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

Summary
EudraCT number	2014-005148-16
Trial protocol	ES DE GB FR IT
Global end of trial date

Results information
Results version number	v3
This version publication date	11 Nov 2017
First version publication date	12 Aug 2017
Other versions	v1 , v2 , v4 , v5 , v6
Version creation reason	Correction of full data set Add DEXA sub-study link

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

201637

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

21 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: 24

Country: Number of subjects enrolled

Australia: 34

Country: Number of subjects enrolled

Canada: 38

Country: Number of subjects enrolled

France: 30

Country: Number of subjects enrolled

Germany: 39

Country: Number of subjects enrolled

Italy: 18

Country: Number of subjects enrolled

Russian Federation: 30

Country: Number of subjects enrolled

Spain: 245

Country: Number of subjects enrolled

Taiwan: 17

Country: Number of subjects enrolled

United States: 40

Country: Number of subjects enrolled

United Kingdom: 3

Worldwide total number of subjects

518

EEA total number of subjects

335

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)

507

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 60 centers in 11 countries.

Screening details

Total 670 participants were screened (152 failed), 518 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 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

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.

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.

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 INSTI, 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	261	255
Completed	245	239
Not completed	16	16
Adverse event, serious fatal	1	-
Consent withdrawn by subject	2	7
Physician decision	-	1
Adverse event, non-fatal	10	1
Subject reached stopping criteria	1	1
Lost to follow-up	1	1
Lack of efficacy	1	2
Protocol deviation	-	3

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 670 subjects were screened, 518 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	261	255
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	43.3 ± 11.34	43.2 ± 9.64	-
Gender categorical
Units: Subjects
Female	62	57	119
Male	199	198	397
Race/Ethnicity, Customized
Units: Subjects
American Indian or Alaska Native	11	8	19
Central/South Asian Heritage	0	1	1
Japanese/East Asian (EA) Heritage (H.)/South EA H.	13	15	28
Black/African American	13	20	33
Native Hawaiian or other Pacific Islander	1	0	1
White	223	210	433
African American/ African H. and White	0	1	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 Week 0 (Day 1), Week 4, 8, 12, 24, 36 and 48. Treatment with DTG + RPV were 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	261 ^[1]	255 ^[2]
Units: Percentage of participants
Participants	94	94

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, INSTI).

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

Method

Parameter type

Risk difference (RD)

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-3.9

upper limit

4.2

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	261 ^[4]	255 ^[5]
Units: Cells per millimeter (mm)^3
arithmetic mean (standard deviation)
Week 24, n=251, 250	42 ± 172.29	42.4 ± 164.85
Week 48, n=245, 241	28 ± 169.35	18.4 ± 159.34

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	261 ^[6]	255 ^[7]
Units: Percentage of participants
Percentage of participants	97	98

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, INSTI). 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

516

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Risk difference (RD)

Point estimate

-1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-4

upper limit

1.8

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 and 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 and 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, drug related AE or SAE, AELD or AE with maximum grade toxicity 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 Week 52

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	261 ^[8]	255 ^[9]
Units: Participants
Common non-serious AE	61	59
Any SAE	18	9
Maximum toxicity Grade 1 AE	119	122
Maximum toxicity Grade 2 AE	59	47
Maximum toxicity Grade 3 AE	16	4
Maximum toxicity Grade 4 AE	1	1
AELD	12	1

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. For all laboratory parameters, one assessment out of range was sufficient to be considered a chemistry toxicity.

End point type

Secondary

End point timeframe

Up to 48 weeks

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	261 ^[10]	255 ^[11]
Units: Participants
Grade 1	92	80
Grade 2	72	79
Grade 3	11	16
Grade 4	1	10

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.

