: Spain: Agencia Espanola de Medicamentos y Productos Sanitarios
Italy: Comitato Etico Fondazione Centro San Raffaele del Monte Tabor - Via Olgettina, 60 - 20132 Milano
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Belgium: Federal Agency for Medicines and Health Products, FAMHP
United States: Food and Drug Administration
Hungary: Országos Gyógyszerészeti Intézet
South Africa: Medicines Control Council
Germany: Bundesinstitut für Arzneimittel und Medizinprodukte
Romania: National Medicines Agency
Denmark: Danish Medicines Agency
France: Agence Française de Sécurité Sanitaire des Produits de Santé
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Canada: Health Canada
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Australia: Therapeutic Goods Administration