Download PDF

Clinical Trial Results:
SMILE: Strategy for Maintenance of HIV suppression with once daiLy Integrase inhibitor +darunavir/ritonavir in childrEn (PENTA 17) - A two-arm, Phase 2/3 multicentre, open-label, randomised study evaluating safety and antiviral effect of current standard antiretroviral therapy compared to once daily integrase inhibitor administered with darunavir/ritonavir (DRV/r) in HIV-1 infected, virologically suppressed paediatric participants.

Summary
EudraCT number	2013-001476-37
Trial protocol	ES PT GB BE DE FR
Global end of trial date	17 Nov 2021

Results information
Results version number	v1(current)
This version publication date	22 Dec 2021
First version publication date	22 Dec 2021
Other versions

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

SMILE-PENTA17-ANRS152

ISRCTN number

ISRCTN11193709

US NCT number

NCT02383108

WHO universal trial number (UTN)

Sponsor organisation name

Fondazione Penta Onlus

Sponsor organisation address

Corso Stati Uniti 4, Padova, Italy, 35127

Public contact

Carlo Giaquinto (Sponsor; carlo.giaquinto@unipd.it); Alexandra Compagnucci (Clinical Project Leader), Inserm SC10-US19, 0033 145 59 52 90, alexandra.compagnucci@inserm.fr

Scientific contact

José Tomas Ramos Amador (CI; josetora@ucm.es); Alexandra Compagnucci (Clinical Project Leader), Inserm SC10-US19, 0033 145 59 52 90, alexandra.compagnucci@inserm.fr

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

Final

Date of interim/final analysis

20 Oct 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

01 Oct 2020

Global end of trial reached?

Yes

Global end of trial date

17 Nov 2021

Was the trial ended prematurely?

Main objective of the trial

To evaluate whether children with chronic HIV infection on ART with suppressed viral load will maintain similar levels of suppression with once daily integrase inhibitor (INSTI) + darunavir/r compared to continued standard of care triple ART.

Protection of trial subjects

Participant protection is evidenced by rigorous informed consent process and the protection of trial data. Participant information used age appropriate language so that participants and parents could make an informed decision. Only participants who were aware of their HIV status were approached for screening to avoid causing distress at disclosure of their status (if they did not know previously). The participant information sheet also explained that trial participants could be withdraw at any time during the trial without giving a reason, and that this would not affect the quality of the medical care they receive. Personal data was pseudonymised to ensure participant's identity is protected. Sites were trained to use an encrypted method to transfer data (i.e. using Galaxkey) and site staff were also trained on Good Clinical Practice. Only authorised study staff had access to trial information. Access to the trial database was restricted and only enabled following the appropriate training and completion of a non-disclosure of password form.

Background therapy

Evidence for comparator

Actual start date of recruitment

10 Jun 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Portugal: 4

Country: Number of subjects enrolled

Spain: 10

Country: Number of subjects enrolled

United Kingdom: 5

Country: Number of subjects enrolled

France: 2

Country: Number of subjects enrolled

Argentina: 13

Country: Number of subjects enrolled

Mexico: 12

Country: Number of subjects enrolled

South Africa: 60

Country: Number of subjects enrolled

Switzerland: 5

Country: Number of subjects enrolled

Thailand: 47

Country: Number of subjects enrolled

Uganda: 110

Country: Number of subjects enrolled

Ukraine: 50

Worldwide total number of subjects

318

EEA total number of subjects

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)

314

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

Screening details

Number of subjects started

358 ^[1]

Number of subjects completed

318

Reason: Number of subjects

Failed ≥1 eligibility criteria: 33

Reason: Number of subjects

Did not return <4wks of Screening: 1

Reason: Number of subjects

Refusal: 4

Reason: Number of subjects

Other: 2

Notes
[1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: 358 participants were screened, but 318 were randomised. Reasons for not randomising are documented here.

Period 1 title

Main trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Intervention (Arm 1) - INSTI+DRV/r

Arm description

Arm 1. NRTI-sparing regimen: Once daily integrase inhibitor (INSTI) + darunavir/ritonavir (DRV/r)

Arm type

Experimental

Investigational medicinal product name

Norvir

Investigational medicinal product code

Other name

Ritonavir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Once daily 100 mg

Investigational medicinal product name

Prezista

Investigational medicinal product code

Other name

Darunavir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Once daily 600 mg

Investigational medicinal product name

Prezista

Investigational medicinal product code

Other name

Darunavir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Once daily 675 mg

Investigational medicinal product name

Prezista

Investigational medicinal product code

Other name

Darunavir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Once daily 800 mg

Investigational medicinal product name

Vitekta

Investigational medicinal product code

Other name

Elvitegravir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Once daily 85 mg

Investigational medicinal product name

Vitekta

Investigational medicinal product code

Other name

Elvitegravir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Once daily 150 mg

Investigational medicinal product name

Tivicay

Investigational medicinal product code

Other name

Dolutegravir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Once daily 50 mg

Standard of care (Arm 2)

Arm description

Arm 2. Standard of care (continuing triple anti-retroviral therapy including 2 NRTIs + boosted PI/NNRTI)

Arm type

Active comparator

Investigational medicinal product name

Comparator

Investigational medicinal product code

Other name

Combination ART

Pharmaceutical forms

Tablet, Capsule, Syrup

Routes of administration

Oral use

Dosage and administration details

Combination ART

Number of subjects in period 1	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Started	158	160
Completed	158	160

Baseline characteristics

Top of page

Reporting group title

Intervention (Arm 1) - INSTI+DRV/r

Reporting group description

Arm 1. NRTI-sparing regimen: Once daily integrase inhibitor (INSTI) + darunavir/ritonavir (DRV/r)

Reporting group title

Standard of care (Arm 2)

Reporting group description

Arm 2. Standard of care (continuing triple anti-retroviral therapy including 2 NRTIs + boosted PI/NNRTI)

Reporting group values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)	Total
Number of subjects	158	160	318
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	2	2	4
Adolescents (12-17 years)	156	158	314
Adults (18-64 years)	0	0	0
From 65-84 years	0	0	0
85 years and over	0	0	0
Age continuous
Units: years
median (inter-quartile range (Q1-Q3))	14.7 (13.5 to 16.4)	14.6 (13.7 to 16.3)	-
Gender categorical
Units: Subjects
Female	92	102	194
Male	66	58	124
Ethnic origin
Units: Subjects
White	32	38	70
Black-African	87	87	174
Black-other	0	1	1
Asian	29	22	51
Mixed black-white	2	1	3
Other	8	11	19
Route of HIV infection
Units: Subjects
Mother to child	146	155	301
Unknown	12	5	17
CDC stage
Units: Subjects
CDC N	40	39	79
CDC A	44	48	92
CDC B	45	50	95
CDC C	29	23	52
Weight-for-age z-score
British 1990 Reference data was used for calculation of BMI, weight and height z-scores. This reference data covers the full age range (0–23 years) of SMILE participants.
Units: Subjects
<-3	4	3	7
≥-3 to <-2	12	10	22
≥-2 to <0	90	96	186
≥0	52	51	103
Height-for-age z-score
British 1990 Reference data was used for calculation of BMI, weight and height z-scores. This reference data covers the full age range (0–23 years) of SMILE participants.
Units: Subjects
<-3	3	1	4
≥-3 to <-2	16	14	30
≥-2 to <0	103	99	202
≥0	36	46	82
BMI-for-age z-score
British 1990 Reference data was used for calculation of BMI, weight and height z-scores. This reference data covers the full age range (0–23 years) of SMILE participants.
Units: Subjects
<-3	1	1	2
≥-3 to <-2	3	2	5
≥-2 to <0	77	85	162
≥0	77	72	149
HIV-1 RNA
To meet the criteria for enrolment, all HIV-1 RNA had to be <50 cp/ml at the screening visit. At the randomisation visit, HIV-1 RNA may be ≥50 cp/ml.
Units: Subjects
HIV-1 RNA<50	154	155	309
HIV-1 RNA≥50	3	5	8
Not recorded	1	0	1
Menarche in females
Units: Subjects
No	12	22	34
Yes	80	80	160
NA - Males	66	58	124
Tanner scores: Pubic hair
Note: SOC arm: 159/160 had a pubic hair measured. Tanner scores should only be measured in children ≥8 years for age but one participant was 7.6 years at baseline. So, this child was classified as "Set to missing", hence not included in the analysis.
Units: Subjects
Score 1	9	3	12
Score 2	25	22	47
Score 3	47	61	108
Score 4	50	51	101
Score 5	27	21	48
Not recorded	0	1	1
Set to missing	0	1	1
Tanner scores: Female breasts
Tanner scores should only be measured in children ≥8 years for age but one participant in SOC arm was 7.6 years at baseline. So, this child was classified as "Set to missing", hence not included in the analysis.
Units: Subjects
Score 1	4	0	4
Score 2	9	11	20
Score 3	25	39	64
Score 4	34	37	71
Score 5	20	14	34
NA - Male	66	58	124
Set to missing	0	1	1
Tanner scores: Male genitalia
Units: Subjects
Score 1	2	1	3
Score 2	13	7	20
Score 3	25	21	46
Score 4	16	21	37
Score 5	10	7	17
Not recorded	0	1	1
NA - Female	92	102	194
Number of different drugs ever received pre-randomisation
Count excludes drugs used for PMTCT as well as booster drugs given as a single entity (Ritonavir and Cobicistat).
Units: Subjects
Three	48	56	104
Four	49	39	88
Five	27	30	57
≥Six	34	35	69
Number of different NRTIs ever received pre-randomisation
NRTI: Nucleoside Reverse Transcriptase Inhibitor
Units: Subjects
Two	54	68	122
Three	63	43	106
≥Four	41	49	90
Number of different NNRTIs ever received pre-randomisation
NNRTI: Non-nucleoside reverse-transcriptase inhibitors
Units: Subjects
Zero	45	37	82
One	95	112	207
Two	18	11	29
Number of different PIs ever received pre-randomisation
PI: Protease Inhibitor
Units: Subjects
Zero	86	87	173
One	50	52	102
Two	20	18	38
Three	2	3	5
Number of different INSTIs ever received pre-randomisation
INSTI: integrase strand transfer inhibitors. Note: One participant had previous exposure to INSTI for 12 days (<2weeks which meets inclusion criteria)
Units: Subjects
Zero	158	159	317
One	0	1	1
Number of participants exposed to:
NNRTI: Non-nucleoside reverse-transcriptase inhibitors; NRTI: Nucleoside Reverse Transcriptase Inhibitor; PI: Protease Inhibitor; INSTI: integrase strand transfer inhibitors.
Units: Subjects
NRTI+PI only	45	37	82
NRTI+NNRTI only	86	87	173
NRTI+NNRTI+PI only	27	35	62
NRTI+NNRTI+PI+INSTI	0	1	1
Baseline regimen same as ART initiation regimen
Units: Subjects
No	102	97	199
Yes	56	63	119
Weight
Units: Kg
median (inter-quartile range (Q1-Q3))	47.3 (42.9 to 51.8)	48.0 (44.0 to 53.0)	-
Height
Units: cm
median (inter-quartile range (Q1-Q3))	157.4 (152.0 to 162.3)	157.6 (152.8 to 163.3)	-
Body mass index
Units: kg/m2
median (inter-quartile range (Q1-Q3))	19.1 (17.7 to 21.1)	19.2 (17.9 to 21.1)	-
CD4%
Units: Percentage
median (inter-quartile range (Q1-Q3))	36 (32 to 40)	36 (32 to 41)	-
CD4
Units: cells/mm3
median (inter-quartile range (Q1-Q3))	775 (636 to 967)	803 (630 to 985)	-
CD8%
CD8 tests are optional, according to feasibility at the sites.
Units: Percent
median (inter-quartile range (Q1-Q3))	30 (25 to 34)	29 (25 to 35)	-
CD8
CD8 tests are optional, according to feasibility at the sites.
Units: cells/mm3
median (inter-quartile range (Q1-Q3))	627 (513 to 847)	680 (544 to 837)	-
CD4%/CD8% ratio
CD8 tests are optional, according to feasibility at the sites.
Units: Ratio
median (inter-quartile range (Q1-Q3))	1.2 (0.9 to 1.5)	1.2 (1.0 to 1.7)	-
Total Lymphocytes
Total lymphocytes tests are optional, according to feasibility at the sites.
Units: cells/mm3
median (inter-quartile range (Q1-Q3))	2171 (1895 to 2630)	2181 (1856 to 2661)	-
Cumulative ART exposure to all classes
Count excludes booster drugs given as a single entity (Ritonavir and Cobicistat)
Units: Years
median (full range (min-max))	11 (1 to 16)	11 (2 to 17)	-
Cumulative exposure to NRTIs
NRTI: Nucleoside Reverse Transcriptase Inhibitor
Units: Years
median (full range (min-max))	11 (1 to 16)	11 (2 to 17)	-
Cumulative exposure to NNRTIs
NNRTI: Non-nucleoside reverse-transcriptase inhibitors
Units: Years
median (full range (min-max))	5 (0 to 15)	5 (0 to 17)	-
Cumulative exposure to PIs
PI: Protease Inhibitor
Units: Years
median (full range (min-max))	0 (0 to 16)	0 (0 to 15)	-

End points

Top of page

Reporting group title

Intervention (Arm 1) - INSTI+DRV/r

Reporting group description

Arm 1. NRTI-sparing regimen: Once daily integrase inhibitor (INSTI) + darunavir/ritonavir (DRV/r)

Reporting group title

Standard of care (Arm 2)

Reporting group description

Arm 2. Standard of care (continuing triple anti-retroviral therapy including 2 NRTIs + boosted PI/NNRTI)

Primary: Virological failure: Confirmed HIV-1 RNA ≥50c/ml by 48 weeks

Top of page

End point title

Virological failure: Confirmed HIV-1 RNA ≥50c/ml by 48 weeks

End point description

Confirmed HIV-1 RNA ≥50 c/mL at any time up to week 48 (end of window is 54 weeks)

End point type

Primary

End point timeframe

Any time from randomisation to 48(+6) weeks after randomisation.

