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Clinical Trial Results:
A Phase III, randomized, multicenter, parallel-group, noninferiority study evaluating the efficacy, safety, and tolerability of switching to dolutegravir plus rilpivirine from current INI-, NNRTI-, or PI-based antiretroviral regimen in HIV-1-infected adults who are virologically suppressed

Summary
EudraCT number	2014-005147-40
Trial protocol	ES DE NL BE GB IT
Global end of trial date

Results information
Results version number	v2
This version publication date	14 Oct 2017
First version publication date	13 Aug 2017
Other versions	v1 , v3 , v4 , v5 , v6
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

201636

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

ViiV Healthcare

Sponsor organisation address

980 Great West Road, Brentford, Middlesex, United Kingdom,

Public contact

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

Scientific contact

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Interim

Date of interim/final analysis

20 Feb 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

16 Sep 2016

Global end of trial reached?

Main objective of the trial

To demonstrate the non-inferior antiviral activity of switching to dolutegravir (DTG) plus rilpivirine (RPV) once daily compared to continuation of current antiretroviral regimen (CAR) over 48 weeks in HIV-1 infected antiretroviral therapy (ART)-experienced virologically suppressed subjects

Protection of trial subjects

Not applicable

Background therapy

Evidence for comparator

Actual start date of recruitment

14 Apr 2015

Long term follow-up planned

Yes

Long term follow-up rationale

Scientific research

Long term follow-up duration

4 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 5

Country: Number of subjects enrolled

Australia: 10

Country: Number of subjects enrolled

Belgium: 18

Country: Number of subjects enrolled

Canada: 29

Country: Number of subjects enrolled

France: 33

Country: Number of subjects enrolled

Germany: 17

Country: Number of subjects enrolled

Italy: 20

Country: Number of subjects enrolled

Netherlands: 9

Country: Number of subjects enrolled

Russian Federation: 35

Country: Number of subjects enrolled

Spain: 191

Country: Number of subjects enrolled

Taiwan: 54

Country: Number of subjects enrolled

United States: 86

Country: Number of subjects enrolled

United Kingdom: 3

Worldwide total number of subjects

510

EEA total number of subjects

291

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

490

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This study was a 148-week, Phase III, randomized, open-label, active-controlled, multicenter, parallel-group, non-inferiority study to assess the antiviral activity and safety of a two-drug regimen of dolutegravir (DTG) + rilpivirine (RPV) compared with current antiretroviral regimen (CAR). The study was conducted in 65 centers in 13 countries.

Screening details

Total 669 participants were screened (159 failed), 510 participants were randomized and 2 subjects withdrew before being exposed to study drug. The study included a Screening phase, an early switch phase, a late switch phase,, and a continuation phase. The results presented are based on the interim analysis of the early switch phase.

Period 1 title

52-Week early switch phase (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

DTG + RPV

Arm description

Participants received DTG 50 milligrams (mg) + RPV 25 mg together once daily at approximately the same time, with a meal, in an open-label fashion up to Week 52 during early switch phase.

Arm type

Experimental

Investigational medicinal product name

Dolutegravir Tablets 50 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received dolutegravir tablets 50 mg once daily, with a meal, in an open-label fashion up to Week 52 during early switch phase.

Investigational medicinal product name

Rilpivirine Tablets 25 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received rilpivirine tablets 25 mg once daily, with a meal, in an open-label fashion up to Week 52 during early switch phase.

Current antiretroviral regimen

Arm description

Participants continued to receive their current antiretroviral regimen (two nucleoside reverse transcriptase inhibitors [NRTIs] + a third agent). A third agent included either an: integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). CAR was administered according to the approved labeling in an open-label fashion up to Week 52 during early switch phase.

Arm type

Active comparator

Investigational medicinal product name

Current antiretroviral regimen (not IMP)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received their current antiretroviral regimen (2 NRTIs + a third agent). A third agent included either of INI, NNRTI, or PI. CAR was administered according to the approved labeling in an open-label fashion up to Week 52 during early switch phase.

Number of subjects in period 1 ^[1]	DTG + RPV	Current antiretroviral regimen
Started	252	256
Completed	239	238
Not completed	13	18
Adverse event, serious fatal	-	1
Consent withdrawn by subject	3	7
Physician decision	-	2
Adverse event, non-fatal	6	1
Lost to follow-up	1	2
Lack of efficacy	2	1
Protocol deviation	1	4

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Total 699 participants were screened and 510 subjects were randomized, and 2 subjects withdrew before being exposed to study drug.

Baseline characteristics

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Reporting group title

DTG + RPV

Reporting group description

Participants received DTG 50 milligrams (mg) + RPV 25 mg together once daily at approximately the same time, with a meal, in an open-label fashion up to Week 52 during early switch phase.

Reporting group title

Current antiretroviral regimen

Reporting group description

Reporting group values	DTG + RPV	Current antiretroviral regimen	Total
Number of subjects	252	256
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	43.6 ( 10.93 )	43.6 ( 10.76 )	-
Gender categorical
Units: Subjects
Female	58	51	109
Male	194	205	399
Race/Ethnicity, Customized
Units: Subjects
American Indian or Alaska Native	3	6	9
Japanese/East Asian (EA) Heritage (H.)/South EA H.	25	34	59
Black/African American	24	27	51
Native Hawaiian or other Pacific Islander	1	0	1
White	198	188	386
American Indian or Alaska Native and white	0	1	1
African American/African H. and Asian	1	0	1

End points

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Reporting group title

DTG + RPV

Reporting group description

Participants received DTG 50 milligrams (mg) + RPV 25 mg together once daily at approximately the same time, with a meal, in an open-label fashion up to Week 52 during early switch phase.

Reporting group title

Current antiretroviral regimen

Reporting group description

Subject analysis set title

DTG 50 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received DTG 50 mg + RPV 25 mg together once daily, with a meal, in an open-label fashion up to Week 52 during early switch phase.

Subject analysis set title

RPV 25 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received DTG 50 mg + RPV 25 mg together once daily, with a meal, in an open-label fashion up to Week 52 during early switch phase.

Primary: Percentage of participants with plasma human immunodeficiency virus (HIV) 1 ribonucleic acid (RNA) <50 copies/milliliter (c/mL) at Week 48 using snapshot algorithm

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End point title

Percentage of participants with plasma human immunodeficiency virus (HIV) 1 ribonucleic acid (RNA) <50 copies/milliliter (c/mL) at Week 48 using snapshot algorithm

End point description

Percentage of participants with plasma HIV 1 RNA < 50 c/mL at Week 48 using the Food and Drug Administration (FDA) snapshot algorithm was assessed to demonstrate the non-inferior antiviral activity of switching to DTG + RPV once daily compared to continuation of CAR over 48 weeks in HIV-1 infected antiretroviral therapy (ART)-experienced participants. Virologic success or failure was determined by the last available HIV-1 RNA assessment while the participant was on-treatment within the window of the visit of interest. Plasma samples were collected for HIV-1 RNA at Baseline (Day 1), Week 4, 8, 12, 24, 36 and 48. Treatment with DTG + RPV was declared non-inferior to CAR if the lower end of a two-sided 95% confidence interval for the difference between the two groups in response rates at Week 48 lies above -10% by Cochran-Mantel Haenszel test. The Intent-to-Treat Exposed (ITT-E) population consisted of all randomly assigned participants who received at least one dose of study drug.

End point type

Primary

End point timeframe

Week 48

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	252 ^[1]	256 ^[2]
Units: Percentage of participants
Percentage of participants	95	96

Notes
[1] - ITT-E Population
[2] - ITT-E Population

Statistical analysis 1

Statistical analysis description

Estimates based on Cochran-Mantel Haenszel stratified analysis adjusting for Baseline stratification factors: Age group (< or >=50 years old) and Baseline third agent (PI, NNRTI, INI).

Comparison groups

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

Method

Parameter type

Risk difference (RD)

Point estimate

-0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-4.3

upper limit

Notes
[3] - Non-inferiority can be concluded if the lower bound of a two-sided 95% confidence interval for the difference in response rates between the two treatment arms is greater than -10%.

Secondary: Changes from Baseline in cluster designation (CD)4+ lymphocyte count at Weeks 24 and 48

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End point title

Changes from Baseline in cluster designation (CD)4+ lymphocyte count at Weeks 24 and 48

End point description

Blood was collected and CD4+ cell count assessment by flow cytometery was carried out at Baseline (Day 1), Week 4, 8, 12, 24, 36 and 48 to evaluate the immunological activity of DTG + RPV once daily compared to continuation of CAR. The full set of lymphocyte sub sets was not evaluated. Change from Baseline was calculated as value at indicated time point minus Baseline value. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles).

End point type

Secondary

End point timeframe

Week 24 and 48

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	252 ^[4]	256 ^[5]
Units: Cells per millimeter (mm)^3
arithmetic mean (standard deviation)
Week 24, n=247, 249	16.2 ( 150.34 )	47.4 ( 179.68 )
Week 48, n=239, 245	32.3 ( 149.52 )	41.8 ( 185.53 )

Notes
[4] - ITT-E Population
[5] - ITT-E Population

No statistical analyses for this end point

Secondary: Percentage of participants with plasma HIV 1 RNA <50 c/mL at Week 24 using snapshot algorithm

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End point title

Percentage of participants with plasma HIV 1 RNA <50 c/mL at Week 24 using snapshot algorithm

End point description

Percentage of participants with plasma HIV 1 RNA < 50 c/mL at Week 24 using the FDA snapshot algorithm was assessed to evaluate the antiviral activity of DTG + RPV once daily compared to continuation of CAR. Virologic success or failure was determined by the last available HIV-1 RNA assessment while the participant was on-treatment within the window of the visit of interest. Plasma samples were collected for HIV-1 RNA at Baseline (Day 1), Week 4, 8, 12 and 24.