End point type

Secondary

End point timeframe

Up to 48 weeks

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	261 ^[12]	255 ^[13]
Units: Participants
Grade 1	11	11
Grade 2	2	2
Grade 3	3	0
Grade 4	1	0

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 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	246 ^[14]	239 ^[15]
Units: mg/ Liter (L)
arithmetic mean (standard deviation)
mg/ Liter (L)	0.1 ± 5.383	0.8 ± 8.527

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	246 ^[16]	237 ^[17]
Units: mg/L
arithmetic mean (standard deviation)
mg/L	-0.02 ± 0.11	-0.01 ± 0.108

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	239 ^[18]	228 ^[19]
Units: Nanomole (nmol)/L FEU
arithmetic mean (standard deviation)
Nanomole (nmol)/L FEU	0.01 ± 1.629	-0.13 ± 2.932

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	261 ^[20]	255 ^[21]
Units: Nanogram/milliliter
arithmetic mean (standard deviation)
FABP, n=245, 236	-1.5 ± 1.278	-0.99 ± 1.441
Soluble CD14, n=245, 237	456.69 ± 731.833	802.26 ± 878.304

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	261 ^[22]	255 ^[23]
Units: Microgram/Liter
arithmetic mean (standard deviation)
Soluble CD163, n=245, 236	65.38 ± 180.869	53.94 ± 215.621
Oxidized LDL, n=245, 237	60.87 ± 504.345	13.92 ± 575.305

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	261 ^[24]	255 ^[25]
Units: mg/ deciliter (dL)
arithmetic mean (standard deviation)
RBP, n=245, 237	-0.13 ± 0.825	0 ± 0.872
Serum creatinine, n=245, 241	0.1 ± 0.1053	-0.003 ± 0.0847
Glucose, n=242, 235	0.187 ± 19.5808	3.22 ± 10.0987

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	235 ^[26]	229 ^[27]
Units: Millimoles (mmol)/ L
arithmetic mean (standard deviation)
Millimoles (mmol)/ L	1.335 ± 16.7211	-0.798 ± 15.3771

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. 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	261 ^[28]	255 ^[29]
Units: Nanomoles (nmol)/ L
arithmetic mean (standard deviation)
B2M, blood, n=245, 238	-16.88 ± 34.8933	-4.7501 ± 43.04355
25 hydroxy-vitamin D, n=243, 239	-13.9 ± 25.3	-9.2 ± 19.55
Urine B2M, n=72, 78	-173.282 ± 1311.24142	62.3209 ± 391.32049
Urine RBP, n=232, 224	-6.8123 ± 24.0965	-0.0631 ± 11.99886

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

Statistical analysis 1

Comparison groups

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

516

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

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.011 ^[32]

Method

ANCOVA

Parameter type

Odds ratio (OR)

Point estimate

0.861

Confidence interval

level

95%

sides

2-sided

lower limit

0.767

upper limit

0.967

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

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

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.745 ^[33]

Method

ANCOVA

Parameter type

Odds ratio (OR)

Point estimate

1.012

Confidence interval

level

95%

sides

2-sided

lower limit

0.943

upper limit

1.085

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

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

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.018 ^[34]

Method

ANCOVA

Parameter type

Odds ratio (OR)

Point estimate

0.877

Confidence interval

level

95%

sides

2-sided

lower limit

0.787

upper limit

0.977

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	261 ^[35]	255 ^[36]
Units: Grams (g)/ mol
arithmetic mean (standard deviation)
Urine albumin/creatinine ratio, n=178, 181	-0.78 ± 5.116	-0.64 ± 9.538
Urine protein/creatinine ratio, n=192, 193	-2.73 ± 12.683	1.23 ± 5.088

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 1 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 1 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 1 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	261 ^[37]	255 ^[38]
Units: Microgram (ug)/ L
arithmetic mean (standard deviation)
Bone-specific alkaline phosphatase, n=246, 236	-3.18 ± 5.678	0.92 ± 4.634
Procollagen type 1 N-propeptide, n=245, 237	-5.8 ± 20	0.3 ± 19.28
Osteocalcin, n=245, 235	-5.11 ± 7.334	-1.14 ± 6.017
Type I Collagen C-Telopeptides, n=243, 238	-0.15 ± 0.31	-0.09 ± 0.344
sVCAM, n=245, 237	-2.63 ± 571.182	37.42 ± 617.486

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

Statistical analysis 1

Comparison groups

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

516

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

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[41]

Method

ANCOVA

Parameter type

Odds ratio (OR)