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	158	160
Units: People
Reached endpoint	8	12
Did not reach endpoint	150	148

Primary analysis

Statistical analysis description

Difference in estimated probability of failure (INSTI+DRV/r - SOC) by 48 weeks, adjusted for stratification factors (adjusted Kaplan-Meier estimates)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[1]

Method

Parameter type

Mean difference (final values)

Point estimate

-0.025

Confidence interval

level

95%

sides

2-sided

lower limit

-0.076

upper limit

0.025

Notes
[1] - Non-inferiority margin is 10%. Non-inferiority will be inferred if the upper bound of the two-sided bias corrected 95% CI for the difference between the two groups (INSTI+DRV/r – SOC) is less than 10%. Point estimate and 95% CI are not presented as percentages; for percentages, values need to be multiplied by 100.

Sensitivity analysis

Statistical analysis description

Difference in the estimated probability of failure (INSTI+DRV/r - SOC) by 48 weeks, unadjusted for stratification factors (unadjusted Kaplan-Meier estimates)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[2]

Method

Parameter type

Mean difference (final values)

Point estimate

-0.025

Confidence interval

level

95%

sides

2-sided

lower limit

-0.081

upper limit

0.032

Notes
[2] - Non-inferiority margin is 10%. Non-inferiority will be inferred if the upper bound of the two-sided bias corrected 95% CI for the difference between the two groups (INSTI+DRV/r – SOC) is less than 10%. Point estimate and 95% CI are not presented as percentages; for percentages, values need to be multiplied by 100.

Per-Protocol analysis (adjusted)

Statistical analysis description

Difference in estimated probability of failure (INSTI+DRV/r - SOC) by 48 weeks, adjusted for stratification factors (adjusted Kaplan-Meier estimates). Per protocol analysis of the primary endpoint was performed by censoring the follow-up of all children who discontinued any component of the allocated treatment for any reason, except for change due to change in national clinical guidelines in the SOC arm. Treatment interruption for >31 days for any reason is defined as treatment discontinuation.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

Method

Parameter type

Mean difference (final values)

Point estimate

-0.026

Confidence interval

level

95%

sides

2-sided

lower limit

-0.077

upper limit

0.022

Notes
[3] - Non-inferiority margin is 10%. Non-inferiority will be inferred if the upper bound of the two-sided bias corrected 95% CI for the difference between the two groups (INSTI+DRV/r – SOC) is less than 10%. Point estimate and 95% CI are not presented as percentages; for percentages, values need to be multiplied by 100.

Per-Protocol analysis (unadjusted)

Statistical analysis description

Difference in estimated probability of failure (INSTI+DRV/r - SOC) by 48 weeks, unadjusted for stratification factors (unadjusted Kaplan-Meier estimates). Per protocol analysis of the primary endpoint was performed by censoring the follow-up of all children who discontinued any component of the allocated treatment for any reason, except for change in national clinical guidelines in the SOC arm. Treatment interruption for >31 days for any reason is defined as treatment discontinuation.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[4]

Method

Parameter type

Mean difference (final values)

Point estimate

-0.025

Confidence interval

level

95%

sides

2-sided

lower limit

-0.076

upper limit

0.027

Notes
[4] - Non-inferiority margin is 10%. Non-inferiority will be inferred if the upper bound of the two-sided bias corrected 95% CI for the difference between the two groups (INSTI+DRV/r – SOC) is less than 10%. Point estimate and 95% CI are not presented as percentages; for percentages, values need to be multiplied by 100.

Time to virological failure (adjusted)

Statistical analysis description

Cox regression analysis examining time to confirmed HIV-1 RNA ≥50c/ml by 48 weeks, adjusted for stratification factors

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.356

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.66

Confidence interval

level

95%

sides

2-sided

lower limit

0.27

upper limit

1.61

Time to virological failure (unadjusted)

Statistical analysis description

Cox regression analysis examining time to confirmed HIV-1 RNA ≥50c/ml by 48 weeks, unadjusted for stratification factors

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.366

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.66

Confidence interval

level

95%

sides

2-sided

lower limit

0.27

upper limit

1.62

Secondary: HIV-1 RNA ≥50c/ml at week 24

Top of page

End point title

HIV-1 RNA ≥50c/ml at week 24

End point description

Comparison of proportion of participants with HIV-1 RNA ≥50c/ml at week 24 [cross sectional comparison]

End point type

Secondary

End point timeframe

Week 24

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	158	160
Units: People
HIV-1 RNA <50	151	153
HIV-1 RNA ≥50	7	7

Difference in proportion with HIV-1 RNA≥50 (unadj)

Statistical analysis description

Difference in proportion of participants with HIV-1 RNA ≥50c/ml at week 24 (Chi-squared test). HIV-1 RNA result nearest to scheduled visit week 24 is used when multiple results fall in the same nominal week window (as described in SAP). Point estimate and 95% CI are not presented as percentages; for percentages, values need to be multiplied by 100.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.981

Method

Chi-squared

Parameter type

Mean difference (final values)

Point estimate

0.001

Confidence interval

level

95%

sides

2-sided

lower limit

-0.045

upper limit

0.046

Difference in proportion with HIV-1 RNA≥50 (adj)

Statistical analysis description

Difference in proportion of participants with HIV-1 RNA ≥50c/ml at week 24 (Logistic regression p-value adjusted for stratification factors). HIV-1 RNA result nearest to scheduled visit week 24 is used when multiple results fall in the same nominal week window (as described in SAP). Point estimate and 95% CI are not presented as percentages; for percentages, values need to be multiplied by 100.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.985

Method

Regression, Logistic

Parameter type

Mean difference (final values)

Point estimate

0.001

Confidence interval

level

95%

sides

2-sided

lower limit

-0.045

upper limit

0.046

Secondary: HIV-1 RNA ≥50c/ml at week 48

Top of page

End point title

HIV-1 RNA ≥50c/ml at week 48

End point description

Comparison of proportion of participants with HIV-1 RNA ≥50c/ml at week 48 [cross sectional comparison]

End point type

Secondary

End point timeframe

Week 48

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	150 ^[5]	156 ^[6]
Units: People
HIV-1 RNA <50	143	143
HIV-1 RNA ≥50	7	13

Notes
[5] - Participants with a measurement at week 48
[6] - Participants with a measurement at week 48

Difference in proportion with HIV-1 RNA≥50 (unadj)

Statistical analysis description

Difference in proportion of participants with HIV-1 RNA ≥50c/ml at week 48 (Chi-squared test). HIV-1 RNA result nearest to scheduled visit week 48 is used when multiple results fall in the same nominal week window (as described in SAP). Point estimate and 95% CI are not presented as percentages; for percentages, values need to be multiplied by 100.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.195

Method

Chi-squared

Parameter type

Mean difference (final values)

Point estimate

-0.037

Confidence interval

level

95%

sides

2-sided

lower limit

-0.092

upper limit

0.018

Difference in proportion with HIV-1 RNA≥50 (adj)

Statistical analysis description

Difference in proportion of participants with HIV-1 RNA ≥50c/ml at week 48 (Logistic regression p-value adjusted for stratification factors). HIV-1 RNA result nearest to scheduled visit week 48 is used when multiple results fall in the same nominal week window (as described in SAP). Point estimate and 95% CI are not presented as percentages; for percentages, values need to be multiplied by 100.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.195

Method

Regression, Logistic

Parameter type

Mean difference (final values)

Point estimate

-0.037

Confidence interval

level

95%

sides

2-sided

lower limit

-0.092

upper limit

0.018

Secondary: HIV-1 RNA ≥50c/ml at week 48 (FDA snapshot)

Top of page

End point title

HIV-1 RNA ≥50c/ml at week 48 (FDA snapshot)

End point description

Comparison of proportion of participants with HIV-1 RNA ≥50c/ml at week 48 [FDA SNAPSHOT ALGORITHM]

End point type

Secondary

End point timeframe

Week 48

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	158	160
Units: People
HIV-1 RNA ≥50 at week 48	7	7
HIV-1 RNA <50c/mL at week 48	139	147
No virologic data in week 48 window	12	6

Difference in proportion with HIV-1 RNA≥50

Statistical analysis description

Difference in proportion (95% CI) at week 48 estimated by Mantel-Haenszel weighted mean of proportions in each stratum. P-value derived from Mantel-Haenszel Chi-squared test.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[7]

P-value

= 0.985

Method

Mantel-Haenszel Chi-squared test

Parameter type

Mean difference (final values)

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-4.6

upper limit

4.69

Notes
[7] - Non-inferiority margin is 10%. Non-inferiority will be inferred if the upper bound of the two-sided bias corrected 95% CI for the difference between the two groups (INSTI+DRV/r – SOC) is less than 10%. Point estimate and 95% CI are presented as percentages.

Secondary: HIV-1 RNA ≥400c/ml at week 24

Top of page

End point title

HIV-1 RNA ≥400c/ml at week 24

End point description

Comparison of proportion of participants with HIV-1 RNA ≥400c/ml at week 24 [cross sectional comparison]

End point type

Secondary

End point timeframe

Week 24

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	158	160
Units: People
HIV-1 RNA <400	156	156
HIV-1 RNA ≥400	2	4

Difference in proportion with HIV1 RNA≥400 (unadj)

Statistical analysis description

Difference in proportion of participants with HIV-1 RNA ≥400c/ml at week 24 (Chi-squared test). HIV-1 RNA result nearest to scheduled visit week 24 is used when multiple results fall in the same nominal week window (as described in SAP). Point estimate and 95% CI are not presented as percentages; for percentages, values need to be multiplied by 100.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.419

Method

Chi-squared

Parameter type

Mean difference (final values)

Point estimate

-0.012

Confidence interval

level

95%

sides

2-sided

lower limit

-0.042

upper limit

0.017

Difference in proportion with HIV1 RNA≥400 (adj)

Statistical analysis description

Difference in proportion of participants with HIV-1 RNA ≥400c/ml at week 24 (Logistic regression p-value adjusted for stratification factors). HIV-1 RNA result nearest to scheduled visit week 24 is used when multiple results fall in the same nominal week window (as described in SAP). Point estimate and 95% CI are not presented as percentages; for percentages, values need to be multiplied by 100.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.428

Method

Regression, Logistic

Parameter type

Mean difference (final values)

Point estimate

-0.012

Confidence interval

level

95%

sides

2-sided

lower limit

-0.042

upper limit

0.017

Secondary: HIV-1 RNA ≥400c/ml at week 48

Top of page

End point title

HIV-1 RNA ≥400c/ml at week 48

End point description

Comparison of proportion of participants with HIV-1 RNA ≥400c/ml at week 48 [cross sectional comparison]

End point type

Secondary

End point timeframe

Week 48

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	150 ^[8]	156 ^[9]
Units: People
HIV-1 RNA <400	146	149
HIV-1 RNA ≥400	4	7

Notes
[8] - Participants with a measurement at week 48
[9] - Participants with a measurement at week 48

Difference in proportion with HIV1 RNA≥400 (unadj)

Statistical analysis description

Difference in proportion of participants with HIV-1 RNA ≥400c/ml at week 48 (Chi-squared test). HIV-1 RNA result nearest to scheduled visit week 48 is used when multiple results fall in the same nominal week window (as described in SAP). Point estimate and 95% CI are not presented as percentages; for percentages, values need to be multiplied by 100.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.392

Method

Chi-squared

Parameter type

Mean difference (final values)

Point estimate

-0.018

Confidence interval

level

95%

sides

2-sided

lower limit

-0.06

upper limit

0.023

Difference in proportion with HIV1 RNA≥400 (adj)

Statistical analysis description

Difference in proportion of participants with HIV-1 RNA ≥400c/ml at week 48 (Logistic regression p-value adjusted for stratification factors). HIV-1 RNA result nearest to scheduled visit week 48 is used when multiple results fall in the same nominal week window (as described in SAP). Point estimate and 95% CI are not presented as percentages; for percentages, values need to be multiplied by 100.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.392

Method

Regression, Logistic

Parameter type

Mean difference (final values)

Point estimate

-0.018

Confidence interval

level

95%

sides

2-sided

lower limit

-0.06

upper limit

0.023

Secondary: New or recurrent CDC stage C or severe stage B* event or death

Top of page

End point title

New or recurrent CDC stage C or severe stage B* event or death

End point description

Severe CDC stage B is defined as severe lung disease including LIP, nephropathy, cardiomyopathy, failure to thrive in absence of remediable causes, recurrent bacterial pneumonia, severe or recurrent oral candidiasis.

End point type

Secondary

End point timeframe

Any time from randomisation to end of trial [defined as latest of trial censoring date (31July2020) or week 48 censoring date (week 54 date)]

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	158 ^[10]	160
Units: People
New CDC stage C event	0	0
New severe CDC stage B event	1	0
Death	0	0

Notes
[10] - Severe CDC stage B event [Nephropathy; Grade 3]

Participants with new CDC stage C/severe stage B

Statistical analysis description

Fisher’s exact test used to compare number of participants with ≥1 new CDC stage C or severe stage B events between arms.

Comparison groups

Standard of care (Arm 2) v Intervention (Arm 1) - INSTI+DRV/r

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.497

Method

Fisher exact

Confidence interval

Secondary: New resistance mutations

Top of page

End point title

New resistance mutations

End point description

Comparison of proportion of participants with resistance mutations. Resistance defined according to IAS 2019. Stored samples (one per participant) were selected for resistance testing in those who have met the primary endpoint (confirmed VL≥50cp/ml) up to week 48 censoring date. The primary aim of selection was to select the latest sample with VL available over limit of detection at site at/after failure and before any treatment change (unless treatment change was prior to first of 2 consecutive VL≥50cp/ml) by week 48 censoring date.

End point type

Secondary

End point timeframe

Any time from randomisation to 48(+6) weeks after randomisation.