End point type

Secondary

End point timeframe

Week 24

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	252 ^[6]	256 ^[7]
Units: Percentage of participants
Percentage of participants	98	96

Notes
[6] - ITT-E Population
[7] - ITT-E Population

Statistical analysis 1

Statistical analysis description

Cochran-Mantel Haenszel stratified analysis adjusting for Baseline stratification factors: Age group (< or >=50 years old) and Baseline third agent (PI, NNRTI, INI). No formal non-inferiority margin has been pre-specified for secondary endpoints.

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Risk difference (RD)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1.9

upper limit

Secondary: Number of participants with common non-serious adverse event (AE), any serious AE (SAE), AE of maximum toxicity grade 1, 2, 3 or 4, AE leading to discontinuation (AELD)

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End point title

Number of participants with common non-serious adverse event (AE), any serious AE (SAE), AE of maximum toxicity grade 1, 2, 3 or 4, AE leading to discontinuation (AELD)

End point description

An AE is 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. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention were categorized as SAE. Number of participants with common non-serious AE, SAE, AELD or AE with maximum grade toxicity experienced over Week 48 was summarized. Common AEs were those with >5 percent incidence for either treatment. Safety Population included all randomly assigned participants who have received at least one dose of study drug.

End point type

Secondary

End point timeframe

Up to 52 weeks

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	252 ^[8]	256 ^[9]
Units: Participants
Common non-serious AE	65	68
Any SAE	9	12
Maximum Grade 1 AE	128	122
Maximum toxicity Grade 2 AE	57	53
Maximum toxicity Grade 3 AE	11	13
Maximum toxicity Grade 4 AE	4	2
AELD	9	2

Notes
[8] - Safety Population
[9] - Safety Population

No statistical analyses for this end point

Secondary: Number of participants with maximum post-baseline emergent chemistry toxicities over 48 weeks

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End point title

Number of participants with maximum post-baseline emergent chemistry toxicities over 48 weeks

End point description

Blood samples were collected at Baseline (Day 1) and at Week 4, 8, 12, 24, 36 and 48 to evaluate alanine aminotransferase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), total bilirubin, chloride, creatinine, glucose, potassium, phosphate, sodium, blood urea nitrogen (BUN), total carbon dioxide, lipase, creatine phosphokinase and creatinine clearance. Value obtained at Day 1 was considered as Baseline value. Change from Baseline was calculated as value at indicated time point minus Baseline value. Number of participants who experienced maximum grade toxicity post-baseline in clinical chemistry over 48 weeks was summarized. Participants were graded using the Division of AIDS Table for Grading Severity of Adult and Pediatric Adverse Events. Grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=potentially life-threatening

End point type

Secondary

End point timeframe

Up to 48 weeks

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	252 ^[10]	256 ^[11]
Units: Participants
Grade 1	95	78
Grade 2	61	86
Grade 3	22	23
Grade 4	5	9

Notes
[10] - Safety Population
[11] - Safety Population

No statistical analyses for this end point

Secondary: Number of participants with maximum post-baseline emergent hematology toxicities over 48 weeks

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End point title

Number of participants with maximum post-baseline emergent hematology toxicities over 48 weeks

End point description

Blood samples were collected at Baseline (Day 1) and at Week 4, 8, 12, 24, 36 and 48 to evaluate hemoglobin, hematocrit, basophils, eosinophils, lymphocytes, monocytes, neutrophils, mean corpuscular volume (MCV), red blood cell (RBC) count, white blood cell (WBC) count and platelet count. Change from Baseline was calculated as value at indicated time point minus Baseline value. Number of participants who experienced maximum grade toxicity post-baseline in hematology over 48 weeks was summarized. Participants were graded using the Division of AIDS Table for Grading Severity of Adult and Pediatric Adverse Events. Grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=potentially life-threatening.

End point type

Secondary

End point timeframe

Up to 48 weeks

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	252 ^[12]	256 ^[13]
Units: Participants
Grade 1	11	11
Grade 2	3	2
Grade 3	3	1
Grade 4	0	1

Notes
[12] - Safety Population
[13] - Safety Population

No statistical analyses for this end point

Secondary: Mean change from Baseline in high-sensitivity C-reactive protein (hs-CRP) at Week 48

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End point title

Mean change from Baseline in high-sensitivity C-reactive protein (hs-CRP) at Week 48

End point description

Blood biomarker samples were collected at Baseline (Day 1) and Week 48 to assess hs-CRP. Change from Baseline was calculated as value at indicated time point minus Baseline value.

End point type

Secondary

End point timeframe

Up to Week 48

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	234 ^[14]	243 ^[15]
Units: mg/ Liter (L)
arithmetic mean (standard deviation)
mg/ Liter (L)	0.11 ( 5.379 )	0.15 ( 4.944 )

Notes
[14] - Safety Population
[15] - Safety Population

No statistical analyses for this end point

Secondary: Mean change from Baseline in cystatin C at Week 48

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End point title

Mean change from Baseline in cystatin C at Week 48

End point description

Blood biomarker samples were collected at Baseline (Day 1) and Week 48 to assess cystatin C Change from Baseline was calculated as value at indicated time point minus Baseline value.

End point type

Secondary

End point timeframe

Up to Week 48

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	237 ^[16]	245 ^[17]
Units: mg/L
arithmetic mean (standard deviation)
mg/L	0 ( 0.113 )	-0.01 ( 0.106 )

Notes
[16] - Safety Population
[17] - Safety Population

No statistical analyses for this end point

Secondary: Mean change from Baseline in D-Dimer at Week 48

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End point title

Mean change from Baseline in D-Dimer at Week 48

End point description

Blood biomarker samples were collected at Baseline (Day 1) and Week 48 to assess D-Dimer. Change from Baseline was calculated as value at indicated time point minus Baseline value.

End point type

Secondary

End point timeframe

Up to Week 48

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	224 ^[18]	238 ^[19]
Units: Nanomole (nmol)/L FEU
arithmetic mean (standard deviation)	-0.02 ( 2.651 )	0.02 ( 2.501 )

Notes
[18] - Safety Population
[19] - Safety Population

No statistical analyses for this end point

Secondary: Mean change from Baseline in fatty acid binding protein 2 (FABP) and soluble CD14 at Week 48

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End point title

Mean change from Baseline in fatty acid binding protein 2 (FABP) and soluble CD14 at Week 48

End point description

Blood biomarker samples were collected at Baseline (Day 1) and Week 48 to assess FABP and soluble CD14. Change from Baseline was calculated as value at indicated time point minus Baseline value. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles).

End point type

Secondary

End point timeframe

Up to Week 48

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	252 ^[20]	256 ^[21]
Units: Nanogram/milliliter
arithmetic mean (standard deviation)
FABP, n=233, 242	-2.79 ( 3.007 )	-1.93 ( 2.15 )
Soluble CD14, n=234, 242	379.72 ( 634.053 )	754.54 ( 656.462 )

Notes
[20] - Safety Population
[21] - Safety Population

No statistical analyses for this end point

Secondary: Mean change from Baseline in Soluble CD163 and oxidized low density lipoprotein (LDL) at Week 48

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End point title

Mean change from Baseline in Soluble CD163 and oxidized low density lipoprotein (LDL) at Week 48

End point description

Blood biomarker samples were collected at Baseline (Day 1) and Week 48 to assess soluble CD163 and oxidized LDL. Change from Baseline was calculated as value at indicated time point minus Baseline value. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles).

End point type

Secondary

End point timeframe

Up to Week 48

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	252 ^[22]	256 ^[23]
Units: Microgram (ug)/Liter
arithmetic mean (standard deviation)
Soluble CD163, n=232, 241	50.18 ( 188.772 )	54.26 ( 238.9 )
Oxidized LDL, n=234, 242	9.49 ( 745.962 )	-41.3 ( 726.014 )

Notes
[22] - Safety Population
[23] - Safety Population

No statistical analyses for this end point

Secondary: Mean change from Baseline in retinol binding protein (RBP), serum creatinine and glucose at Week 48

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End point title

Mean change from Baseline in retinol binding protein (RBP), serum creatinine and glucose at Week 48

End point description

Blood biomarker samples were collected at Baseline (Day 1) and Week 48 to assess RBP, serum creatinine and glucose. Change from Baseline was calculated as value at indicated time point minus Baseline value. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles).

End point type

Secondary

End point timeframe

Up to Week 48

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	252 ^[24]	256 ^[25]
Units: mg/ deciliter (dL)
arithmetic mean (standard deviation)
RBP, n=235, 243	-0.13 ( 1.023 )	0.03 ( 0.974 )
Serum creatinine, n=238, 243	0.087 ( 0.1074 )	0.011 ( 0.0876 )
Glucose, n=227, 227	0.762 ( 13.6194 )	2.492 ( 12.1674 )

Notes
[24] - Safety Population
[25] - Safety Population

No statistical analyses for this end point

Secondary: Mean change from Baseline in urine phosphate at Week 48

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End point title

Mean change from Baseline in urine phosphate at Week 48

End point description

Urine biomarker samples were collected to at Baseline (Day 1) and Week 48 to assess urine phosphate. Change from Baseline was calculated as value at indicated time point minus Baseline value.

