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Clinical Trial Results:
A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Versus Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate in HIV-1 Positive, Antiretroviral Treatment- Naïve Adults

Summary
EudraCT number	2013-000102-37
Trial protocol	BE SE IT AT DE NL PT GB ES
Global end of trial date	03 Oct 2018

Results information
Results version number	v1(current)
This version publication date	17 Oct 2019
First version publication date	17 Oct 2019
Other versions

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

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Trial information

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Sponsor protocol code

GS-US-292-0111

ISRCTN number

US NCT number

NCT01797445

WHO universal trial number (UTN)

Sponsor organisation name

Gilead Sciences

Sponsor organisation address

333 Lakeside Drive, Foster City, CA, United States, 94404

Public contact

Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com

Scientific contact

Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com

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

03 Oct 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

19 Sep 2014

Global end of trial reached?

Yes

Global end of trial date

03 Oct 2018

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study was to evaluate the efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) fixed-dose combination (FDC) versus elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF) in HIV-1 positive, antiretroviral treatment-naive adults.

Protection of trial subjects

The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.

Background therapy

Evidence for comparator

Actual start date of recruitment

12 Mar 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Mexico: 28

Country: Number of subjects enrolled

Canada: 43

Country: Number of subjects enrolled

Dominican Republic: 65

Country: Number of subjects enrolled

United States: 559

Country: Number of subjects enrolled

Puerto Rico: 7

Country: Number of subjects enrolled

Netherlands: 14

Country: Number of subjects enrolled

Portugal: 37

Country: Number of subjects enrolled

Sweden: 11

Country: Number of subjects enrolled

United Kingdom: 56

Country: Number of subjects enrolled

France: 34

Country: Number of subjects enrolled

Italy: 18

Worldwide total number of subjects

872

EEA total number of subjects

170

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

867

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants were enrolled at study sites in North America and Europe. The first participant was screened on 12 March 2013. The last study visit occurred on 03 October 2018.

Screening details

1070 participants were screened.

Period 1 title

Double-Blind Phase

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

E/C/F/TAF

Arm description

Double-Blind Phase: E/C/F/TAF (150/150/200/10 mg) FDC tablet plus E/C/F/TDF placebo tablet administered orally once daily for 144 weeks.

Arm type

Experimental

Investigational medicinal product name

Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide

Investigational medicinal product code

Other name

E/C/F/TAF, Genvoya®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

150/150/200/10 mg FDC tablet administered orally once daily

Investigational medicinal product name

Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered orally once daily

E/C/F/TDF

Arm description

Double-Blind Phase: E/C/F/TDF (150/150/200/300 mg) FDC tablet plus E/C/F/TAF placebo tablet administered orally once daily for 144 weeks.

Arm type

Active comparator

Investigational medicinal product name

Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

E/C/F/TDF, Stribild®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

150/150/200/300 mg FDC tablet administered orally once daily

Investigational medicinal product name

Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered orally once daily

Number of subjects in period 1 ^[1]	E/C/F/TAF	E/C/F/TDF
Started	431	435
Completed	348	348
Not completed	83	87
Noncompliance with Study Drug	5	1
Withdrew Consent	20	35
Adverse Event	3	-
Death	5	4
Investigator's Discretion	15	17
Pregnancy	-	1
Protocol Violation	-	1
Lost to follow-up	34	26
Lack of efficacy	1	2

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: 6 participants who were randomized but not treated are not included in the subject disposition table.

Period 2 title

Open-Label Extension Phase

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

E/C/F/TAF to E/C/F/TAF

Arm description

Open-Label Extension Phase: After the unblinding visit, in countries where E/C/F/TAF FDC was not commercially available, participants (except in UK) were given the option to receive the open-label E/C/F/TAF FDC until it became commercially available, or until Gilead terminated the study in that country.

