Trial Outcomes & Findings for A Study of GSK1349572 Versus Raltegravir (RAL) With Investigator Selected Background Regimen in Antiretroviral-Experienced, Integrase Inhibitor-Naive Adults (NCT NCT01231516)

Last Updated: 2022-03-15

Results Overview

The percentage of participants with Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) \<50 c/mL at Week 48 was assessed using the Missing, Switch or Discontinuation = Failure (MSDF), as codified by the Food and Drug Administration (FDA) "snapshot" algorithm. This algorithm treated all participants without HIV-1 RNA at Week 48 as nonresponders, as well as participants who switched their concomitant ART prior to Week 48 as follows: background ART substitutions non-permitted per protocol (one background ART substitution was permitted for safety or tolerability); background ART substitutions permitted per protocol unless the decision to switch was documented as being before or at the first on-treatment visit where HIV-1 RNA was assessed. Otherwise, virologic success or failure was determined by the last available HIV-1 RNA assessment while the participant was on-treatment in the randomized phase of the study.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

724 participants

Primary outcome timeframe

At Week 48

Results posted on

2022-03-15

Participant Flow

This study was conducted to demonstrate non-inferior antiviral activity of dolutegravir (DTG) 50 milligram (mg) once daily versus raltegravir (RAL) 400 mg twice daily in participants with human immunodeficiency viruses (HIV)-1. Long-term antiviral activity, tolerability \& safety were also evaluated

1441 participants screened; 724 participants randomized, of which 5 participants did not receive study treatment. 719 participants received at least 1 dose of study medication creating the intent to treat exposed (ITT-E) Population.

Participant milestones

Participant milestones
Measure	DTG 50 mg OD Participants received dolutegravir (DTG) 50 milligrams (mg) once daily (OD) + matching Raltegravir (RAL) placebo twice daily (BID), one in the morning (AM dose) and one in the evening (PM dose) + investigator selected background antiretroviral (ART) therapy for 48 weeks. Participants who successfully completed 48 weeks of treatment continued to have access to DTG in the Open-Label phase of the study.	RAL 400 mg BID Participants received matching DTG placebo OD + RAL 400 mg BID as AM and PM doses + investigator selected background ART therapy for 48 weeks. Participants were discontinued from the study after completion of the Week 48 visit unless a participant successfully completed Week 48 and RAL was not approved and commercially available within the country, GlaxoSmithKline (GSK) continued to supply RAL in the Open-Label Phase until commercially available.
Double-blind Phase (Up to Week [Wk] 48) STARTED	360	364
Double-blind Phase (Up to Week [Wk] 48) ITT-E Population	357	362
Double-blind Phase (Up to Week [Wk] 48) Modified (m)ITT-E Population	354	361
Double-blind Phase (Up to Week [Wk] 48) COMPLETED	299	283
Double-blind Phase (Up to Week [Wk] 48) NOT COMPLETED	61	81
Open-label Phase:From Wk 48 up to Wk 480 STARTED	295	126
Open-label Phase:From Wk 48 up to Wk 480 COMPLETED	227	109
Open-label Phase:From Wk 48 up to Wk 480 NOT COMPLETED	68	17

Reasons for withdrawal

Reasons for withdrawal
Measure	DTG 50 mg OD Participants received dolutegravir (DTG) 50 milligrams (mg) once daily (OD) + matching Raltegravir (RAL) placebo twice daily (BID), one in the morning (AM dose) and one in the evening (PM dose) + investigator selected background antiretroviral (ART) therapy for 48 weeks. Participants who successfully completed 48 weeks of treatment continued to have access to DTG in the Open-Label phase of the study.	RAL 400 mg BID Participants received matching DTG placebo OD + RAL 400 mg BID as AM and PM doses + investigator selected background ART therapy for 48 weeks. Participants were discontinued from the study after completion of the Week 48 visit unless a participant successfully completed Week 48 and RAL was not approved and commercially available within the country, GlaxoSmithKline (GSK) continued to supply RAL in the Open-Label Phase until commercially available.
Double-blind Phase (Up to Week [Wk] 48) Adverse Event	4	11
Double-blind Phase (Up to Week [Wk] 48) Lack of Efficacy	20	42
Double-blind Phase (Up to Week [Wk] 48) Protocol Violation	9	6
Double-blind Phase (Up to Week [Wk] 48) Met Protocol-Defined Stopping Criteria	5	3
Double-blind Phase (Up to Week [Wk] 48) Lost to Follow-up	5	10
Double-blind Phase (Up to Week [Wk] 48) Physician Decision	1	1
Double-blind Phase (Up to Week [Wk] 48) Withdrawal by Subject	11	5
Double-blind Phase (Up to Week [Wk] 48) Site Closed	3	1
Double-blind Phase (Up to Week [Wk] 48) Randomized, but did not receive treatment	3	2
Open-label Phase:From Wk 48 up to Wk 480 Physician Decision	5	0
Open-label Phase:From Wk 48 up to Wk 480 Lack of Efficacy	27	11
Open-label Phase:From Wk 48 up to Wk 480 Protocol Violation	10	0
Open-label Phase:From Wk 48 up to Wk 480 Withdrawal by Subject	6	3
Open-label Phase:From Wk 48 up to Wk 480 Met protocol-defined stopping criteria	2	0
Open-label Phase:From Wk 48 up to Wk 480 Adverse Event	6	1
Open-label Phase:From Wk 48 up to Wk 480 Lost to Follow-up	12	2

Baseline Characteristics

A Study of GSK1349572 Versus Raltegravir (RAL) With Investigator Selected Background Regimen in Antiretroviral-Experienced, Integrase Inhibitor-Naive Adults