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	6 ^[11]	5 ^[12]
Units: People
Major IAS mutation	1	2
No major IAS mutation	5	3

Notes
[11] - Participants meeting primary endpoint by week 48 with resistance test available
[12] - Participants meeting primary endpoint by week 48 with resistance test available

Proportions with major resistance (unadjusted)

Statistical analysis description

Comparison of proportions with major resistance (%) of those meeting primary endpoint by week 48 and with a test available (Chi-squared test). Point estimate and 95% CI are presented as percentages.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.387

Method

Chi-squared

Parameter type

Mean difference (final values)

Point estimate

-23.33

Confidence interval

level

95%

sides

2-sided

lower limit

-75.61

upper limit

28.95

Proportions with major resistance (adjusted)

Statistical analysis description

Comparison of proportions with major resistance (%) of those meeting primary endpoint by week 48 and with a test available (Logistic regression p-value adjusted for stratification factors). Point estimate and 95% CI are presented as percentages.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.711

Method

Regression, Logistic

Parameter type

Mean difference (final values)

Point estimate

-23.33

Confidence interval

level

95%

sides

2-sided

lower limit

-75.61

upper limit

28.95

Secondary: Mean change in CD4% from randomisation to week 24

Top of page

End point title

Mean change in CD4% from randomisation to week 24

End point description

Reporting mean change from the global baseline value (across both arms).

End point type

Secondary

End point timeframe

Randomisation and week 24 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	158	158 ^[13]
Units: Percentage
arithmetic mean (standard error)	-1.6 ( 0.3 )	-0.1 ( 0.3 )

Notes
[13] - Participants with a measurement at week 24

Difference in mean change from baseline to week 24

Statistical analysis description

Linear regression of CD4% at week 24, adjusting for baseline CD4% and stratification factors. Presenting difference in mean change from baseline to week 24 between arms (INSTI+DRV/r-SOC)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

316

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.001

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-1.5

Confidence interval

level

95%

sides

2-sided

lower limit

-2.3

upper limit

-0.6

Secondary: Mean change in CD4% from randomisation to week 48

Top of page

End point title

Mean change in CD4% from randomisation to week 48

End point description

Reporting mean change from the global baseline value (across both arms).

End point type

Secondary

End point timeframe

Randomisation and week 48 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	150 ^[14]	156 ^[15]
Units: Percentage
arithmetic mean (standard error)	-1.8 ( 0.4 )	0.2 ( 0.4 )

Notes
[14] - Participants with a measurement at week 48
[15] - Participants with a measurement at week 48

Difference in mean change from baseline to week 48

Statistical analysis description

Linear regression of CD4% at week 48, adjusting for baseline CD4% and stratification factors. Presenting difference in mean change from baseline to week 48 between arms (INSTI+DRV/r-SOC)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-1.9

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

-0.9

Secondary: Mean change in CD4 count from randomisation to week 24

Top of page

End point title

Mean change in CD4 count from randomisation to week 24

End point description

Reporting mean change from the global baseline value (across both arms).

End point type

Secondary

End point timeframe

Randomisation and week 24 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	158	158 ^[16]
Units: cells/mm3
arithmetic mean (standard error)	-31.2 ( 16.3 )	0.1 ( 16.3 )

Notes
[16] - Participants with a measurement at week 24

Difference in mean change from baseline to week 24

Statistical analysis description

Linear regression of CD4 count at week 24, adjusting for baseline CD4 count and stratification factors. Presenting difference in mean change from baseline to week 24 between arms (INSTI+DRV/r-SOC)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

316

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.17

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-31.5

Confidence interval

level

95%

sides

2-sided

lower limit

-76.5

upper limit

13.5

Secondary: Mean change in CD4 count from randomisation to week 48

Top of page

End point title

Mean change in CD4 count from randomisation to week 48

End point description

Reporting mean change from the global baseline value (across both arms).

End point type

Secondary

End point timeframe

Randomisation and week 48 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	150 ^[17]	156 ^[18]
Units: cells/mm3
arithmetic mean (standard error)	-43.8 ( 16.5 )	5.2 ( 16.1 )

Notes
[17] - Participants with a measurement at week 48
[18] - Participants with a measurement at week 48

Difference in mean change from baseline to week 48

Statistical analysis description

Linear regression of CD4 count at week 48, adjusting for baseline CD4 count and stratification factors. Presenting difference in mean change from baseline to week 48 between arms (INSTI+DRV/r-SOC)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.036

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-48.3

Confidence interval

level

95%

sides

2-sided

lower limit

-93.4

upper limit

-3.2

Secondary: Changes in ART regimen

Top of page

End point title

Changes in ART regimen

End point description

ART changes that do not involve switch of any of the ART components to a different one are not included: change for “body size change/recalculation”, “regimen changes to mornings”, “switch to FDC containing the same ART components”, “switch from trial DRV to non-trial DRV”. ART change is defined as any change after randomisation day.

End point type

Secondary

End point timeframe

Any time from randomisation to end of trial [defined as latest of trial censoring date (31July2020) or week 48 censoring date (week 54 date)]

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	158	160
Units: People
On initial regimen at end of trial	145	131
Not on initial regimen at end of trial	13	29

Time to first ART change (adjusted)

Statistical analysis description

End of trial is defined as latest of trial censoring date (31July2020) or week 48 censoring date (week 54 date). With the exception of changes for change in national clinical guidelines, any other ART changes for any reason are included in the analysis. Regimen interruptions for >31 days are considered as ART discontinuations and are also included in the analysis. Cox regression model examining time to first ART change, adjusted for stratification factors.

Comparison groups

Standard of care (Arm 2) v Intervention (Arm 1) - INSTI+DRV/r

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.777

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.12

Confidence interval

level

95%

sides

2-sided

lower limit

0.52

upper limit

2.38

Time to first ART change (unadjusted)

Statistical analysis description

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.82

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.09

Confidence interval

level

95%

sides

2-sided

lower limit

0.51

upper limit

2.33

Secondary: Mean change in fasting total cholesterol from randomisation to week 24

Top of page

End point title

Mean change in fasting total cholesterol from randomisation to week 24

End point description

Reporting mean change from the global fasting baseline value (across both arms).

End point type

Secondary

End point timeframe

Randomisation and week 24 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	148 ^[19]	141 ^[20]
Units: mg/dL
arithmetic mean (standard error)	4.3 ( 2.0 )	-2.2 ( 2.0 )

Notes
[19] - Participants with a fasting measurement at week 24
[20] - Participants with a fasting measurement at week 24

Difference in mean change from baseline to week 24

Statistical analysis description

Linear regression of fasting total cholesterol at week 24, adjusting for baseline total cholesterol and stratification factors. Presenting difference in mean change from baseline to week 24 between arms (INSTI+DRV/r-SOC)

Comparison groups

Standard of care (Arm 2) v Intervention (Arm 1) - INSTI+DRV/r

Number of subjects included in analysis

289

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.022

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

6.4

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

11.9

Secondary: Mean change in fasting total cholesterol from randomisation to week 48

Top of page

End point title

Mean change in fasting total cholesterol from randomisation to week 48

End point description

Reporting mean change from the global fasting baseline value (across both arms).

End point type

Secondary

End point timeframe

Randomisation and week 48 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	136 ^[21]	143 ^[22]
Units: mg/dL
arithmetic mean (standard error)	-0.6 ( 2.2 )	-1.0 ( 2.2 )

Notes
[21] - Participants with a fasting measurement at week 48
[22] - Participants with a fasting measurement at week 48

Difference in mean change from baseline to week 48

Statistical analysis description

Linear regression of fasting total cholesterol at week 48, adjusting for baseline total cholesterol and stratification factors. Presenting difference in mean change from baseline to week 48 between arms (INSTI+DRV/r-SOC)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

279

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.916

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-5.7

upper limit

6.4

Secondary: Mean change in fasting triglycerides from randomisation to week 24

Top of page

End point title

Mean change in fasting triglycerides from randomisation to week 24

End point description

Reporting mean change from the global fasting baseline value (across both arms).

End point type

Secondary

End point timeframe

Randomisation and week 24 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	148 ^[23]	141 ^[24]
Units: mg/dL
arithmetic mean (standard error)	1.5 ( 4.4 )	-0.7 ( 4.4 )

Notes
[23] - Participants with a fasting measurement at week 24
[24] - Participants with a fasting measurement at week 24

Difference in mean change from baseline to week 24

Statistical analysis description

Linear regression of fasting triglycerides at week 24, adjusting for baseline triglycerides and stratification factors. Presenting difference in mean change from baseline to week 24 between arms (INSTI+DRV/r-SOC)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

289

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.697

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

2.4

Confidence interval

level

95%

sides

2-sided

lower limit

-9.8

upper limit

14.6

Secondary: Mean change in fasting triglycerides from randomisation to week 48

Top of page

End point title

Mean change in fasting triglycerides from randomisation to week 48

End point description

Reporting mean change from the global fasting baseline value (across both arms).

End point type

Secondary

End point timeframe

Randomisation and week 48 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	136 ^[25]	143 ^[26]
Units: mg/dL
arithmetic mean (standard error)	3.3 ( 5.6 )	5.6 ( 5.4 )

Notes
[25] - Participants with a fasting measurement at week 48
[26] - Participants with a fasting measurement at week 48

Difference in mean change from baseline to week 48

Statistical analysis description

Linear regression of fasting triglycerides at week 48, adjusting for baseline triglycerides and stratification factors. Presenting difference in mean change from baseline to week 48 between arms (INSTI+DRV/r-SOC)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

279

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.774

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-2.2

Confidence interval

level

95%

sides

2-sided

lower limit

-17.3

upper limit

12.9

Secondary: Mean change in fasting LDL from randomisation to week 24

Top of page

End point title

Mean change in fasting LDL from randomisation to week 24

End point description

Reporting mean change from the global fasting baseline value (across both arms).

End point type

Secondary

End point timeframe

Randomisation and week 24 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	148 ^[27]	141 ^[28]
Units: mg/dL
arithmetic mean (standard error)	9.0 ( 1.7 )	-1.0 ( 1.7 )

Notes
[27] - Participants with a fasting measurement at week 24
[28] - Participants with a fasting measurement at week 24

Difference in mean change from baseline to week 24

Statistical analysis description

Linear regression of fasting LDL at week 24, adjusting for baseline LDL and stratification factors. Presenting difference in mean change from baseline to week 24 between arms (INSTI+DRV/r-SOC)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

289

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

9.9

Confidence interval

level

95%

sides

2-sided

lower limit

5.2

upper limit

14.6

Secondary: Mean change in fasting LDL from randomisation to week 48

Top of page

End point title

Mean change in fasting LDL from randomisation to week 48

End point description

Reporting mean change from the global fasting baseline value (across both arms).

End point type

Secondary

End point timeframe

Randomisation and week 48 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	136 ^[29]	141 ^[30]
Units: mg/dL
arithmetic mean (standard error)	2.8 ( 1.9 )	-2.1 ( 1.9 )

Notes
[29] - Participants with a fasting measurement at week 48
[30] - Participants with a fasting measurement at week 48

Difference in mean change from baseline to week 48

Statistical analysis description

Linear regression of fasting LDL at week 48, adjusting for baseline LDL and stratification factors. Presenting difference in mean change from baseline to week 48 between arms (INSTI+DRV/r-SOC)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

277

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.088

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

4.7

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

Secondary: Mean change in fasting HDL from randomisation to week 24

Top of page

End point title

Mean change in fasting HDL from randomisation to week 24

End point description

Reporting mean change from the global fasting baseline value (across both arms).

End point type

Secondary

End point timeframe

Randomisation and week 24 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	148 ^[31]	141 ^[32]
Units: mg/dL
arithmetic mean (standard error)	-5.6 ( 0.9 )	-1.8 ( 0.9 )

Notes
[31] - Participants with a fasting measurement at week 24
[32] - Participants with a fasting measurement at week 24

Difference in mean change from baseline to week 24

Statistical analysis description

Linear regression of fasting HDL at week 24, adjusting for baseline HDL and stratification factors. Presenting difference in mean change from baseline to week 24 between arms (INSTI+DRV/r-SOC)

Comparison groups

Standard of care (Arm 2) v Intervention (Arm 1) - INSTI+DRV/r

Number of subjects included in analysis

289

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.002

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-3.9

Confidence interval

level

95%

sides

2-sided

lower limit

-6.3

upper limit

-1.5

Secondary: Mean change in fasting HDL from randomisation to week 48

Top of page

End point title

Mean change in fasting HDL from randomisation to week 48

End point description

Reporting mean change from the global fasting baseline value (across both arms).

End point type

Secondary

End point timeframe

Randomisation and week 48 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	136 ^[33]	141 ^[34]
Units: mg/dL
arithmetic mean (standard error)	-6.4 ( 1.0 )	-2.4 ( 0.9 )

Notes
[33] - Participants with a fasting measurement at week 48
[34] - Participants with a fasting measurement at week 48

Difference in mean change from baseline to week 48

Statistical analysis description

Linear regression of fasting HDL at week 48, adjusting for baseline HDL and stratification factors. Presenting difference in mean change from baseline to week 48 between arms (INSTI+DRV/r-SOC)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

277

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.003

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-4.1

Confidence interval

level

95%

sides

2-sided

lower limit

-6.7

upper limit

-1.4

Secondary: Mean change in weight from randomisation to week 24

Top of page

End point title

Mean change in weight from randomisation to week 24

End point description

Reporting mean change from the global baseline value (across both arms).

End point type

Secondary

End point timeframe

Randomisation and week 24 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	158	160
Units: Kg
arithmetic mean (standard error)	3.07 ( 0.2 )	1.79 ( 0.2 )

Difference in mean change from baseline to week 24

Statistical analysis description

Linear regression of weight at week 24, adjusting for baseline weight and stratification factors. Presenting difference in mean change from baseline to week 24 between arms (INSTI+DRV/r-SOC)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

1.27

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

1.9

Secondary: Mean change in weight from randomisation to week 48

Top of page

End point title

Mean change in weight from randomisation to week 48

End point description

Reporting mean change from the global baseline value (across both arms).