Point estimate

0.728

Confidence interval

level

95%

sides

2-sided

lower limit

0.686

upper limit

0.773

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

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004 ^[42]

Method

ANCOVA

Parameter type

Odds ratio (OR)

Point estimate

0.865

Confidence interval

level

95%

sides

2-sided

lower limit

0.785

upper limit

0.954

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

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

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[43]

Method

ANCOVA

Parameter type

Odds ratio (OR)

Point estimate

0.788

Confidence interval

level

95%

sides

2-sided

lower limit

0.719

upper limit

0.864

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

Statistical analysis 5

Comparison groups

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

other ^[44]

P-value

= 0.677 ^[45]

Method

ANCOVA

Confidence interval

Notes
[44] - Since statistical significance at the 10% level was not observed, results are presented overall only.
[45] - 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

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[46]

Method

ANCOVA

Parameter type

Odds ratio (OR)

Point estimate

0.867

Confidence interval

level

95%

sides

2-sided

lower limit

0.823

upper limit

0.914

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

Statistical analysis 7

Comparison groups

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

other ^[47]

P-value

< 0.001 ^[48]

Method

ANCOVA

Confidence interval

Notes
[47] - Since statistical significance at the 10% level was observed, results are presented separately per Baseline third agent.
[48] - 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

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[49]

Method

ANCOVA

Parameter type

Odds ratio (OR)

Point estimate

0.853

Confidence interval

level

95%

sides

2-sided

lower limit

0.799

upper limit

0.91

Notes
[49] - 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

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.028 ^[50]

Method

ANCOVA

Parameter type

Odds ratio (OR)

Point estimate

0.886

Confidence interval

level

95%

sides

2-sided

lower limit

0.796

upper limit

0.987

Notes
[50] - P value to assess difference between treatment groups (osteocalcin - INSTI)

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

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[51]

Method

ANCOVA

Parameter type

Odds ratio (OR)

Point estimate

0.743

Confidence interval

level

95%

sides

2-sided

lower limit

0.672

upper limit

0.822

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

Statistical analysis 11

Comparison groups

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

other ^[52]

P-value

= 0.782 ^[53]

Method

ANCOVA

Confidence interval

Notes
[52] - Since statistical significance at the 10% level was not observed, results are presented overall only.
[53] - 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

DTG + RPV v Current antiretroviral regimen

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[54]

Method

ANCOVA

Parameter type

Odds ratio (OR)

Point estimate

0.818

Confidence interval

level

95%

sides

2-sided

lower limit

0.751

upper limit

0.891

Notes
[54] - 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	245 ^[55]	237 ^[56]
Units: Nanograms (ng)/L
arithmetic mean (standard deviation)
Nanograms (ng)/L	-0.08 ± 2.373	-0.07 ± 2.761

Notes
[55] - Safety Population
[56] - 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, 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	237 ^[57]	224 ^[58]
Units: HOMA-IR score
arithmetic mean (standard deviation)
Cateogry title 1	0.5 ± 4.78	0.8 ± 3.938

Notes
[57] - Safety Population
[58] - 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	261 ^[59]	255 ^[60]
Units: Millimoles (mmol)/ L
arithmetic mean (standard deviation)
Total cholesterol, Week 24, n=237, 229	-0.015 ± 0.7539	0.02 ± 0.5777
Total cholesterol, Week 48, n=237, 230	-0.079 ± 0.7926	-0.038 ± 0.6148
LDL cholesterol calculation, Week 24, n=231, 221	0.085 ± 0.594	0.055 ± 0.5232
LDL cholesterol calculation, Week 48, n=229, 220	-0.049 ± 0.6276	-0.076 ± 0.528
HDL cholesterol direct, Week 24, n=237, 229	-0.024 ± 0.2365	-0.051 ± 0.2258
HDL cholesterol direct, Week 48, n=237, 230	0.051 ± 0.2386	0.049 ± 0.2489
Triglycerides, Week 24, n=237, 229	-0.184 ± 1.0102	0.04 ± 0.9164
Triglycerides, Week 48, n=237, 230	-0.169 ± 1.0062	-0.021 ± 1.0156

Notes
[59] - Safety Population
[60] - 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 indicates that data was not available. Genotypic Resistance Data only shown for Drugs Received for Participants Meeting Confirmed Virologic Withdrawal Criteria.