End point type

Secondary

End point timeframe

Up to Week 48

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	218 ^[26]	224 ^[27]
Units: Millimoles (mmol)/ L
arithmetic mean (standard deviation)
Millimoles (mmol)/ L	-1.079 ( 16.9226 )	-1.511 ( 15.8515 )

Notes
[26] - Safety Population
[27] - Safety Population

No statistical analyses for this end point

Secondary: Mean change from Baseline in beta-2-microglobulin (B2M) (blood and urine), urine RBP and 25 hydroxy-vitamin D at Week 48

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End point title

Mean change from Baseline in beta-2-microglobulin (B2M) (blood and urine), urine RBP and 25 hydroxy-vitamin D at Week 48

End point description

Blood biomarker samples were collected at Baseline (Day 1) and Week 48 to assess B2M and 25 hydroxy-vitamin D. Urine biomarker samples were collected at Baseline (Day 1) and Week 48 to assess urine B2M and urine RBP. Change from Baseline was calculated as value at indicated time point minus Baseline value. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). For 25 hydroxy-vitamin D, analysis of changes from baseline was performed on log-transformed data. Results were transformed back via exponential transformation such that treatment comparisons are assessed via odds ratios.

End point type

Secondary

End point timeframe

Up to Week 48

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	252 ^[28]	256 ^[29]
Units: Nanomoles (nmol)/ L
arithmetic mean (standard deviation)
B2M, blood, n=233, 241	-15.1452 ( 44.55903 )	-4.5995 ( 38.90474 )
25 hydroxy-vitamin D, n=235, 244	-13.9 ( 22.76 )	-8.2 ( 24.43 )
Urine B2M, n=89, 96	-128.2045 ( 726.38825 )	39.8394 ( 253.43025 )
Urine RBP, n=221, 231	-8.8395 ( 28.83977 )	-0.5851 ( 27.56405 )

Notes
[28] - Safety Population
[29] - Safety Population

Statistical analysis 1

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

other ^[30]

P-value

= 0.007 ^[31]

Method

ANCOVA

Confidence interval

Notes
[30] - Since statistical significance at the 10% level was observed, results are presented separately per Baseline third agent.
[31] - P-value for interaction between treatment group and baseline third agent (25 hydroxy-vitamin D)

Statistical analysis 2

Statistical analysis description

Estimates are calculated from an ANCOVA model adjusting for Baseline third agent class, age, sex, BMI category, smoking status and baseline biomarker level.

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.275 ^[32]

Method

ANCOVA

Parameter type

Odds ratio (OR)

Point estimate

0.958

Confidence interval

level

95%

sides

2-sided

lower limit

0.888

upper limit

1.034

Notes
[32] - P value to assess difference between treatment groups (25 hydroxy-vitamin D - NNRTI)

Statistical analysis 3

Statistical analysis description

Estimates are calculated from an ANCOVA model adjusting for Baseline third agent class, age, sex, BMI category, smoking status and baseline biomarker level.

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.112 ^[33]

Method

ANCOVA

Parameter type

Odds ratio (OR)

Point estimate

0.902

Confidence interval

level

95%

sides

2-sided

lower limit

0.793

upper limit

1.025

Notes
[33] - P value to assess difference between treatment groups (25 hydroxy-vitamin D - INI)

Statistical analysis 4

Statistical analysis description

Estimates are calculated from an ANCOVA model adjusting for Baseline third agent class, age, sex, BMI category, smoking status and baseline biomarker level.

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002 ^[34]

Method

ANCOVA

Parameter type

Odds ratio (OR)

Point estimate

0.847

Confidence interval

level

95%

sides

2-sided

lower limit

0.763

upper limit

0.942

Notes
[34] - P value to assess difference between treatment groups (25 hydroxy-vitamin D - PI)

Secondary: Mean change from Baseline in urine albumin/creatinine ratio and urine protein/creatinine ratio at Week 48

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End point title

Mean change from Baseline in urine albumin/creatinine ratio and urine protein/creatinine ratio at Week 48

End point description

Urine biomarker samples were collected at Baseline (Day 1) and Week 48 to assess urine albumin/creatinine ratio and urine protein/creatinine ratio. Change from Baseline was calculated as value at indicated time point minus Baseline value. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles).

End point type

Secondary

End point timeframe

Up to Week 48

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	252 ^[35]	256 ^[36]
Units: Grams (g)/ mol
arithmetic mean (standard deviation)
Urine albumin/creatinine ratio, n=166, 171	-1.19 ( 3.916 )	-2.59 ( 28.878 )
urine protein/creatinine ratio, n=176, 182	-5.63 ( 17.219 )	-1.43 ( 42.832 )

Notes
[35] - Safety Population
[36] - Safety Population

No statistical analyses for this end point

Secondary: Mean change from Baseline in bone-specific alkaline phosphatase, procollagen 1 N-terminal propeptide, osteocalcin, Type I Collagen C-Telopeptides and soluble vascular cell adhesion molecule (sVCAM) at Week 48

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End point title

Mean change from Baseline in bone-specific alkaline phosphatase, procollagen 1 N-terminal propeptide, osteocalcin, Type I Collagen C-Telopeptides and soluble vascular cell adhesion molecule (sVCAM) at Week 48

End point description

Blood biomarker samples were collected at Baseline (Day 1) and Week 48 to assess bone-specific alkaline phosphatase, procollagen 1 N-terminal propeptide, osteocalcin, Type I Collagen C-Telopeptides and sVCAM. Change from Baseline was calculated as value at indicated time point minus Baseline value. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). For bone-specific alkaline phosphatase, procollagen 1-N-propeptide, osteocalcin and type 1 collagen C-telopeptide, analyses of changes from baseline were performed on log-transformed data. Results were transformed back via exponential transformation such that treatment comparisons are assessed via odds ratios.

End point type

Secondary

End point timeframe

Up to Week 48

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	252 ^[37]	256 ^[38]
Units: ug/ L
arithmetic mean (standard deviation)
Bone-specific alkaline phosphatase, n=234, 244	-2.89 ( 4.024 )	0.9 ( 4.129 )
Procollagen type 1 N-propeptide, n=234, 242	-9.1 ( 20.34 )	-1.4 ( 18.95 )
Osteocalcin, n=233, 242	-4.4 ( 7.605 )	-0.68 ( 6.579 )
Type I Collagen C-Telopeptides, n=234, 241	-0.18 ( 0.307 )	-0.04 ( 1.16 )
sVCAM, n=234, 243	-2.21 ( 1291.994 )	89.07 ( 1239.465 )

Notes
[37] - Safety Population
[38] - Safety Population

Statistical analysis 1

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

other ^[39]

P-value

= 0.001 ^[40]

Method

ANCOVA

Confidence interval

Notes
[39] - Since statistical significance at the 10% level was observed, results are presented separately per Baseline third agent.
[40] - P-value for interaction between treatment group and baseline third agent (bone-specific alkaline phosphatase)

Statistical analysis 2

Statistical analysis description

Estimates are calculated from an ANCOVA model adjusting for Baseline third agent class, age, sex, BMI category, smoking status and baseline biomarker level.

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[41]

Method

ANCOVA

Parameter type

Odds ratio (OR)

Point estimate

0.724

Confidence interval

level

95%

sides

2-sided

lower limit

0.679

upper limit

0.772

Notes
[41] - P value to assess difference between treatment groups (bone-specific alkaline phosphatase - NNRTI)

Statistical analysis 3

Statistical analysis description

Estimates are calculated from an ANCOVA model adjusting for Baseline third agent class, age, sex, BMI category, smoking status and baseline biomarker level.

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[42]

Method

ANCOVA

Parameter type

Odds ratio (OR)

Point estimate

0.825

Confidence interval

level

95%

sides

2-sided

lower limit

0.742

upper limit

0.918

Notes
[42] - P value to assess difference between treatment groups (bone-specific alkaline phosphatase - INI)

Statistical analysis 4

Statistical analysis description

Estimates are calculated from an ANCOVA model adjusting for Baseline third agent class, age, sex, BMI category, smoking status and baseline biomarker level.

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[43]

Method

ANCOVA

Parameter type

Odds ratio (OR)

Point estimate

0.81

Confidence interval

level

95%

sides

2-sided

lower limit

0.742

upper limit

0.884

Notes
[43] - P value to assess difference between treatment groups (bone-specific alkaline phosphatase - PI)

Statistical analysis 5

Statistical analysis description

Since statistical significance at the 10% level was not observed, results are presented overall only

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.677 ^[44]

Method

ANCOVA

Confidence interval

Notes
[44] - P-value for interaction between treatment group and baseline third agent (procollagen type 1-N-propeptide)

Statistical analysis 6

Statistical analysis description

Estimates are calculated from an ANCOVA model adjusting for Baseline third agent class, age, sex, BMI category, smoking status and baseline biomarker level.

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[45]

Method

ANCOVA

Parameter type

Odds ratio (OR)

Point estimate

0.817

Confidence interval

level

95%

sides

2-sided

lower limit

0.774

upper limit

0.863

Notes
[45] - P value to assess difference between treatment groups (procollagen type 1-N-propeptide)

Statistical analysis 7

Statistical analysis description

Since statistical significance at the 10% level was observed, results are presented separately per Baseline third agent.

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001 ^[46]

Method

ANCOVA

Confidence interval

Notes
[46] - P-value for interaction between treatment group and baseline third agent (osteocalcin)

Statistical analysis 8

Statistical analysis description

Estimates are calculated from an ANCOVA model adjusting for Baseline third agent class, age, sex, BMI category, smoking status and baseline biomarker level.

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[47]

Method

ANCOVA

Parameter type

Odds ratio (OR)

Point estimate

0.881

Confidence interval

level

95%

sides

2-sided

lower limit

0.823

upper limit

0.943

Notes
[47] - P value to assess difference between treatment groups (osteocalcin - NNRTI)

Statistical analysis 9

Statistical analysis description

Estimates are calculated from an ANCOVA model adjusting for Baseline third agent class, age, sex, BMI category, smoking status and baseline biomarker level.