End point type

Secondary

End point timeframe

Randomisation and week 48 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	146 ^[35]	155 ^[36]
Units: Kg
arithmetic mean (standard error)	5.08 ( 0.3 )	3.11 ( 0.3 )

Notes
[35] - Participants with a measurement at week 48
[36] - Participants with a measurement at week 48

Difference in mean change from baseline to week 48

Statistical analysis description

Linear regression of weight at week 48, adjusting for baseline weight and stratification factors. Presenting difference in mean change from baseline to week 48 between arms (INSTI+DRV/r-SOC)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

301

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

1.97

Confidence interval

level

95%

sides

2-sided

lower limit

1.1

upper limit

2.9

Secondary: Mean change in weight-for-age z-score from randomisation to week 24

Top of page

End point title

Mean change in weight-for-age z-score from randomisation to week 24

End point description

Reporting mean change from the global baseline value (across both arms).

End point type

Secondary

End point timeframe

Randomisation and week 24 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	158	160
Units: z-score
arithmetic mean (standard error)	0.15 ( 0.0 )	0.01 ( 0.0 )

Difference in mean change from baseline to week 24

Statistical analysis description

Linear regression of weight-for-age z-score at week 24, adjusting for baseline weight-for-age z-score and stratification factors. Presenting difference in mean change from baseline to week 24 between arms (INSTI+DRV/r-SOC). British 1990 Reference data was used for calculation of BMI, weight and height z-scores. This reference data covers the full age range (0–23 years) of SMILE participants.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

0.14

Confidence interval

level

95%

sides

2-sided

lower limit

0.1

upper limit

0.2

Secondary: Mean change in weight-for-age z-score from randomisation to week 48

Top of page

End point title

Mean change in weight-for-age z-score from randomisation to week 48

End point description

Reporting mean change from the global baseline value (across both arms).

End point type

Secondary

End point timeframe

Randomisation and week 48 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	146 ^[37]	155 ^[38]
Units: z-score
arithmetic mean (standard error)	0.19 ( 0.0 )	-0.02 ( 0.0 )

Notes
[37] - Participants with a measurement at week 48
[38] - Participants with a measurement at week 48

Difference in mean change from baseline to week 48

Statistical analysis description

Linear regression of weight-for-age z-score at week 48, adjusting for baseline weight-for-age z-score and stratification factors. Presenting difference in mean change from baseline to week 48 between arms (INSTI+DRV/r-SOC). British 1990 Reference data was used for calculation of BMI, weight and height z-scores. This reference data covers the full age range (0–23 years) of SMILE participants.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

301

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

0.21

Confidence interval

level

95%

sides

2-sided

lower limit

0.1

upper limit

0.3

Secondary: Mean change in height from randomisation to week 24

Top of page

End point title

Mean change in height from randomisation to week 24

End point description

Reporting mean change from the global baseline value (across both arms).

End point type

Secondary

End point timeframe

Randomisation and week 24 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	158	160
Units: cm
arithmetic mean (standard error)	1.64 ( 0.1 )	1.55 ( 0.1 )

Difference in mean change from baseline to week 24

Statistical analysis description

Linear regression of height at week 24, adjusting for baseline height and stratification factors. Presenting difference in mean change from baseline to week 24 between arms (INSTI+DRV/r-SOC)

Comparison groups

Standard of care (Arm 2) v Intervention (Arm 1) - INSTI+DRV/r

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.641

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-0.3

upper limit

0.4

Secondary: Mean change in height from randomisation to week 48

Top of page

End point title

Mean change in height from randomisation to week 48

End point description

Reporting mean change from the global baseline value (across both arms).

End point type

Secondary

End point timeframe

Randomisation and week 48 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	145 ^[39]	153 ^[40]
Units: cm
arithmetic mean (standard error)	3.10 ( 0.2 )	2.76 ( 0.2 )

Notes
[39] - Participants with a measurement at week 48
[40] - Participants with a measurement at week 48

Difference in mean change from baseline to week 48

Statistical analysis description

Linear regression of height at week 48, adjusting for baseline height and stratification factors. Presenting difference in mean change from baseline to week 48 between arms (INSTI+DRV/r-SOC)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

298

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.23

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

0.36

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

0.9

Secondary: Mean change in height-for-age z-score from randomisation to week 24

Top of page

End point title

Mean change in height-for-age z-score from randomisation to week 24

End point description

Reporting mean change from the global baseline value (across both arms).

End point type

Secondary

End point timeframe

Randomisation and week 24 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	158	160
Units: z-score
arithmetic mean (standard error)	0.00 ( 0.0 )	0.01 ( 0.0 )

Difference in mean change from baseline to week 24

Statistical analysis description

Linear regression of height-for-age z-score at week 24, adjusting for baseline height-for-age z-score and stratification factors. Presenting difference in mean change from baseline to week 24 between arms (INSTI+DRV/r-SOC). British 1990 Reference data was used for calculation of BMI, weight and height z-scores. This reference data covers the full age range (0–23 years) of SMILE participants.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.847

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: Mean change in height-for-age z-score from randomisation to week 48

Top of page

End point title

Mean change in height-for-age z-score from randomisation to week 48

End point description

Reporting mean change from the global baseline value (across both arms).

End point type

Secondary

End point timeframe

Randomisation and week 48 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	145 ^[41]	153 ^[42]
Units: z-score
arithmetic mean (standard error)	0.01 ( 0.0 )	-0.00 ( 0.0 )

Notes
[41] - Participants with a measurement at week 48
[42] - Participants with a measurement at week 48

Difference in mean change from baseline to week 48

Statistical analysis description

Linear regression of height-for-age z-score at week 48, adjusting for baseline height-for-age z-score and stratification factors. Presenting difference in mean change from baseline to week 48 between arms (INSTI+DRV/r-SOC). British 1990 Reference data was used for calculation of BMI, weight and height z-scores. This reference data covers the full age range (0–23 years) of SMILE participants.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

298

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.754

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

0.1

Secondary: Onset of menarche at week 48

Top of page

End point title

Onset of menarche at week 48

End point description

Comparison of proportion of female participants reaching menarche at week 48

End point type

Secondary

End point timeframe

Week 48

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	12 ^[43]	22 ^[44]
Units: People
No (not reached menarche at week 48)	4	4
Yes (reached menarche at week 48))	8	18

Notes
[43] - Number of female participants who had not already reached menarche at baseline.
[44] - Number of female participants who had not already reached menarche at baseline.

Difference in proportion reaching menarche at w48

Statistical analysis description

Difference in proportion of female participants reaching menarche at week 48 (Logistic regression p-value adjusted for stratification factors)

Comparison groups

Standard of care (Arm 2) v Intervention (Arm 1) - INSTI+DRV/r

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.332

Method

Regression, Logistic

Confidence interval

Secondary: Changes in tanner scores (pubic hair) by week 48

Top of page

End point title

Changes in tanner scores (pubic hair) by week 48

End point description

Reporting proportion changes in ordered categorical variable (Tanner Score - pubic hair) from baseline, week 24 and 48

End point type

Secondary

End point timeframe

Randomisation, week 24 and week 48

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	143 ^[45]	153 ^[46]
Units: People	143	153

Notes
[45] - Participants with a measurement at week 48
[46] - Participants with a measurement at week 48

Changes in pubic hair tanner scores by week 48

Statistical analysis description

Ordered logistic mixed model comparing ordered outcome across treatment arms over time up to week 48 with a random effect for intercept and fixed effects for treatment group, post-randomisation study visits and adjustment covariates [baseline Tanner scores, age at randomisation and Region; assuming proportional odds.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

296

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.05

Method

Ordered logistic mixed model

Parameter type

Odds ratio (OR)

Point estimate

1.52

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

2.32

Secondary: Changes in tanner scores (female breast) by week 48

Top of page

End point title

Changes in tanner scores (female breast) by week 48

End point description

Reporting proportion changes in ordered categorical variable (Tanner Score - female breast) from baseline, week 24 and 48

End point type

Secondary

End point timeframe

Randomisation, week 24 and week 48

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	86 ^[47]	101 ^[48]
Units: People	86	101

Notes
[47] - Female participants with a measurement at week 48, out of 92 females enrolled in arm 1.
[48] - Female participants with a measurement at week 48, out of 102 females enrolled in arm 2.

Changes in female breast tanner scores by week 48

Statistical analysis description

Ordered logistic mixed model was fitted to compare ordered outcome across treatment arms over time up to week 48 with a random effect for intercept and fixed effects for treatment group, post-randomisation study visits and adjustment covariates [baseline Tanner scores and strata]; assuming proportional odds.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

187

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.097

Method

Ordered logistic mixed model

Parameter type

Odds ratio (OR)

Point estimate

1.57

Confidence interval

level

95%

sides

2-sided

lower limit

0.92

upper limit

2.66

Secondary: Changes in tanner scores (male genital) by week 48

Top of page

End point title

Changes in tanner scores (male genital) by week 48

End point description

Reporting proportion changes in ordered categorical variable (Tanner Score - male genital) from baseline, week 24 and 48

End point type

Secondary

End point timeframe

Randomisation, week 24 and week 48

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	58 ^[49]	52 ^[50]
Units: People	58	52

Notes
[49] - Male participants with a measurement at week 48, out of 66 males enrolled in arm 1.
[50] - Male participants with a measurement at week 48, out of 58 males enrolled in arm 2.

Changes in male genital scores by week 48

Statistical analysis description

Comparison groups

Standard of care (Arm 2) v Intervention (Arm 1) - INSTI+DRV/r

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.009

Method

Ordered logistic mixed model

Parameter type

Odds ratio (OR)

Point estimate

2.99

Confidence interval

level

95%

sides

2-sided

lower limit

1.31

upper limit

6.84

Secondary: Adherence (participant response): Missed a dose over the last 3 days

Top of page

End point title

Adherence (participant response): Missed a dose over the last 3 days

End point description

Participants were asked if they missed a dose over the last 3 days

End point type

Secondary

End point timeframe

Collected at weeks 0, 4, 12, 24, 36, 48 and every 12 weeks thereafter to end of trial, defined as latest of trial censoring date (31July2020) or week 48 censoring date.

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	158 ^[51]	160 ^[52]
Units: People
Missed a dose over the last 3 days: week 4	6	6
Missed a dose over the last 3 days: week 12	6	5
Missed a dose over the last 3 days: week 24	6	7
Missed a dose over the last 3 days: week 36	6	9
Missed a dose over the last 3 days: week 48	7	5

Notes
[51] - Denominator differed by study week: Week 4=157; Week 12=158; Week 24=158; Week 36=155; Week 48=151
[52] - Denominator differed by study week: Week 4=159; Week 12=159; Week 24=157; Week 36=155; Week 48=156

Proportions missed a dose over the last 3 days

Statistical analysis description

Logistic mixed model was fitted to compare binary outcome across treatment arms over time with a random effect for intercept and fixed effects for treatment group, post-randomisation study visits and adjustment covariates [baseline answer and strata].

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.342

Method

Logistic mixed model

Confidence interval

Secondary: Adherence (participant response): Missed any dose since last clinic visit

Top of page

End point title

Adherence (participant response): Missed any dose since last clinic visit

End point description

Participants were asked if they missed any dose since last clinic visit

End point type

Secondary

End point timeframe

Collected at weeks 0, 4, 12, 24, 36, 48 and every 12 weeks thereafter to end of trial, defined as latest of trial censoring date (31July2020) or week 48 censoring date.

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	158 ^[53]	160 ^[54]
Units: People
Missed any dose since last clinic visit: Week 4	15	18
Missed any dose since last clinic visit: Week 12	23	17
Missed any dose since last clinic visit: Week 24	32	28
Missed any dose since last clinic visit: Week 36	26	23
Missed any dose since last clinic visit: Week 48	24	17

Notes
[53] - Denominator differed by study week: Week 4=157; Week 12=158; Week 24=158; Week 36=155; Week 48=151
[54] - Denominator differed by study week: Week 4=159; Week 12=159; Week 24=157; Week 36=155; Week 48=156

Proportions missed any dose since last visit

Statistical analysis description

Comparison groups

Standard of care (Arm 2) v Intervention (Arm 1) - INSTI+DRV/r

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.32

Method

Logistic mixed model

Confidence interval

Secondary: Adherence (participant response): Adherence rating since the last clinic visit

Top of page

End point title

Adherence (participant response): Adherence rating since the last clinic visit

End point description

Participants were asked to complete adherence rating since the last clinic visit

End point type

Secondary

End point timeframe

Collected at weeks 0, 4, 12, 24, 36, 48 and every 12 weeks thereafter to end of trial, defined as latest of trial censoring date (31July2020) or week 48 censoring date.

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	158 ^[55]	160 ^[56]
Units: People
Week 4: Excellent	81	73
Week 4: Very Good	61	70
Week 4: Fair	10	6
Week 4: Not that good	0	3
Week 4: Not recorded	5	7
Week 12: Excellent	83	69
Week 12: Very Good	54	75
Week 12: Fair	15	9
Week 12: Not that good	1	1
Week 12: Not recorded	5	5
Week 24: Excellent	74	65
Week 24: Very Good	64	77
Week 24: Fair	10	10
Week 24: Not that good	2	1
Week 24: Not recorded	8	4
Week 36: Excellent	74	79
Week 36: Very Good	66	59
Week 36: Fair	11	9
Week 36: Not that good	0	3
Week 36: Not recorded	4	5
Week 48: Excellent	63	62
Week 48: Very Good	76	80
Week 48: Fair	7	7
Week 48: Not that good	1	1
Week 48: Not recorded	4	6

Notes
[55] - Denominator differed by study week: Week 4=157; Week 12=158; Week 24=158; Week 36=155; Week 48=151
[56] - Denominator differed by study week: Week 4=159; Week 12=159; Week 24=157; Week 36=155; Week 48=156

Comparing adherence rating since the last visit

Statistical analysis description

Ordered logistic mixed model was fitted to compare ordered outcome across treatment arms with a random effect for intercept and fixed effects for treatment group, post-randomisation study visits and adjustment covariates [baseline answers and strata].

