VIKING-3: A Study to Assess Dolutegravir in HIV-infected Subjects With Treatment Failure on an Integrase Inhibitor Containing Regimen.

• Sponsor: ViiV Healthcare (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01328041
• Collaborator: Shionogi (Industry), GlaxoSmithKline (Industry)
• Enrollment: 183
• Locations: 89
• Arm: 1
• Duration (Months): 48
• Patients Per Site: 2.1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this trial is to assess the antiviral activity and safety of a dolutegravir (DTG) containing regimen in HIV-1 infected, antiretroviral therapy (ART)-experienced adults with current or historical failure on an integrase inhibitor (INI) containing regimen. The study will assess DTG 50mg twice daily administered initially with the current failing ART regimen but then with an optimised background ART regimen (OBR) after Day 7. The first analyses will be conducted after the last subject enrolled has completed 24 weeks. Subjects may remain on study after Week 24.

Condition or Disease	Intervention/Treatment	Phase
Infection, Human Immunodeficiency Virus	Drug: dolutegravir	Phase 3

Detailed Description

ING112574 is a Phase 3, multicentre, open-label, single arm study to assess the antiviral activity and safety of DTG containing regimen in HIV-1 infected ART-experienced adults with historical or current evidence of resistance to RAL or ELV. Initially, a minimum of 100 subjects will be enrolled to receive DTG 50mg twice daily with the current failing regimen for 7 days but with OBR from Day 8. Subjects must also have documented genotypic and/or phenotypic resistance to at least one compound in two or more of the other approved classes of ART but must also be able to include at least one fully active drug in the OBR to be started Day 8. The first data cut will take place after the (approximate) 100th subject enrolled completes the Week 24 visit. Enrollment will continue until a further 50 to 100 subjects have been recruited. All subjects who successfully complete 24 weeks of treatment will continue to have access to DTG until it is locally available as long as they continue to derive clinical benefit.

ViiV Healthcare is the sponsor of this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 183 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Study to Demonstrate the Antiviral Activity and Safety of Dolutegravir in HIV-1 Infected Adult Subjects With Treatment Failure on an Integrase Inhibitor Containing Regimen.
• Study Start Date: May 1, 2011
• Actual Primary Completion Date: May 1, 2012
• Actual Study Completion Date: May 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: dolutegravir dolutegravir plus background antiretroviral therapy optimised at Day 8	Drug: dolutegravir; 50 mg twice daily

Outcome Measures

Primary Outcome Measures

1. Mean Change From Baseline in Plasma HIV-1 RNA at Day 8 [Baseline and Day 8]

   Mean change from Baseline in Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) at Day 8 was calculated as the Day 8 value minus the Baseline value. The last observation was carried forward if a participant had missed the Day 8 visit. The Baseline observation was carried forward if a participant had discontinued the treatment before Day 8. Blood samples for assessment of HIV-1 RNA levels were collected at Baseline and Day 8.

2. Number of Participants With HIV-1 RNA Less Than 50 Copies/mL at Week 24 [Week 24]

   The number of participants who had viral load <50 copies/mL at Week 24 based on the Food and Drug Administration's Snapshot algorithm was assessed. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (VOI [due to missing data/discontinuation of investigational product prior to the visit window]) as nonresponders, as well as participants who switched their concomitant antiretroviral (ART) prior to the VOI as follows: background ART substitutions not permitted per protocol; background ART substitutions permitted per protocol, however the decision to switch was not documented as being before or at the first on-treatment visit after switching to optimized background regimen (i.e., Week 4) where HIV-1 RNA was assessed. Otherwise, virologic success/failure was to be determined by the last available HIV-1 RNA assessment while the participant was on treatment within the VOI analysis window.

3. Number of Participants With HIV-1 RNA Less Than 50 Copies/mL at Week 48 [Week 48]

   The number of participants who had viral load <50 copies/mL at Week 48 based on the Food and Drug Administration's Snapshot algorithm was assessed. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (VOI [due to missing data/discontinuation of investigational product prior to the visit window]) as nonresponders, as well as participants who switched their concomitant antiretroviral (ART) prior to the VOI as follows: background ART substitutions not permitted per protocol; background ART substitutions permitted per protocol, however the decision to switch was not documented as being before or at the first on-treatment visit after switching to optimized background regimen (i.e., Week 4) where HIV-1 RNA was assessed. Otherwise, virologic success/failure was to be determined by the last available HIV-1 RNA assessment while the participant was on treatment within the VOI analysis window.

4. Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE) [From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)]

   An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury.

5. Number of Participants With Adverse Events of the Indicated Severity, Per the Division of Acquired Immune Deficiency Syndrome (DAIDS) Grading Scale [From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)]

   An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. AE/SAE severity was graded according to the DAIDS grading scale. The DAIDS displays events as Grades 1-4 based on this general guideline: Grade (G) 1, mild; G2, moderate; G3, severe; G4, potentially life threatening.

6. Number of Participants With the Maximum Post-Baseline-emergent Clinical Chemistry Toxicities of the Indicated Grade [From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)]

   The severity of clinical chemistry toxicities was graded according to the DAIDS toxicity scale. The DAIDS displays events as Grades 1-5 based on this general guideline: Grade (G) 1, mild; G2, moderate; G3, severe; G4, life threatening; G5, death related to toxicity.

7. Number of Participants With the Maximum Post-Baseline-emergent Hematology Toxicities of the Indicated Grade [From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)]

   The severity of hematology toxicities was graded according to the DAIDS. The DAIDS displays events as Grades 1-5 based on this general guideline: Grade (G) 1, mild; G2, moderate; G3, severe; G4, life threatening; G5, death related to toxicity.

Secondary Outcome Measures

1. Number of Participants With Plasma HIV-1 RNA Less Than 400 and 50 Copies/mL at Baseline; Day 8; and Weeks 4, 8, 12, 16, 24, 32, 40, and 48 [Baseline; Day 8; and Weeks 4, 8, 12, 16, 24, 32, 40, and 48]

   The number of participants with plasma HIV-1 RNA less than 400 and 50 copies (c)/mL at Baseline; Day 8; and Weeks 4, 8, 12, 16, 24, 32, 40 and 48 based on the Food and Drug Administration's Snapshot algorithm was assessed. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (VOI [due to missing data/discontinuation of investigational product prior to the visit window]) as nonresponders, as well as participants who switched their concomitant antiretroviral (ART) prior to the VOI as follows: background ART substitutions not permitted per protocol; background ART substitutions permitted per protocol, however the decision to switch was not documented as being before or at the first on-treatment visit after switching to optimized background regimen (i.e., Week 4) where HIV-1 RNA was assessed. Otherwise, virologic success/failure was to be determined by the last available HIV-1 RNA assessment while the par. was on treatment within the VOI analysis window

2. Number of Participants With Plasma HIV-1 RNA Less Than 400 and 50 Copies/mL From Week 48 Every 12 Weeks up to Study Completion [From Week 48 every 12 weeks up to study completion.]