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001 ^[48]

Method

ANCOVA

Parameter type

Odds ratio (OR)

Point estimate

0.829

Confidence interval

level

95%

sides

2-sided

lower limit

0.74

upper limit

0.93

Notes
[48] - P value to assess difference between treatment groups (osteocalcin - INI)

Statistical analysis 10

Statistical analysis description

Estimates are calculated from an ANCOVA model adjusting for Baseline third agent class, age, sex, BMI category, smoking status and baseline biomarker level.

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[49]

Method

ANCOVA

Parameter type

Odds ratio (OR)

Point estimate

0.691

Confidence interval

level

95%

sides

2-sided

lower limit

0.628

upper limit

0.759

Notes
[49] - P value to assess difference between treatment groups (osteocalcin - PI)

Statistical analysis 11

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

other ^[50]

P-value

= 0.782 ^[51]

Method

ANCOVA

Confidence interval

Notes
[50] - Since statistical significance at the 10% level was not observed, results are presented overall only.
[51] - P-value for interaction between treatment group and baseline third agent (type 1 collagen cross-linked C-telopeptide)

Statistical analysis 12

Statistical analysis description

Estimates are calculated from an ANCOVA model adjusting for Baseline third agent class, age, sex, BMI category, smoking status and baseline biomarker level.

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[52]

Method

ANCOVA

Parameter type

Odds ratio (OR)

Point estimate

0.804

Confidence interval

level

95%

sides

2-sided

lower limit

0.742

upper limit

0.872

Notes
[52] - P value to assess difference between treatment groups (type 1 collagen cross-linked C-telopeptide)

Secondary: Mean change from Baseline in interleukin 6 (IL-6) at Week 48

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End point title

Mean change from Baseline in interleukin 6 (IL-6) at Week 48

End point description

Blood biomarker samples were collected at Baseline (Day 1) and Week 48 to assess IL-6. Change from Baseline was calculated as value at indicated time point minus Baseline value.

End point type

Secondary

End point timeframe

Up to Week 48

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	233 ^[53]	243 ^[54]
Units: Nanograms (ng)/ L
arithmetic mean (standard deviation)
Nanograms (ng)/ L	0.17 ( 2.736 )	-0.18 ( 2.944 )

Notes
[53] - Safety Population
[54] - Safety Population

No statistical analyses for this end point

Secondary: Mean change from Baseline in insulin resistance based on homeostasis model assessment of insulin resistance (HOMA-IR) at Week 48

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End point title

Mean change from Baseline in insulin resistance based on homeostasis model assessment of insulin resistance (HOMA-IR) at Week 48

End point description

Blood biomarker samples were collected at Baseline (Day 1) and Week 48 to assess insulin resistance. Change from Baseline was calculated as value at indicated time point minus Baseline value. The homeostatic model assessment (HOMA) of insulin resistance (HOMA-IR) index, the product of basal glucose and insulin levels divided by 22.5 (1,2), is regarded as a simple, inexpensive, and reliable surrogate measure of insulin resistance.

End point type

Secondary

End point timeframe

Up to Week 48

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	229 ^[55]	237 ^[56]
Units: HOMA-IR Score
arithmetic mean (standard deviation)
HOMA-IR Score	-0.3 ( 5.74 )	0.51 ( 3.53 )

Notes
[55] - Safety Population
[56] - Safety Population

No statistical analyses for this end point

Secondary: Mean change from Baseline in fasting lipids at Weeks 24 and 48

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End point title

Mean change from Baseline in fasting lipids at Weeks 24 and 48

End point description

Blood samples were collected at Baseline (Day 1), Week 24 and Week 48 to assess fasting lipids which included total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol and triglycerides. Change from Baseline was calculated as value at indicated time point minus Baseline value. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles).

End point type

Secondary

End point timeframe

Up to Week 48

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	252 ^[57]	256 ^[58]
Units: mmol/ L
arithmetic mean (standard deviation)
Total cholesterol, Week 24, n=228, 223	0.076 ( 0.8398 )	0.061 ( 0.7368 )
Total cholesterol, Week 48, n=221, 218	0.089 ( 0.8488 )	0.064 ( 0.7197 )
LDL cholesterol calculation, Week 24, n=224, 217	0.165 ( 0.7065 )	0.103 ( 0.6503 )
LDL cholesterol calculation, Week 48, n=215, 211	0.108 ( 0.7178 )	0.029 ( 0.6134 )
HDL cholesterol direct, Week 24, n=228, 223	-0.03 ( 0.2601 )	-0.044 ( 0.2394 )
HDL cholesterol direct, Week 48, n=221, 218	0.023 ( 0.2757 )	0.018 ( 0.2722 )
Triglycerides, Week 24, n=228, 223	-0.154 ( 0.7324 )	-0.001 ( 0.7712 )
Triglycerides, Week 48, n=221, 218	-0.093 ( 0.9767 )	0.046 ( 0.8274 )

Notes
[57] - Safety Population
[58] - Safety Population

No statistical analyses for this end point

Secondary: Genotypic resistance data for drugs received for participants meeting confirmed virologic withdrawal criteria

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End point title

Genotypic resistance data for drugs received for participants meeting confirmed virologic withdrawal criteria

End point description

Genotypic resistance data for drugs received for participants meeting confirmed virologic withdrawal criteria are presented below. Confirmed Virologic Withdrawal (CVW) Population consisted of all participants in the ITT-E Population who met CVW (1 CVW per arm). 99999 indicate that data was Not applicable based on drugs were not received. Genotypic Resistance Data only shown for Drugs Received for Participants Meeting Confirmed Virologic Withdrawal Criteria.

End point type

Secondary

End point timeframe

Day 1

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	1 ^[59]	1 ^[60]
Units: Participants
NNRTI, RPV, Susceptible	1	99999
NNRTI, RPV, Potential low-level resistance	0	99999
NNRTI, RPV, Low-level resistance	0	99999
NNRTI, RPV, Intermediate resistance	0	99999
NNRTI, RPV, High-level resistance	0	99999
INI, DTG, Susceptible	1	99999
INI, DTG, Potential low-level resistance	0	99999
INI, DTG, Low-level resistance	0	99999
INI, DTG, Intermediate resistance	0	99999
INI, DTG, High-level resistance	0	99999
NRTI, FTC, Susceptible	99999	1
NRTI, FTC, Potential low-level resistance	99999	0
NRTI, FTC, Low-level resistance	99999	0
NRTI, FTC, Intermediate resistance	99999	0
NRTI, FTC, High-level resistance	99999	0
NRTI, TDF, Susceptible	99999	1
NRTI, TDF, Potential low-level resistance	99999	0
NRTI, TDF, Low-level resistance	99999	0
NRTI, TDF, Intermediate resistance	99999	0
NRTI, TDF, High-level resistance	99999	0
PI, DRV/r, Susceptible	99999	1
PI, DRV/r, Potential low-level resistance	99999	0
PI, DRV/r, Low-level resistance	99999	0
PI, DRV/r, Intermediate resistance	99999	0
PI, DRV/r, High-level resistance	99999	0

Notes
[59] - CVW Population
[60] - CVW Population

No statistical analyses for this end point

Secondary: Phenotypic resistance data for drugs received for participants meeting confirmed virologic withdrawal criteria

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End point title

Phenotypic resistance data for drugs received for participants meeting confirmed virologic withdrawal criteria

End point description

Phenotypic resistance data for drugs received for participants meeting confirmed virologic withdrawal criteria are presented below. Confirmed Virologic Withdrawal (CVW) Population consisted of all participants in the ITT-E Population who met CVW (1 CVW per arm). 99999 indicate that data was Not applicable based on drugs were not received. Phenotypic Resistance Data only shown for Drugs Received for Participants Meeting Confirmed Virologic Withdrawal Criteria.

End point type

Secondary

End point timeframe

Day 1

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	1 ^[61]	1 ^[62]
Units: Participants
INI, DTG, Resistant	0	99999
INI, DTG, Partially Sensitive	0	99999
INI, DTG, Sensitive	1	99999
INI, RAL, Resistant	99999	99999
INI, RAL, Sensitive	99999	99999
INI, EVG, Resistant	99999	99999
INI, EVG, Sensitive	99999	99999
NNRTI, RPV, Resistant	0	99999
NNRTI, RPV, Sensitive	1	99999
NNRTI, ETR, Resistant	99999	99999
NNRTI, ETR, Partially Sensitive	99999	99999
NNRTI, ETR, Sensitive	99999	99999
NRTI, 3TC, Resistant	99999	99999
NRTI, 3TC, Sensitive	99999	99999
NRTI, ABC, Resistant	99999	99999
NRTI, ABC, Partially Sensitive	99999	99999
NRTI, ABC, Sensitive	99999	99999
NRTI, FTC, Resistant	99999	0
NRTI, FTC, Sensitive	99999	1
NRTI, TDF, Resistant	99999	0
NRTI, TDF, Partially Sensitive	99999	0
NRTI, TDF, Sensitive	99999	1
NRTI, d4T, Resistant	99999	99999
NRTI, d4T, Sensitive	99999	99999
NRTI, ddI, Resistant	99999	99999
NRTI, ddI, Partially Sensitive	99999	99999
NRTI, ddI, Sensitive	99999	99999
PI, ATV/r, Resistant	99999	99999
PI, ATV/r, Sensitive	99999	99999
PI, DRV/r, Resistant	99999	0
PI, DRV/r, Partially Sensitive	99999	0
PI, DRV/r, Sensitive	99999	1
PI, FPV/r, Resistant	99999	99999
PI, FPV/r, Partially Sensitive	99999	99999
PI, FPV/r, Sensitive	99999	99999
PI, IDV/r, Resistant	99999	99999
PI, IDV/r, Sensitive	99999	99999
PI, LPV/r, Resistant	99999	99999
PI, LPV/r, Partially Sensitive	99999	99999
PI, LPV/r, Sensitive	99999	99999
PI, SQV/r, Resistant	99999	99999
PI, SQV/r, Partially Sensitive	99999	99999
PI, SQV/r, Sensitive	99999	99999
PI, TPV/r, Resistant	99999	99999
PI, TPV/r, Partially Sensitive	99999	99999
PI, TPV/r, Sensitive	99999	99999

Notes
[61] - CVW Population
[62] - CVW Population

No statistical analyses for this end point

Secondary: Pre-dose concentrations of DTG and RPV at Weeks 4, 24 and 48 or withdrawal in participants switching to DTG + RPV

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End point title

Pre-dose concentrations of DTG and RPV at Weeks 4, 24 and 48 or withdrawal in participants switching to DTG + RPV

End point description

Two separate blood samples for DTG and RPV were collected pre-dose at Weeks 4, 24 and 48. Pre-dose concentrations of DTG and RPV at Weeks 4, 24 and 48 or withdrawal were summarized for the participants switching to DTG + RPV in the early switch phase. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). Pharmacokinetic (PK) Parameter Population consisted of all participants who received DTG +RPV and provided at least one evaluable estimate of predose concentration (C0).