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.423

Method

Ordered logistic mixed model

Confidence interval

Secondary: Adherence (parent response): Missed a dose over the last 3 days

Top of page

End point title

Adherence (parent response): Missed a dose over the last 3 days

End point description

Collected at weeks 0, 4, 12, 24, 36, 48 and every 12 weeks thereafter to end of trial, defined as latest of trial censoring date (31July2020) or week 48 censoring date.

End point type

Secondary

End point timeframe

Parents/carers were asked if their child has missed a dose over the last 3 days

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	158 ^[57]	160 ^[58]
Units: People
Missed a dose over the last 3 days: week 4	2	6
Missed a dose over the last 3 days: week 12	4	4
Missed a dose over the last 3 days: week 24	4	2
Missed a dose over the last 3 days: week 36	5	6
Missed a dose over the last 3 days: week 48	4	4

Notes
[57] - Denominator differed by study week: Week 4=143; Week 12=138; Week 24=137; Week 36=130; Week 48=124
[58] - Denominator differed by study week: Week 4=147; Week 12=143; Week 24=134; Week 36=134; Week 48=138

Proportions missed a dose over the last 3 days

Statistical analysis description

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.793

Method

Logistic mixed model

Confidence interval

Secondary: Adherence (parent response): Missed any dose since last clinic visit

Top of page

End point title

Adherence (parent response): Missed any dose since last clinic visit

End point description

Parents/carers were asked if their child has missed any dose since last clinic visit

End point type

Secondary

End point timeframe

Collected at weeks 0, 4, 12, 24, 36, 48 and every 12 weeks thereafter to end of trial, defined as latest of trial censoring date (31July2020) or week 48 censoring date.

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	158 ^[59]	160 ^[60]
Units: People
Missed any dose since last clinic visit: Week 4	10	15
Missed any dose since last clinic visit: Week 12	15	13
Missed any dose since last clinic visit: Week 24	24	18
Missed any dose since last clinic visit: Week 36	20	17
Missed any dose since last clinic visit: Week 48	14	13

Notes
[59] - Denominator differed by study week: Week 4=143; Week 12=138; Week 24=137; Week 36=130; Week 48=124
[60] - Denominator differed by study week: Week 4=147; Week 12=143; Week 24=134; Week 36=134; Week 48=138

Proportions missed any dose since last visit

Statistical analysis description

Comparison groups

Standard of care (Arm 2) v Intervention (Arm 1) - INSTI+DRV/r

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.328

Method

Logistic mixed model

Confidence interval

Secondary: Adherence (parent response): Adherence rating since the last clinic visit

Top of page

End point title

Adherence (parent response): Adherence rating since the last clinic visit

End point description

Parents/carers were asked to complete adherence rating since the last clinic visit for their child

End point type

Secondary

End point timeframe

Collected at weeks 0, 4, 12, 24, 36, 48 and every 12 weeks thereafter to end of trial, defined as latest of trial censoring date (31July2020) or week 48 censoring date.

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	158 ^[61]	160 ^[62]
Units: People
Week 4: Excellent	70	71
Week 4: Very Good	61	63
Week 4: Fair	7	6
Week 4: Not recorded	5	7
Week 12: Excellent	73	64
Week 12: Very Good	49	67
Week 12: Fair	10	6
Week 12: Not that good	1	1
Week 12: Not recorded	5	5
Week 24: Excellent	64	66
Week 24: Very Good	55	57
Week 24: Fair	11	4
Week 24: Not that good	1	1
Week 24: Not recorded	6	6
Week 36: Excellent	51	70
Week 36: Very Good	61	50
Week 36: Fair	14	6
Week 36: Not that good	0	3
Week 36: Not recorded	4	5
Week 48: Excellent	40	47
Week 48: Very Good	76	72
Week 48: Fair	4	12
Week 48: Not that good	1	0
Week 48: Not recorded	3	7

Notes
[61] - Denominator differed by study week: Week 4=143; Week 12=138; Week 24=137; Week 36=130; Week 48=124
[62] - Denominator differed by study week: Week 4=147; Week 12=143; Week 24=134; Week 36=134; Week 48=138

Comparing adherence rating since the last visit

Statistical analysis description

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.411

Method

Ordered logistic mixed model

Confidence interval

Secondary: Acceptability (participant response): Mood-related symptoms at week 48

Top of page

End point title

Acceptability (participant response): Mood-related symptoms at week 48

End point description

Participants were asked if they had mood-related symptoms

End point type

Secondary

End point timeframe

Week 48

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	148 ^[63]	154 ^[64]
Units: People
Dizziness or room spinning: Week 48	13	14
Low mood or feeling sad often: Week 48	14	9
Problems concentrating: Week 48	6	8
Hurting or harming him/herself: Week 48	2	3
Feeling worried often: Week 48	4	10
Thinking life is not worth living: Week 48	3	3
Feeling angry or aggressive often: Week 48	10	7
Thinking about ending life: Week 48	2	4

Notes
[63] - Questionnaires completed at week 48
[64] - Questionnaires completed at week 48

Comparing dizziness/room spinning at week 48

Statistical analysis description

Comparing proportions reporting dizziness/room spinning at week 48 (logistic regression p-value adjusted for baseline answer and stratification factors)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.966

Method

Regression, Logistic

Confidence interval

Comparing low mood/feeling sad often at week 48

Statistical analysis description

Comparing proportions reporting low mood/feeling sad often at week 48 (logistic regression p-value adjusted for baseline answer and stratification factors)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.19

Method

Regression, Logistic

Confidence interval

Comparing problems concentrating at week 48

Statistical analysis description

Comparing proportions reporting problems concentrating at week 48 (logistic regression p-value adjusted for baseline answer and stratification factors)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.545

Method

Regression, Logistic

Confidence interval

Comparing hurting/harming him/herself at week 48

Statistical analysis description

Comparing proportions reporting hurting/harming him/herself at week 48 (logistic regression p-value adjusted for baseline answer and stratification factors)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.682

Method

Regression, Logistic

Confidence interval

Comparing feeling worried often at week 48

Statistical analysis description

Comparing proportions reporting feeling worried often at week 48 (logistic regression p-value adjusted for baseline answer and stratification factors)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.121

Method

Regression, Logistic

Confidence interval

Comparing thinking life is not worth living at w48

Statistical analysis description

Comparing proportions reporting thinking life is not worth living at week 48 (logistic regression p-value adjusted for baseline answer and stratification factors)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.9

Method

Regression, Logistic

Confidence interval

Comparing feeling angry/aggressive often at w48

Statistical analysis description

Comparing proportions reporting feeling angry or aggressive often at week 48 (logistic regression p-value adjusted for baseline answer and stratification factors)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.289

Method

Regression, Logistic

Confidence interval

Comparing thinking about ending life at week 48

Statistical analysis description

Comparing proportions reporting thinking about ending life at week 48 (logistic regression p-value adjusted for baseline answer and stratification factors)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.46

Method

Regression, Logistic

Confidence interval

Secondary: Acceptability (participant response): Sleep quality at week 48

Top of page

End point title

Acceptability (participant response): Sleep quality at week 48

End point description

Participants were asked about the time taken to sleep and overall sleep quality, as well as if they had nightmares or vivid dreams

End point type

Secondary

End point timeframe

Week 48

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	148 ^[65]	154 ^[66]
Units: People
Time taken to sleep (Week 48): ≤15 minutes	71	73
Time taken to sleep (Week 48): 15-30 minutes	42	44
Time taken to sleep (Week 48): 30 minutes - 1 hour	14	12
Time taken to sleep (Week 48): ≥1 hour	5	4
Time taken to sleep (Week 48): Don't know	12	16
Time taken to sleep (Week 48): Not recorded	4	5
Nightmares (Week 48): Never	120	126
Nightmares (Week 48): Infrequently	13	17
Nightmares (Week 48): Occasionally	8	3
Nightmares (Week 48): Frequently	1	1
Nightmares (Week 48): Don't know	1	4
Nightmares (Week 48): Not recorded	5	3
Vivid dreams (Week 48): Never	89	98
Vivid dreams (Week 48): Infrequently	23	17
Vivid dreams (Week 48): Occasionally	18	20
Vivid dreams (Week 48): Frequently	11	13
Vivid dreams (Week 48): Don't know	2	3
Vivid dreams (Week 48): Not recorded	5	3
Sleep quality (Week 48): Very Good	70	66
Sleep quality (Week 48): Good	53	58
Sleep quality (Week 48): Fair	14	21
Sleep quality (Week 48): Not that good	5	3
Sleep quality (Week 48): Very bad	0	1
Sleep quality (Week 48): Don't know	0	1
Sleep quality (Week 48): Not recorded	6	4

Notes
[65] - Questionnaires completed at week 48
[66] - Questionnaires completed at week 48

Comparing time taken to sleep at week 48

Statistical analysis description

Ordered logistic regression p-value adjusted for baseline answers and strata.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.754

Method

Ordered logistic regression

Confidence interval

Comparing nightmares at week 48

Statistical analysis description

Ordered logistic regression p-value adjusted for baseline answers and strata.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.821

Method

Ordered logistic regression

Confidence interval

Comparing vivid dreams at week 48

Statistical analysis description

Ordered logistic regression p-value adjusted for baseline answers and strata.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.673

Method

Ordered logistic regression

Confidence interval

Comparing sleep quality at week 48

Statistical analysis description

Ordered logistic regression p-value adjusted for baseline answers and strata.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.179

Method

Ordered logistic regression

Confidence interval

Secondary: Acceptability (parent response): Mood-related symptoms at week 48

Top of page

End point title

Acceptability (parent response): Mood-related symptoms at week 48

End point description

Parents/carers were asked if their children had mood-related symptoms

End point type

Secondary

End point timeframe

Week 48

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	122 ^[67]	135 ^[68]
Units: People
Dizziness or room spinning: Week 48	5	6
Low mood or feeling sad often: Week 48	12	14
Problems concentrating: Week 48	1	5
Hurting or harming him/herself: Week 48	0	1
Feeling worried often: Week 48	2	6
Thinking life is not worth living: Week 48	1	2
Feeling angry or aggressive often: Week 48	8	10
Thinking about ending life: Week 48	1	1
Other: Week 48	0	0

Notes
[67] - Questionnaires completed at week 48
[68] - Questionnaires completed at week 48

Comparing dizziness/room spinning at week 48

Statistical analysis description

Comparing proportions reporting dizziness/room spinning at week 48 (logistic regression p-value adjusted for baseline answer and stratification factors)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

257

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.895

Method

Regression, Logistic

Confidence interval

Comparing low mood/feeling sad often at week 48

Statistical analysis description

Comparing proportions reporting low mood/feeling sad often at week 48 (logistic regression p-value adjusted for baseline answer and stratification factors)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

257

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.839

Method

Regression, Logistic

Confidence interval

Comparing problems concentrating at week 48

Statistical analysis description

Comparing proportions reporting problems concentrating at week 48 (logistic regression p-value adjusted for baseline answer and stratification factors)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

257

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.108

Method

Regression, Logistic

Confidence interval

Comparing hurting/harming him/herself at week 48

Statistical analysis description

Comparing proportions reporting hurting/harming him/herself at week 48

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

257

Analysis specification

Pre-specified

Analysis type

other

P-value

= 1

Method

Fisher exact

Confidence interval

Comparing feeling worried often at week 48

Statistical analysis description

Comparing proportions reporting feeling worried often at week 48 (logistic regression p-value adjusted for baseline answer and stratification factors)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

257

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.18

Method

Regression, Logistic

Confidence interval

Comparing thinking life is not worth living at w48

Statistical analysis description

Comparing proportions reporting thinking life is not worth living at week 48 (logistic regression p-value adjusted for baseline answer and stratification factors)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

257

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.612

Method

Regression, Logistic

Confidence interval

Comparing feeling angry/aggressive often at w48

Statistical analysis description

Comparing proportions reporting feeling angry or aggressive often at week 48 (logistic regression p-value adjusted for baseline answer and stratification factors)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

257

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.904

Method

Regression, Logistic

Confidence interval

Comparing thinking about ending life at week 48

Statistical analysis description

Comparing proportions reporting thinking about ending life at week 48 (logistic regression p-value adjusted for baseline answer and stratification factors)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

257

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.945

Method

Regression, Logistic

Confidence interval

Secondary: Acceptability (parent response): Sleep quality at week 48

Top of page

End point title

Acceptability (parent response): Sleep quality at week 48

End point description

Parents/carers were asked questions about their children: time taken to sleep and overall sleep quality, as well as if their children had nightmares or vivid dreams

End point type

Secondary

End point timeframe

Week 48

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	122 ^[69]	135 ^[70]
Units: People
Time taken to sleep (Week 48): ≤15 minutes	57	65
Time taken to sleep (Week 48): 15-30 minutes	33	39
Time taken to sleep (Week 48): 30 minutes - 1 hour	15	7
Time taken to sleep (Week 48): ≥1 hour	2	0
Time taken to sleep (Week 48): Don't know	11	20
Time taken to sleep (Week 48): Not recorded	4	4
Nightmares (Week 48): Never	84	94
Nightmares (Week 48): Infrequently	11	7
Nightmares (Week 48): Occasionally	4	2
Nightmares (Week 48): Frequently	1	0
Nightmares (Week 48): Don't know	19	26
Nightmares (Week 48): Not recorded	3	6
Vivid dreams (Week 48): Never	71	78
Vivid dreams (Week 48): Infrequently	15	9
Vivid dreams (Week 48): Occasionally	3	10
Vivid dreams (Week 48): Frequently	5	1
Vivid dreams (Week 48): Don't know	25	31
Vivid dreams (Week 48): Not recorded	3	6
Sleep quality (Week 48): Very Good	48	57
Sleep quality (Week 48): Good	57	57
Sleep quality (Week 48): Fair	8	13
Sleep quality (Week 48): Not that good	2	1
Sleep quality (Week 48): Very bad	1	0
Sleep quality (Week 48): Don't know	2	1
Sleep quality (Week 48): Not recorded	4	6

Notes
[69] - Questionnaires completed at week 48
[70] - Questionnaires completed at week 48

Comparing time taken to sleep at week 48

Statistical analysis description

Ordered logistic regression p-value adjusted for baseline answers and strata.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

257

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.276

Method

Ordered logistic regression

Confidence interval

Comparing nightmares at week 48

Statistical analysis description

Ordered logistic regression p-value adjusted for baseline answers and strata.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

257

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.128

Method

Ordered logistic regression

Confidence interval

Comparing vivid dreams at week 48

Statistical analysis description

Ordered logistic regression p-value adjusted for baseline answers and strata.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

257

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.511

Method

Ordered logistic regression

Confidence interval

Comparing sleep quality at week 48

Statistical analysis description

Ordered logistic regression p-value adjusted for baseline answers and strata.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

257

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.554

Method

Ordered logistic regression

Confidence interval

Secondary: How did taking INSTI+DRV/r make things for you compared to previous meds (participant response)?