   The number of participants with plasma HIV-1 RNA less than 400 and 50 copies (c)/mL was assessed at Weeks 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 and 180 using data of observed cases. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).

3. Mean Change From Baseline in Plasma HIV-1 RNA at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and From Week 48 Every 12 Weeks up to Study Completion [Baseline; Day 8; Weeks 4, 8, 12, 16, 24, 32, 40, and From Week 48 Every 12 Weeks up to Study completion (Up to Week 180)]

   Mean change from Baseline in plasma HIV-1 RNA was assesseed at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, 48 , 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, and 180 using data of the observed cases. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

4. Absolute Values for CD4+ Cell Counts at Baseline, Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and 48 and for CD8+ Cell Counts at Baseline and Weeks 4, 12, 24, and 48 [Baseline, Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and 48]

   Absolute values for CD4+ cell counts were assessed at Baseline, Day 8 and Weeks 4, 8, 12, 16, and 24, and absolute values for CD8+ cell counts were assessed at Baseline and Weeks 4, 12, 24, and 48.

5. Median Change From Baseline in CD4+ Cell Counts at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and From Week 48 Every 12 Weeks Until Study Completion [Baseline; Day 8; Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 and 180. v]

   Median change from Baseline in CD4+ cell counts was assessed at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, and 180. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

6. Ratio of CD4+/CD8+ Cell Count at Baseline and Weeks 4, 12, 24, and 48 [Baseline; Weeks 4, 12, 24, and 48]

   The ratio of CD4+/CD8+ cell count (measured in cells/mm^3) was assessed at Baseline and at Weeks 4, 12, 24, and 48. The ratio was calculated as the CD4+ cell count divided by CD8+ cell count.

7. Number of Participants With HIV-1 Disease Progression (Acquired Immune Deficiency Syndrome [AIDS] or Death) [From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)]

   The number of participants with HIV-1 disease progression (AIDS or death) was assessed per the Centers for Disease Control and Prevention (CDC) 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. The CDC classifies HIV infection as Category A (participants with asymptomatic HIV infection, acute HIV infection with accompanying illness, or persistent generalized lymphadenopathy), Category B (participants with symptomatic non-AIDS condition, i.e., conditions that are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection), and Category C (includes AIDS indicator conditions as defined by diagnostic or presumptive measures).

8. Cmax and Ctau of DTG [Day 8, Week 4, and Week 24]

   The maximum plasma concentration (Cmax) and the concentration at the end of a dosing interval (Ctau) of DTG were assessed by a population pharmacokinetic (PK) modeling approach using pooled DTG PK data from multiple studies. For this study, blood samples for pharmacokinetic assessments were collected pre-dose on Day 8 and at Weeks 4 and 24, at 1-3 hours post-dose on Day 8, and at 1-3 hours or 4-12 hours post-dose at Weeks 4 and 24.

9. AUC(0-tau) and AUC(0-24) of DTG [Day 8, Week 4, and Week 24]

   The area under the time concentration curve over the dosing interval (AUC[0-tau]) and from 0 to 24 hours (AUC[0-24]) of DTG was assessed by a population PK modeling approach using pooled DTG PK data from multiple studies. For this study, blood samples for pharmacokinetic assessments were collected pre-dose on Day 8 and at Weeks 4 and 24, at 1-3 hours post-dose on Day 8, and at 1-3 hours or 4-12 hours post-dose at Weeks 4 and 24.

10. C0 Assessment of DTG [Day 8, Week 4, and Week 24]

    The plasma DTG concentration immediately prior to dosing at steady state (C0) was assessed at Day 8, Week 4, and Week 24. Blood samples for pharmacokinetic assessments were collected pre-dose and 1-3 hours post-dose on Day 8 and at Week 4 and 4-12 hours post-dose at Week 24. Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the Pharmacokinetic Parameter Population.

11. Number of Participants With the Indicated Treatment-emergent Integrase (IN) Mutations Detected at the Time of Protocol-defined Virologic Failure (PDVF) as a Measure of Genotypic Resistance [From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)]

    An analysis of changes at specific amino acids in the IN coding region associated with resistance to raltegravir, elvitegravir, or DTG was performed at Day 1 and at the time of PDVF. PDVF is a <0.5 log10 copies(c)/mL decrease in plasma HIV-1 RNA at Day 8 unless the absolute value is <400 c/mL. PDVF after Day 8 is defined as virological non-respones (decrease in plasma HIV-1 RNA of <1 log10 c/mL by Week 16, with subsequent confirmation, unless plasma HIV-1 RNA <400 c/mL and confirmed plasma HIV-1 RNA levels >=400 c/mL on or after Week 24) and virological rebound (confirmed rebound in plasma HIV-1 RNA levels to >=400 c/mL after prior confirmed suppression to <400 c/mL and confirmed plasma HIV-1 RNA levels >1 log10 c/mL above the nadir value [nadir: >=400 c/mL]).

12. Number of Participants With the Indicated Fold Increase in DTG FC (Fold Change in IC50 Relative to Wild-type Virus) Between Baseline and the Time of PDVF, as a Measure of Post-Baseline Phenotypic Resistance [From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)]

    The FC in IC50 (50% inhibitory concentration) for DTG relative to wild-type virus was determined for virus isolated at Baseline and at the time of PDVF. The number of participants with the indicated change (ratio) in the two values at the time of PDVF is presented. PDVF is defined as a <0.5 log10 copies/mL decrease in plasma HIV-1 RNA at Day 8 unless the absolute value is <400 copies/mL. PDVF after Day 8 was defined for virological non-response (decrease in plasma HIV-1 RNA of less than 1 log10 copies/mL by Week 16, with subsequent confirmation, unless plasma HIV-1 RNA <400 copies/mL and confirmed plasma HIV-1 RNA levels >=400 copies/mL on or after Week 24) and virological rebound (confirmed rebound in plasma HIV-1 RNA levels to >=400 copies/mL after prior confirmed suppression to <400 copies/mL and confirmed plasma HIV-1 RNA levels >1 log10 copies/mL above the nadir value, where nadir is >=400 copies/mL).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Screening plasma HIV-1 RNA ≥500 copies/mL

• ART-experienced, INI-experienced, DTG naïve

• Experienced virological failure on raltegravir (RAL) or elvitegravir (ELV) regimen

• The subject's HIV-1 shows resistance to RAL or ELV at Screening or at prior time point of virological failure on RAL or ELV

• Documented resistance to at least one drug from each of three or more of all approved classes of ART

• Be able to receive at least one fully active drug as part of the OBR from Day 8

• Women capable of becoming pregnant must use appropriate contraception during the study (as defined by the protocol)

• Willing and able to understand and provide signed and dated written informed consent prior to Screening.