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	DTG 50 mg OD n=354 Participants Participants received dolutegravir (DTG) 50 milligrams (mg) once daily (OD) + matching Raltegravir (RAL) placebo twice daily (BID), one in the morning (AM dose) and one in the evening (PM dose) + investigator selected background antiretroviral (ART) therapy for 48 weeks. Participants who successfully completed 48 weeks of treatment continued to have access to DTG in the Open-Label phase of the study.	RAL 400 mg BID n=361 Participants Participants received matching DTG placebo OD + RAL 400 mg BID as AM and PM doses + investigator selected background ART therapy for 48 weeks. Participants were discontinued from the study after completion of the Week 48 visit unless a participant successfully completed Week 48 and RAL was not approved and commercially available within the country, GlaxoSmithKline (GSK) continued to supply RAL in the Open-Label Phase until commercially available.	Total n=715 Participants Total of all reporting groups
Age, Continuous	42.6 Years STANDARD_DEVIATION 10.45 • n=93 Participants	42.5 Years STANDARD_DEVIATION 9.81 • n=4 Participants	42.5 Years STANDARD_DEVIATION 10.13 • n=27 Participants
Sex: Female, Male Female	107 Participants n=93 Participants	123 Participants n=4 Participants	230 Participants n=27 Participants
Sex: Female, Male Male	247 Participants n=93 Participants	238 Participants n=4 Participants	485 Participants n=27 Participants
Race/Ethnicity, Customized African American/African Heritage	143 Participants n=93 Participants	160 Participants n=4 Participants	303 Participants n=27 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	10 Participants n=93 Participants	17 Participants n=4 Participants	27 Participants n=27 Participants
Race/Ethnicity, Customized Asian-Central/South Asian Heritage	2 Participants n=93 Participants	2 Participants n=4 Participants	4 Participants n=27 Participants
Race/Ethnicity, Customized Asian-East Asian Heritage	6 Participants n=93 Participants	4 Participants n=4 Participants	10 Participants n=27 Participants
Race/Ethnicity, Customized Asian-South East Asian Heritage	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants
Race/Ethnicity, Customized White-Arabic/North African Heritage	3 Participants n=93 Participants	3 Participants n=4 Participants	6 Participants n=27 Participants
Race/Ethnicity, Customized White-White/Caucasian/European Heritage	175 Participants n=93 Participants	172 Participants n=4 Participants	347 Participants n=27 Participants
Race/Ethnicity, Customized Mixed Race	12 Participants n=93 Participants	2 Participants n=4 Participants	14 Participants n=27 Participants
Race/Ethnicity, Customized Unknown	1 Participants n=93 Participants	1 Participants n=4 Participants	2 Participants n=27 Participants

PRIMARY outcome

Timeframe: At Week 48

Population: Modified Intent-To-Treat Exposed (mITT-E) Population: All randomized participants who received at least one dose of investigational product (IP) excluding four participants at one site, which was closed due to Good Clinical Practice (GCP) non-compliance issues in another ViiV sponsored trial.

Outcome measures

Outcome measures
Measure	DTG 50 mg OD n=354 Participants Participants received dolutegravir (DTG) 50 milligrams (mg) once daily (OD) + matching Raltegravir (RAL) placebo twice daily (BID), one in the morning (AM dose) and one in the evening (PM dose) + investigator selected background antiretroviral (ART) therapy for 48 weeks. Participants who successfully completed 48 weeks of treatment continued to have access to DTG in the Open-Label phase of the study.	RAL 400 mg BID n=361 Participants Participants received matching DTG placebo OD + RAL 400 mg BID as AM and PM doses + investigator selected background ART therapy for 48 weeks. Participants were discontinued from the study after completion of the Week 48 visit unless a participant successfully completed Week 48 and RAL was not approved and commercially available within the country, GlaxoSmithKline (GSK) continued to supply RAL in the Open-Label Phase until commercially available.
Percentage of Participants With HIV-1 Ribonucleic Acid (RNA) <50 Copies/Milliliter (c/mL) at Week 48	71 Percentage of participants	64 Percentage of participants

SECONDARY outcome

Timeframe: Baseline (Day 1) until PDVF (Up to Week 48)

Population: mITT-E Population

For par. meeting one of the criteria for PDVF, plasma samples collected at the time point of virologic failure and Baseline were tested to evaluate any potential genotypic and/or phenotypic evolution of resistance. PDVF was defined as (A) virologic non-response: a decrease in plasma HIV-1 RNA of \<1 logarithm to base 10 (log10) copies/mL by Week 16, with subsequent confirmation, unless plasma HIV-1 RNA is \<400 copies/ mL; confirmed plasma HIV-1 RNA levels \>=400 copies/mL on or after Week 24 or (B) virologic rebound: confirmed rebound in plasma HIV-1 RNA levels to \>=400 copies/mL after prior confirmed suppression to \<400 copies/mL; confirmed plasma HIV-1 RNA levels \>1 log10 copies/mL above the nadir value, where nadir is \>=400 copies/mL.Treatment-emergent IN mutations are those detected at the time of PDVF but not at Baseline.

Outcome measures

Outcome measures
Measure	DTG 50 mg OD n=354 Participants Participants received dolutegravir (DTG) 50 milligrams (mg) once daily (OD) + matching Raltegravir (RAL) placebo twice daily (BID), one in the morning (AM dose) and one in the evening (PM dose) + investigator selected background antiretroviral (ART) therapy for 48 weeks. Participants who successfully completed 48 weeks of treatment continued to have access to DTG in the Open-Label phase of the study.	RAL 400 mg BID n=361 Participants Participants received matching DTG placebo OD + RAL 400 mg BID as AM and PM doses + investigator selected background ART therapy for 48 weeks. Participants were discontinued from the study after completion of the Week 48 visit unless a participant successfully completed Week 48 and RAL was not approved and commercially available within the country, GlaxoSmithKline (GSK) continued to supply RAL in the Open-Label Phase until commercially available.
Number of Participants (Par.) With Detectable Virus That Has Genotypic or Phenotypic Evidence of Treatment-emergent Integrase Inhibitor (INI) Resistance at Time of Protocol Defined Virology Failure (PDVF)	4 Participants	17 Participants

SECONDARY outcome

Timeframe: At Week 24

Population: mITT-E Population

The number of participants with Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) \<50 c/mL at Week 24 was assessed using the Missing, Switch or Discontinuation = Failure (MSDF), as codified by the Food and Drug Administration (FDA) "snapshot" algorithm. This algorithm treated all participants without HIV-1 RNA at Week 24 as nonresponders, as well as participants who switched their concomitant ART prior to Week 24 as follows: background ART substitutions non-permitted per protocol (one background ART substitution was permitted for safety or tolerability); background ART substitutions permitted per protocol unless the decision to switch was documented as being before or at the first on-treatment visit where HIV-1 RNA was assessed. Otherwise, virologic success or failure was determined by the last available HIV-1 RNA measurement through Week 24 (within window) while the participant was on-treatment. The result below corresponds to the Week 24 interim analysis.