Top of page

End point title

How did taking INSTI+DRV/r make things for you compared to previous meds (participant response)? ^[71]

End point description

At end of study visit participants were asked: How did taking INSTI+DRV/r make things for you compared to previous meds? No statistical analyses for this end point.

End point type

Secondary

End point timeframe

End of study visit defined as the participant's study exit visit, which takes place on/after trial censoring date (31 July 2020).

Notes
[71] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Questionnaire only answered by participants or parents/carers of participants in INSTI+DRV/r arm. This is not applicable to SOC arm.

End point values	Intervention (Arm 1) - INSTI+DRV/r
Number of subjects analysed	157 ^[72]
Units: People
A lot easier	52
A little easier	13
No difference	14
A little more difficult	2
Not recorded	76

Notes
[72] - Questionnaires completed. Only answered by those in INSTI+DRV/r arm.

No statistical analyses for this end point

Secondary: Overall, how did you feel whilst taking INSTI+DRV/r compared with pre-study meds (participant response)?

Top of page

End point title

Overall, how did you feel whilst taking INSTI+DRV/r compared with pre-study meds (participant response)? ^[73]

End point description

At end of study visit participants were asked: Overall, how did you feel whilst taking INSTI+DRV/r compared with pre-study meds. No statistical analyses for this end point.

End point type

Secondary

End point timeframe

End of study visit defined as the participant's study exit visit, which takes place on/after trial censoring date (31 July 2020).

Notes
[73] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Questionnaire only answered by participants or parents/carers of participants in INSTI+DRV/r arm. This is not applicable to SOC arm.

End point values	Intervention (Arm 1) - INSTI+DRV/r
Number of subjects analysed	157 ^[74]
Units: People
I felt better before the study	2
I felt better on Tivicay or Elvitegravir and Prezi	55
No difference	25
Not recorded	75

Notes
[74] - Questionnaires completed. Only answered by those in INSTI+DRV/r arm.

No statistical analyses for this end point

Secondary: Would you be happy to stay on INSTI+DRV/r (participant response)?

Top of page

End point title

Would you be happy to stay on INSTI+DRV/r (participant response)? ^[75]

End point description

At end of study visit participants were asked: Would you be happy to stay on INSTI+DRV/r? No statistical analyses for this end point.

End point type

Secondary

End point timeframe

End of study visit defined as the participant's study exit visit, which takes place on/after trial censoring date (31 July 2020).

Notes
[75] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Questionnaire only answered by participants or parents/carers of participants in INSTI+DRV/r arm. This is not applicable to SOC arm.

End point values	Intervention (Arm 1) - INSTI+DRV/r
Number of subjects analysed	157 ^[76]
Units: People
Yes	66
No	11
Not sure	2
NA: I have already restarted pre-study meds	2
Not recorded	76

Notes
[76] - Questionnaires completed. Only answered by those in INSTI+DRV/r arm.

No statistical analyses for this end point

Secondary: How did taking INSTI+DRV/r make things for you compared to your child's previous meds (parent response)?

Top of page

End point title

How did taking INSTI+DRV/r make things for you compared to your child's previous meds (parent response)? ^[77]

End point description

At end of study visit parent/carer were asked: How did taking INSTI+DRV/r make things for you compared to your child's previous meds. No statistical analyses for this end point.

End point type

Secondary

End point timeframe

End of study visit defined as the participant's study exit visit, which takes place on/after trial censoring date (31 July 2020).

Notes
[77] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Questionnaire only answered by participants or parents/carers of participants in INSTI+DRV/r arm. This is not applicable to SOC arm.

End point values	Intervention (Arm 1) - INSTI+DRV/r
Number of subjects analysed	116 ^[78]
Units: People
A lot easier	38
A little easier	8
No difference	8
A little more difficult	6
Not recorded	56

Notes
[78] - Questionnaires completed. Only answered by participant's parents/carers in INSTI+DRV/r arm.

No statistical analyses for this end point

Secondary: Overall, how did your child feel whilst taking INSTI+DRV/r compared with your child's pre-study meds (parent response)?

Top of page

End point title

Overall, how did your child feel whilst taking INSTI+DRV/r compared with your child's pre-study meds (parent response)? ^[79]

End point description

At end of study visit parents/carers were asked: Overall, how did your child feel whilst taking INSTI+DRV/r compared with your child's pre-study meds. No statistical analyses for this end point.

End point type

Secondary

End point timeframe

End of study visit defined as the participant's study exit visit, which takes place on/after trial censoring date (31 July 2020).

Notes
[79] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Questionnaire only answered by participants or parents/carers of participants in INSTI+DRV/r arm. This is not applicable to SOC arm.

End point values	Intervention (Arm 1) - INSTI+DRV/r
Number of subjects analysed	116 ^[80]
Units: People
Felt better before the study	1
Better on Tivicay/Elvitegravir+Prezista/Norvir	41
No difference	18
Not recorded	56

Notes
[80] - Questionnaires completed. Only answered by participant's parents/carers in INSTI+DRV/r arm.

No statistical analyses for this end point

Secondary: Would you be happy for your child to stay on INSTI+DRV/r (parent response)?

Top of page

End point title

Would you be happy for your child to stay on INSTI+DRV/r (parent response)? ^[81]

End point description

At end of study visit parents/carers were asked: Would you be happy for your child to stay on INSTI+DRV/r? No statistical analyses for this end point.

End point type

Secondary

End point timeframe

End of study visit defined as the participant's study exit visit, which takes place on/after trial censoring date (31 July 2020).

Notes
[81] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Questionnaire only answered by participants or parents/carers of participants in INSTI+DRV/r arm. This is not applicable to SOC arm.

End point values	Intervention (Arm 1) - INSTI+DRV/r
Number of subjects analysed	116 ^[82]
Units: People
Yes	49
No	9
Not sure	1
NA: My child has already restarted pre-study meds	2
Not recorded	55

Notes
[82] - Questionnaires completed. Only answered by participant's parents/carers in INSTI+DRV/r arm.

No statistical analyses for this end point

Secondary: Mean change in PedsQL Total Score from randomisation to week 48 (participant response)

Top of page

End point title

Mean change in PedsQL Total Score from randomisation to week 48 (participant response)

End point description

Reporting mean change from the global baseline value (across both arms). PedsQL total Score is composed of 23 items comprising all 4 dimensions (Physical, Emotional, Social and School Functioning Scales)

End point type

Secondary

End point timeframe

Randomisation and week 48 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	151 ^[83]	154 ^[84]
Units: PedsQL score
arithmetic mean (standard error)	3.5 ( 0.8 )	4.3 ( 0.7 )

Notes
[83] - Questionnaires completed at week 48
[84] - Questionnaires completed at week 48

Difference in mean change from baseline to week 48

Statistical analysis description

Linear regression of PedsQL Total Score at week 48, adjusting for baseline PedsQL Total Score and stratification factors. Presenting difference in mean change from baseline to week 48 between arms (INSTI+DRV/r-SOC)

Comparison groups

Standard of care (Arm 2) v Intervention (Arm 1) - INSTI+DRV/r

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.458

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-2.9

upper limit

1.3

Secondary: Mean change in PedsQL Physical Health Score from randomisation to week 48 (participant response)

Top of page

End point title

Mean change in PedsQL Physical Health Score from randomisation to week 48 (participant response)

End point description

Reporting mean change from the global baseline value (across both arms).

End point type

Secondary

End point timeframe

Randomisation and week 48 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	151 ^[85]	154 ^[86]
Units: PedsQL score
arithmetic mean (standard error)	1.9 ( 0.8 )	2.9 ( 0.8 )

Notes
[85] - Questionnaires completed at week 48
[86] - Questionnaires completed at week 48

Difference in mean change from baseline to week 48

Statistical analysis description

Linear regression of PedsQL Physical Health Score at week 48, adjusting for baseline PedsQL Physical Health Score and stratification factors. Presenting difference in mean change from baseline to week 48between arms (INSTI+DRV/r-SOC)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.402

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-3.3

upper limit

1.3

Secondary: Mean change in PedsQL Psychosocial Health Score from randomisation to week 48 (participant response)

Top of page

End point title

Mean change in PedsQL Psychosocial Health Score from randomisation to week 48 (participant response)

End point description

Reporting mean change from the global baseline value (across both arms). PedsQL Psychosocial Health score is composed of 15 items comprising 3 dimensions (Emotional, Social, and School Functioning Scales).

End point type

Secondary

End point timeframe

Randomisation and week 48 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	151 ^[87]	154 ^[88]
Units: PedsQL score
arithmetic mean (standard error)	4.3 ( 0.9 )	5.0 ( 0.8 )

Notes
[87] - Questionnaires completed at week 48
[88] - Questionnaires completed at week 48

Difference in mean change from baseline to week 48

Statistical analysis description

Linear regression of PedsQL Psychosocial Health Score at week 48, adjusting for baseline PedsQL Psychosocial Health Score and stratification factors. Presenting difference in mean change from baseline to week 48 between arms (INSTI+DRV/r-SOC)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.575

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

1.7

Secondary: Mean change in PedsQL Total Score from randomisation to week 48 (parent response)

Top of page

End point title

Mean change in PedsQL Total Score from randomisation to week 48 (parent response)

End point description

End point type

Secondary

End point timeframe

Randomisation and week 48 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	119 ^[89]	126 ^[90]
Units: PedsQL score
arithmetic mean (standard error)	4.1 ( 1.0 )	2.6 ( 1.0 )

Notes
[89] - Questionnaires completed at week 48
[90] - Questionnaires completed at week 48

Difference in mean change from baseline to week 48

Statistical analysis description

Comparison groups

Standard of care (Arm 2) v Intervention (Arm 1) - INSTI+DRV/r

Number of subjects included in analysis

245

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.364

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-1.5

upper limit

Secondary: Mean change in PedsQL Physical Health Score from randomisation to week 48 (parent response)

Top of page

End point title

Mean change in PedsQL Physical Health Score from randomisation to week 48 (parent response)

End point description

Reporting mean change from the global baseline value (across both arms).

End point type

Secondary

End point timeframe

Randomisation and week 48 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	119 ^[91]	126 ^[92]
Units: PedsQL score
arithmetic mean (standard error)	2.4 ( 1.1 )	0.6 ( 1.1 )

Notes
[91] - Questionnaires completed at week 48
[92] - Questionnaires completed at week 48

Difference in mean change from baseline to week 48

Statistical analysis description

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

245

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.268

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

1.7

Confidence interval

level

95%

sides

2-sided

lower limit

-1.3

upper limit

4.7

Secondary: Mean change in PedsQL Psychosocial Health Score from randomisation to week 48 (parent response)

Top of page

End point title

Mean change in PedsQL Psychosocial Health Score from randomisation to week 48 (parent response)

End point description

End point type

Secondary

End point timeframe

Randomisation and week 48 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	119 ^[93]	126 ^[94]
Units: PedsQL score
arithmetic mean (standard error)	4.9 ( 1.1 )	3.7 ( 1.1 )

Notes
[93] - Questionnaires completed at week 48
[94] - Questionnaires completed at week 48

Difference in mean change from baseline to week 48

Statistical analysis description

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

245

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.518

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

3.9

Secondary: Serious adverse events reported to end of trial

Top of page

End point title

Serious adverse events reported to end of trial

End point description

End point type

Secondary

End point timeframe

Any time from randomisation to end of trial [defined as latest of trial censoring date (31July2020) or week 48 censoring date (week 54 date)]

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	158 ^[95]	160 ^[96]
Units: People
SAEs reported	4	4
No SAEs reported	154	156

Notes
[95] - 4 participants reported 4 SAEs
[96] - 4 participants reported 5 SAEs.

Serious adverse event incidence rate ratio

Statistical analysis description

SAEs are analysed as episodes, with all components of the same clinical SAE presented as one episode (Major depression + Suicidal ideation). Each hospital admission is reported as a separate SAE. Poisson regression adjusted for stratification factors and event clustering within individuals.

Comparison groups

Standard of care (Arm 2) v Intervention (Arm 1) - INSTI+DRV/r

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.763

Method

Poisson regression

Parameter type

Rate Ratio

Point estimate

0.81

Confidence interval

level

95%

sides

2-sided

lower limit

0.2

upper limit

3.22

Time to first serious adverse event

Statistical analysis description

SAEs are analysed as episodes, with all components of the same clinical SAE presented as one episode (Major depression + Suicidal ideation). Each hospital admission is reported as a separate SAE. Cox regression analysis examining time to first serious adverse event adjusted for stratification factors.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.993

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.01

Confidence interval

level

95%

sides

2-sided

lower limit

0.25

upper limit

4.02

Proportion of participants with ≥1 SAEs reported

Statistical analysis description

Comparison of proportion of participants with ≥1 SAEs between arms (Chi-squared test).