Exclusion Criteria:

• Women who are pregnant or breast feeding

• An active AIDS-defining condition at Screening (except cutaneous Kaposi's sarcoma not requiring systemic therapy or CD4+ <200c/mm3)

• Moderate to severe hepatic impairment as defined by Child-Pugh classification

• Anticipated need for HCV therapy during the first 24 weeks of the study

• Recent history of any upper or lower gastrointestinal bleed, with the exception of anal or rectal bleeding

• Allergy or intolerance to the study drugs or their components or drugs of their class

• Malignancy within the past 6 months

• Treatment with an HIV-1 therapeutic vaccine within 90 days of Screening

• Treatment with radiation therapy, cytotoxic chemotherapeutic agents or any immunomodulator within 28 days of Screening

• Treatment with any agent, other than licensed ART, with documented activity against HIV-1 in vitro within 28 days of first dose of investigational product

• Treatment with etravirine, efavirenz, or nevirapine within 14 days of Day 1(etravirine may be used if coadministered with lopinivir/ritonavir or darunavir/ritonavir)

• Treatment with tipranivir/ritonavir, fosamprenavir, or fosamprenavir/ritonavir within 28 days prior to Screening

• Verified Grade 4 laboratory abnormality at Screening

• ALT> 5 times the upper limit of normal (ULN) at Screening

• ALT ≥ 3X ULN and bilirubin > 1.5 X ULN (with 35% direct bilirubin) at Screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Beverly Hills	California	United States	90211
2	GSK Investigational Site	Fountain Valley	California	United States	92708
3	GSK Investigational Site	Los Angeles	California	United States	90033
4	GSK Investigational Site	Los Angeles	California	United States	90069
5	GSK Investigational Site	San Diego	California	United States	92103-8208
6	GSK Investigational Site	San Francisco	California	United States	94109
7	GSK Investigational Site	New Haven	Connecticut	United States	06510
8	GSK Investigational Site	Norwalk	Connecticut	United States	06850
9	GSK Investigational Site	Washington	District of Columbia	United States	20007
10	GSK Investigational Site	Washington	District of Columbia	United States	20009
11	GSK Investigational Site	Fort Lauderdale	Florida	United States	33316
12	GSK Investigational Site	Fort Pierce	Florida	United States	34982
13	GSK Investigational Site	Miami Beach	Florida	United States	33139
14	GSK Investigational Site	Orlando	Florida	United States	32804
15	GSK Investigational Site	Atlanta	Georgia	United States	30308
16	GSK Investigational Site	Augusta	Georgia	United States	30912
17	GSK Investigational Site	Lafayette	Louisiana	United States	70506
18	GSK Investigational Site	Boston	Massachusetts	United States	02115
19	GSK Investigational Site	Jackson	Mississippi	United States	39216-4505
20	GSK Investigational Site	Las Vegas	Nevada	United States	89106
21	GSK Investigational Site	Newark	New Jersey	United States	07103
22	GSK Investigational Site	Albany	New York	United States	12209
23	GSK Investigational Site	Bronx	New York	United States	10461
24	GSK Investigational Site	Bronx	New York	United States	10467
25	GSK Investigational Site	Buffalo	New York	United States	14215
26	GSK Investigational Site	New York	New York	United States	10011
27	GSK Investigational Site	New York	New York	United States	10016
28	GSK Investigational Site	Valhalla	New York	United States	10595
29	GSK Investigational Site	Chapel Hill	North Carolina	United States	27599
30	GSK Investigational Site	Durham	North Carolina	United States	27710
31	GSK Investigational Site	Toledo	Ohio	United States	43614
32	GSK Investigational Site	Portland	Oregon	United States	97210
33	GSK Investigational Site	Philadelphia	Pennsylvania	United States	19104
34	GSK Investigational Site	Philadelphia	Pennsylvania	United States	19107
35	GSK Investigational Site	Providence	Rhode Island	United States	02906
36	GSK Investigational Site	Austin	Texas	United States	78705
37	GSK Investigational Site	Dallas	Texas	United States	75204
38	GSK Investigational Site	Dallas	Texas	United States	75246
39	GSK Investigational Site	Houston	Texas	United States	77004
40	GSK Investigational Site	Houston	Texas	United States	77098
41	GSK Investigational Site	Annandale	Virginia	United States	22003
42	GSK Investigational Site	Seattle	Washington	United States	98104
43	GSK Investigational Site	Bruxelles		Belgium	1000
44	GSK Investigational Site	Liege		Belgium	4000
45	GSK Investigational Site	Vancouver	British Columbia	Canada	V6Z 1Y6
46	GSK Investigational Site	Vancouver	British Columbia	Canada	V6Z 2C7
47	GSK Investigational Site	Hamilton	Ontario	Canada	L8N 3Z5
48	GSK Investigational Site	Toronto	Ontario	Canada	M4N 3M5
49	GSK Investigational Site	Toronto	Ontario	Canada	M4T 3A7
50	GSK Investigational Site	Toronto	Ontario	Canada	M5B 1L6
51	GSK Investigational Site	Montreal	Quebec	Canada	H2L 4P9
52	GSK Investigational Site	Montreal	Quebec	Canada	H2L 5B1
53	GSK Investigational Site	Montreal	Quebec	Canada	H2W 1T8
54	GSK Investigational Site	Montreal	Quebec	Canada	H2X 2P4
55	GSK Investigational Site	Montreal	Quebec	Canada	H3G 1A4
56	GSK Investigational Site	Aulnay-sous-Bois		France	93602
57	GSK Investigational Site	Bobigny		France	93009
58	GSK Investigational Site	Bordeaux		France	33000
59	GSK Investigational Site	Garches		France	92380
60	GSK Investigational Site	Gonesse cedex		France	95503
61	GSK Investigational Site	Marseille		France	13003
62	GSK Investigational Site	Marseille		France	13009
63	GSK Investigational Site	Nice		France	06202
64	GSK Investigational Site	Orléans Cedex 2		France	45067
65	GSK Investigational Site	Paris Cedex 10		France	75475
66	GSK Investigational Site	Paris Cedex 13		France	75651
67	GSK Investigational Site	Paris cedex 14		France	75679
68	GSK Investigational Site	Paris cedex 15		France	75743
69	GSK Investigational Site	Paris Cedex 20		France	75970
70	GSK Investigational Site	Paris		France	75018
71	GSK Investigational Site	Genova	Liguria	Italy	16138
72	GSK Investigational Site	Bergamo	Lombardia	Italy	24127
73	GSK Investigational Site	Milano	Lombardia	Italy	20127
74	GSK Investigational Site	Torino	Piemonte	Italy	10149
75	GSK Investigational Site	Bagno a Ripoli (FI)	Toscana	Italy	50011
76	GSK Investigational Site	Firenze	Toscana	Italy	50134
77	GSK Investigational Site	Amadora		Portugal
78	GSK Investigational Site	Coimbra		Portugal	3030
79	GSK Investigational Site	Lisboa		Portugal	1150
80	GSK Investigational Site	Lisboa		Portugal	1349-019
81	GSK Investigational Site	Lisboa		Portugal	1649-035
82	GSK Investigational Site	Alicante		Spain	03010
83	GSK Investigational Site	Badalona		Spain	08916
84	GSK Investigational Site	Barcelona		Spain	08036
85	GSK Investigational Site	La Coruña		Spain	15006
86	GSK Investigational Site	Madrid		Spain	28029
87	GSK Investigational Site	Madrid		Spain	28034
88	GSK Investigational Site	Madrid		Spain	28046
89	GSK Investigational Site	Sevilla		Spain	41013

Sponsors and Collaborators

• ViiV Healthcare
• Shionogi
• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, ViiV Healthcare

Study Documents (Full-Text)

None provided.