End point type

Secondary

End point timeframe

Pre-dose at Week 4, 24 and 48 or at withdrawal visit

End point values	DTG 50 mg	RPV 25 mg
Number of subjects analysed	239 ^[63]	239 ^[64]
Units: ug/ L
arithmetic mean (standard deviation)
Week 4, n=130, 130	1581.06 ( 1146.86 )	92.046 ( 138.288 )
Week 24, n=210, 210	1835.68 ( 1120.539 )	87.875 ( 39.1412 )
Week 48, n=215, 211	1915.11 ( 1304.238 )	95.405 ( 48.2978 )

Notes
[63] - PK Parameter Population
[64] - PK Parameter Population

No statistical analyses for this end point

Secondary: Pre-dose concentrations of DTG and RPV at Weeks 2, 4 and 8 in the first 20 participants who switch from efavirenz (EFV) or nevirapine (NVP) to DTG + RPV

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End point title

Pre-dose concentrations of DTG and RPV at Weeks 2, 4 and 8 in the first 20 participants who switch from efavirenz (EFV) or nevirapine (NVP) to DTG + RPV

End point description

Two blood samples were collected pre-dose for DTG and RPV at Weeks 2 and 8 only for the first 20 participants who switch from EFV or NVP to DTG + RPV. One blood sample was collected pre-dose for EFV or NVP at Week 2 for the first 20 participants who switch from EFV or NVP to DTG + RPV. PK Parameter NNRTI Subset Extra Sampling Population consisted of the first approximately 20 participants in the PK Parameter NNRTI Subset population who have extra PK samples at weeks 2 and 8. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles).

End point type

Secondary

End point timeframe

Pre-dose at Week 2, 4 and 8

End point values	DTG 50 mg	RPV 25 mg
Number of subjects analysed	26 ^[65]	26 ^[66]
Units: ug/ L
arithmetic mean (standard deviation)
Week 2, n=16, 15	821.25 ( 574.607 )	65.36 ( 31.2965 )
Week 4, n=19, 19	994 ( 581.201 )	67.374 ( 27.5663 )
Week 8, n=19, 19	1561.34 ( 1096.381 )	77.416 ( 37.7129 )

Notes
[65] - PK Parameter NNRTI Subset extra sampling Population
[66] - PK Parameter NNRTI Subset extra sampling Population

No statistical analyses for this end point

Secondary: Percentage of participants with plasma HIV 1 RNA <50 c/mL at Week 48 using snapshot algorithm by Baseline third agent treatment class

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End point title

Percentage of participants with plasma HIV 1 RNA <50 c/mL at Week 48 using snapshot algorithm by Baseline third agent treatment class

End point description

Percentage of participants with plasma HIV 1 RNA < 50 c/mL at Week 48 using the FDA snapshot algorithm was assessed by Baseline third agent class to assess the impact of Baseline third agent class (INI, NNRTI, or PI) on efficacy of DTG +RPV compared to continuation of CAR. Plasma samples were collected for HIV-1 RNA at Baseline (Day 1), Week 4, 8, 12, 24, 36 and 48. The analysis was done using cochran-mantel haenszel test stratified by current antiretroviral third-agent class. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles).

End point type

Secondary

End point timeframe

Up to Week 48

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	252 ^[67]	256 ^[68]
Units: Percentage of participants
NNRTI, n=131, 134	95	98
INI, n=46, 48	98	96
PI, n=75, 74	95	92

Notes
[67] - ITT-E Population
[68] - ITT-E Population

Statistical analysis 1

Comparison groups

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.317 ^[69]

Method

Chi-squared corrected

Confidence interval

Notes
[69] - One-sided p-value from weighted least squares chi-squared statistic. A p-value <=0.10 was used to indicate statistically significant evidence of heterogeneity in the difference in proportions across levels of each analysis strata.

Statistical analysis 2

Statistical analysis description

NNRTI: No formal non-inferiority margin has been pre-specified for secondary endpoints.

Comparison groups

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Risk difference (RD)

Point estimate

-3.1

Confidence interval

level

95%

sides

2-sided

lower limit

-7.7

upper limit

1.5

Statistical analysis 3

Statistical analysis description

INI: No formal non-inferiority margin has been pre-specified for secondary endpoints.

Comparison groups

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Risk difference (RD)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-5.1

upper limit

Statistical Analysis 4

Statistical analysis description

PI: No formal non-inferiority margin has been pre-specified for secondary endpoints.

Comparison groups

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Risk difference (RD)

Point estimate

2.8

Confidence interval

level

95%

sides

2-sided

lower limit

-5.3

upper limit

10.8

Secondary: Changes from Baseline in cluster designation (CD)4+ lymphocyte count at Week 48 by Baseline third agent treatment class

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End point title

Changes from Baseline in cluster designation (CD)4+ lymphocyte count at Week 48 by Baseline third agent treatment class

End point description

Blood for CD4 cell count assessment by flow cytometery was carried out at Baseline (Day 1), Week 4, 8, 12, 24, 36 and 48 to assess the impact of Baseline third agent class (INI, NNRTI, or PI) on efficacy, safety and tolerability of DTG +RPV compared to continuation of CAR. The full set of lymphocyte sub sets was not evaluated. Change from Baseline was calculated as value at indicated time point minus Baseline value. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles).

End point type

Secondary

End point timeframe

Baseline and up to Week 48

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	252 ^[70]	256 ^[71]
Units: Cells per mm^3
arithmetic mean (standard deviation)
NNRTI, n=124, 130	47.9 ( 142.9 )	25 ( 151.27 )
INI, n=45, 46	19.9 ( 148.63 )	39.9 ( 200.38 )
PI, n=70, 69	12.5 ( 160.27 )	74.7 ( 227.78 )

Notes
[70] - ITT-E Population
[71] - ITT-E Population

No statistical analyses for this end point

Secondary: Number of participants with any AE, AELD or AE with grade 1, 2, 3 or 4 toxicity over 48 weeks by Baseline third agent treatment class

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End point title

Number of participants with any AE, AELD or AE with grade 1, 2, 3 or 4 toxicity over 48 weeks by Baseline third agent treatment class

End point description

An AE is 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. Number of participants with any AE, AELD or AE with maximum grade toxicity experienced by any one participant over 48 weeks by Baseline third agent class (INI, NNRTI, or PI) was summarized. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles).

End point type

Secondary

End point timeframe

Up to 48 weeks

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	252 ^[72]	256 ^[73]
Units: Participants
Any AE, NNRTI, n=131, 134	102	98
Any AE, INI, n=46, 48	38	34
Any AE, PI, n=75, 74	60	58
NNRTI, Maximum toxicity Grade 1 AE, n=131, 134	69	72
NNRTI, Maximum toxicity Grade 2 AE, n=131, 134	27	23
NNRTI, Maximum toxicity Grade 3 AE, n=131, 134	5	2
NNRTI, Maximum toxicity Grade 4 AE, n=131, 134	1	1
INI, Maximum toxicity Grade 1 AE, n=46, 48	28	20
INI, Maximum toxicity Grade 2 AE, n=46, 48	7	12
INI, Maximum toxicity Grade 3 AE, n=46, 48	2	2
INI, Maximum toxicity Grade 4 AE, n=46, 48	1	0
PI, Maximum toxicity Grade 1 AE, n=75, 74	31	30
PI, Maximum toxicity Grade 2 AE, n=75, 74	23	18
PI, Maximum toxicity Grade 3 AE, n=75, 74	4	9
PI, Maximum toxicity Grade 4 AE, n=75, 74	2	1
AELD, NNRTI, n=131, 134	3	0
AELD, INI, n=46, 48	2	0
AELD, PI, n=75, 74	4	2

Notes
[72] - Safety Population
[73] - Safety Population

No statistical analyses for this end point

Secondary: Number of participants with maximum post-baseline emergent chemistry toxicities over 48 weeks by Baseline third agent treatment class

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End point title

Number of participants with maximum post-baseline emergent chemistry toxicities over 48 weeks by Baseline third agent treatment class

End point description

Blood samples were collected at Baseline (Day 1) and at Week 4, 8, 12, 24, 36 and 48 to evaluate ALT, albumin, ALP, AST, total bilirubin, chloride, creatinine, glucose, potassium, phosphate, sodium, BUN, total carbon dioxide, lipase, creatine phosphokinase and creatinine clearance. Change from Baseline was calculated as value at indicated time point minus Baseline value. Number of participants who experienced maximum toxicity grade post-baseline in chemistry parameters over 48 weeks by Baseline third agent treatment class (INI, NNRTI, PI) was summarized. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles).