Arm type

Experimental

Investigational medicinal product name

Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide

Investigational medicinal product code

Other name

E/C/F/TAF, Genvoya®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

150/150/200/10 mg FDC tablet administered orally once daily

E/C/F/TDF to E/C/F/TAF

Arm description

Arm type

Experimental

Investigational medicinal product name

Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide

Investigational medicinal product code

Other name

E/C/F/TAF, Genvoya®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

150/150/200/10 mg FDC tablet administered orally once daily

Number of subjects in period 2 ^[2]	E/C/F/TAF to E/C/F/TAF	E/C/F/TDF to E/C/F/TAF
Started	141	119
Completed	140	119
Not completed	1	0
Investigator's Discretion	1	-

Notes
[2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: 436 participants (E/C/F/TAF: N = 207; E/C/F/TDF: N = 229) completed the Double-Blind Phase, but did not enter the Open-Label Extension Phase.

Baseline characteristics

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Reporting group title

E/C/F/TAF

Reporting group description

Double-Blind Phase: E/C/F/TAF (150/150/200/10 mg) FDC tablet plus E/C/F/TDF placebo tablet administered orally once daily for 144 weeks.

Reporting group title

E/C/F/TDF

Reporting group description

Double-Blind Phase: E/C/F/TDF (150/150/200/300 mg) FDC tablet plus E/C/F/TAF placebo tablet administered orally once daily for 144 weeks.

Reporting group values	E/C/F/TAF	E/C/F/TDF	Total
Number of subjects	431	435	866
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	35 ± 10.8	36 ± 10.9	-
Gender categorical
Units: Subjects
Female	62	71	133
Male	369	364	733
Race
Units: Subjects
American Indian or Alaska Native	1	3	4
Asian	15	12	27
Black	129	132	261
Native Hawaiian or Pacific Islander	4	1	5
White	235	243	478
Other	47	44	91
Ethnicity
Units: Subjects
Hispanic or Latino	107	97	204
Not Hispanic or Latino	323	336	659
Not Permitted	1	1	2
Missing	0	1	1
HIV-1 RNA Category
Units: Subjects
≤ 100,000 copies/mL	339	336	675
> 100,000 to ≤ 400,000 copies/mL	68	82	150
> 400,000 copies/mL	24	17	41
CD4 Cell Count Category
Units: Subjects
< 50 cells/μL	14	15	29
≥ 50 to < 200 cells/μL	40	49	89
≥ 200 to < 350 cells/μL	115	89	204
≥ 350 to < 500 cells/μL	134	149	283
≥ 500 cells/μL	127	133	260
Missing	1	0	1
HIV Disease Status
Units: Subjects
Asymptomatic	377	394	771
Symptomatic HIV Infection	30	19	49
AIDS	22	19	41
Unknown	2	3	5
HIV-1 RNA
Units: log10 copies/mL
arithmetic mean (standard deviation)	4.53 ± 0.647	4.50 ± 0.690	-
CD4 Cell Count
Measure Analysis Population Description: Participants in the Safety Analysis Set with available data were analyzed (E/C/F/TAF: N = 430; E/C/F/TDF: N = 435)
Units: cells/µL
arithmetic mean (standard deviation)	414 ± 206.8	431 ± 226.8	-

End points

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Reporting group title

E/C/F/TAF

Reporting group description

Double-Blind Phase: E/C/F/TAF (150/150/200/10 mg) FDC tablet plus E/C/F/TDF placebo tablet administered orally once daily for 144 weeks.

Reporting group title

E/C/F/TDF

Reporting group description

Double-Blind Phase: E/C/F/TDF (150/150/200/300 mg) FDC tablet plus E/C/F/TAF placebo tablet administered orally once daily for 144 weeks.