Outcome measures

Outcome measures
Measure	DTG 50 mg OD n=354 Participants Participants received dolutegravir (DTG) 50 milligrams (mg) once daily (OD) + matching Raltegravir (RAL) placebo twice daily (BID), one in the morning (AM dose) and one in the evening (PM dose) + investigator selected background antiretroviral (ART) therapy for 48 weeks. Participants who successfully completed 48 weeks of treatment continued to have access to DTG in the Open-Label phase of the study.	RAL 400 mg BID n=361 Participants Participants received matching DTG placebo OD + RAL 400 mg BID as AM and PM doses + investigator selected background ART therapy for 48 weeks. Participants were discontinued from the study after completion of the Week 48 visit unless a participant successfully completed Week 48 and RAL was not approved and commercially available within the country, GlaxoSmithKline (GSK) continued to supply RAL in the Open-Label Phase until commercially available.
Number of Participants With Plasma HIV-1 RNA <50 c/mL at Week 24	281 Participants	252 Participants

SECONDARY outcome

Timeframe: At Week 24 and Week 48

Population: mITT-E Population

The number of participants with Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) \<400 c/mL at the visit of interest was assessed using the Missing, Switch or Discontinuation = Failure (MSDF), as codified by the Food and Drug Administration (FDA) "snapshot" algorithm. This algorithm treated all participants without HIV-1 RNA at the visit of interest as nonresponders, as well as participants who switched their concomitant ART prior to the visit of interest as follows: background ART substitutions non-permitted per protocol (one background ART substitution was permitted for safety or tolerability); background ART substitutions permitted per protocol unless the decision to switch was documented as being before or at the first on-treatment visit where HIV-1 RNA was assessed. Otherwise, virologic success or failure was determined by the last available HIV-1 RNA measurment (within window) for the timepoint of interest while the participant was on-treatment.

Outcome measures

Outcome measures
Measure	DTG 50 mg OD n=354 Participants Participants received dolutegravir (DTG) 50 milligrams (mg) once daily (OD) + matching Raltegravir (RAL) placebo twice daily (BID), one in the morning (AM dose) and one in the evening (PM dose) + investigator selected background antiretroviral (ART) therapy for 48 weeks. Participants who successfully completed 48 weeks of treatment continued to have access to DTG in the Open-Label phase of the study.	RAL 400 mg BID n=361 Participants Participants received matching DTG placebo OD + RAL 400 mg BID as AM and PM doses + investigator selected background ART therapy for 48 weeks. Participants were discontinued from the study after completion of the Week 48 visit unless a participant successfully completed Week 48 and RAL was not approved and commercially available within the country, GlaxoSmithKline (GSK) continued to supply RAL in the Open-Label Phase until commercially available.
Number of Participants With Plasma HIV-1 RNA <400 c/mL at Week 24 and Week 48 Week 24	307 Participants	287 Participants
Number of Participants With Plasma HIV-1 RNA <400 c/mL at Week 24 and Week 48 Week 48	278 Participants	257 Participants

SECONDARY outcome

Timeframe: Baseline (Day 1) and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 96 and 144

Population: mITT-E Population. Only those participants with data available at the specified time points were analyzed (represented by "n=X" in the category titles).

Blood samples were collected at specified time points to assess CD4+ using flow cytometry. Median and interquartile range are presented. Baseline was the latest pre-dose assessment value (Day 1).

Outcome measures

Outcome measures
Measure	DTG 50 mg OD n=354 Participants Participants received dolutegravir (DTG) 50 milligrams (mg) once daily (OD) + matching Raltegravir (RAL) placebo twice daily (BID), one in the morning (AM dose) and one in the evening (PM dose) + investigator selected background antiretroviral (ART) therapy for 48 weeks. Participants who successfully completed 48 weeks of treatment continued to have access to DTG in the Open-Label phase of the study.	RAL 400 mg BID n=361 Participants Participants received matching DTG placebo OD + RAL 400 mg BID as AM and PM doses + investigator selected background ART therapy for 48 weeks. Participants were discontinued from the study after completion of the Week 48 visit unless a participant successfully completed Week 48 and RAL was not approved and commercially available within the country, GlaxoSmithKline (GSK) continued to supply RAL in the Open-Label Phase until commercially available.
Absolute Values of Cluster of Differentiation 4+ (CD4+) Cell Counts at Baseline (Day 1) and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 96 and 144 Week 8, n=338, 346	280.0 Cells per cubic millimeter Interval 179.0 to 423.0	268.0 Cells per cubic millimeter Interval 163.0 to 445.0
Absolute Values of Cluster of Differentiation 4+ (CD4+) Cell Counts at Baseline (Day 1) and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 96 and 144 Baseline (Day 1), n=354, 361	204.5 Cells per cubic millimeter Interval 88.0 to 368.0	193.0 Cells per cubic millimeter Interval 96.0 to 365.0
Absolute Values of Cluster of Differentiation 4+ (CD4+) Cell Counts at Baseline (Day 1) and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 96 and 144 Week 4, n=341, 351	266.0 Cells per cubic millimeter Interval 164.0 to 416.0	253.0 Cells per cubic millimeter Interval 153.0 to 425.0
Absolute Values of Cluster of Differentiation 4+ (CD4+) Cell Counts at Baseline (Day 1) and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 96 and 144 Week 12, n=335, 345	296.0 Cells per cubic millimeter Interval 188.0 to 451.0	289.0 Cells per cubic millimeter Interval 174.0 to 443.0
Absolute Values of Cluster of Differentiation 4+ (CD4+) Cell Counts at Baseline (Day 1) and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 96 and 144 Week 16, n=327, 338	299.0 Cells per cubic millimeter Interval 179.0 to 462.0	293.0 Cells per cubic millimeter Interval 186.0 to 460.0
Absolute Values of Cluster of Differentiation 4+ (CD4+) Cell Counts at Baseline (Day 1) and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 96 and 144 Week 24, n=326, 326	334.5 Cells per cubic millimeter Interval 201.0 to 488.0	326.5 Cells per cubic millimeter Interval 198.0 to 473.0
Absolute Values of Cluster of Differentiation 4+ (CD4+) Cell Counts at Baseline (Day 1) and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 96 and 144 Week 32, n=309, 309	332.0 Cells per cubic millimeter Interval 229.0 to 482.0	338.0 Cells per cubic millimeter Interval 215.0 to 484.0
Absolute Values of Cluster of Differentiation 4+ (CD4+) Cell Counts at Baseline (Day 1) and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 96 and 144 Week 40, n=299, 292	376.0 Cells per cubic millimeter Interval 239.0 to 523.0	349.0 Cells per cubic millimeter Interval 227.0 to 500.0
Absolute Values of Cluster of Differentiation 4+ (CD4+) Cell Counts at Baseline (Day 1) and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 96 and 144 Week 48, n=298, 286	387.0 Cells per cubic millimeter Interval 247.0 to 565.0	378.5 Cells per cubic millimeter Interval 247.0 to 521.0
Absolute Values of Cluster of Differentiation 4+ (CD4+) Cell Counts at Baseline (Day 1) and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 96 and 144 Week 96, n=260, 22	436.5 Cells per cubic millimeter Interval 300.0 to 616.0	484.5 Cells per cubic millimeter Interval 393.0 to 573.0
Absolute Values of Cluster of Differentiation 4+ (CD4+) Cell Counts at Baseline (Day 1) and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 96 and 144 Week 144, n=192, 18	500.0 Cells per cubic millimeter Interval 346.0 to 657.0	535.0 Cells per cubic millimeter Interval 371.0 to 579.0