More Information

Publications

• Eron JJ, Clotet B, Durant J, Katlama C, Kumar P, Lazzarin A, Poizot-Martin I, Richmond G, Soriano V, Ait-Khaled M, Fujiwara T, Huang J, Min S, Vavro C, Yeo J; VIKING Study Group. Safety and efficacy of dolutegravir in treatment-experienced subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING Study. J Infect Dis. 2013 Mar 1;207(5):740-8. doi: 10.1093/infdis/jis750. Epub 2012 Dec 7.

• Responsible Party: ViiV Healthcare
• ClinicalTrials.gov Identifier: NCT01328041
• Other Study ID Numbers: 112574
• First Posted: Apr 4, 2011
• Last Update Posted: Jan 7, 2016
• Last Verified: Dec 1, 2015

• Keywords provided by ViiV Healthcare: GSK1349572; resistance to raltegravir or elvitegravir; Integrase inhibitor; ART-experienced; dolutegravir
• Additional relevant MeSH terms: Acquired Immunodeficiency Syndrome; HIV Infections; Dolutegravir

Study Results

Participant Flow

Recruitment Details	Participants (par.) having documented Human immunodeficiency virus type 1 (HIV-1) infection with a plasma HIV-1 Ribonucleic acid(RNA) >=500 copies per milliliter (c/mL) at Screening, Antiretroviral therapy (ART)-experienced and on stable ART for at least one month prior to Screening were enrolled
Pre-assignment Detail	A total of 139 par. were screen failures and 183 par. entered the single arm, open-label study.

Arm/Group Title	Dolutegravir 50 mg BID
Arm/Group Description	Participants received dolutegravir (DTG) 50 milligrams (mg) twice a day (BID).
Period Title: Overall Study
STARTED	183
COMPLETED	126
NOT COMPLETED	57

Baseline Characteristics

Arm/Group Title	Dolutegravir 50 mg BID
Arm/Group Description	Participants received DTG 50 mg BID.
Overall Participants	183
Age (Years) [Median (Full Range) ]
Median (Full Range) [Years]	48
Sex: Female, Male (Count of Participants)
Female	42 23%
Male	141 77%
Race/Ethnicity, Customized (participants) [Number]
African American/African Heritage	49 26.8%
American Indian or Alaska Native and White	1 0.5%
Asian-Central/South Asian Heritage	1 0.5%
White	130 71%
White and African American/African Heritage	2 1.1%

Outcome Measures

1. Primary Outcome

Title	Mean Change From Baseline in Plasma HIV-1 RNA at Day 8
Description	Mean change from Baseline in Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) at Day 8 was calculated as the Day 8 value minus the Baseline value. The last observation was carried forward if a participant had missed the Day 8 visit. The Baseline observation was carried forward if a participant had discontinued the treatment before Day 8. Blood samples for assessment of HIV-1 RNA levels were collected at Baseline and Day 8.
Time Frame	Baseline and Day 8

Outcome Measure Data

Analysis Population Description

Intent-to-Treat-Exposed (ITT-E) Population: all participants who received at least one dose of study drug. Only participants who had Day 8 observations were considered for analysis.

Arm/Group Title	Dolutegravir 50 mg BID
Arm/Group Description	Participants received DTG 50 mg BID.
Measure Participants	182
Mean (Standard Deviation) [log10 copies/milliliter (mL)]	-1.432 (0.6070)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dolutegravir 50 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The P value was derived by the null hypothesis testing of no change from Baseline in HIV-1 RNA at Day 8 at the two-sided 5% significance level using a single sample t-test.
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	T distribution
	Estimated Value	-1.432
	Confidence Interval	(2-Sided) 95%; -1.520 to -1.343
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Number of Participants With HIV-1 RNA Less Than 50 Copies/mL at Week 24
Description	The number of participants who had viral load <50 copies/mL at Week 24 based on the Food and Drug Administration's Snapshot algorithm was assessed. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (VOI [due to missing data/discontinuation of investigational product prior to the visit window]) as nonresponders, as well as participants who switched their concomitant antiretroviral (ART) prior to the VOI as follows: background ART substitutions not permitted per protocol; background ART substitutions permitted per protocol, however the decision to switch was not documented as being before or at the first on-treatment visit after switching to optimized background regimen (i.e., Week 4) where HIV-1 RNA was assessed. Otherwise, virologic success/failure was to be determined by the last available HIV-1 RNA assessment while the participant was on treatment within the VOI analysis window.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

ITT-E Population

Arm/Group Title	Dolutegravir 50 mg BID
Arm/Group Description	Participants received DTG 50 mg BID.
Measure Participants	183
Number [participants]	126 68.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dolutegravir 50 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	percentage of participants
	Estimated Value	69
	Confidence Interval	(2-Sided) 95%; 62 to 76
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimated value represents the percentage of participants with HIV-1 RNA less than 50 copies/mL at Week 24.

3. Primary Outcome

Title	Number of Participants With HIV-1 RNA Less Than 50 Copies/mL at Week 48
Description	The number of participants who had viral load <50 copies/mL at Week 48 based on the Food and Drug Administration's Snapshot algorithm was assessed. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (VOI [due to missing data/discontinuation of investigational product prior to the visit window]) as nonresponders, as well as participants who switched their concomitant antiretroviral (ART) prior to the VOI as follows: background ART substitutions not permitted per protocol; background ART substitutions permitted per protocol, however the decision to switch was not documented as being before or at the first on-treatment visit after switching to optimized background regimen (i.e., Week 4) where HIV-1 RNA was assessed. Otherwise, virologic success/failure was to be determined by the last available HIV-1 RNA assessment while the participant was on treatment within the VOI analysis window.
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

ITT-E Population

Arm/Group Title	Dolutegravir 50 mg BID
Arm/Group Description	Participants received DTG 50 mg BID.
Measure Participants	183
Number [participants]	116 63.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dolutegravir 50 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	percentage of participants
	Estimated Value	63
	Confidence Interval	(2-Sided) 95%; 56 to 70
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimated value represents the percentage of participants with HIV-1 RNA less than 50 copies/mL at Week 48.