Reporting group title

E/C/F/TAF to E/C/F/TAF

Reporting group description

Reporting group title

E/C/F/TDF to E/C/F/TAF

Reporting group description

Primary: Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Week 48

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End point title

Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Week 48

End point description

The percentage of participants achieving HIV-1 RNA < 50 copies/mL at Week 48 was analyzed using the snapshot algorithm, which defines a patient's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. The Full Analysis Set included participants who were randomized and received at least 1 dose of study drug.

End point type

Primary

End point timeframe

Week 48

End point values	E/C/F/TAF	E/C/F/TDF
Number of subjects analysed	431	435
Units: percentage of participants
number (not applicable)	91.6	88.5

Statistical Analysis - E/C/F/TAF vs E/C/F/TDF

Statistical analysis description

Null hypothesis: the E/C/F/TAF group was ≥ 12% worse than the E/C/F/TDF group with respect to the percentage of participants achieving HIV-1 RNA < 50 copies/mL at Week 48; alternative hypothesis: the E/C/F/TAF group was < 12% worse than the E/C/F/TDF group.

Comparison groups

E/C/F/TAF v E/C/F/TDF

Number of subjects included in analysis

866

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.13 ^[2]

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Percentages

Point estimate

3.1

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

7.1

Notes
[1] - P-value was from the Cochran-Mantel-Haenszel (CMH) test stratified by baseline HIV-1 RNA (≤ 100,000 or > 100,000 copies/mL) and region (US vs ex-US).
[2] - The difference in percentages and its 95.002% confidence interval (CI) were calculated based on the Mantel-Haenszel (MH) proportions adjusted by baseline HIV-1 RNA and region stratum.

Secondary: Percentage of participants with HIV-1 RNA < 50 copies/mL at Week 96

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End point title

Percentage of participants with HIV-1 RNA < 50 copies/mL at Week 96

End point description

The percentage of participants achieving HIV-1 RNA < 50 copies/mL at Week 96 was analyzed using the snapshot algorithm, which defines a patient's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Participants in the Full Analysis Set were analyzed.

End point type

Secondary

End point timeframe

Week 96

End point values	E/C/F/TAF	E/C/F/TDF
Number of subjects analysed	431	435
Units: percentage of participants
number (not applicable)	84.0	82.3

No statistical analyses for this end point

Secondary: Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Weeks 48 and 96

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End point title

Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Weeks 48 and 96

End point description

The percentage of participants achieving HIV-1 RNA < 20 copies/mL at Weeks 48 and 96 was analyzed using the snapshot algorithm, which defines a patient's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Participants in the Full Analysis Set were analyzed.

End point type

Secondary

End point timeframe

Weeks 48 and 96

End point values	E/C/F/TAF	E/C/F/TDF
Number of subjects analysed	431	435
Units: percentage of participants
number (not applicable)
Week 48	82.4	80.7
Week 96	78.7	76.8

No statistical analyses for this end point

Secondary: Change From Baseline in CD4+ Cell Count at Week 48

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End point title

Change From Baseline in CD4+ Cell Count at Week 48

End point description

Participants in the Full Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Baseline; Week 48

End point values	E/C/F/TAF	E/C/F/TDF
Number of subjects analysed	404	400
Units: cells/µL
arithmetic mean (standard deviation)	225 ± 171.2	200 ± 162.5

No statistical analyses for this end point

Secondary: Change From Baseline in CD4+ Cell Count at Week 96

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End point title

Change From Baseline in CD4+ Cell Count at Week 96

End point description

Participants in the Full Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Baseline; Week 96

End point values	E/C/F/TAF	E/C/F/TDF
Number of subjects analysed	369	369
Units: cells/µL
arithmetic mean (standard deviation)	274 ± 184.0	260 ± 179.6

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 48

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End point title

Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 48

End point description

Hip BMD was assessed by dual energy x-ray absorptiometry (DXA) scan. The Hip DXA Analysis Set included all participants who were randomized and received at least 1 dose of study drug, and have nonmissing baseline hip BMD values. Participants were grouped according to the treatment they actually received. The missing-equals-excluded approach where participants with missing data were excluded from the analysis.