SECONDARY outcome

Timeframe: Baseline (Day 1) and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 96 and 144

Population: mITT-E Population Only those participants with data available at the specified data points were assessed (represented by "n=X" in the category titles).

Blood samples were collected at specified time points to assess CD4+. It was evaluated by flow cytometry. Baseline was the latest pre-dose assessment value (Day 1). Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Median and interquartile range is presented.

Outcome measures

Outcome measures
Measure	DTG 50 mg OD n=354 Participants Participants received dolutegravir (DTG) 50 milligrams (mg) once daily (OD) + matching Raltegravir (RAL) placebo twice daily (BID), one in the morning (AM dose) and one in the evening (PM dose) + investigator selected background antiretroviral (ART) therapy for 48 weeks. Participants who successfully completed 48 weeks of treatment continued to have access to DTG in the Open-Label phase of the study.	RAL 400 mg BID n=361 Participants Participants received matching DTG placebo OD + RAL 400 mg BID as AM and PM doses + investigator selected background ART therapy for 48 weeks. Participants were discontinued from the study after completion of the Week 48 visit unless a participant successfully completed Week 48 and RAL was not approved and commercially available within the country, GlaxoSmithKline (GSK) continued to supply RAL in the Open-Label Phase until commercially available.
Change From Baseline in CD4+ Cell Counts at Weeks 4, 8, 12,16, 24, 32, 40, 48, 96 and 144 Week 4, n=341, 351	53.0 Cells per cubic millimeter Interval 0.0 to 109.0	45.0 Cells per cubic millimeter Interval 5.0 to 99.0
Change From Baseline in CD4+ Cell Counts at Weeks 4, 8, 12,16, 24, 32, 40, 48, 96 and 144 Week 8, n=338, 346	60.5 Cells per cubic millimeter Interval 15.0 to 117.0	59.0 Cells per cubic millimeter Interval 12.0 to 124.0
Change From Baseline in CD4+ Cell Counts at Weeks 4, 8, 12,16, 24, 32, 40, 48, 96 and 144 Week 12, n=335, 345	74.0 Cells per cubic millimeter Interval 25.0 to 135.0	75.0 Cells per cubic millimeter Interval 22.0 to 141.0
Change From Baseline in CD4+ Cell Counts at Weeks 4, 8, 12,16, 24, 32, 40, 48, 96 and 144 Week 16, n=327, 338	76.0 Cells per cubic millimeter Interval 20.0 to 156.0	79.5 Cells per cubic millimeter Interval 28.0 to 158.0
Change From Baseline in CD4+ Cell Counts at Weeks 4, 8, 12,16, 24, 32, 40, 48, 96 and 144 Week 24, n=326, 326	99.0 Cells per cubic millimeter Interval 34.0 to 184.0	93.0 Cells per cubic millimeter Interval 46.0 to 166.0
Change From Baseline in CD4+ Cell Counts at Weeks 4, 8, 12,16, 24, 32, 40, 48, 96 and 144 Week 32, n=309, 309	107.0 Cells per cubic millimeter Interval 49.0 to 188.0	116.0 Cells per cubic millimeter Interval 52.0 to 173.0
Change From Baseline in CD4+ Cell Counts at Weeks 4, 8, 12,16, 24, 32, 40, 48, 96 and 144 Week 40, n=299, 292	125.0 Cells per cubic millimeter Interval 57.0 to 212.0	117.5 Cells per cubic millimeter Interval 51.5 to 192.0
Change From Baseline in CD4+ Cell Counts at Weeks 4, 8, 12,16, 24, 32, 40, 48, 96 and 144 Week 48, n=298, 286	144.0 Cells per cubic millimeter Interval 73.0 to 239.0	137.0 Cells per cubic millimeter Interval 65.0 to 222.0
Change From Baseline in CD4+ Cell Counts at Weeks 4, 8, 12,16, 24, 32, 40, 48, 96 and 144 Week 96, n=260, 22	198.5 Cells per cubic millimeter Interval 92.5 to 299.5	270 Cells per cubic millimeter Interval 209.0 to 348.0
Change From Baseline in CD4+ Cell Counts at Weeks 4, 8, 12,16, 24, 32, 40, 48, 96 and 144 Week 144, n= 192, 18	243.0 Cells per cubic millimeter Interval 138.0 to 357.0	302.5 Cells per cubic millimeter Interval 154.0 to 390.0

SECONDARY outcome

Timeframe: Up to Week 480

Population: mITT-E Population

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 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 clinical course or to require management that is complicated by HIV infection; and not included among CON listed in clinical CAT C. CAT C:Clinical CON listed in acquired immunodeficiency syndrome (AIDS) surveillance case definition. Indicators of CDP defined as:CDC CAT A at Baseline (BS) to CDC CAT C event (EV); CDC CAT B at BS to CDC CAT C EV; CDC CAT C at BS to new CDC CAT C EV; or CDC CAT A, B, or C at BS to death.