End point type

Secondary

End point timeframe

Up to 48 weeks

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	252 ^[74]	256 ^[75]
Units: Participants
NNRTI, Grades 1, n=131, 134	47	42
NNRTI, Grades 2, n=131, 134	32	48
NNRTI, Grades 3, n=131, 134	13	13
NNRTI, Grades 4, n=131, 134	2	3
INI, Grades 1, n= 46, 48	13	11
INI, Grades 2, n= 46, 48	19	15
INI, Grades 3, n= 46, 48	1	1
INI, Grades 4, n= 46, 48	3	2
PI, Grades 1, n= 75, 74	35	25
PI, Grades 2, n= 75, 74	10	23
PI, Grades 3, n= 75, 74	8	9
PI, Grades 4, n= 75, 74	0	4

Notes
[74] - Safety Population
[75] - Safety Population

No statistical analyses for this end point

Secondary: Number of participants with maximum post-baseline emergent hematology toxicities over 48 weeks by Baseline third agent treatment class

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End point title

Number of participants with maximum post-baseline emergent hematology toxicities over 48 weeks by Baseline third agent treatment class

End point description

Blood samples were collected at Baseline (Day 1) and at Week 4, 8, 12, 24, 36 and 48 to evaluate hemoglobin, hematocrit, basophils, eosinophils, lymphocytes, monocytes, neutrophils, MCV, RBC count, WBC count and platelet count. Change from Baseline was calculated as value at indicated time point minus Baseline value. Number of participants who experienced maximum toxicity grade post-baseline in hematology parameters over 48 weeks by Baseline third agent treatment class (INSTI, NNRTI, PI) was summarized.

End point type

Secondary

End point timeframe

Up to 48 weeks

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	252 ^[76]	256 ^[77]
Units: Participants
NNRTI; Grade 1; n= 131, 134	5	3
NNRTI; Grade 2; n= 131, 134	1	1
NNRTI; Grade 3; n= 131, 134	1	1
NNRTI; Grade 4; n= 131, 134	0	1
INI; Grade 1; n= 46, 48	2	2
INI; Grade 2; n= 46, 48	1	0
INI; Grade 3; n= 46, 48	0	0
INI; Grade 4; n= 46, 48	0	0
PI; Grade 1; n= 75, 74	4	6
PI; Grade 2; n= 75, 74	1	1
PI; Grade 3; n= 75, 74	2	0
PI; Grade 4; n= 75, 74	0	0

Notes
[76] - Safety Population
[77] - Safety Population

No statistical analyses for this end point

Secondary: Number of participants with observed genotypic resistance for participants meeting virologic withdrawal criteria by Baseline third agent treatment class

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End point title

Number of participants with observed genotypic resistance for participants meeting virologic withdrawal criteria by Baseline third agent treatment class

End point description

For all participants who meet virologic withdrawal criteria, plasma samples with HIV-1 RNA level >=200 c/mL were to be analyzed in an attempt to obtain genotype data on as many samples as possible. Samples for drug resistance testing (genotypic) were to be collected at Day 1. Number of participants with genotypic resistance to CAR and to DTG or RPV for those meeting virologic withdrawal criteria in subgroups stratified based on Baseline third agent treatment class (INSTI, NNRTI, PI) were to be summarized. This outcome has not been analyzed as the number of participants was low (1 CVW per arm) and summaries by Baseline third agent were not provided. Therefore, data are not available for this outcome measure due to the insufficient number of participants with events.

End point type

Secondary

End point timeframe

Day 1

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	0 ^[78]	0 ^[79]
Units: Participants
Participants

Notes
[78] - CVW Population
[79] - CVW Population

No statistical analyses for this end point

Secondary: Number of participants with observed phenotypic resistance for participants meeting virologic withdrawal criteria by Baseline third agent treatment class

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End point title

Number of participants with observed phenotypic resistance for participants meeting virologic withdrawal criteria by Baseline third agent treatment class

End point description

For all participants who meet virologic withdrawal criteria, plasma samples with HIV-1 RNA level >=200 c/mL were to be analyzed in an attempt to obtain phenotype data on as many samples as possible. Samples for drug resistance testing (phenotypic) were to be collected at Day 1. Number of participants with phenotypic resistance to CAR and to DTG or RPV for those meeting virologic withdrawal criteria in subgroups stratified based on Baseline third agent treatment class (INSTI, NNRTI, PI) were to be summarized. This outcome was not analyzed as the number of participants was low (1 CVW per arm) and summaries by Baseline third agent were not provided. Therefore, data are not available for this outcome measure due to the insufficient number of participants with events.

End point type

Secondary

End point timeframe

Day 1

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	0 ^[80]	0 ^[81]
Units: Participants
Participants

Notes
[80] - CVW Population
[81] - CVW Population

No statistical analyses for this end point

Secondary: Change from Baseline in fasting lipids at Weeks 24 and 48 by Baseline third agent treatment class

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End point title

Change from Baseline in fasting lipids at Weeks 24 and 48 by Baseline third agent treatment class

End point description

Blood samples were collected at Baseline (Day 1), 24 and 48 to assess fasting lipids which included total cholesterol (CHO), LDL cholesterol, HDL cholesterol and triglycerides. Change from Baseline was calculated as value at indicated time point minus Baseline value. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). 99999 indicate that data were not available.

End point type

Secondary

End point timeframe

Up to Week 48

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	252 ^[82]	256 ^[83]
Units: mmol/ mL
arithmetic mean (standard deviation)
CHO, Week 24, overall, n=228, 223	3.239 ( 18.1556 )	2.375 ( 14.8357 )
CHO, Week 48, overall, n=221, 218	3.596 ( 18.7072 )	2.472 ( 14.7202 )
CHO, Week 24, NNRTI, n=0, 118	99999 ( 99999 )	3.383 ( 13.3685 )
CHO, Week 48, NNRTI, n=0, 118	99999 ( 99999 )	4.099 ( 13.8992 )
CHO, Week 24, INI, n=0, 44	99999 ( 99999 )	1.288 ( 14.8933 )
CHO, Week 48, INI, n=0, 43	99999 ( 99999 )	0.524 ( 15.3143 )
CHO, Week 24, PI, n=0, 61	99999 ( 99999 )	1.211 ( 17.3972 )
CHO, Week 48, PI, n=0, 57	99999 ( 99999 )	0.575 ( 15.7475 )
HDL CHO direct, Overall, Week 24, n=228, 223	0.017 ( 18.7575 )	-2.478 ( 16.6754 )
HDL CHO direct, Overall, Week 48, n=221, 218	3.975 ( 21.1039 )	3.095 ( 18.8909 )
HDL CHO direct, NNRTI, Week 24, n=0, 118	99999 ( 99999 )	0.062 ( 15.93 )
HDL CHO direct, NNRTI, Week 48, n=0, 118	99999 ( 99999 )	4.818 ( 16.2253 )
HDL CHO direct, INI, Week 24, n=0, 44	99999 ( 99999 )	-4.968 ( 16.2973 )
HDL CHO direct, INI, Week 48, n=0, 43	99999 ( 99999 )	0.539 ( 22.6496 )
HDL CHO direct, PI, Week 24, n=0, 61	99999 ( 99999 )	-5.594 ( 17.7923 )
HDL CHO direct, PI, Week 48, n=0, 57	99999 ( 99999 )	1.457 ( 20.8346 )
LDL CHO calculation, Overall, Week 24, n=224, 217	11.504 ( 36.9087 )	6.196 ( 24.0104 )
LDL CHO calculation, Overall, Week 48, n=215, 211	8.257 ( 33.0405 )	3.258 ( 22.3644 )
LDL CHO calculation, NNRTI, Week 24, n=0, 116	99999 ( 99999 )	6.816 ( 20.9081 )
LDL CHO calculation, NNRTI, Week 48, n=0, 114	99999 ( 99999 )	4.92 ( 20.93 )
LDL CHO calculation, INI, Week 24, n=0, 44	99999 ( 99999 )	6.355 ( 24.1747 )
LDL CHO calculation, INI, Week 48, n=0, 43	99999 ( 99999 )	3.49 ( 23.3198 )
LDL CHO calculation, PI, Week 24, n=0, 57	99999 ( 99999 )	4.813 ( 29.5705 )
LDL CHO calculation, PI, Week 48, n=0, 54	99999 ( 99999 )	-0.434 ( 24.4332 )
Triglycerides, Overall, Week 24, n=228, 223	0.096 ( 55.6357 )	8.649 ( 48.8249 )
Triglycerides, Overall, Week 48, n=221, 218	3.605 ( 54.4914 )	11.068 ( 54.6321 )
Triglycerides, NNRTI, Week 24, n=0, 118	99999 ( 99999 )	6.867 ( 44.8605 )
Triglycerides, NNRTI, Week 48, n=0, 118	99999 ( 99999 )	10.215 ( 58.4055 )
Triglycerides, INI, Week 24, n=0, 44	99999 ( 99999 )	8.386 ( 54.1265 )
Triglycerides, INI, Week 48, n=0, 43	99999 ( 99999 )	4.644 ( 48.8708 )
Triglycerides, PI, Week 24, n=0, 61	99999 ( 99999 )	12.283 ( 52.6943 )
Triglycerides, PI, Week 48, n=0, 57	99999 ( 99999 )	17.681 ( 50.6912 )

Notes
[82] - Safety Population
[83] - Safety Population

No statistical analyses for this end point

Secondary: Change from Baseline in pre-specified treatment symptoms using the Symptom Distress Module at Weeks 4, 24 and 48 or withdrawal from the study

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End point title

Change from Baseline in pre-specified treatment symptoms using the Symptom Distress Module at Weeks 4, 24 and 48 or withdrawal from the study

End point description

The Symptom Distress Module, also called the HIV Symptom Index or Symptoms Impact Questionnaire, is a 20-item self-reported measure that addresses the presence and perceived distress linked to symptoms commonly associated with HIV or its treatment. Between and within treatment group comparisons were assessed on change from Baseline in pre-specified treatment symptoms using the Symptom Distress Module at Weeks 4, 24 and 48 or withdrawal from the study. Change from Baseline in Symptom count and symptom bother score have been summarized. The symptom bother score is based on the score for each symptom present ranging from 1 (it doesn't bother me) to 4 (it bothers me a lot). The symptom bother score ranges from 0 to 80. Last observation carried forward (LOCF) was used as primary method of analysis. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles).