End point type

Secondary

End point timeframe

Baseline; Week 48

End point values	E/C/F/TAF	E/C/F/TDF
Number of subjects analysed	380	381
Units: percent change
arithmetic mean (standard deviation)	-0.420 ± 3.2268	-2.603 ± 3.1482

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Hip BMD at Week 96

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End point title

Percent Change From Baseline in Hip BMD at Week 96

End point description

Hip BMD was assessed by DXA scan. Participants in the Hip DXA Analysis Set were analyzed. Participants were grouped according to the treatment they actually received. The missing-equals-excluded approach where participants with missing data were excluded from the analysis.

End point type

Secondary

End point timeframe

Baseline; Week 96

End point values	E/C/F/TAF	E/C/F/TDF
Number of subjects analysed	341	346
Units: percent change
arithmetic mean (standard deviation)	-0.364 ± 3.8990	-3.023 ± 3.9796

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Spine BMD at Week 48

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End point title

Percent Change From Baseline in Spine BMD at Week 48

End point description

Spine BMD was assessed by DXA scan. The Spine DXA Analysis Set included all participants who were randomized and received at least 1 dose of study drug, and have nonmissing baseline spine BMD values. Participants were grouped according to the treatment they actually received. The missing-equals-excluded approach where participants with missing data were excluded from the analysis.

End point type

Secondary

End point timeframe

Baseline; Week 48

End point values	E/C/F/TAF	E/C/F/TDF
Number of subjects analysed	386	385
Units: percent change
arithmetic mean (standard deviation)	-1.278 ± 3.0098	-2.759 ± 3.0024

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Spine BMD at Week 96

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End point title

Percent Change From Baseline in Spine BMD at Week 96

End point description

Spine BMD was assessed by DXA scan. Participants in the Spine DXA Analysis Set were analyzed. Participants were grouped according to the treatment they actually received. The missing-equals-excluded approach where participants with missing data were exclu

End point type

Secondary

End point timeframe

Baseline; Week 96

End point values	E/C/F/TAF	E/C/F/TDF
Number of subjects analysed	346	347
Units: percent change
arithmetic mean (standard deviation)	-1.017 ± 3.3957	-2.516 ± 3.8612

No statistical analyses for this end point

Secondary: Change From Baseline in Serum Creatinine at Week 48

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End point title

Change From Baseline in Serum Creatinine at Week 48

End point description

The Safety Analysis Set included participants who were randomized and received at least 1 dose of study drug. The missing-equals-excluded approach where participants with missing data were excluded from the analysis.

End point type

Secondary

End point timeframe

Baseline; Week 48

End point values	E/C/F/TAF	E/C/F/TDF
Number of subjects analysed	405	402
Units: mg/dL
arithmetic mean (standard deviation)	0.08 ± 0.136	0.12 ± 0.283

No statistical analyses for this end point

Secondary: Change From Baseline in Serum Creatinine at Week 96

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End point title

Change From Baseline in Serum Creatinine at Week 96

End point description

Participants in the Safety Analysis Set were analyzed. The missing-equals-excluded approach where participants with missing data were excluded from the analysis.

End point type

Secondary

End point timeframe

Baseline; Week 96

End point values	E/C/F/TAF	E/C/F/TDF
Number of subjects analysed	373	370
Units: mg/dL
arithmetic mean (standard deviation)	0.04 ± 0.119	0.07 ± 0.122

No statistical analyses for this end point

Secondary: Percentage of Participants With Treatment-emergent Proteinuria Through Week 48

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End point title

Percentage of Participants With Treatment-emergent Proteinuria Through Week 48

End point description

Grades 1 (mild), 2 (moderate), and 3 (severe) were the highest treatment-emergent postbaseline grades for urine protein using the dipstick method. The worst postbaseline value is presented for each participant. Participants in the Safety Analysis Set with at least 1 postbaseline urine protein value were analyzed.