Outcome measures

Outcome measures
Measure	DTG 50 mg OD n=354 Participants Participants received dolutegravir (DTG) 50 milligrams (mg) once daily (OD) + matching Raltegravir (RAL) placebo twice daily (BID), one in the morning (AM dose) and one in the evening (PM dose) + investigator selected background antiretroviral (ART) therapy for 48 weeks. Participants who successfully completed 48 weeks of treatment continued to have access to DTG in the Open-Label phase of the study.	RAL 400 mg BID n=361 Participants Participants received matching DTG placebo OD + RAL 400 mg BID as AM and PM doses + investigator selected background ART therapy for 48 weeks. Participants were discontinued from the study after completion of the Week 48 visit unless a participant successfully completed Week 48 and RAL was not approved and commercially available within the country, GlaxoSmithKline (GSK) continued to supply RAL in the Open-Label Phase until commercially available.
Number of Participants With Post-Baseline HIV-associated Conditions, Excluding Recurrences, and Disease Progressions Any CAT	32 Participants	25 Participants
Number of Participants With Post-Baseline HIV-associated Conditions, Excluding Recurrences, and Disease Progressions CAT B	16 Participants	14 Participants
Number of Participants With Post-Baseline HIV-associated Conditions, Excluding Recurrences, and Disease Progressions CAT C	12 Participants	8 Participants
Number of Participants With Post-Baseline HIV-associated Conditions, Excluding Recurrences, and Disease Progressions Death	6 Participants	4 Participants
Number of Participants With Post-Baseline HIV-associated Conditions, Excluding Recurrences, and Disease Progressions Progression from CAT A to CAT C	2 Participants	1 Participants
Number of Participants With Post-Baseline HIV-associated Conditions, Excluding Recurrences, and Disease Progressions Progression from CAT B to CAT C	0 Participants	1 Participants
Number of Participants With Post-Baseline HIV-associated Conditions, Excluding Recurrences, and Disease Progressions Progression from CAT C to New CAT C	9 Participants	5 Participants
Number of Participants With Post-Baseline HIV-associated Conditions, Excluding Recurrences, and Disease Progressions Progression from CAT A, B, or C to Death	6 Participants	4 Participants

SECONDARY outcome

Timeframe: From Baseline (Day 1) until Week 48, including participants with post-treatment events occurring after Week 48 for participants not entering the post-Week 48 Open-Label phase of the study

Population: Safety Population comprised of all participants who received at least one dose of IP (i.e., DTG or RAL)

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, 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. Higher the grade, more severe the symptoms.

Outcome measures

Outcome measures
Measure	DTG 50 mg OD n=357 Participants Participants received dolutegravir (DTG) 50 milligrams (mg) once daily (OD) + matching Raltegravir (RAL) placebo twice daily (BID), one in the morning (AM dose) and one in the evening (PM dose) + investigator selected background antiretroviral (ART) therapy for 48 weeks. Participants who successfully completed 48 weeks of treatment continued to have access to DTG in the Open-Label phase of the study.	RAL 400 mg BID n=362 Participants Participants received matching DTG placebo OD + RAL 400 mg BID as AM and PM doses + investigator selected background ART therapy for 48 weeks. Participants were discontinued from the study after completion of the Week 48 visit unless a participant successfully completed Week 48 and RAL was not approved and commercially available within the country, GlaxoSmithKline (GSK) continued to supply RAL in the Open-Label Phase until commercially available.
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities ALT	47 Participants	46 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Albumin	4 Participants	3 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities ALP	27 Participants	42 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities AST	49 Participants	52 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities CO2 content/bicarbonate	97 Participants	109 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Cholesterol	99 Participants	103 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities CK	28 Participants	29 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Creatinine	18 Participants	13 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hyperglycaemia	71 Participants	80 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hyperkalemia	7 Participants	6 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hypernatremia	5 Participants	7 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hypoglycaemia	21 Participants	14 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hypokalemia	37 Participants	41 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hyponatremia	76 Participants	79 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities LDL cholesterol calculation	68 Participants	82 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Lipase	63 Participants	68 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Total bilirubin	56 Participants	53 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Triglycerides	14 Participants	24 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hemoglobin	19 Participants	27 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Platelet count	36 Participants	32 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Total neutrophils	49 Participants	49 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities White Blood Cell count	19 Participants	29 Participants

SECONDARY outcome

Timeframe: From Week 48 to Week 480

Population: Safety Population. Only those participants who completed Week 48 and continued into open-label phase were included in this analysis.

Blood samples were collected for the analysis of clinical chemistry and hematology parameters: Alanine aminotransferase (ALT), albumin, alkaline phosphate (ALP), aspartate aminotransferase (AST), carbon dioxide (CO2) content/bicarbonate, cholesterol, creatine kinase (CK), creatinine, hyperglycemia, hyperkalemia, hypernatremia, hypoglycemia, hypokalemia, hypoonatremia, LDL cholesterol, lipase, total bilirubin, triglycerides, hemoglibin, neutrophils, platelets, white blood cells. Any abnormality in clinical chemistry and hematology parameters were evaluated according to the DAIDS toxicity scale From Grade 1 to 4: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) and Grade 4 (Potentially life-threatening).Higher the grade, more severe the symptoms.