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.986

Method

Chi-squared

Confidence interval

Secondary: Grade 3 or 4 adverse events reported to end of trial

Top of page

End point title

Grade 3 or 4 adverse events reported to end of trial

End point description

Note: grade 3/4 clinical or laboratory AEs include any events reported at grade 3 or 4. These events may be part of SAEs or be reported as ART modifying AEs or notable events.

End point type

Secondary

End point timeframe

Any time from randomisation to end of trial [defined as latest of trial censoring date (31July2020) or week 48 censoring date (week 54 date)]

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	158 ^[97]	160 ^[98]
Units: People
Grade 3 or 4 AEs reported	13	19
No Grade 3 or 4 AEs reported	145	141

Notes
[97] - 13 participants reported 13 Grade 3 or 4 AEs.
[98] - 19 participants reported 25 Grade 3 or 4 AEs.

Grade 3/4 adverse event incidence rate ratio

Statistical analysis description

Grade 3 or 4 clinical and laboratory adverse events. Poisson regression adjusted for stratification factors and event clustering within individuals.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.079

Method

Poisson regression

Parameter type

Rate Ratio

Point estimate

0.52

Confidence interval

level

95%

sides

2-sided

lower limit

0.26

upper limit

1.08

Time to first grade 3 or 4 AE

Statistical analysis description

Grade 3 or 4 clinical and laboratory adverse events. Cox regression analysis examining time to first grade 3 or 4 AE adjusted for stratification factors.

Comparison groups

Standard of care (Arm 2) v Intervention (Arm 1) - INSTI+DRV/r

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.237

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.65

Confidence interval

level

95%

sides

2-sided

lower limit

0.32

upper limit

1.32

Proportion of participants with ≥1 Grade 3/4 AEs

Statistical analysis description

Comparison of proportion of participants with ≥1 Grade 3/4 AEs between arms (Chi-squared test).

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.28

Method

Chi-squared

Confidence interval

Secondary: ART modifying AEs (all grades) reported to end of trial

Top of page

End point title

ART modifying AEs (all grades) reported to end of trial

End point description

ART modifying AEs (all grades) include all events that are ART modifying. These events may be part of SAEs or be reported as grade 3/4 AEs or notable events. ART modifying AEs are analysed as episodes, with all components of the same clinical ART modifying AE presented as one episode (Behaviour disorder + Decreased appetite + Depression).

End point type

Secondary

End point timeframe

Any time from randomisation to end of trial [defined as latest of trial censoring date (31July2020) or week 48 censoring date (week 54 date)]

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	158 ^[99]	160 ^[100]
Units: People
ART modifying AEs reported	4	4
No ART modifying AEs reported	154	156

Notes
[99] - 4 participants reported 4 ART modifying AEs.
[100] - 4 participants reported 6 ART modifying AEs

ART modifying AE incidence rate ratio

Statistical analysis description

ART modifying AEs are defined as events reported at any grade leading to treatment modification including events leading to treatment interruption/stop. Poisson regression adjusted for stratification factors and event clustering within individuals.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.575

Method

Poisson regression

Parameter type

Rate Ratio

Point estimate

0.67

Confidence interval

level

95%

sides

2-sided

lower limit

0.17

upper limit

2.67

Time to first ART modifying AE

Statistical analysis description

Cox regression analysis examining time to first ART modifying AE adjusted for stratification factors.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.959

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.26

upper limit

4.15

Proportion with ≥1 ART modifying AEs

Statistical analysis description

Comparison of proportion of participants with ≥1 ART modifying AEs between arms (Chi-squared test).

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.986

Method

Chi-squared

Confidence interval

Other pre-specified: Mean change in BMI from randomisation to week 24

Top of page

End point title

Mean change in BMI from randomisation to week 24

End point description

Reporting mean change from the global baseline value (across both arms).

End point type

Other pre-specified

End point timeframe

Randomisation and week 24 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	158	160
Units: kg/m2
arithmetic mean (standard error)	0.83 ( 0.1 )	0.33 ( 0.1 )

Difference in mean change from baseline to week 24

Statistical analysis description

Linear regression of BMI at week 24, adjusting for baseline BMI and stratification factors. Presenting difference in mean change from baseline to week 24 between arms (INSTI+DRV/r-SOC)

Comparison groups

Standard of care (Arm 2) v Intervention (Arm 1) - INSTI+DRV/r

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

0.49

Confidence interval

level

95%

sides

2-sided

lower limit

0.3

upper limit

0.7

Other pre-specified: Mean change in BMI from randomisation to week 48

Top of page

End point title

Mean change in BMI from randomisation to week 48

End point description

Reporting mean change from the global baseline value (across both arms).

End point type

Other pre-specified

End point timeframe

Randomisation and week 48 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	145 ^[101]	153 ^[102]
Units: kg/m2
arithmetic mean (standard error)	1.25 ( 0.1 )	0.59 ( 0.1 )

Notes
[101] - Participants with a measurement at week 48
[102] - Participants with a measurement at week 48

Difference in mean change from baseline to week 48

Statistical analysis description

Linear regression of BMI at week 48, adjusting for baseline BMI and stratification factors. Presenting difference in mean change from baseline to week 48 between arms (INSTI+DRV/r-SOC)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

298

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

0.66

Confidence interval

level

95%

sides

2-sided

lower limit

0.3

upper limit

Other pre-specified: Mean change in BMI-for-age z-score from randomisation to week 24

Top of page

End point title

Mean change in BMI-for-age z-score from randomisation to week 24

End point description

Reporting mean change from the global baseline value (across both arms).

End point type

Other pre-specified

End point timeframe

Randomisation and week 24 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	158	160
Units: z-score
arithmetic mean (standard error)	0.19 ( 0.0 )	0.03 ( 0.0 )

Difference in mean change from baseline to week 24

Statistical analysis description

Linear regression of BMI-for-age z-score at week 24, adjusting for baseline BMI-for-age z-score and stratification factors. Presenting difference in mean change from baseline to week 24 between arms (INSTI+DRV/r-SOC). British 1990 Reference data was used for calculation of BMI, weight and height z-scores. This reference data covers the full age range (0–23 years) of SMILE participants.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

318

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

0.16

Confidence interval

level

95%

sides

2-sided

lower limit

0.1

upper limit

0.3

Other pre-specified: Mean change in BMI-for-age z-score from randomisation to week 48

Top of page

End point title

Mean change in BMI-for-age z-score from randomisation to week 48

End point description

Reporting mean change from the global baseline value (across both arms).

End point type

Other pre-specified

End point timeframe

Randomisation and week 48 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	145 ^[103]	153 ^[104]
Units: z-score
arithmetic mean (standard error)	0.23 ( 0.0 )	0.01 ( 0.0 )

Notes
[103] - Participants with a measurement at week 48
[104] - Participants with a measurement at week 48

Difference in mean change from baseline to week 48

Statistical analysis description

Linear regression of BMI-for-age z-score at week 48, adjusting for baseline BMI-for-age z-score and stratification factors. Presenting difference in mean change from baseline to week 48 between arms (INSTI+DRV/r-SOC). British 1990 Reference data was used for calculation of BMI, weight and height z-scores. This reference data covers the full age range (0–23 years) of SMILE participants.

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

298

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

0.22

Confidence interval

level

95%

sides

2-sided

lower limit

0.1

upper limit

0.3

Other pre-specified: Notable events reported to end of trial

Top of page

End point title

Notable events reported to end of trial

End point description

Notable events include Covid-19 events, Liver events, Pregnancies and Suicidal ideation reported at any grade. These events may be part of SAEs or reported as grade 3 or 4 AEs or ART modifying AEs.

End point type

Other pre-specified

End point timeframe

Any time from randomisation to end of trial [defined as latest of trial censoring date (31July2020) or week 48 censoring date (week 54 date)]

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	158	160
Units: People
Pregnancy	1	2
Suicidal ideation	0	1
Drug induced liver injury	2	1
COVID-19 contact	1	0
No notable events reported	154	156

No statistical analyses for this end point

Other pre-specified: Mean change in CD8% from randomisation to week 24

Top of page

End point title

Mean change in CD8% from randomisation to week 24

End point description

Reporting mean change from the global baseline value (across both arms).

End point type

Other pre-specified

End point timeframe

Randomisation and week 24 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	115 ^[105]	125 ^[106]
Units: Percentage
arithmetic mean (standard error)	-0.7 ( 0.4 )	-0.4 ( 0.4 )

Notes
[105] - Participants with a measurement at week 24. CD8 tests are optional, according to feasibility.
[106] - Participants with a measurement at week 24. CD8 tests are optional, according to feasibility.

Difference in mean change from baseline to week 24

Statistical analysis description

Linear regression of CD8% at week 24, adjusting for baseline CD8% and stratification factors. Presenting difference in mean change from baseline to week 24 between arms (INSTI+DRV/r-SOC)

Comparison groups

Standard of care (Arm 2) v Intervention (Arm 1) - INSTI+DRV/r

Number of subjects included in analysis

240

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.627

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-1.2

upper limit

0.7

Other pre-specified: Mean change in CD8% from randomisation to week 48

Top of page

End point title

Mean change in CD8% from randomisation to week 48

End point description

Reporting mean change from the global baseline value (across both arms).

End point type

Other pre-specified

End point timeframe

Randomisation and week 48 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	121 ^[107]	130 ^[108]
Units: Percentage
arithmetic mean (standard error)	-0.5 ( 0.5 )	-0.6 ( 0.5 )

Notes
[107] - Participants with a measurement at week 48. CD8 tests are optional, according to feasibility.
[108] - Participants with a measurement at week 48. CD8 tests are optional, according to feasibility.

Difference in mean change from baseline to week 48

Statistical analysis description

Linear regression of CD8% at week 48, adjusting for baseline CD8% and stratification factors. Presenting difference in mean change from baseline to week 48 between arms (INSTI+DRV/r-SOC)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

251

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.82

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-1.2

upper limit

1.5

Other pre-specified: Mean change in CD8 count from randomisation to week 24

Top of page

End point title

Mean change in CD8 count from randomisation to week 24

End point description

Reporting mean change from the global baseline value (across both arms).

End point type

Other pre-specified

End point timeframe

Randomisation and week 24 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	115 ^[109]	125 ^[110]
Units: cells/mm3
arithmetic mean (standard error)	-20.1 ( 19.2 )	-3.9 ( 18.8 )

Notes
[109] - Participants with a measurement at week 24. CD8 tests are optional, according to feasibility.
[110] - Participants with a measurement at week 24. CD8 tests are optional, according to feasibility.

Difference in mean change from baseline to week 24

Statistical analysis description

Linear regression of CD8 count at week 24, adjusting for baseline CD8 count and stratification factors. Presenting difference in mean change from baseline to week 24 between arms (INSTI+DRV/r-SOC)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

240

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.565

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-15.5

Confidence interval

level

95%

sides

2-sided

lower limit

-68.7

upper limit

37.6

Other pre-specified: Mean change in CD8 count from randomisation to week 48

Top of page

End point title

Mean change in CD8 count from randomisation to week 48

End point description

Reporting mean change from the global baseline value (across both arms).

End point type

Other pre-specified

End point timeframe

Randomisation and week 48 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	121 ^[111]	130 ^[112]
Units: Percentage
arithmetic mean (standard error)	2.6 ( 22.8 )	-25.7 ( 22.1 )

Notes
[111] - Participants with a measurement at week 48. CD8 tests are optional, according to feasibility.
[112] - Participants with a measurement at week 48. CD8 tests are optional, according to feasibility.

Difference in mean change from baseline to week 48

Statistical analysis description

Linear regression of CD8 count at week 48, adjusting for baseline CD8 count and stratification factors. Presenting difference in mean change from baseline to week 48 between arms (INSTI+DRV/r-SOC)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

251

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.373

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

28.5

Confidence interval

level

95%

sides

2-sided

lower limit

-34.5

upper limit

91.5

Other pre-specified: Mean change in CD4%/CD8% ratio from randomisation to week 24

Top of page

End point title

Mean change in CD4%/CD8% ratio from randomisation to week 24

End point description

Reporting mean change from the global baseline value (across both arms).

End point type

Other pre-specified

End point timeframe

Randomisation and week 24 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	115 ^[113]	125 ^[114]
Units: Ratio
arithmetic mean (standard error)	0.00 ( 0.03 )	0.02 ( 0.03 )

Notes
[113] - Participants with a measurement at week 24. CD8 tests are optional, according to feasibility.
[114] - Participants with a measurement at week 24. CD8 tests are optional, according to feasibility.

Difference in mean change from baseline to week 24

Statistical analysis description

Linear regression of CD4%/CD8% ratio at week 24, adjusting for baseline CD4%/CD8% ratio and stratification factors. Presenting difference in mean change from baseline to week 24 between arms (INSTI+DRV/r-SOC)

Comparison groups

Standard of care (Arm 2) v Intervention (Arm 1) - INSTI+DRV/r

Number of subjects included in analysis

240

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.482

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

Other pre-specified: Mean change in CD4%/CD8% ratio from randomisation to week 48

Top of page

End point title

Mean change in CD4%/CD8% ratio from randomisation to week 48

End point description

Reporting mean change from the global baseline value (across both arms).

End point type

Other pre-specified

End point timeframe

Randomisation and week 48 visit

End point values	Intervention (Arm 1) - INSTI+DRV/r	Standard of care (Arm 2)
Number of subjects analysed	121 ^[115]	129 ^[116]
Units: Ratio
arithmetic mean (standard error)	-0.04 ( 0.03 )	0.03 ( 0.03 )

Notes
[115] - Participants with a measurement at week 48. CD8 tests are optional, according to feasibility.
[116] - Participants with a measurement at week 48. CD8 tests are optional, according to feasibility.