End point type

Secondary

End point timeframe

Up to Week 48

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	252 ^[84]	256 ^[85]
Units: Scores on a scale
arithmetic mean (standard deviation)
Symptom count, Week 4, n=212, 197	-1.6 ( 4.19 )	0.2 ( 4.26 )
Symptom count, Week 24, n=214, 201	-0.8 ( 5.19 )	-0.2 ( 4.06 )
Symptom count, Week 48, n=214, 201	-0.4 ( 5.52 )	0 ( 4.49 )
Symptom Bother Score, Week 4, n=212, 197	-3 ( 7.25 )	-0.8 ( 7.82 )
Symptom Bother Score, Week 24, n=214, 201	-1.7 ( 8.47 )	-1.3 ( 8.53 )
Symptom Bother Score, Week 48, n=214, 201	-1.4 ( 8.32 )	-0.7 ( 9.03 )

Notes
[84] - ITT-E Population
[85] - ITT-E Population

Statistical analysis 1

Comparison groups

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.94 ^[86]

Method

ANCOVA

Confidence interval

Notes
[86] - P-value for interaction between treatment group and Baseline symptom bother score (Week 4)

Statistical analysis 2

Statistical analysis description

Estimates are calculated from an ANCOVA model adjusting for age, Baseline third agent, gender, race and baseline score.

Comparison groups

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[87]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-2.924

Confidence interval

level

95%

sides

2-sided

lower limit

-4.26

upper limit

-1.588

Notes
[87] - P value to assess difference between treatment groups (Week 4)

Statistical analysis 3

Comparison groups

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.001 ^[88]

Method

ANCOVA

Confidence interval

Notes
[88] - P-value for interaction between treatment group and Baseline symptom bother score (Week 24)

Statistical analysis 4

Statistical analysis description

Estimates are calculated from an ANCOVA model adjusting for age, Baseline third agent, gender, race and baseline score.

Comparison groups

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.11 ^[89]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-1.192

Confidence interval

level

95%

sides

2-sided

lower limit

-2.656

upper limit

0.271

Notes
[89] - P value to assess difference between treatment groups (Week 24)

Statistical analysis 5

Comparison groups

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.048 ^[90]

Method

ANCOVA

Confidence interval

Notes
[90] - P-value for interaction between treatment group and Baseline symptom bother score (Week 48)

Statistical analysis 6

Statistical analysis description

Estimates are calculated from an ANCOVA model adjusting for age, Baseline third agent, gender, race and baseline score.

Comparison groups

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.038 ^[91]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-1.569

Confidence interval

level

95%

sides

2-sided

lower limit

-3.048

upper limit

-0.09

Notes
[91] - P value to assess difference between treatment groups (Week 48)

Secondary: Change from Baseline treatment satisfaction using the HIV treatment satisfaction questionnaire (HIV TSQ) at Weeks 4, 24 and 48 or withdrawal from the study

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End point title

Change from Baseline treatment satisfaction using the HIV treatment satisfaction questionnaire (HIV TSQ) at Weeks 4, 24 and 48 or withdrawal from the study

End point description

The HIV TSQ is a 10-item self-reported scale that measures overall satisfaction with treatment and by specific domains e.g., convenience, flexibility. Each item is scored 0-6 where a higher score indicates the greater improvement in the past few weeks. These items are summed up to produce a treatment satisfaction total score (0 to 60) and 2 subscales: general satisfaction/clinical and lifestyle/ease subscales (0 to 30). The HIV TSQ was administered as a paper questionnaire. Between and within treatment group comparisons were assessed on change from Baseline treatment satisfaction using the HIV TSQ at Weeks 4, 24 and 48 or withdrawal from the study. Total score, lifestyle/ease score and General satisfaction/clinical sub-score (CS) have been summarized. LOCF was used as primary method of analysis. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles).

End point type

Secondary

End point timeframe

Up to Week 48

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	252 ^[92]	256 ^[93]
Units: Scores on a scale
median (full range (min-max))
Total score, Week 4, n=250, 249	0 (-16 to 33)	0 (-25 to 21)
Total score, Week 24, n=252, 254	1 (-18 to 33)	0 (-28 to 28)
Total score, Week 48, n=252, 254	0.5 (-24 to 33)	0 (-28 to 20)
lifestyle/ease Sub-score, Week 4, n=248, 249	0 (-7 to 15)	0 (-9 to 13)
lifestyle/ease Sub-score, Week 24, n=252, 254	0 (-11 to 15)	0 (-14 to 12)
lifestyle/ease Sub-score, Week 48, n=252, 254	0 (-13 to 16)	0 (-14 to 13)
General Satisfaction/CS, Week 4, n=249, 249	0 (-10 to 18)	0 (-16 to 13)
General Satisfaction/CS, Week 24, n=252, 254	0 (-7 to 18)	0 (-14 to 17)
General Satisfaction/CS, Week 48, n=252, 254	0 (-14 to 18)	0 (-14 to 10)

Notes
[92] - ITT-E Population
[93] - ITT-E Population

Statistical analysis 1

Comparison groups

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002 ^[94]

Method

Wilcoxon rank sum test

Confidence interval

Notes
[94] - P-value to assess HIVTSQs Total Score difference between treatment groups (Week 4)

Statistical analysis 2

Comparison groups

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[95]

Method

Wilcoxon rank sum test

Confidence interval

Notes
[95] - P-value to assess HIVTSQs Total Score difference between treatment groups (Week 24)

Statistical analysis 3

Comparison groups

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.024 ^[96]

Method

Wilcoxon rank sum test

Confidence interval

Notes
[96] - P-value to assess HIVTSQs Total score difference between treatment groups (Week 48)

Statistical analysis 4

Comparison groups

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[97]

Method

Wilcoxon rank sum test

Confidence interval

Notes
[97] - P-value to assess HIVTSQs lifestyle/ease sub- score difference between treatment groups (Week 4)

Statistical analysis 5

Comparison groups

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[98]

Method

Wilcoxon rank sum test

Confidence interval

Notes
[98] - P-value to assess HIVTSQs lifestyle/ease sub- score difference between treatment groups (Week 24)

Statistical analysis 6

Comparison groups

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.005 ^[99]

Method

Wilcoxon rank sum test

Confidence interval

Notes
[99] - P-value to assess HIVTSQs lifestyle/ease sub- score difference between treatment groups (Week 48)

Statistical analysis 7

Comparison groups

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.063 ^[100]

Method

Wilcoxon rank sum test

Confidence interval

Notes
[100] - P-value to assess HIVTSQs General satisfaction/CS sub- score difference between treatment groups (Week 4)

Statistical analysis 8

Comparison groups

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002 ^[101]

Method

Wilcoxon rank sum test

Confidence interval

Notes
[101] - P-value to assess HIVTSQs General satisfaction/CS sub- score difference between treatment groups (Week 24)

Statistical analysis 9

Comparison groups

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

508

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.099 ^[102]

Method

Wilcoxon rank sum test

Confidence interval

Notes
[102] - P-value to assess HIVTSQs General satisfaction/CS sub- score difference between treatment groups (Week 48)

Adverse events

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Timeframe for reporting adverse events

On-treatment SAEs and non-serious AEs were collected from the start of the study treatment up to 52 weeks (until interim analysis). They were planned to be assessed up to 148 weeks and every 12 weeks after 148 weeks.

Adverse event reporting additional description

On treatment SAEs and non-serious AEs were reported for the Safety Population.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

Current antiretroviral regimen

Reporting group description

Participants continued to receive their current antiretroviral regimen (two nucleoside reverse transcriptase inhibitors [NRTIs] + a third agent). A third agent included either integrase inhibitor (INI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or protease inhibitor (PI). CAR was administered according to the approved labeling in an open-label fashion up to Week 52 during early switch phase.

Reporting group title

DTG + RPV

Reporting group description

Participants received DTG 50 milligrams (mg) + RPV 25 mg together once daily at approximately the same time, with a meal, in an open-label fashion up to Week 52 during early switch phase.

Serious adverse events	Current antiretroviral regimen	DTG + RPV
Total subjects affected by serious adverse events
subjects affected / exposed	12 / 256 (4.69%)	9 / 252 (3.57%)
number of deaths (all causes)	1	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer
subjects affected / exposed	1 / 256 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hodgkin's disease mixed cellularity stage unspecified
subjects affected / exposed	0 / 256 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	1 / 256 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Plasmablastic lymphoma
subjects affected / exposed	0 / 256 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Wrist fracture
subjects affected / exposed	0 / 256 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Toxic encephalopathy
subjects affected / exposed	1 / 256 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Non-cardiac chest pain
subjects affected / exposed	1 / 256 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 256 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Anal fistula
subjects affected / exposed	1 / 256 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 256 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Proctitis
subjects affected / exposed	1 / 256 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Drug-induced liver injury
subjects affected / exposed	0 / 256 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Panic attack
subjects affected / exposed	0 / 256 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion
subjects affected / exposed	1 / 256 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 256 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 256 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis C
subjects affected / exposed	1 / 256 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 256 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonsillar abscess
subjects affected / exposed	1 / 256 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 256 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal abscess
subjects affected / exposed	1 / 256 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thyroglossal cyst infection
subjects affected / exposed	1 / 256 (0.39%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Current antiretroviral regimen	DTG + RPV
Total subjects affected by non serious adverse events
subjects affected / exposed	68 / 256 (26.56%)	65 / 252 (25.79%)
Nervous system disorders
Headache
subjects affected / exposed	17 / 256 (6.64%)	23 / 252 (9.13%)
occurrences all number	19	24
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	16 / 256 (6.25%)	21 / 252 (8.33%)
occurrences all number	17	23
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	19 / 256 (7.42%)	9 / 252 (3.57%)
occurrences all number	19	10
Infections and infestations
Nasopharyngitis
subjects affected / exposed	28 / 256 (10.94%)	28 / 252 (11.11%)
occurrences all number	32	34

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Were there any global substantial amendments to the protocol? Yes

26 Feb 2015

Protocol was amended to include additional pharmacokinetic visits for the first 20 participants in the NNRTI subset who switch from EFV or NVP in the early switch phase and additional pharmacokinetic visits for all participants in the late switch phase, addition of stratification by planned participation in the DEXA substudy, revisions to inclusion and exclusion criteria, revision to the definition of study completion, edits to the time and events table, revisions to suicidal risk monitoring section, and minor clarifications and corrections of typographical errors.