Outcome measures

Outcome measures
Measure	DTG 50 mg OD n=295 Participants Participants received dolutegravir (DTG) 50 milligrams (mg) once daily (OD) + matching Raltegravir (RAL) placebo twice daily (BID), one in the morning (AM dose) and one in the evening (PM dose) + investigator selected background antiretroviral (ART) therapy for 48 weeks. Participants who successfully completed 48 weeks of treatment continued to have access to DTG in the Open-Label phase of the study.	RAL 400 mg BID n=126 Participants Participants received matching DTG placebo OD + RAL 400 mg BID as AM and PM doses + investigator selected background ART therapy for 48 weeks. Participants were discontinued from the study after completion of the Week 48 visit unless a participant successfully completed Week 48 and RAL was not approved and commercially available within the country, GlaxoSmithKline (GSK) continued to supply RAL in the Open-Label Phase until commercially available.
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Cholesterol, Grades 1 to 4	138 Participants	26 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Cholesterol, Grades 2 to 4	66 Participants	16 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Cholesterol, Grades 3 to 4	11 Participants	3 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities CK, Grades 1 to 4	35 Participants	4 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities CK, Grades 2 to 4	11 Participants	1 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities CK, Grades 3 to 4	2 Participants	1 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Creatinine, Grades 1 to 4	20 Participants	2 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Creatinine, Grades 2 to 4	8 Participants	2 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Creatinine, Grades 3 to 4	2 Participants	1 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hyperglycemia, Grades 1 to 4	94 Participants	10 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hyperglycemia, Grades 2 to 4	40 Participants	6 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hyperglycemia, Grades 3 to 4	7 Participants	1 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hyperkalemia, Grades 1 to 4	9 Participants	1 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hyperkalemia, Grades 2 to 4	4 Participants	1 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hyperkalemia, Grades 3 to 4	2 Participants	0 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hypernatremia, Grades 1 to 4	7 Participants	1 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hypernatremia, Grades 2 to 4	1 Participants	0 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hypernatremia, Grades 3 to 4	0 Participants	0 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hypoglycemia, Grades 1 to 4	22 Participants	4 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hypoglycemia, Grades 2 to 4	2 Participants	1 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hypoglycemia, Grades 3 to 4	0 Participants	0 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hypokalemia, Grades 1 to 4	29 Participants	13 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hypokalemia, Grades 2 to 4	1 Participants	1 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hypokalemia, Grades 3 to 4	0 Participants	0 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hyponatremia, Grades 1 to 4	55 Participants	15 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hyponatremia, Grades 2 to 4	2 Participants	0 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hyponatremia, Grades 3 to 4	0 Participants	0 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities LDL cholesterol, Grades 1 to 4	107 Participants	22 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities LDL cholesterol, Grades 2 to 4	46 Participants	10 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities LDL cholesterol, Grades 3 to 4	15 Participants	3 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Lipase, Grades 1 to 4	67 Participants	7 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Lipase, Grades 2 to 4	35 Participants	3 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Lipase, Grades 3 to 4	12 Participants	0 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Total bilirubin, Grades 1 to 4	52 Participants	11 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Total bilirubin, Grades 2 to 4	42 Participants	10 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Total bilirubin, Grades 3 to 4	18 Participants	6 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Triglycerides, Grades 1 to 4	23 Participants	2 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Triglycerides, Grades 2 to 4	23 Participants	2 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Triglycerides, Grades 3 to 4	11 Participants	1 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hemoglobin, Grades 1 to 4	11 Participants	6 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hemoglobin, Grades 2 to 4	6 Participants	0 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Hemoglobin, Grades 3 to 4	2 Participants	0 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Neutrophils, Grades 1 to 4	37 Participants	9 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Neutrophils, Grades 2 to 4	14 Participants	4 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Neutrophils, Grades 3 to 4	7 Participants	2 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Platelets, Grades 1 to 4	22 Participants	7 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Platelets, Grades 2 to 4	11 Participants	1 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Platelets, Grades 3 to 4	4 Participants	0 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities White Blood Cells, Grades 1 to 4	17 Participants	3 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities White Blood Cells, Grades 2 to 4	7 Participants	1 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities White Blood Cells, Grades 3 to 4	0 Participants	0 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities AST, Grades 2 to 4	14 Participants	0 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities ALT, Grades 1 to 4	36 Participants	9 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities ALT, Grades 2 to 4	11 Participants	3 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities ALT, Grades 3 to 4	4 Participants	0 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Albumin, Grades 1 to 4	3 Participants	0 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Albumin, Grades 2 to 4	3 Participants	0 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities Albumin, Grades 3 to 4	0 Participants	0 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities ALP, Grades 1 to 4	20 Participants	1 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities ALP, Grades 2 to 4	4 Participants	1 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities ALP, Grades 3 to 4	1 Participants	1 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities AST, Grades 1 to 4	36 Participants	8 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities AST, Grades 3 to 4	1 Participants	0 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities CO2 content/bicarbonate, Grades 1 to 4	100 Participants	21 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities CO2 content/bicarbonate, Grades 2 to 4	12 Participants	3 Participants
Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities CO2 content/bicarbonate, Grades 3 to 4	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Pre-dose and at 1 to 3 hours or 4 to 12 hours post-dose at Week 4; Pre-dose at Week 24; Pre-dose and 1 to 3 hours or 4 to 12 hours post-dose at Week 48

Population: PK Concentration Population comprised of all participants who received DTG, underwent sparse PK sampling during the study, and provided evaluable DTG plasma concentration data. Only those participants with data available at the specified data points were assessed (represented by "n=X" in the category titles).

Cmax, Cmin and C0\_avg were assessed by population pharmacokinetic (PK) modeling using sparse PK samples which were collected as follows: one pre-dose sample and one post-dose sample at 1 to 3 hours/4 to 12 hours at Week 4, one pre-dose sample at Week 24, and one pre-dose sample and one post-dose sample at 1 to 3 hours/4 to 12 hours at Week 48. Cmax, Cmin and C0\_avg were estimated and reported here.

Outcome measures

Outcome measures
Measure	DTG 50 mg OD n=342 Participants Participants received dolutegravir (DTG) 50 milligrams (mg) once daily (OD) + matching Raltegravir (RAL) placebo twice daily (BID), one in the morning (AM dose) and one in the evening (PM dose) + investigator selected background antiretroviral (ART) therapy for 48 weeks. Participants who successfully completed 48 weeks of treatment continued to have access to DTG in the Open-Label phase of the study.	RAL 400 mg BID Participants received matching DTG placebo OD + RAL 400 mg BID as AM and PM doses + investigator selected background ART therapy for 48 weeks. Participants were discontinued from the study after completion of the Week 48 visit unless a participant successfully completed Week 48 and RAL was not approved and commercially available within the country, GlaxoSmithKline (GSK) continued to supply RAL in the Open-Label Phase until commercially available.
DTG PK Parameters Including Maximum Plasma Drug Concentration (Cmax), Minimal Plasma Drug Concentration (Cmin), and Average Plasma Pre-dose Concentration (C0_avg) Cmax, n=340	3.21 microgram/milliliter (µg/mL) Geometric Coefficient of Variation 26.7	—
DTG PK Parameters Including Maximum Plasma Drug Concentration (Cmax), Minimal Plasma Drug Concentration (Cmin), and Average Plasma Pre-dose Concentration (C0_avg) C0_avg, n=342	0.926 microgram/milliliter (µg/mL) Geometric Coefficient of Variation 131	—
DTG PK Parameters Including Maximum Plasma Drug Concentration (Cmax), Minimal Plasma Drug Concentration (Cmin), and Average Plasma Pre-dose Concentration (C0_avg) Cmin, n=340	0.849 microgram/milliliter (µg/mL) Geometric Coefficient of Variation 76.5	—

SECONDARY outcome

Timeframe: Pre-dose at Weeks 4, 24 and 48

C0 was assessed by population PK modeling using sparse PK samples which were collected as follows: one pre-dose sample and one post-dose sample at 1 to 3 hours/4 to 12 hours at Week 4, one pre-dose sample at Week 24, and one pre-dose sample and one post-dose sample at 1 to 3 hours/4 to 12 hours at Week 48. DTG predose concentration (C0) at Week 4, Week 24, and Week 48 was estimated and reported here.