End point type

Secondary

End point timeframe

Week 48

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	1 ^[61]	0 ^[62]
Units: Participants
INSTI, DTG, Susceptible	1
INSTI, DTG, Potential low-level resistance	0
INSTI, DTG, Low-level resistance	0
INSTI, DTG, Intermediate resistance	0
INSTI, DTG, High-level resistance	0
NNRTI, RPV, Susceptible	0
NNRTI, RPV, Potential low-level resistance	0
NNRTI, RPV, Low-level resistance	0
NNRTI, RPV, Intermediate resistance	1
NNRTI, RPV, High-level resistance	0

Notes
[61] - CVW Population
[62] - 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 were not available 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

Week 48

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	1 ^[63]	0 ^[64]
Units: Participants
INI, DTG, Resistant	0
INI, DTG, Partially Sensitive	0
INI, DTG, Sensitive	1
INI, RAL, Resistant	99999
INI, RAL, Sensitive	99999
INI, EVG, Resistant	99999
INI, EVG, Sensitive	99999
NNRTI, RPV, Resistant	0
NNRTI, RPV, Sensitive	1
NNRTI, ETR, Resistant	99999
NNRTI, ETR, Partially Sensitive	99999
NNRTI, ETR, Sensitive	99999
NRTI, 3TC, Resistant	99999
NRTI, 3TC, Sensitive	99999
NRTI, ABC, Resistant	99999
NRTI, ABC, Partially Sensitive	99999
NRTI, ABC, Sensitive	99999
NRTI, TDF, Resistant	99999
NRTI, TDF, Partially Sensitive	99999
NRTI, TDF, Sensitive	99999
NRTI, d4T, Resistant	99999
NRTI, d4T, Sensitive	99999
NRTI, ddI, Resistant	99999
NRTI, ddI, Partially Sensitive	99999
NRTI, ddI, Sensitive	99999
PI, ATV/r, Resistant	99999
PI, ATV/r, Sensitive	99999
PI, DRV/r, Resistant	99999
PI, DRV/r, Partially Sensitive	99999
PI, DRV/r, Sensitive	99999
PI, FPV/r, Resistant	99999
PI, FPV/r, Partially Sensitive	99999
PI, FPV/r, Sensitive	99999
PI, IDV/r, Resistant	99999
PI, IDV/r, Sensitive	99999
PI, LPV/r, Resistant	99999
PI, LPV/r, Partially Sensitive	99999
PI, LPV/r, Sensitive	99999
PI, SQV/r, Resistant	99999
PI, SQV/r, Partially Sensitive	99999
PI, SQV/r, Sensitive	99999
PI, TPV/r, Resistant	99999
PI, TPV/r, Partially Sensitive	99999
PI, TPV/r, Sensitive	99999

Notes
[63] - CVW Population
[64] - CVW Population. 99999 indicates not applicable based on drugs were not received.

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. Pharmacokinetic (PK) Parameter Population consisted of all participants who received DTG +RPV and provided at least one evaluable estimate of predose concentration (C0). 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 4, 24 and 48 or at withdrawal visit

End point values	dtg 50 mg	rpv 25 mg
Number of subjects analysed	242 ^[65]	242 ^[66]
Units: ug/ L
arithmetic mean (standard deviation)
Week 4, n=176, 175	1578.88 ± 1170.967	79.504 ± 38.2305
Week 24, n=207, 207	1447.23 ± 917.677	90.207 ± 46.3022
Week 48, n=215, 215	1384.36 ± 889.829	91.799 ± 47.1371

Notes
[65] - PK Parameter Population
[66] - 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, in addition to the pre-dose blood sample collected at Week 4 for all subjects. 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	28 ^[67]	28 ^[68]
Units: ug/ L
arithmetic mean (standard deviation)
Week 2, n=19, 19	834.58 ± 639.622	57.342 ± 29.5436
Week 4, n=22, 21	1218.23 ± 842.703	78.338 ± 31.4825
Week 8, n=26, 26	1472.5 ± 818.774	79.652 ± 40.7546