4. Primary Outcome

Title	Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE)
Description	An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury.
Time Frame	From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)

Outcome Measure Data

Analysis Population Description

Safety Population: all participants who received at least one dose of study drug

Arm/Group Title	Dolutegravir 50 mg BID
Arm/Group Description	Participants received DTG 50 mg BID.
Measure Participants	183
Any AE	169 92.3%
Any SAE	46 25.1%

5. Primary Outcome

Title	Number of Participants With Adverse Events of the Indicated Severity, Per the Division of Acquired Immune Deficiency Syndrome (DAIDS) Grading Scale
Description	An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. AE/SAE severity was graded according to the DAIDS grading scale. The DAIDS displays events as Grades 1-4 based on this general guideline: Grade (G) 1, mild; G2, moderate; G3, severe; G4, potentially life threatening.
Time Frame	From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Dolutegravir 50 mg BID
Arm/Group Description	Participants received DTG 50 mg BID.
Measure Participants	183
Grade 1	45 24.6%
Grade 2	64 35%
Grade 3	44 24%
Grade 4	16 8.7%

6. Primary Outcome

Title	Number of Participants With the Maximum Post-Baseline-emergent Clinical Chemistry Toxicities of the Indicated Grade
Description	The severity of clinical chemistry toxicities was graded according to the DAIDS toxicity scale. The DAIDS displays events as Grades 1-5 based on this general guideline: Grade (G) 1, mild; G2, moderate; G3, severe; G4, life threatening; G5, death related to toxicity.
Time Frame	From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Dolutegravir 50 mg BID
Arm/Group Description	Participants received DTG 50 mg BID.
Measure Participants	183
Grade 1	49 26.8%
Grade 2	67 36.6%
Grade 3	43 23.5%
Grade 4	16 8.7%

7. Primary Outcome

Title	Number of Participants With the Maximum Post-Baseline-emergent Hematology Toxicities of the Indicated Grade
Description	The severity of hematology toxicities was graded according to the DAIDS. The DAIDS displays events as Grades 1-5 based on this general guideline: Grade (G) 1, mild; G2, moderate; G3, severe; G4, life threatening; G5, death related to toxicity.
Time Frame	From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Dolutegravir 50 mg BID
Arm/Group Description	Participants received DTG 50 mg BID.
Measure Participants	183
Grade 1	31 16.9%
Grade 2	15 8.2%
Grade 3	4 2.2%
Grade 4	2 1.1%

8. Secondary Outcome

Title	Number of Participants With Plasma HIV-1 RNA Less Than 400 and 50 Copies/mL at Baseline; Day 8; and Weeks 4, 8, 12, 16, 24, 32, 40, and 48
Description	The number of participants with plasma HIV-1 RNA less than 400 and 50 copies (c)/mL at Baseline; Day 8; and Weeks 4, 8, 12, 16, 24, 32, 40 and 48 based on the Food and Drug Administration's Snapshot algorithm was assessed. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (VOI [due to missing data/discontinuation of investigational product prior to the visit window]) as nonresponders, as well as participants who switched their concomitant antiretroviral (ART) prior to the VOI as follows: background ART substitutions not permitted per protocol; background ART substitutions permitted per protocol, however the decision to switch was not documented as being before or at the first on-treatment visit after switching to optimized background regimen (i.e., Week 4) where HIV-1 RNA was assessed. Otherwise, virologic success/failure was to be determined by the last available HIV-1 RNA assessment while the par. was on treatment within the VOI analysis window
Time Frame	Baseline; Day 8; and Weeks 4, 8, 12, 16, 24, 32, 40, and 48

Outcome Measure Data

Analysis Population Description

ITT-E Population

Arm/Group Title	Dolutegravir 50 mg BID
Arm/Group Description	Participants received DTG 50 mg BID.
Measure Participants	183
HIV-1 RNA <50 c/mL, Baseline	1 0.5%
HIV-1 RNA <50 c/mL, Day 8	28 15.3%
HIV-1 RNA <50 c/mL, Week 4	98 53.6%
HIV-1 RNA <50 c/mL, Week 8	112 61.2%
HIV-1 RNA <50 c/mL, Week 12	116 63.4%
HIV-1 RNA <50 c/mL, Week 16	116 63.4%
HIV-1 RNA <50 c/mL, Week 24	126 68.9%
HIV-1 RNA <50 c/mL, Week 32	117 63.9%
HIV-1 RNA <50 c/mL, Week 40	108 59%
HIV-1 RNA <50 c/mL, Week 48	116 63.4%
HIV-1 RNA <400 c/mL, Baseline	8 4.4%
HIV-1 RNA <400 c/mL, Day 8	82 44.8%
HIV-1 RNA <400 c/mL, Week 4	145 79.2%
HIV-1 RNA <400 c/mL, Week 8	146 79.8%
HIV-1 RNA <400 c/mL, Week 12	142 77.6%
HIV-1 RNA <400 c/mL, Week 16	139 76%
HIV-1 RNA <400 c/mL, Week 24	135 73.8%
HIV-1 RNA <400 c/mL, Week 32	127 69.4%
HIV-1 RNA <400 c/mL, Week 40	119 65%
HIV-1 RNA <400 c/mL, Week 48	125 68.3%

9. Secondary Outcome

Title	Number of Participants With Plasma HIV-1 RNA Less Than 400 and 50 Copies/mL From Week 48 Every 12 Weeks up to Study Completion
Description	The number of participants with plasma HIV-1 RNA less than 400 and 50 copies (c)/mL was assessed at Weeks 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 and 180 using data of observed cases. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).
Time Frame	From Week 48 every 12 weeks up to study completion.

Outcome Measure Data

Analysis Population Description

ITT-E Population

Arm/Group Title	Dolutegravir 50 mg BID
Arm/Group Description	Participants received DTG 50 mg BID.
Measure Participants	183
HIV-1 RNA <50 c/mL, Week 48, n =146	121 66.1%
HIV-1 RNA <50 c/mL, Week 60, n=142	110 60.1%
HIV-1 RNA <50 c/mL, Week 72, n=138	116 63.4%
HIV-1 RNA <50 c/mL, Week 84, n=138	108 59%
HIV-1 RNA <50 c/mL, Week 96, n=120	101 55.2%
HIV-1 RNA <50 c/mL, Week 108, n=98	81 44.3%
HIV-1 RNA <50 c/mL, Week 120, n=82	72 39.3%
HIV-1 RNA <50 c/mL, Week 132, n=61	49 26.8%
HIV-1 RNA <50 c/mL, Week 144, n=45	37 20.2%
HIV-1 RNA <50 c/mL, Week 156, n=32	28 15.3%
HIV-1 RNA <50 c/mL, Week 168, n=24	20 10.9%
HIV-1 RNA <50 c/mL, Week 180, n=6	4 2.2%
HIV-1 RNA <400 c/mL, Week 48, n=146	134 73.2%
HIV-1 RNA <400 c/mL, Week 60, n=142	131 71.6%
HIV-1 RNA <400 c/mL, Week 72, n=138	130 71%
HIV-1 RNA <400 c/mL, Week 84, n=138	127 69.4%
HIV-1 RNA <400 c/mL, Week 96, n=120	111 60.7%
HIV-1 RNA <400 c/mL, Week 108, n=98	92 50.3%
HIV-1 RNA <400 c/mL, Week 120, n=82	80 43.7%
HIV-1 RNA <400 c/mL, Week 132, n=61	59 32.2%
HIV-1 RNA <400 c/mL, Week 144, n=45	44 24%
HIV-1 RNA <400 c/mL, Week 156, n=32	31 16.9%
HIV-1 RNA <400 c/mL, Week 168, n=24	23 12.6%
HIV-1 RNA <400 c/mL, Week 180, n=6	5 2.7%