Outcome measures

Outcome measures
Measure	DTG 50 mg OD n=342 Participants Participants received dolutegravir (DTG) 50 milligrams (mg) once daily (OD) + matching Raltegravir (RAL) placebo twice daily (BID), one in the morning (AM dose) and one in the evening (PM dose) + investigator selected background antiretroviral (ART) therapy for 48 weeks. Participants who successfully completed 48 weeks of treatment continued to have access to DTG in the Open-Label phase of the study.	RAL 400 mg BID Participants received matching DTG placebo OD + RAL 400 mg BID as AM and PM doses + investigator selected background ART therapy for 48 weeks. Participants were discontinued from the study after completion of the Week 48 visit unless a participant successfully completed Week 48 and RAL was not approved and commercially available within the country, GlaxoSmithKline (GSK) continued to supply RAL in the Open-Label Phase until commercially available.
DTG PK Parameter Including Pre-dose Concentration (C0) Week 4, n=329	0.786 microgram/milliliter (µg/mL) Geometric Coefficient of Variation 143	—
DTG PK Parameter Including Pre-dose Concentration (C0) Week 24, n=298	0.940 microgram/milliliter (µg/mL) Geometric Coefficient of Variation 132	—
DTG PK Parameter Including Pre-dose Concentration (C0) Week 48, n=276	0.932 microgram/milliliter (µg/mL) Geometric Coefficient of Variation 152	—

SECONDARY outcome

Timeframe: Pre-dose and at 1 to 3 hours or 4 to 12 hours post-dose at Week 4; Pre-dose at Week 24; Pre-dose and 1 to 3 hours or 4 to 12 hours post-dose at Week 48

Population: PK Concentration Population: all participants who received DTG, underwent sparse PK sampling during the study, and provided evaluable DTG plasma concentration data. Only those participants available at the indicated time points were assessed.

AUC is defined as the area under the DTG concentration-time curve as a measure of drug exposure over time. AUC(0-tau) is defined as the area under the plasma concentration-time curve from time zero to time tau over a dosing interval at steady state, where tau is the length of the dosing interval of DTG. AUC was assessed by population pharmacokinetic (PK) modeling using sparse PK samples which were collected as follows: one pre-dose sample and one post-dose sample at 1 to 3 hours/4 to 12 hours at Week 4, one pre-dose sample at Week 24, and one pre-dose sample and one post-dose sample at 1 to 3 hours/4 to 12 hours at Week 48.

Outcome measures

Outcome measures
Measure	DTG 50 mg OD n=340 Participants Participants received dolutegravir (DTG) 50 milligrams (mg) once daily (OD) + matching Raltegravir (RAL) placebo twice daily (BID), one in the morning (AM dose) and one in the evening (PM dose) + investigator selected background antiretroviral (ART) therapy for 48 weeks. Participants who successfully completed 48 weeks of treatment continued to have access to DTG in the Open-Label phase of the study.	RAL 400 mg BID Participants received matching DTG placebo OD + RAL 400 mg BID as AM and PM doses + investigator selected background ART therapy for 48 weeks. Participants were discontinued from the study after completion of the Week 48 visit unless a participant successfully completed Week 48 and RAL was not approved and commercially available within the country, GlaxoSmithKline (GSK) continued to supply RAL in the Open-Label Phase until commercially available.
DTG PK Parameters Including Area Under the Plasma Concentration-time Curve From Time Zero to Time Tau Over a Dosing Interval at Steady State (AUC[0-tau])	44.7 Microgramshour/milliliter (µghr/mL) Geometric Coefficient of Variation 40.5	—

SECONDARY outcome

Timeframe: Baseline (Day 1) and at Weeks 24 and 48

Population: mITT-E Population. Only those participants with data available at the specified data points were assessed (represented by "n=X" in the category titles).

The EQ-5D-3L questionnaire provides a profile of participant function and a global health state rating. The five-item measure has one question assessing each of five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression and 3 levels for each dimension including 1=no problems, 2=some problems, 3=extreme problems. The health state is defined by combining the levels of answers from each of the 5 questions. Each health state is referred to in terms of a 5 digit code. Health state 5 digit code is translated into utility score, which is valued up to 1 (perfect health) with lower values meaning worse state. EQ-5D-3L utility score ranges from -0.594 to 1. Higher scores indicate better health. Baseline was the latest pre-dose assessment value (Day 1) and change from Baseline=post-dose value minus Baseline value.

Outcome measures

Outcome measures
Measure	DTG 50 mg OD n=354 Participants Participants received dolutegravir (DTG) 50 milligrams (mg) once daily (OD) + matching Raltegravir (RAL) placebo twice daily (BID), one in the morning (AM dose) and one in the evening (PM dose) + investigator selected background antiretroviral (ART) therapy for 48 weeks. Participants who successfully completed 48 weeks of treatment continued to have access to DTG in the Open-Label phase of the study.	RAL 400 mg BID n=361 Participants Participants received matching DTG placebo OD + RAL 400 mg BID as AM and PM doses + investigator selected background ART therapy for 48 weeks. Participants were discontinued from the study after completion of the Week 48 visit unless a participant successfully completed Week 48 and RAL was not approved and commercially available within the country, GlaxoSmithKline (GSK) continued to supply RAL in the Open-Label Phase until commercially available.
Change From Baseline in European Quality of Life-5 Dimensions-3 Levels (EQ-5D-3L) Utility Score Week 24, n=350, 356	0.010 Scores on a scale Standard Deviation 0.202	0.019 Scores on a scale Standard Deviation 0.204
Change From Baseline in European Quality of Life-5 Dimensions-3 Levels (EQ-5D-3L) Utility Score Week 48, n=350, 356	0.028 Scores on a scale Standard Deviation 0.179	0.013 Scores on a scale Standard Deviation 0.222

SECONDARY outcome

Timeframe: Baseline (Day 1) and at Weeks 24 and 48

Population: mITT-E Population. Only those participants with data available at the specified data points were assessed (represented by "n=X" in the category titles).

The EQ-5D-3L questionnaire provides a profile of participant function and a global health state rating. The five-item measure has one question assessing each of five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression and 3 levels for each dimension including 1=no problems, 2=some problems, 3=extreme problems. EQ-5D-3L included EQ visual Analogue scale (EQ VAS) 'Thermometer' which provided Self-rated current health status. Participants were asked to rate their current health status using the visual analogue scale 'Thermometer'. Score ranged from 0 (worst imaginable health state) to 100 (best imaginable health state). Higher scores indicate better heath. Baseline was the latest pre-dose assessment value (Day 1) and change from Baseline=post-dose value minus Baseline value.