Notes
[67] - PK Parameter NNRTI Subset extra sampling Population
[68] - 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 (INSTI, NNRTI, or PI) on efficacy, safety and tolerability 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	261 ^[69]	255 ^[70]
Units: Percentage of participants
NNRTI, n=144, 144	97	93
INSTI, n=59, 49	92	94
PI, n=58, 62	91	97

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

Statistical analysis 1

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.179 ^[71]

Method

Chi-squared corrected

Confidence interval

Notes
[71] - 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

516

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Risk difference (RD)

Point estimate

3.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1.6

upper limit

8.6

Statistical Analysis 3

Statistical analysis description

INSTI: 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

516

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Risk difference (RD)

Point estimate

-2.4

Confidence interval

level

95%

sides

2-sided

lower limit

-12.1

upper limit

7.4

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

516

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Risk difference (RD)

Point estimate

-5.4

Confidence interval

level

95%

sides

2-sided

lower limit

-13.9

upper limit

3.1

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 (INSTI, 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	261 ^[72]	255 ^[73]
Units: Cells per mm^3
arithmetic mean (standard deviation)
NNRTI, n=139, 133	49.7 ± 166.4	24.3 ± 160.32
INSTI, n=53, 46	-11.2 ± 176.56	10.3 ± 155.53
PI, n=53, 61	10.5 ± 163.67	12.2 ± 163.32

Notes
[72] - ITT-E Population
[73] - 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 (INSTI, 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	261 ^[74]	255 ^[75]
Units: Participants
Any AE, NNRTI, n=144, 144	106	96
Any AE, INSTI, n=59, 49	47	36
Any AE, PI, n=58, 62	42	42
NNRTI, Maximum toxicity Grade 1 AE, n=144, 144	68	76
NNRTI, Maximum toxicity Grade 2 AE, n=144, 144	30	19
NNRTI, Maximum toxicity Grade 3 AE, n=144, 144	8	0
NNRTI, Maximum toxicity Grade 4 AE, n=144, 144	0	1
INSTI, Maximum toxicity Grade 1 AE, n=59, 49	27	20
INSTI, Maximum toxicity Grade 2 AE, n=59, 49	15	15
INSTI, Maximum toxicity Grade 3 AE, n=59, 49	5	1
INSTI, Maximum toxicity Grade 4 AE, n=59, 49	0	0
PI, Maximum toxicity Grade 1 AE, n=58, 62	24	26
PI, Maximum toxicity Grade 2 AE, n=58, 62	14	13
PI, Maximum toxicity Grade 3 AE, n=58, 62	3	3
PI, Maximum toxicity Grade 4 AE, n=58, 62	1	0
AELD, NNRTI, n=144, 144	5	1
AELD, INSTI, n=59, 49	4	0
AELD, PI, n=58, 62	3	0

Notes
[74] - Safety Population
[75] - 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 (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	261 ^[76]	255 ^[77]
Units: Participants
NNRTI, Grades 1, n=144, 144	51	52
NNRTI, Grades 2, n=144, 144	31	40
NNRTI, Grades 3, n=144, 144	7	4
NNRTI, Grades 4, n=144, 144	1	5
INSTI, Grades 1, n= 59, 49	19	11
INSTI, Grades 2, n=59, 49	23	18
INSTI, Grades 3, n= 59, 49	3	3
INSTI, Grades 4, n= 59, 49	0	2
PI, Grades 1, n= 58, 62	22	17
PI, Grades 2, n= 58, 62	18	21
PI, Grades 3, n= 58, 62	1	9
PI, Grades 4, n= 58, 62	0	3

Notes
[76] - Safety Population
[77] - 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	261 ^[78]	255 ^[79]
Units: Participants
NNRTI; Grade 1; n= 144, 144	7	6
NNRTI; Grade 2; n= 144, 144	1	2
NNRTI; Grade 3; n= 144, 144	1	0
NNRTI; Grade 4; n= 144, 144	1	0
INI; Grade 1; n= 59, 49	1	1
INI; Grade 2; n= 59, 49	0	0
INI; Grade 3; n= 59, 49	0	0
INI; Grade 4; n= 59, 49	0	0
PI; Grade 1; n= 58, 62	3	4
PI; Grade 2; n= 58, 62	1	0
PI; Grade 3; n= 58, 62	2	0
PI; Grade 4; n= 58, 62	0	0