10. Secondary Outcome

Title	Mean Change From Baseline in Plasma HIV-1 RNA at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and From Week 48 Every 12 Weeks up to Study Completion
Description	Mean change from Baseline in plasma HIV-1 RNA was assesseed at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, 48 , 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, and 180 using data of the observed cases. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time Frame	Baseline; Day 8; Weeks 4, 8, 12, 16, 24, 32, 40, and From Week 48 Every 12 Weeks up to Study completion (Up to Week 180)

Outcome Measure Data

Analysis Population Description

ITT-E Population. Only those participants with data available at the indicated time points were considered for analysis (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the ITT-E Population.

Arm/Group Title	Dolutegravir 50 mg BID
Arm/Group Description	Participants received DTG 50 mg BID.
Measure Participants	183
Day 8, n=182	-1.432 (0.607)
Week 4, n=180	-2.088 (0.885)
Week 8, n=179	-2.101 (0.987)
Week 12, n=174	-2.113 (1.069)
Week 16, n=165	-2.216 (1.005)
Week 24, n=164	-2.211 (1.023)
Week 32, n=146	-2.373 (0.926)
Week 40, n=144	-2.301 (0.955)
Week 48, n=146	-2.321 (0.981)
Week 60, n=142	-2.356 (0.928)
Week 72, n=138	-2.390 (0.941)
Week 84, n=138	-2.311 (0.996)
Week 96, n=120	-2.346 (1.008)
Week 108, n=98	-2.394 (0.966)
Week 120, n=82	-2.515 (0.904)
Week 132, n=61	-2.456 (0.988)
Week 144, n=45	-2.585 (0.983)
Week 156, n=32	-2.595 (1.009)
Week 168, n=24	-2.719 (0.898)
Week 180, n=6	-2.425 (1.557)

11. Secondary Outcome

Title	Absolute Values for CD4+ Cell Counts at Baseline, Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and 48 and for CD8+ Cell Counts at Baseline and Weeks 4, 12, 24, and 48
Description	Absolute values for CD4+ cell counts were assessed at Baseline, Day 8 and Weeks 4, 8, 12, 16, and 24, and absolute values for CD8+ cell counts were assessed at Baseline and Weeks 4, 12, 24, and 48.
Time Frame	Baseline, Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and 48

Outcome Measure Data

Analysis Population Description

ITT-E Population. Only those participants with data available at the indicated time points were considered for analysis (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the ITT-E Population.

Arm/Group Title	Dolutegravir 50 mg BID
Arm/Group Description	Participants received DTG 50 mg BID.
Measure Participants	183
CD4+, Baseline, n=183	140.0 (0.607)
CD4+, Day 8, n=181	170.0 (0.885)
CD4+, Week 4, n=178	185.0 (0.987)
CD4+, Week 8, n=178	210.0 (1.069)
CD4+, Week 12, n=171	210.0 (1.005)
CD4+, Week 16, n=165	210.0 (1.023)
CD4+, Week 24, n=163	250.0 (0.926)
CD4+, Week 32, n=147	270.0 (0.955)
CD4+, Week 40, n=143	290.0 (0.981)
CD4+, Week 48, n=145	310.0 (0.928)
CD8+, Week 4, n=181	860.0 (0.941)
CD8+, Week 4, n=176	970.0 (0.996)
CD8+, Week 12, n=170	1015.0 (1.008)
CD8+, Week 24, n=154	1020.0 (0.966)
CD8+, Week 48, n=140	1000.0 (0.904)

12. Secondary Outcome

Title	Median Change From Baseline in CD4+ Cell Counts at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and From Week 48 Every 12 Weeks Until Study Completion
Description	Median change from Baseline in CD4+ cell counts was assessed at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, and 180. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time Frame	Baseline; Day 8; Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 and 180. v

Outcome Measure Data

Analysis Population Description

ITT-E Population. Only those participants with data available at the indicated time points were considered for analysis (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the ITT-E Population.

Arm/Group Title	Dolutegravir 50 mg BID
Arm/Group Description	Participants received DTG 50 mg BID.
Measure Participants	183
CD4+, Day 8, n=181	20.0
CD4+, Week 4, n=178	30.0
CD4+, Week 8, n=178	40.0
CD4+, Week 12, n=171	50.0
CD4+, Week 16, n=165	60.0
CD4+, Week 24, n=163	61.0
CD4+, Week 32, n=147	100.0
CD4+, Week 40, n=143	90.0
CD4+, Week 48, n=145	110.0
CD4+, Week 60, n=142	120.0
CD4+, Week 72, n=138	140.0
CD4+, Week 84, n=137	150.0
CD4+, Week 96, n=117	160.0
CD4+, Week 108, n=98	180.5
CD4+, Week 120, n=82	180.0
CD4+, Week 132, n=61	221.0
CD4+, Week 144, n=46	205.0
CD4+, Week 156, n=32	225.0
CD4+, Week168, n=24	265.0
CD4+, Week180, n=6	170.5

13. Secondary Outcome

Title	Ratio of CD4+/CD8+ Cell Count at Baseline and Weeks 4, 12, 24, and 48
Description	The ratio of CD4+/CD8+ cell count (measured in cells/mm^3) was assessed at Baseline and at Weeks 4, 12, 24, and 48. The ratio was calculated as the CD4+ cell count divided by CD8+ cell count.
Time Frame	Baseline; Weeks 4, 12, 24, and 48

Outcome Measure Data

Analysis Population Description

ITT-E Population. Only those participants with data available at the indicated time points were considered for analysis (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the ITT-E Population.