Outcome measures

Outcome measures
Measure	DTG 50 mg OD n=354 Participants Participants received dolutegravir (DTG) 50 milligrams (mg) once daily (OD) + matching Raltegravir (RAL) placebo twice daily (BID), one in the morning (AM dose) and one in the evening (PM dose) + investigator selected background antiretroviral (ART) therapy for 48 weeks. Participants who successfully completed 48 weeks of treatment continued to have access to DTG in the Open-Label phase of the study.	RAL 400 mg BID n=361 Participants Participants received matching DTG placebo OD + RAL 400 mg BID as AM and PM doses + investigator selected background ART therapy for 48 weeks. Participants were discontinued from the study after completion of the Week 48 visit unless a participant successfully completed Week 48 and RAL was not approved and commercially available within the country, GlaxoSmithKline (GSK) continued to supply RAL in the Open-Label Phase until commercially available.
Change From Baseline in European Quality of Life-5 Dimensions-3 Levels (EQ-5D-3L) Thermometer Scores Week 24, n=350, 355	6.800 Scores on a scale Standard Deviation 21.413	4.645 Scores on a scale Standard Deviation 18.279
Change From Baseline in European Quality of Life-5 Dimensions-3 Levels (EQ-5D-3L) Thermometer Scores Week 48, n=350, 355	8.894 Scores on a scale Standard Deviation 20.356	5.597 Scores on a scale Standard Deviation 18.821

OTHER_PRE_SPECIFIED outcome

Timeframe: At Weeks 4, 8, 12, 16, 24, 32, 40, and 48

Population: mITT-E Population. This was an other pre-specified outcome measure. The results for this outcome measure will never be posted.

The absolute value data for CD8+ cell count was planned to be evaluated. The results for this outcome measure will never be posted.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Day 1); Weeks 4, 8, 12, 16, 24, 32, 40, and 48

Population: mITT-E Population. This was an other pre-specified outcome measure. The results for this outcome measure will never be posted.

Change from Baseline data for CD8+ cell count was planned to be evaluated. The results for this outcome measure will never be posted.

Outcome measures

Outcome data not reported

Adverse Events

DTG~50mg QD

Serious events: 73 serious events

Other events: 250 other events

Deaths: 6 deaths

RAL~400mg BID

Serious events: 46 serious events

Other events: 206 other events

Deaths: 4 deaths

Serious adverse events

Other adverse events

Additional Information

GSK Response Center

ViiV Healthcare

Phone: 866-435-7343

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Measure	DTG~50mg QD n=357 participants at risk Participants received dolutegravir (DTG) 50 milligrams (mg) once daily (OD) + matching Raltegravir (RAL) placebo twice daily (BID), one in the morning (AM dose) and one in the evening (PM dose) + investigator selected background antiretroviral (ART) therapy for 48 weeks. Participants who successfully completed 48 weeks of treatment continued to have access to DTG in the Open-Label phase of the study.	RAL~400mg BID n=362 participants at risk Participants received matching DTG placebo OD + RAL 400 mg BID as AM and PM doses + investigator selected background ART therapy for 48 weeks. Participants were discontinued from the study after completion of the Week 48 visit unless a participant successfully completed Week 48 and RAL was not approved and commercially available within the country, GSK continued to supply RAL in the Open-Label Phase until it was commercially available.
Gastrointestinal disorders Diarrhoea	25.8% 92/357 • Number of events 134 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.	17.7% 64/362 • Number of events 86 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.
Infections and infestations Upper respiratory tract infection	20.2% 72/357 • Number of events 168 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.	10.2% 37/362 • Number of events 82 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.
Nervous system disorders Headache	12.0% 43/357 • Number of events 57 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.	9.9% 36/362 • Number of events 41 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.
Gastrointestinal disorders Nausea	9.8% 35/357 • Number of events 41 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.	8.6% 31/362 • Number of events 38 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.
Respiratory, thoracic and mediastinal disorders Cough	12.9% 46/357 • Number of events 61 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.	7.2% 26/362 • Number of events 31 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.
Infections and infestations Influenza	11.8% 42/357 • Number of events 69 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.	9.4% 34/362 • Number of events 50 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.
Infections and infestations Nasopharyngitis	12.0% 43/357 • Number of events 67 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.	6.1% 22/362 • Number of events 23 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.
Infections and infestations Urinary tract infection	9.8% 35/357 • Number of events 43 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.	5.5% 20/362 • Number of events 24 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.
Gastrointestinal disorders Vomiting	7.6% 27/357 • Number of events 32 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.	5.5% 20/362 • Number of events 30 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.
General disorders Fatigue	5.3% 19/357 • Number of events 21 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.	7.2% 26/362 • Number of events 29 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.
Skin and subcutaneous tissue disorders Rash	8.4% 30/357 • Number of events 34 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.	5.8% 21/362 • Number of events 21 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.
Infections and infestations Sinusitis	8.7% 31/357 • Number of events 41 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.	4.7% 17/362 • Number of events 20 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.
Infections and infestations Bronchitis	7.6% 27/357 • Number of events 45 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.	4.1% 15/362 • Number of events 18 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.
Infections and infestations Gastroenteritis	5.9% 21/357 • Number of events 22 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.	1.9% 7/362 • Number of events 9 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.
Gastrointestinal disorders Abdominal pain	5.9% 21/357 • Number of events 24 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.	2.2% 8/362 • Number of events 8 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.
Gastrointestinal disorders Abdominal pain upper	6.4% 23/357 • Number of events 25 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.	1.4% 5/362 • Number of events 5 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.
Musculoskeletal and connective tissue disorders Arthralgia	9.5% 34/357 • Number of events 38 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.	7.5% 27/362 • Number of events 29 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.
Musculoskeletal and connective tissue disorders Back pain	8.4% 30/357 • Number of events 37 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.	4.4% 16/362 • Number of events 17 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.
Musculoskeletal and connective tissue disorders Pain in extremity	6.4% 23/357 • Number of events 25 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.	5.5% 20/362 • Number of events 24 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.
Nervous system disorders Dizziness	5.6% 20/357 • Number of events 21 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.	3.6% 13/362 • Number of events 13 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.
Vascular disorders Hypertension	10.9% 39/357 • Number of events 43 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.	4.1% 15/362 • Number of events 16 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.
Psychiatric disorders Depression	5.0% 18/357 • Number of events 19 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.	1.9% 7/362 • Number of events 7 • Serious adverse events (SAEs), non-serious AEs and all-cause mortality were collected from the start of study medication to the end of the study (up to Week 480) SAEs, non-serious AEs and all-cause mortality were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.