Notes
[78] - Safety Population
[79] - 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

Week 48

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: 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

Week 48

End point values	DTG + RPV	Current antiretroviral regimen
Number of subjects analysed	0 ^[82]	0 ^[83]
Units: Participants
Participants

Notes
[82] - CVW Population
[83] - 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 indicates that data was not available.

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	261 ^[84]	255 ^[85]
Units: mmol/ L
arithmetic mean (standard deviation)
CHO, Week 24, overall, n=237, 229	1.015 ± 15.7472	1.3 ± 12.2269
CHO, Week 48, overall, n=237, 230	-0.165 ± 15.9301	0.194 ± 13.1071
CHO, Week 24, NNRTI, n=0, 132	99999 ± 99999	1.238 ± 12.4889
CHO, Week 48, NNRTI, n=0, 128	99999 ± 99999	0.281 ± 12.2469
CHO, Week 24, INSTI, n=0, 42	99999 ± 99999	1.973 ± 12.1365
CHO, Week 48, INSTI, n=0, 44	99999 ± 99999	2.798 ± 16.1468
CHO, Week 24, PI, n=0, 55	99999 ± 99999	0.936 ± 11.853
CHO, Week 48, PI, n=0, 58	99999 ± 99999	-1.971 ± 12.2195
HDL CHO direct, Overall, Week 24, n=237, 229	0.557 ± 19.4929	-2.533 ± 16.3641
HDL CHO direct, Overall, Week 48, n=237,230	6.384 ± 20.9244	4.723 ± 18.3253
HDL CHO direct, NNRTI, Week 24, n=0, 132	99999 ± 99999	-2.562 ± 15.3521
HDL CHO direct, NNRTI, Week 48, n=0, 128	99999 ± 99999	4.307 ± 17.8013
HDL CHO direct, INSTI, Week 24, n=0, 42	99999 ± 99999	-3.097 ± 20.0002
HDL CHO direct, INSTI, Week 48, n=0, 44	99999 ± 99999	5.386 ± 20.6791
HDL CHO direct, PI, Week 24, n=0, 55	99999 ± 99999	-2.031 ± 15.9582
HDL CHO direct, PI, Week 48, n=0, 58	99999 ± 99999	5.14 ± 17.8779
LDL CHO calculation, Overall, Week 24, n=231, 221	5.838 ± 22.9614	4.395 ± 21.6685
LDL CHO calculation, Overall, Week 48, n=229, 220	1.137 ± 23.3849	-0.598 ± 20.6931
LDL CHO calculation, NNRTI, Week 24, n=0, 129	99999 ± 99999	5.959 ± 21.5692
LDL CHO calculation, NNRTI, Week 48, n=0, 124	99999 ± 99999	0.747 ± 19.2299
LDL CHO calculation, INSTI, Week 24, n=0, 40	99999 ± 99999	3.787 ± 17.6755
LDL CHO calculation, INSTI, Week 48, n=0, 42	99999 ± 99999	2.647 ± 24.043
LDL CHO calculation, PI, Week 24, n=0, 52	99999 ± 99999	0.983 ± 24.5052
LDL CHO calculation, PI, Week 48, n=0, 54	99999 ± 99999	-6.212 ± 20.4774
Triglycerides, Overall, Week 24, n=237, 229	-0.825 ± 42.5565	9.379 ± 45.5529
Triglycerides, Overall, Week 48, n=237, 230	1.169 ± 51.9844	7.183 ± 44.7044
Triglycerides, NNRTI, Week 24, n=0, 132	99999 ± 99999	4.962 ± 40.6201
Triglycerides, NNRTI, Week 48, n=0, 128	99999 ± 99999	5.248 ± 41.7728
Triglycerides, INSTI, Week 24, n=0, 42	99999 ± 99999	18.204 ± 47.2348
Triglycerides, INSTI, Week 48, n=0, 44	99999 ± 99999	14.627 ± 56.2824
Triglycerides, PI, Week 24, n=0,55	99999 ± 99999	13.241 ± 54.2327
Triglycerides, PI, Week 48, n=0, 58	99999 ± 99999	5.806 ± 41.2106