Arm/Group Title	Dolutegravir 50 mg BID
Arm/Group Description	Participants received DTG 50 mg BID.
Measure Participants	183
Baseline, n=180	0.15
Week 4, n=176	0.19
Week 12, n=170	0.21
Week 24, n=154	0.26
Week 48, n=140	0.32

14. Secondary Outcome

Title	Number of Participants With HIV-1 Disease Progression (Acquired Immune Deficiency Syndrome [AIDS] or Death)
Description	The number of participants with HIV-1 disease progression (AIDS or death) was assessed per the Centers for Disease Control and Prevention (CDC) 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. The CDC classifies HIV infection as Category A (participants with asymptomatic HIV infection, acute HIV infection with accompanying illness, or persistent generalized lymphadenopathy), Category B (participants with symptomatic non-AIDS condition, i.e., conditions that are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection), and Category C (includes AIDS indicator conditions as defined by diagnostic or presumptive measures).
Time Frame	From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)

Outcome Measure Data

Analysis Population Description

ITT-E Population

Arm/Group Title	Dolutegravir 50 mg BID
Arm/Group Description	Participants received DTG 50 mg BID.
Measure Participants	183
Progression from CDC Class A to Class C Event	1 0.5%
Progression from CDC Class B to Class C Event	2 1.1%
Progression from CDC Class C to New Class C Event	6 3.3%
Progression from Classes A, B, or C to Death	2 1.1%

15. Secondary Outcome

Title	Cmax and Ctau of DTG
Description	The maximum plasma concentration (Cmax) and the concentration at the end of a dosing interval (Ctau) of DTG were assessed by a population pharmacokinetic (PK) modeling approach using pooled DTG PK data from multiple studies. For this study, blood samples for pharmacokinetic assessments were collected pre-dose on Day 8 and at Weeks 4 and 24, at 1-3 hours post-dose on Day 8, and at 1-3 hours or 4-12 hours post-dose at Weeks 4 and 24.
Time Frame	Day 8, Week 4, and Week 24

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) Concentration Population: all subjects who received DTG, had undergone PK sampling during the study, and provided evaluable DTG plasma concentration data.

Arm/Group Title	Dolutegravir 50 mg BID
Arm/Group Description	Participants received DTG 50 mg BID.
Measure Participants	183
Cmax	4.74
Ctau	2.60

16. Secondary Outcome

Title	AUC(0-tau) and AUC(0-24) of DTG
Description	The area under the time concentration curve over the dosing interval (AUC[0-tau]) and from 0 to 24 hours (AUC[0-24]) of DTG was assessed by a population PK modeling approach using pooled DTG PK data from multiple studies. For this study, blood samples for pharmacokinetic assessments were collected pre-dose on Day 8 and at Weeks 4 and 24, at 1-3 hours post-dose on Day 8, and at 1-3 hours or 4-12 hours post-dose at Weeks 4 and 24.
Time Frame	Day 8, Week 4, and Week 24

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) Concentration Population: all subjects who received DTG, had undergone PK sampling during the study, and provided evaluable DTG plasma concentration data.

Arm/Group Title	Dolutegravir 50 mg BID
Arm/Group Description	Participants received DTG 50 mg BID.
Measure Participants	183
AUC(0-tau)	36.7 (91)
AUC(0-24)	73.5 (113)

17. Secondary Outcome

Title	C0 Assessment of DTG
Description	The plasma DTG concentration immediately prior to dosing at steady state (C0) was assessed at Day 8, Week 4, and Week 24. Blood samples for pharmacokinetic assessments were collected pre-dose and 1-3 hours post-dose on Day 8 and at Week 4 and 4-12 hours post-dose at Week 24. Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the Pharmacokinetic Parameter Population.
Time Frame	Day 8, Week 4, and Week 24

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Parameter Population: all participants who received DTG, underwent PK sampling during the study, and provided an evaluable estimate of C0. Only participants with data available at the indicated time points were considered for analysis.

Arm/Group Title	Dolutegravir 50 mg BID
Arm/Group Description	Participants received DTG 50 mg BID.
Measure Participants	161
Day 8, n=148	2.36 (91)
Week 4, n=161	1.90 (113)
Week 24, n=135	2.14 (93)

18. Secondary Outcome

Title	Number of Participants With the Indicated Treatment-emergent Integrase (IN) Mutations Detected at the Time of Protocol-defined Virologic Failure (PDVF) as a Measure of Genotypic Resistance
Description	An analysis of changes at specific amino acids in the IN coding region associated with resistance to raltegravir, elvitegravir, or DTG was performed at Day 1 and at the time of PDVF. PDVF is a <0.5 log10 copies(c)/mL decrease in plasma HIV-1 RNA at Day 8 unless the absolute value is <400 c/mL. PDVF after Day 8 is defined as virological non-respones (decrease in plasma HIV-1 RNA of <1 log10 c/mL by Week 16, with subsequent confirmation, unless plasma HIV-1 RNA <400 c/mL and confirmed plasma HIV-1 RNA levels >=400 c/mL on or after Week 24) and virological rebound (confirmed rebound in plasma HIV-1 RNA levels to >=400 c/mL after prior confirmed suppression to <400 c/mL and confirmed plasma HIV-1 RNA levels >1 log10 c/mL above the nadir value [nadir: >=400 c/mL]).
Time Frame	From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)

Outcome Measure Data

Analysis Population Description

PDVF Genotypic Resistance Populations: all participants in the ITT-E Population with available on-treatment genotypic resistance data at the time of PDVF. Only participants with Baseline IN mutations with PDVF who had paired Baseline and time of PDVF samples were considered for analysis.

Arm/Group Title	Dolutegravir 50 mg BID
Arm/Group Description	Participants received DTG 50 mg BID.
Measure Participants	42
Any IN mutation	25 13.7%
T97A	8 4.4%
T97T/A	4 2.2%
E138A	1 0.5%
E138E/A	1 0.5%
E138E/K	3 1.6%
E138K	4 2.2%
E138T/A	1 0.5%
N155H	6 3.3%
N155N/H	1 0.5%
Q148H	3 1.6%
Q148Q/H	2 1.1%
Q148R	1 0.5%
Q148Q/R/K	1 0.5%
G140G/S	1 0.5%
G140S	3 1.6%
L74L/M/V	1 0.5%
L74L/M	1 0.5%
L74I	1 0.5%
E92E/Q	2 1.1%
S147G	2 1.1%
E157E/Q	1 0.5%
V151V/M/I	1 0.5%
Y143Y/H	1 0.5%

19. Secondary Outcome

Title	Number of Participants With the Indicated Fold Increase in DTG FC (Fold Change in IC50 Relative to Wild-type Virus) Between Baseline and the Time of PDVF, as a Measure of Post-Baseline Phenotypic Resistance
Description	The FC in IC50 (50% inhibitory concentration) for DTG relative to wild-type virus was determined for virus isolated at Baseline and at the time of PDVF. The number of participants with the indicated change (ratio) in the two values at the time of PDVF is presented. PDVF is defined as a <0.5 log10 copies/mL decrease in plasma HIV-1 RNA at Day 8 unless the absolute value is <400 copies/mL. PDVF after Day 8 was defined for virological non-response (decrease in plasma HIV-1 RNA of less than 1 log10 copies/mL by Week 16, with subsequent confirmation, unless plasma HIV-1 RNA <400 copies/mL and confirmed plasma HIV-1 RNA levels >=400 copies/mL on or after Week 24) and virological rebound (confirmed rebound in plasma HIV-1 RNA levels to >=400 copies/mL after prior confirmed suppression to <400 copies/mL and confirmed plasma HIV-1 RNA levels >1 log10 copies/mL above the nadir value, where nadir is >=400 copies/mL).
Time Frame	From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)

Outcome Measure Data

Analysis Population Description

PDVF Phenotypic Resistance Populations. Only participants with Baseline DTG IC50 with PDVF who had paired Baseline and time of virological failure samples were considered for analysis.