End point type

Secondary

End point timeframe

Baseline to Week 48

End point values	E/C/F/TAF	E/C/F/TDF
Number of subjects analysed	428	434
Units: percentage of participants
number (not applicable)
Grade 1	27.3	31.6
Grade 2	4.7	4.6
Grade 3	0	0

No statistical analyses for this end point

Secondary: Percentage of Participants With Treatment-emergent Proteinuria Through Week 96

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End point title

Percentage of Participants With Treatment-emergent Proteinuria Through Week 96

End point description

End point type

Secondary

End point timeframe

Baseline to Week 96

End point values	E/C/F/TAF	E/C/F/TDF
Number of subjects analysed	428	434
Units: percentage of participants
number (not applicable)
Grade 1	31.8	36.9
Grade 2	5.4	5.1
Grade 3	0	0

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Urine Retinol Binding Protein (RBP) to Creatinine Ratio at Week 48

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End point title

Percent Change From Baseline in Urine Retinol Binding Protein (RBP) to Creatinine Ratio at Week 48

End point description

Urine RBP is a renal biomarker which is used to detect drug-induced kidney injury. Participants in the Safety Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Baseline; Week 48

End point values	E/C/F/TAF	E/C/F/TDF
Number of subjects analysed	400	397
Units: percent change
median (inter-quartile range (Q1-Q3))	13.3 (-22.6 to 52.4)	51.7 (2.6 to 138.6)

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Urine RBP to Creatinine Ratio at Week 96

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End point title

Percent Change From Baseline in Urine RBP to Creatinine Ratio at Week 96

End point description

Urine RBP is a renal biomarker which is used to detect drug-induced kidney injury. Participants in the Safety Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Baseline; Week 96

End point values	E/C/F/TAF	E/C/F/TDF
Number of subjects analysed	379	363
Units: percent change
median (inter-quartile range (Q1-Q3))	16.9 (-18.6 to 72.4)	73.7 (10.4 to 196.3)

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio at Week 48

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End point title

Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio at Week 48

End point description

Urine Beta-2-microglobulin is a renal biomarker which is used to detect drug-induced kidney injury. Participants in the Safety Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Baseline; Week 48

End point values	E/C/F/TAF	E/C/F/TDF
Number of subjects analysed	395	392
Units: percent change
median (inter-quartile range (Q1-Q3))	-29.3 (-55.1 to 6.1)	32.3 (-36.4 to 159.9)

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio at Week 96

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End point title

Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio at Week 96

End point description

Urine Beta-2-microglobulin is a renal biomarker which is used to detect drug-induced kidney injury. Participants in the Safety Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Baseline; Week 96

End point values	E/C/F/TAF	E/C/F/TDF
Number of subjects analysed	375	360
Units: percent change
median (inter-quartile range (Q1-Q3))	-31.0 (-62.7 to 6.1)	35.2 (-27.5 to 248.8)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

First dose date to last dose date (maximum duration: 185 weeks during Double-Blind Phase and 102 weeks during Open-Label Extension Phase) plus 30 days

Adverse event reporting additional description

The Safety Analysis Set included participants who were randomized and received at least 1 dose of study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

E/C/F/TAF (Double-Blind Phase)

Reporting group description

Adverse events reported occurred during the Double-Blind Phase in participants from the E/C/F/TAF group, who received E/C/F/TAF (150/150/200/10 mg) FDC tablet plus E/C/F/TDF placebo tablet administered orally once daily for 144 weeks.

Reporting group title

E/C/F/TDF (Double-Blind Phase)

Reporting group description

Adverse events reported occurred during the Double-Blind Phase in participants from the E/C/F/TDF group, who received E/C/F/TDF (150/150/200/300 mg) FDC tablet plus E/C/F/TAF placebo tablet administered orally once daily for 144 weeks.