08 Jun 2015

Protocol was amended to include reasons for switch for PI-class aligned with other ART class switches, revisions to stratified analysis of the primary endpoint, revisions to virologic withdrawal criteria, references to study drug versus investigational product , and minor clarifications and corrections of typographical errors.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of participants with plasma human immunodeficiency virus (HIV) 1 ribonucleic acid (RNA) <50 copies/milliliter (c/mL) at Week 48 using snapshot algorithm

Primary: Percentage of participants with plasma human immunodeficiency virus (HIV) 1 ribonucleic acid (RNA) <50 copies/milliliter (c/mL) at Week 48 using snapshot algorithm

Secondary: Changes from Baseline in cluster designation (CD)4+ lymphocyte count at Weeks 24 and 48

Secondary: Changes from Baseline in cluster designation (CD)4+ lymphocyte count at Weeks 24 and 48

Secondary: Percentage of participants with plasma HIV 1 RNA <50 c/mL at Week 24 using snapshot algorithm

Secondary: Percentage of participants with plasma HIV 1 RNA <50 c/mL at Week 24 using snapshot algorithm

Secondary: Number of participants with common non-serious adverse event (AE), any serious AE (SAE), AE of maximum toxicity grade 1, 2, 3 or 4, AE leading to discontinuation (AELD)

Secondary: Number of participants with common non-serious adverse event (AE), any serious AE (SAE), AE of maximum toxicity grade 1, 2, 3 or 4, AE leading to discontinuation (AELD)

Secondary: Number of participants with maximum post-baseline emergent chemistry toxicities over 48 weeks

Secondary: Number of participants with maximum post-baseline emergent chemistry toxicities over 48 weeks

Secondary: Number of participants with maximum post-baseline emergent hematology toxicities over 48 weeks

Secondary: Number of participants with maximum post-baseline emergent hematology toxicities over 48 weeks

Secondary: Mean change from Baseline in high-sensitivity C-reactive protein (hs-CRP) at Week 48

Secondary: Mean change from Baseline in high-sensitivity C-reactive protein (hs-CRP) at Week 48

Secondary: Mean change from Baseline in cystatin C at Week 48

Secondary: Mean change from Baseline in cystatin C at Week 48

Secondary: Mean change from Baseline in D-Dimer at Week 48

Secondary: Mean change from Baseline in D-Dimer at Week 48

Secondary: Mean change from Baseline in fatty acid binding protein 2 (FABP) and soluble CD14 at Week 48

Secondary: Mean change from Baseline in fatty acid binding protein 2 (FABP) and soluble CD14 at Week 48

Secondary: Mean change from Baseline in Soluble CD163 and oxidized low density lipoprotein (LDL) at Week 48

Secondary: Mean change from Baseline in Soluble CD163 and oxidized low density lipoprotein (LDL) at Week 48

Secondary: Mean change from Baseline in retinol binding protein (RBP), serum creatinine and glucose at Week 48

Secondary: Mean change from Baseline in retinol binding protein (RBP), serum creatinine and glucose at Week 48

Secondary: Mean change from Baseline in urine phosphate at Week 48

Secondary: Mean change from Baseline in urine phosphate at Week 48

Secondary: Mean change from Baseline in beta-2-microglobulin (B2M) (blood and urine), urine RBP and 25 hydroxy-vitamin D at Week 48

Secondary: Mean change from Baseline in beta-2-microglobulin (B2M) (blood and urine), urine RBP and 25 hydroxy-vitamin D at Week 48

Secondary: Mean change from Baseline in urine albumin/creatinine ratio and urine protein/creatinine ratio at Week 48

Secondary: Mean change from Baseline in urine albumin/creatinine ratio and urine protein/creatinine ratio at Week 48

Secondary: Mean change from Baseline in bone-specific alkaline phosphatase, procollagen 1 N-terminal propeptide, osteocalcin, Type I Collagen C-Telopeptides and soluble vascular cell adhesion molecule (sVCAM) at Week 48

Secondary: Mean change from Baseline in bone-specific alkaline phosphatase, procollagen 1 N-terminal propeptide, osteocalcin, Type I Collagen C-Telopeptides and soluble vascular cell adhesion molecule (sVCAM) at Week 48

Secondary: Mean change from Baseline in interleukin 6 (IL-6) at Week 48

Secondary: Mean change from Baseline in interleukin 6 (IL-6) at Week 48

Secondary: Mean change from Baseline in insulin resistance based on homeostasis model assessment of insulin resistance (HOMA-IR) at Week 48

Secondary: Mean change from Baseline in insulin resistance based on homeostasis model assessment of insulin resistance (HOMA-IR) at Week 48

Secondary: Mean change from Baseline in fasting lipids at Weeks 24 and 48

Secondary: Mean change from Baseline in fasting lipids at Weeks 24 and 48

Secondary: Genotypic resistance data for drugs received for participants meeting confirmed virologic withdrawal criteria

Secondary: Genotypic resistance data for drugs received for participants meeting confirmed virologic withdrawal criteria

Secondary: Phenotypic resistance data for drugs received for participants meeting confirmed virologic withdrawal criteria

Secondary: Phenotypic resistance data for drugs received for participants meeting confirmed virologic withdrawal criteria

Secondary: Pre-dose concentrations of DTG and RPV at Weeks 4, 24 and 48 or withdrawal in participants switching to DTG + RPV

Secondary: Pre-dose concentrations of DTG and RPV at Weeks 4, 24 and 48 or withdrawal in participants switching to DTG + RPV

Secondary: Pre-dose concentrations of DTG and RPV at Weeks 2, 4 and 8 in the first 20 participants who switch from efavirenz (EFV) or nevirapine (NVP) to DTG + RPV

Secondary: Pre-dose concentrations of DTG and RPV at Weeks 2, 4 and 8 in the first 20 participants who switch from efavirenz (EFV) or nevirapine (NVP) to DTG + RPV

Secondary: Percentage of participants with plasma HIV 1 RNA <50 c/mL at Week 48 using snapshot algorithm by Baseline third agent treatment class

Secondary: Percentage of participants with plasma HIV 1 RNA <50 c/mL at Week 48 using snapshot algorithm by Baseline third agent treatment class

Secondary: Changes from Baseline in cluster designation (CD)4+ lymphocyte count at Week 48 by Baseline third agent treatment class

Secondary: Changes from Baseline in cluster designation (CD)4+ lymphocyte count at Week 48 by Baseline third agent treatment class

Secondary: Number of participants with any AE, AELD or AE with grade 1, 2, 3 or 4 toxicity over 48 weeks by Baseline third agent treatment class

Secondary: Number of participants with any AE, AELD or AE with grade 1, 2, 3 or 4 toxicity over 48 weeks by Baseline third agent treatment class

Secondary: Number of participants with maximum post-baseline emergent chemistry toxicities over 48 weeks by Baseline third agent treatment class

Secondary: Number of participants with maximum post-baseline emergent chemistry toxicities over 48 weeks by Baseline third agent treatment class

Secondary: Number of participants with maximum post-baseline emergent hematology toxicities over 48 weeks by Baseline third agent treatment class

Secondary: Number of participants with maximum post-baseline emergent hematology toxicities over 48 weeks by Baseline third agent treatment class

Secondary: Number of participants with observed genotypic resistance for participants meeting virologic withdrawal criteria by Baseline third agent treatment class

Secondary: Number of participants with observed genotypic resistance for participants meeting virologic withdrawal criteria by Baseline third agent treatment class

Secondary: Number of participants with observed phenotypic resistance for participants meeting virologic withdrawal criteria by Baseline third agent treatment class

Secondary: Number of participants with observed phenotypic resistance for participants meeting virologic withdrawal criteria by Baseline third agent treatment class

Secondary: Change from Baseline in fasting lipids at Weeks 24 and 48 by Baseline third agent treatment class

Secondary: Change from Baseline in fasting lipids at Weeks 24 and 48 by Baseline third agent treatment class

Secondary: Change from Baseline in pre-specified treatment symptoms using the Symptom Distress Module at Weeks 4, 24 and 48 or withdrawal from the study

Secondary: Change from Baseline in pre-specified treatment symptoms using the Symptom Distress Module at Weeks 4, 24 and 48 or withdrawal from the study

Secondary: Change from Baseline treatment satisfaction using the HIV treatment satisfaction questionnaire (HIV TSQ) at Weeks 4, 24 and 48 or withdrawal from the study

Secondary: Change from Baseline treatment satisfaction using the HIV treatment satisfaction questionnaire (HIV TSQ) at Weeks 4, 24 and 48 or withdrawal from the study

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)