Arm/Group Title	Dolutegravir 50 mg BID
Arm/Group Description	Participants received DTG 50 mg BID.
Measure Participants	45
<1 fold	6 3.3%
1-<2 fold	16 8.7%
2-<4 fold	4 2.2%
4-<8 fold	4 2.2%
>=8 fold	12 6.6%
Missing	3 1.6%

Adverse Events

Time Frame	On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from start of study treament until the end of treatment visit for each participant (up to Week 180)
Adverse Event Reporting Description	On-treatment SAEs and non-serious AEs were reported for the Safety population consisted of all participants who received at least one dose of investigational product.
Arm/Group Title	Dolutegravir 50 mg BID
Arm/Group Description	Participants received DTG 50 mg BID.
All Cause Mortality
	Dolutegravir 50 mg BID
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Dolutegravir 50 mg BID
	Affected / at Risk (%)	# Events
Total	46/183 (25.1%)
Cardiac disorders
Cardiac failure congestive	2/183 (1.1%)
Angina pectoris	1/183 (0.5%)
Coronary artery disease	1/183 (0.5%)
Gastrointestinal disorders
Constipation	1/183 (0.5%)
Dysphagia	1/183 (0.5%)
Parotid gland enlargement	1/183 (0.5%)
Diarrhoea	2/183 (1.1%)
Gastritis	1/183 (0.5%)
Haematochezia	1/183 (0.5%)
Rectal haemorrhage	1/183 (0.5%)
Aphthous stomatitis	1/183 (0.5%)
General disorders
Pyrexia	3/183 (1.6%)
Hepatobiliary disorders
Cholecystitis acute	1/183 (0.5%)
Cholelithiasis	2/183 (1.1%)
Hepatic cirrhosis	1/183 (0.5%)
Hepatitis acute	1/183 (0.5%)
Hyperbilirubinaemia	1/183 (0.5%)
Bile duct obstruction	1/183 (0.5%)
Drug-induced liver injury	1/183 (0.5%)
Hepatocellular injury	1/183 (0.5%)
Nodular regenerative hyperplasia	1/183 (0.5%)
Immune system disorders
Immune reconstitution inflammatory syndrome	1/183 (0.5%)
Infections and infestations
Pneumonia	5/183 (2.7%)
Progressive multifocal leukoencephalopathy	2/183 (1.1%)
Cytomegalovirus infection	1/183 (0.5%)
Cytomegalovirus viraemia	1/183 (0.5%)
Epstein-Barr virus infection	1/183 (0.5%)
Gastroenteritis viral	1/183 (0.5%)
Herpes ophthalmic	1/183 (0.5%)
Herpes zoster	1/183 (0.5%)
Lung infection	1/183 (0.5%)
Oesophageal candidiasis	1/183 (0.5%)
Pneumococcal sepsis	1/183 (0.5%)
Septic shock	1/183 (0.5%)
Streptococcal sepsis	1/183 (0.5%)
Viral infection	1/183 (0.5%)
Eye infection toxoplasmal	1/183 (0.5%)
Gastroenteritis	1/183 (0.5%)
Herpes virus infection	1/183 (0.5%)
Hepatitis B	1/183 (0.5%)
Oral candidiasis	1/183 (0.5%)
Orchitis	1/183 (0.5%)
Investigations
Alanine aminotransferase increased	1/183 (0.5%)
Metabolism and nutrition disorders
Dehydration	3/183 (1.6%)
Musculoskeletal and connective tissue disorders
Tendonitis	1/183 (0.5%)
Joint destruction	1/183 (0.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bowen's disease	1/183 (0.5%)
Squamous cell carcinoma	2/183 (1.1%)
Anogenital warts	1/183 (0.5%)
Bile duct cancer	1/183 (0.5%)
Hodgkin's disease recurrent	1/183 (0.5%)
Anal cancer stage I	1/183 (0.5%)
B-cell lymphoma	1/183 (0.5%)
Hodgkin's disease	1/183 (0.5%)
Lip and/or oral cavity cancer	1/183 (0.5%)
Lip and/or oral cavity cancer stage 0	1/183 (0.5%)
Squamous cell carcinoma of the cervix	1/183 (0.5%)
Nervous system disorders
Cerebrovascular accident	1/183 (0.5%)
Convulsion	1/183 (0.5%)
Nerve compression	1/183 (0.5%)
Syncope	1/183 (0.5%)
Transient ischaemic attack	1/183 (0.5%)
Seizure	1/183 (0.5%)
Psychiatric disorders
Bipolar disorder	1/183 (0.5%)
Depression	1/183 (0.5%)
Renal and urinary disorders
Renal failure	1/183 (0.5%)
Acute kidney injury	1/183 (0.5%)
Reproductive system and breast disorders
Ovarian mass	1/183 (0.5%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	2/183 (1.1%)
Acute respiratory failure	1/183 (0.5%)
Productive cough	1/183 (0.5%)
Pulmonary embolism	1/183 (0.5%)
Lung disorder	2/183 (1.1%)
Bronchopneumopathy	1/183 (0.5%)
Skin and subcutaneous tissue disorders
Drug eruption	1/183 (0.5%)
Pruritus	1/183 (0.5%)
Rash	1/183 (0.5%)
Rash generalised	1/183 (0.5%)
Vascular disorders
Hypertensive emergency	1/183 (0.5%)
Other (Not Including Serious) Adverse Events
	Dolutegravir 50 mg BID
	Affected / at Risk (%)	# Events
Total	143/183 (78.1%)
Gastrointestinal disorders
Diarrhoea	41/183 (22.4%)
Nausea	26/183 (14.2%)
Vomiting	13/183 (7.1%)
Abdominal pain upper	14/183 (7.7%)
Constipation	12/183 (6.6%)
General disorders
Fatigue	17/183 (9.3%)
Pyrexia	19/183 (10.4%)
Asthenia	13/183 (7.1%)
Injection site reaction	12/183 (6.6%)
Infections and infestations
Bronchitis	25/183 (13.7%)
Upper respiratory tract infection	22/183 (12%)
Nasopharyngitis	12/183 (6.6%)
Rhinitis	11/183 (6%)
Influenza	11/183 (6%)
Sinusitis	11/183 (6%)
Musculoskeletal and connective tissue disorders
Back pain	18/183 (9.8%)
Arthralgia	12/183 (6.6%)
Pain in extremity	11/183 (6%)
Nervous system disorders
Headache	24/183 (13.1%)
Psychiatric disorders
Insomnia	14/183 (7.7%)
Anxiety	10/183 (5.5%)
Respiratory, thoracic and mediastinal disorders
Cough	29/183 (15.8%)
Oropharyngeal pain	10/183 (5.5%)
Skin and subcutaneous tissue disorders
Rash	17/183 (9.3%)
Pruritus	11/183 (6%)
Vascular disorders
Hypertension	11/183 (6%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.