Reporting group title

Open-Label E/C/F/TAF From E/C/F/TAF

Reporting group description

Adverse events reported occurred during the Open-Label Extension Phase in participants who enrolled into the Open-Label Extension Phase from the E/C/F/TAF group and received E/C/F/TAF (150/150/200/10 mg) FDC tablet once daily.

Reporting group title

Open-Label E/C/F/TAF from E/C/F/TDF

Reporting group description

Adverse events reported occurred during the Open-Label Extension Phase in participants who enrolled into the Open-Label Extension Phase from the E/C/F/TDF group and received E/C/F/TAF (150/150/200/10 mg) FDC tablet once daily.

Serious adverse events	E/C/F/TAF (Double-Blind Phase)	E/C/F/TDF (Double-Blind Phase)	Open-Label E/C/F/TAF From E/C/F/TAF	Open-Label E/C/F/TAF from E/C/F/TDF
Total subjects affected by serious adverse events
subjects affected / exposed	54 / 431 (12.53%)	68 / 435 (15.63%)	4 / 141 (2.84%)	2 / 119 (1.68%)
number of deaths (all causes)	5	4	0	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hodgkin's disease
subjects affected / exposed	2 / 431 (0.46%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anal squamous cell carcinoma
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cervix carcinoma
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphoma
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphoproliferative disorder
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meningioma
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to liver
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine leiomyoma
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 431 (0.00%)	3 / 435 (0.69%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 431 (0.23%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Systemic inflammatory response syndrome
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Immune reconstitution inflammatory syndrome
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Vaginal dysplasia
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	3 / 431 (0.70%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchospasm
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumomediastinum
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	1 / 431 (0.23%)	3 / 435 (0.69%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	2 / 431 (0.46%)	2 / 435 (0.46%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Completed suicide
subjects affected / exposed	2 / 431 (0.46%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
Depression suicidal
subjects affected / exposed	0 / 431 (0.00%)	2 / 435 (0.46%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychotic disorder
subjects affected / exposed	2 / 431 (0.46%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	0 / 431 (0.00%)	2 / 435 (0.46%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute psychosis
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Affective disorder
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bipolar II disorder
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Homicidal ideation
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Major depression
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase abnormal
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Overdose
subjects affected / exposed	0 / 431 (0.00%)	3 / 435 (0.69%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	0 / 431 (0.00%)	2 / 435 (0.46%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Alcohol poisoning
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cervical vertebral fracture
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gun shot wound
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Labelled drug-drug interaction medication error
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Muscle strain
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative respiratory failure
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stab wound
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thoracic vertebral fracture
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Traumatic liver injury
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic cardiomyopathy
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	1 / 431 (0.23%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Dysaesthesia
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Facial paralysis
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intracranial pressure increased
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Migraine
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nerve compression
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Paraesthesia
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sciatica
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Unresponsive to stimuli