Notes
[84] - Safety Population
[85] - 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	261 ^[86]	255 ^[87]
Units: Scores on a scale
arithmetic mean (standard deviation)
Symptom count, Week 4, n=224, 229	-1.1 ± 4.11	-0.8 ± 4.02
Symptom count, Week 24, n=228, 232	-0.7 ± 4.31	-0.8 ± 4.64
Symptom count, Week 48, n=228, 231	-0.5 ± 4.33	-0.4 ± 4.82
Symptom Bother Score, Week 4, n=224, 229	-2.8 ± 7.44	-1.8 ± 7.24
Symptom Bother Score, Week 24, n=228, 232	-1.8 ± 8.4	-1.7 ± 8.72
Symptom Bother Score, Week 48, n=228, 231	-1.5 ± 7.97	-0.7 ± 9.3

Notes
[86] - ITT-E Population
[87] - ITT-E Population

Statistical analysis 1

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.43 ^[88]

Method

ANCOVA

Confidence interval

Notes
[88] - 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

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.039 ^[89]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-1.239

Confidence interval

level

95%

sides

2-sided

lower limit

-2.414

upper limit

-0.064

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

Statistical analysis 3

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.542 ^[90]

Method

ANCOVA

Confidence interval

Notes
[90] - 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

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.448 ^[91]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.528

Confidence interval

level

95%

sides

2-sided

lower limit

-1.896

upper limit

0.84

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

Statistical analysis 5

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.402 ^[92]

Method

ANCOVA

Confidence interval

Notes
[92] - 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

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.164 ^[93]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-1.037

Confidence interval

level

95%

sides

2-sided

lower limit

-2.501

upper limit

0.426

Notes
[93] - 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	261 ^[94]	255 ^[95]
Units: Score on a scale
median (full range (min-max))
Total score, Week 4, n=253, 250	0 (-21 to 23)	0 (-22 to 22)
Total score, Week 24, n=257, 252	0 (-27 to 23)	0 (-24 to 24)
Total score, Week 48, n=257, 251	0 (-27 to 25)	0 (-50 to 23)
lifestyle/ease Sub-score, Week 4, n=252, 249	0 (-11 to 15)	0 (-11 to 7)
lifestyle/ease Sub-score, Week 24, n=257, 251	0 (-18 to 14)	0 (-17 to 10)
lifestyle/ease Sub-score, Week 48, n=257, 250	0 (-18 to 12)	0 (-21 to 11)
General Satisfaction/CS, Week 4, n=253, 250	0 (-13 to 14)	0 (-17 to 15)
General Satisfaction/CS, Week 24, n=257, 252	0 (-12 to 12)	0 (-15 to 15)
General Satisfaction/CS, Week 48, n=257, 251	0 (-13 to 14)	0 (-29 to 14)

Notes
[94] - ITT-E Population
[95] - ITT-E Population

Statistical analysis 1

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.037 ^[96]

Method

Wilcoxon rank sum test

Confidence interval

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

Statistical analysis 2

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.101 ^[97]

Method

Wilcoxon rank sum test

Confidence interval

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

Statistical analysis 3

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.042 ^[98]

Method

Wilcoxon rank sum test

Confidence interval

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

Statistical analysis 4

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.132 ^[99]

Method

Wilcoxon rank sum test

Confidence interval

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

Statistical analysis 5

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.022 ^[100]

Method

Wilcoxon rank sum test

Confidence interval

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

Statistical analysis 6

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004 ^[101]

Method

Wilcoxon rank sum test

Confidence interval

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

Statistical analysis 7

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.076 ^[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 4)

Statistical analysis 8

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.073 ^[103]

Method

Wilcoxon rank sum test

Confidence interval

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

Statistical analysis 9

Comparison groups

Current antiretroviral regimen v DTG + RPV

Number of subjects included in analysis

516

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.547 ^[104]

Method

Wilcoxon rank sum test

Confidence interval

Notes
[104] - 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 are 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

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

Participants continued to receive their current antiretroviral regimen (two nucleoside reverse transcriptase inhibitor [NRTIs] + a third agent). A third agent included either of integrase strand transfer inhibitor integrase inhibitor (INSTI), 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.