Difference in mean change from baseline to week 48

Statistical analysis description

Linear regression of CD4%/CD8% ratio at week 48, adjusting for baseline CD4%/CD8% ratio and stratification factors. Presenting difference in mean change from baseline to week 48 between arms (INSTI+DRV/r-SOC)

Comparison groups

Intervention (Arm 1) - INSTI+DRV/r v Standard of care (Arm 2)

Number of subjects included in analysis

250

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.071

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

Adverse events

Top of page

Timeframe for reporting adverse events

Any time from randomisation to end of trial [defined as latest of trial censoring date (31July2020) or week 48 censoring date (week 54 date)]

Adverse event reporting additional description

For non-serious adverse events, we reported grade 3 or 4 clinical or laboratory adverse events, ART-modifying adverse events (any grade) and notable events, excluding those meeting criteria for serious adverse events (SAE). Notable events include Covid-19 events, Liver events, Pregnancies and Suicidal ideation.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

INSTI+DRV/r (Arm 1)

Reporting group description

Arm 1. NRTI-sparing regimen: Once daily integrase inhibitor (INSTI) + darunavir/ritonavir (DRV/r)

Reporting group title

Standard of care (Arm 2)

Reporting group description

Arm 2. Standard of care (continuing triple anti-retroviral therapy including 2 NRTIs + boosted PI/NNRTI)

Serious adverse events	INSTI+DRV/r (Arm 1)	Standard of care (Arm 2)
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 158 (2.53%)	4 / 160 (2.50%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Injury, poisoning and procedural complications
Post lumbar puncture syndrome
Additional description: Serious adverse event causality assessment to treatment is reported as per site investigator's decision, which cannot be overruled by any other clinical reviewers.
subjects affected / exposed	0 / 158 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Gastritis
Additional description: Serious adverse event causality assessment to treatment is reported as per site investigator's decision, which cannot be overruled by any other clinical reviewers.
subjects affected / exposed	1 / 158 (0.63%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Hepatitis acute
Additional description: Serious adverse event causality assessment to treatment is reported as per site investigator's decision, which cannot be overruled by any other clinical reviewers.
subjects affected / exposed	1 / 158 (0.63%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Nephropathy
Additional description: SAE and Severe CDC stage B event. Serious adverse event causality assessment to treatment is reported as per site investigator's decision, which cannot be overruled by any other clinical reviewers.
subjects affected / exposed	1 / 158 (0.63%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Major depression
Additional description: SAEs are analysed as episodes, with all components of the same clinical SAE presented as one episode (Major depression + Suicidal ideation). Each hospital admission is a separate SAE. Causality assessment reported as per site investigator's decision.
subjects affected / exposed	0 / 158 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Psychotic disorder
Additional description: Serious adverse event causality assessment to treatment is reported as per site investigator's decision, which cannot be overruled by any other clinical reviewers.
subjects affected / exposed	0 / 158 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Suicidal ideation
Additional description: SAEs are analysed as episodes, with all components of the same clinical SAE presented as one episode (Major depression + Suicidal ideation). Each hospital admission is a separate SAE. Causality assessment reported as per site investigator's decision.
subjects affected / exposed	0 / 158 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Pilonidal cyst
Additional description: Serious adverse event causality assessment to treatment is reported as per site investigator's decision, which cannot be overruled by any other clinical reviewers.
subjects affected / exposed	1 / 158 (0.63%)	0 / 160 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Plasmodium falciparum infection
Additional description: Serious adverse event causality assessment to treatment is reported as per site investigator's decision, which cannot be overruled by any other clinical reviewers.
subjects affected / exposed	0 / 158 (0.00%)	1 / 160 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	INSTI+DRV/r (Arm 1)	Standard of care (Arm 2)
Total subjects affected by non serious adverse events
subjects affected / exposed	12 / 158 (7.59%)	18 / 160 (11.25%)
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 158 (0.63%)	1 / 160 (0.63%)
occurrences all number	1	1
Aspartate aminotransferase increased
subjects affected / exposed	0 / 158 (0.00%)	1 / 160 (0.63%)
occurrences all number	0	1
Blood alkaline phosphatase increased
subjects affected / exposed	3 / 158 (1.90%)	0 / 160 (0.00%)
occurrences all number	3	0
Blood bilirubin increased
subjects affected / exposed	0 / 158 (0.00%)	3 / 160 (1.88%)
occurrences all number	0	3
Blood calcium decreased
subjects affected / exposed	1 / 158 (0.63%)	0 / 160 (0.00%)
occurrences all number	1	0
Blood cholesterol increased
subjects affected / exposed	0 / 158 (0.00%)	1 / 160 (0.63%)
occurrences all number	0	1
Hepatic enzyme increased
subjects affected / exposed	0 / 158 (0.00%)	1 / 160 (0.63%)
occurrences all number	0	1
Low density lipoprotein increased
subjects affected / exposed	1 / 158 (0.63%)	0 / 160 (0.00%)
occurrences all number	1	0
Pregnancy test positive
subjects affected / exposed	1 / 158 (0.63%)	0 / 160 (0.00%)
occurrences all number	1	0
Weight decreased
subjects affected / exposed	0 / 158 (0.00%)	1 / 160 (0.63%)
occurrences all number	0	1
Injury, poisoning and procedural complications
Exposure to SARS-CoV-2
subjects affected / exposed	1 / 158 (0.63%)	0 / 160 (0.00%)
occurrences all number	1	0
Nervous system disorders
Meningism
subjects affected / exposed	0 / 158 (0.00%)	1 / 160 (0.63%)
occurrences all number	0	1
Pregnancy, puerperium and perinatal conditions
Abortion incomplete
subjects affected / exposed	0 / 158 (0.00%)	1 / 160 (0.63%)
occurrences all number	0	1
Pregnancy
subjects affected / exposed	0 / 158 (0.00%)	1 / 160 (0.63%)
occurrences all number	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 158 (0.63%)	0 / 160 (0.00%)
occurrences all number	1	0
Neutropenia
subjects affected / exposed	0 / 158 (0.00%)	3 / 160 (1.88%)
occurrences all number	0	3
Gastrointestinal disorders
Vomiting
subjects affected / exposed	1 / 158 (0.63%)	0 / 160 (0.00%)
occurrences all number	1	0
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 158 (0.00%)	4 / 160 (2.50%)
occurrences all number	0	6
Psychiatric disorders
Adjustment disorder with mixed disturbance of emotion and conduct
subjects affected / exposed	1 / 158 (0.63%)	0 / 160 (0.00%)
occurrences all number	1	0
Behaviour disorder
subjects affected / exposed	1 / 158 (0.63%)	0 / 160 (0.00%)
occurrences all number	1	0
Depression
subjects affected / exposed	1 / 158 (0.63%)	0 / 160 (0.00%)
occurrences all number	1	0
Renal and urinary disorders
Proteinuria
subjects affected / exposed	1 / 158 (0.63%)	1 / 160 (0.63%)
occurrences all number	1	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 158 (0.63%)	0 / 160 (0.00%)
occurrences all number	1	0
Hypertriglyceridaemia
subjects affected / exposed	1 / 158 (0.63%)	0 / 160 (0.00%)
occurrences all number	1	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

24 Jul 2017

Protocol amendment #1 was due to a temporary halt following the withdrawal of Elvitegravir (EVG). The notification of temporary suspension was submitted to any countries that had already received approval for the trial. The notification dates will vary from country to country. Protocol v2.0 was drafted and released on 27 July 2017. The amendment dates vary from country to country, but the first approval for v2.0 was granted on 30 August 2017 in Belgium. For countries that have enrolled participants, approval for v2.0 was first granted on 25 September 2017 in Spain. Protocol v2.0 replaced EVG with another INSTI called Dolutegravir (DTG). Note that because the protocol amendment dates will vary from country to country we have entered it as the protocol v2.0 date of 24 July 2017.

05 Aug 2020

Protocol amendment #2 was for protocol v4.0. This was to incorporate the continuation phase for countries that did not have access to SMILE IMP after end of main trial (LPLV in main trial was 01 October 2020). It also included details on COVID-19 management and additional information on DTG pregnancy management due to the safety alert initially released in May 2018. This updated protocol was only submitted in countries that did not have access to SMILE IMP through their National programme at the end of the trial. These countries were South Africa, Uganda, Thailand and Ukraine. Protocol v4.0 was released globally on 18 Sept 2020, however the dates of submission will vary from country to country. Therefore, we have entered it as the protocol v4.0 date of 05 August 2020. Additional Continuation phase information: In order to ensure that all SMILE participants had equal access to the SMILE regimen (at least for a further 12 months after the end of the main trial), the Sponsor incorporated a continuation phase “access programme” into the trial protocol and this was submitted for approval in the aforementioned countries. Pharmaceutical companies providing dolutegravir and darunavir for SMILE were happy to provide the drug at no extra cost for a further 12 month period but required notification of any reportable safety events in participants receiving drug through this access programme. No other data was collected during this period and no further analyses were carried out using continuation phase data as the continuation phase was purely to ensure access to the SMILE regimen”. The LPLV date in the continuation phase was 17 November 2021. This is the global end of trial date for SMILE.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
06 Oct 2016	Gilead withdrew Elvitegravir from the market as a single entity leading to temporary suspension of recruitment on 6 October 2016 (date PIs received notification of suspension of recruitment). Enrolments re-started on 12 February 2018 once Elvitegravir was replaced by Dolutegravir. First approval of protocol version 2.0 for restart was 30 August 2017 in Belgium. For countries that have enrolled participants, approval for v2.0 was first granted on 25 September 2017 in Spain.	12 Feb 2018

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

None reported

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Virological failure: Confirmed HIV-1 RNA ≥50c/ml by 48 weeks

Primary: Virological failure: Confirmed HIV-1 RNA ≥50c/ml by 48 weeks

Secondary: HIV-1 RNA ≥50c/ml at week 24

Secondary: HIV-1 RNA ≥50c/ml at week 24

Secondary: HIV-1 RNA ≥50c/ml at week 48

Secondary: HIV-1 RNA ≥50c/ml at week 48

Secondary: HIV-1 RNA ≥50c/ml at week 48 (FDA snapshot)

Secondary: HIV-1 RNA ≥50c/ml at week 48 (FDA snapshot)

Secondary: HIV-1 RNA ≥400c/ml at week 24

Secondary: HIV-1 RNA ≥400c/ml at week 24

Secondary: HIV-1 RNA ≥400c/ml at week 48

Secondary: HIV-1 RNA ≥400c/ml at week 48

Secondary: New or recurrent CDC stage C or severe stage B* event or death

Secondary: New or recurrent CDC stage C or severe stage B* event or death

Secondary: New resistance mutations

Secondary: New resistance mutations

Secondary: Mean change in CD4% from randomisation to week 24

Secondary: Mean change in CD4% from randomisation to week 24

Secondary: Mean change in CD4% from randomisation to week 48

Secondary: Mean change in CD4% from randomisation to week 48

Secondary: Mean change in CD4 count from randomisation to week 24

Secondary: Mean change in CD4 count from randomisation to week 24

Secondary: Mean change in CD4 count from randomisation to week 48

Secondary: Mean change in CD4 count from randomisation to week 48

Secondary: Changes in ART regimen

Secondary: Changes in ART regimen

Secondary: Mean change in fasting total cholesterol from randomisation to week 24

Secondary: Mean change in fasting total cholesterol from randomisation to week 24

Secondary: Mean change in fasting total cholesterol from randomisation to week 48

Secondary: Mean change in fasting total cholesterol from randomisation to week 48

Secondary: Mean change in fasting triglycerides from randomisation to week 24

Secondary: Mean change in fasting triglycerides from randomisation to week 24

Secondary: Mean change in fasting triglycerides from randomisation to week 48

Secondary: Mean change in fasting triglycerides from randomisation to week 48

Secondary: Mean change in fasting LDL from randomisation to week 24

Secondary: Mean change in fasting LDL from randomisation to week 24

Secondary: Mean change in fasting LDL from randomisation to week 48

Secondary: Mean change in fasting LDL from randomisation to week 48

Secondary: Mean change in fasting HDL from randomisation to week 24

Secondary: Mean change in fasting HDL from randomisation to week 24

Secondary: Mean change in fasting HDL from randomisation to week 48

Secondary: Mean change in fasting HDL from randomisation to week 48

Secondary: Mean change in weight from randomisation to week 24

Secondary: Mean change in weight from randomisation to week 24

Secondary: Mean change in weight from randomisation to week 48

Secondary: Mean change in weight from randomisation to week 48

Secondary: Mean change in weight-for-age z-score from randomisation to week 24

Secondary: Mean change in weight-for-age z-score from randomisation to week 24

Secondary: Mean change in weight-for-age z-score from randomisation to week 48

Secondary: Mean change in weight-for-age z-score from randomisation to week 48

Secondary: Mean change in height from randomisation to week 24

Secondary: Mean change in height from randomisation to week 24

Secondary: Mean change in height from randomisation to week 48

Secondary: Mean change in height from randomisation to week 48

Secondary: Mean change in height-for-age z-score from randomisation to week 24

Secondary: Mean change in height-for-age z-score from randomisation to week 24

Secondary: Mean change in height-for-age z-score from randomisation to week 48

Secondary: Mean change in height-for-age z-score from randomisation to week 48

Secondary: Onset of menarche at week 48

Secondary: Onset of menarche at week 48

Secondary: Changes in tanner scores (pubic hair) by week 48

Secondary: Changes in tanner scores (pubic hair) by week 48

Secondary: Changes in tanner scores (female breast) by week 48

Secondary: Changes in tanner scores (female breast) by week 48

Secondary: Changes in tanner scores (male genital) by week 48

Secondary: Changes in tanner scores (male genital) by week 48

Secondary: Adherence (participant response): Missed a dose over the last 3 days

Secondary: Adherence (participant response): Missed a dose over the last 3 days

Secondary: Adherence (participant response): Missed any dose since last clinic visit

Secondary: Adherence (participant response): Missed any dose since last clinic visit

Secondary: Adherence (participant response): Adherence rating since the last clinic visit