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Leukocytosis
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sickle cell anaemia with crisis
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Iridocyclitis
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Retinal detachment
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Pancreatitis acute
subjects affected / exposed	0 / 431 (0.00%)	3 / 435 (0.69%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	1 / 431 (0.23%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	1 / 431 (0.23%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	2 / 431 (0.46%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hiatus hernia
subjects affected / exposed	0 / 431 (0.00%)	0 / 435 (0.00%)	1 / 141 (0.71%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Impaired gastric emptying
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mouth ulceration
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Palatal dysplasia
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	2 / 431 (0.46%)	2 / 435 (0.46%)	1 / 141 (0.71%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 2	1 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis acute
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Hidradenitis
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Ureterolithiasis
subjects affected / exposed	1 / 431 (0.23%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal haematoma
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Goitre
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Rhabdomyolysis
subjects affected / exposed	2 / 431 (0.46%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 431 (0.23%)	4 / 435 (0.92%)	1 / 141 (0.71%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	4 / 431 (0.93%)	0 / 435 (0.00%)	1 / 141 (0.71%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	2 / 431 (0.46%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	2 / 431 (0.46%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	1 / 431 (0.23%)	1 / 435 (0.23%)	0 / 141 (0.00%)	1 / 119 (0.84%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abscess limb
subjects affected / exposed	0 / 431 (0.00%)	2 / 435 (0.46%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	1 / 119 (0.84%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	2 / 431 (0.46%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Streptococcal bacteraemia
subjects affected / exposed	2 / 431 (0.46%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 431 (0.00%)	2 / 435 (0.46%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis perforated
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chorioretinitis
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dengue fever
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea infectious
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Encephalitis
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis A
subjects affected / exposed	0 / 431 (0.00%)	0 / 435 (0.00%)	1 / 141 (0.71%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Herpes simplex
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infectious colitis
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung abscess
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mastoiditis
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis meningococcal
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Orchitis
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Otitis externa
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Penile abscess
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Periorbital cellulitis
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Perirectal abscess
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngitis streptococcal
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia necrotising
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectal abscess
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Scrotal abscess
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Secondary syphilis
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Shigella infection
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vulval abscess
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
West Nile viral infection
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic complication
subjects affected / exposed	1 / 431 (0.23%)	0 / 435 (0.00%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 431 (0.00%)	1 / 435 (0.23%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	E/C/F/TAF (Double-Blind Phase)	E/C/F/TDF (Double-Blind Phase)	Open-Label E/C/F/TAF From E/C/F/TAF	Open-Label E/C/F/TAF from E/C/F/TDF
Total subjects affected by non serious adverse events
subjects affected / exposed	374 / 431 (86.77%)	366 / 435 (84.14%)	32 / 141 (22.70%)	27 / 119 (22.69%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Anogenital warts