Serious adverse events	DTG + RPV	Current antiretroviral regimen
Total subjects affected by serious adverse events
subjects affected / exposed	18 / 261 (6.90%)	9 / 255 (3.53%)
number of deaths (all causes)	1	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Kaposi's sarcoma
subjects affected / exposed	1 / 261 (0.38%)	0 / 255 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 261 (0.00%)	1 / 255 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Jarisch-Herxheimer reaction
subjects affected / exposed	0 / 261 (0.00%)	1 / 255 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Eosinophilic pneumonia acute
subjects affected / exposed	1 / 261 (0.38%)	0 / 255 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 261 (0.00%)	1 / 255 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Suicide attempt
subjects affected / exposed	1 / 261 (0.38%)	1 / 255 (0.39%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Depression
subjects affected / exposed	1 / 261 (0.38%)	0 / 255 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Alcohol poisoning
subjects affected / exposed	1 / 261 (0.38%)	0 / 255 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Facial bones fracture
subjects affected / exposed	1 / 261 (0.38%)	0 / 255 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fibula fracture
subjects affected / exposed	0 / 261 (0.00%)	1 / 255 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Foreign body
subjects affected / exposed	0 / 261 (0.00%)	1 / 255 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Joint injury
subjects affected / exposed	0 / 261 (0.00%)	1 / 255 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	1 / 261 (0.38%)	0 / 255 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Headache
subjects affected / exposed	1 / 261 (0.38%)	0 / 255 (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
Tympanic membrane perforation
subjects affected / exposed	0 / 261 (0.00%)	1 / 255 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Keratitis
subjects affected / exposed	0 / 261 (0.00%)	1 / 255 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Retinal detachment
subjects affected / exposed	0 / 261 (0.00%)	1 / 255 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 261 (0.38%)	0 / 255 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 261 (0.38%)	0 / 255 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis chronic
subjects affected / exposed	1 / 261 (0.38%)	0 / 255 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 261 (0.38%)	0 / 255 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal colic
subjects affected / exposed	1 / 261 (0.38%)	0 / 255 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Haemarthrosis
subjects affected / exposed	1 / 261 (0.38%)	0 / 255 (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
Pneumonia
subjects affected / exposed	2 / 261 (0.77%)	0 / 255 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abscess limb
subjects affected / exposed	1 / 261 (0.38%)	0 / 255 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphogranuloma venereum
subjects affected / exposed	1 / 261 (0.38%)	0 / 255 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Orchitis
subjects affected / exposed	1 / 261 (0.38%)	0 / 255 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Periorbital cellulitis
subjects affected / exposed	1 / 261 (0.38%)	0 / 255 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary sepsis
subjects affected / exposed	1 / 261 (0.38%)	0 / 255 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rotavirus infection
subjects affected / exposed	1 / 261 (0.38%)	0 / 255 (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	DTG + RPV	Current antiretroviral regimen
Total subjects affected by non serious adverse events
subjects affected / exposed	61 / 261 (23.37%)	59 / 255 (23.14%)
Nervous system disorders
Headache
subjects affected / exposed	17 / 261 (6.51%)	6 / 255 (2.35%)
occurrences all number	36	6
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	17 / 261 (6.51%)	27 / 255 (10.59%)
occurrences all number	19	41
Nasopharyngitis
subjects affected / exposed	21 / 261 (8.05%)	22 / 255 (8.63%)
occurrences all number	26	24
Bronchitis
subjects affected / exposed	16 / 261 (6.13%)	10 / 255 (3.92%)
occurrences all number	19	12

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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 efavirenz (EFV) or nevirapine (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.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.

DEXA sub-study 202094 (NCT02478632) Results available on ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/results/NCT02478632?term=202094&rank=1

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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 and 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 and 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 1 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 1 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)