subjects affected / exposed	29 / 431 (6.73%)	25 / 435 (5.75%)	0 / 141 (0.00%)	1 / 119 (0.84%)
occurrences all number	30	29	0	1
Vascular disorders
Hypertension
subjects affected / exposed	26 / 431 (6.03%)	11 / 435 (2.53%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences all number	26	11	0	0
Nervous system disorders
Headache
subjects affected / exposed	98 / 431 (22.74%)	80 / 435 (18.39%)	4 / 141 (2.84%)	2 / 119 (1.68%)
occurrences all number	139	114	4	2
Dizziness
subjects affected / exposed	27 / 431 (6.26%)	28 / 435 (6.44%)	1 / 141 (0.71%)	0 / 119 (0.00%)
occurrences all number	31	31	1	0
Blood and lymphatic system disorders
Lymphadenopathy
subjects affected / exposed	29 / 431 (6.73%)	24 / 435 (5.52%)	2 / 141 (1.42%)	2 / 119 (1.68%)
occurrences all number	30	24	2	2
General disorders and administration site conditions
Fatigue
subjects affected / exposed	53 / 431 (12.30%)	52 / 435 (11.95%)	1 / 141 (0.71%)	0 / 119 (0.00%)
occurrences all number	59	56	1	0
Pyrexia
subjects affected / exposed	37 / 431 (8.58%)	32 / 435 (7.36%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences all number	45	42	0	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	99 / 431 (22.97%)	114 / 435 (26.21%)	0 / 141 (0.00%)	2 / 119 (1.68%)
occurrences all number	124	142	0	2
Nausea
subjects affected / exposed	78 / 431 (18.10%)	86 / 435 (19.77%)	1 / 141 (0.71%)	2 / 119 (1.68%)
occurrences all number	91	118	1	2
Vomiting
subjects affected / exposed	44 / 431 (10.21%)	46 / 435 (10.57%)	0 / 141 (0.00%)	2 / 119 (1.68%)
occurrences all number	52	61	0	2
Abdominal pain
subjects affected / exposed	33 / 431 (7.66%)	34 / 435 (7.82%)	0 / 141 (0.00%)	2 / 119 (1.68%)
occurrences all number	34	43	0	2
Constipation
subjects affected / exposed	24 / 431 (5.57%)	33 / 435 (7.59%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences all number	26	36	0	0
Haemorrhoids
subjects affected / exposed	26 / 431 (6.03%)	27 / 435 (6.21%)	1 / 141 (0.71%)	1 / 119 (0.84%)
occurrences all number	27	29	1	1
Toothache
subjects affected / exposed	26 / 431 (6.03%)	19 / 435 (4.37%)	1 / 141 (0.71%)	1 / 119 (0.84%)
occurrences all number	34	21	1	1
Dyspepsia
subjects affected / exposed	23 / 431 (5.34%)	15 / 435 (3.45%)	1 / 141 (0.71%)	0 / 119 (0.00%)
occurrences all number	27	15	1	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	62 / 431 (14.39%)	49 / 435 (11.26%)	1 / 141 (0.71%)	3 / 119 (2.52%)
occurrences all number	74	64	1	3
Oropharyngeal pain
subjects affected / exposed	25 / 431 (5.80%)	39 / 435 (8.97%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences all number	28	49	0	0
Nasal congestion
subjects affected / exposed	16 / 431 (3.71%)	22 / 435 (5.06%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences all number	16	27	0	0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	47 / 431 (10.90%)	42 / 435 (9.66%)	1 / 141 (0.71%)	0 / 119 (0.00%)
occurrences all number	51	50	1	0
Psychiatric disorders
Insomnia
subjects affected / exposed	51 / 431 (11.83%)	37 / 435 (8.51%)	1 / 141 (0.71%)	0 / 119 (0.00%)
occurrences all number	56	39	1	0
Anxiety
subjects affected / exposed	34 / 431 (7.89%)	43 / 435 (9.89%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences all number	37	45	0	0
Depression
subjects affected / exposed	34 / 431 (7.89%)	26 / 435 (5.98%)	0 / 141 (0.00%)	1 / 119 (0.84%)
occurrences all number	37	28	0	1
Renal and urinary disorders
Proteinuria
subjects affected / exposed	11 / 431 (2.55%)	22 / 435 (5.06%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences all number	12	28	0	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	63 / 431 (14.62%)	53 / 435 (12.18%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences all number	70	59	0	0
Arthralgia
subjects affected / exposed	61 / 431 (14.15%)	49 / 435 (11.26%)	2 / 141 (1.42%)	0 / 119 (0.00%)
occurrences all number	67	55	2	0
Osteopenia
subjects affected / exposed	34 / 431 (7.89%)	38 / 435 (8.74%)	2 / 141 (1.42%)	1 / 119 (0.84%)
occurrences all number	35	43	2	1
Pain in extremity
subjects affected / exposed	31 / 431 (7.19%)	26 / 435 (5.98%)	2 / 141 (1.42%)	0 / 119 (0.00%)
occurrences all number	34	31	2	0
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	87 / 431 (20.19%)	82 / 435 (18.85%)	2 / 141 (1.42%)	2 / 119 (1.68%)
occurrences all number	125	123	5	2
Nasopharyngitis
subjects affected / exposed	68 / 431 (15.78%)	75 / 435 (17.24%)	5 / 141 (3.55%)	5 / 119 (4.20%)
occurrences all number	115	128	6	5
Syphilis
subjects affected / exposed	42 / 431 (9.74%)	44 / 435 (10.11%)	2 / 141 (1.42%)	3 / 119 (2.52%)
occurrences all number	50	50	2	3
Bronchitis
subjects affected / exposed	38 / 431 (8.82%)	26 / 435 (5.98%)	2 / 141 (1.42%)	1 / 119 (0.84%)
occurrences all number	42	30	2	1
Sinusitis
subjects affected / exposed	25 / 431 (5.80%)	28 / 435 (6.44%)	2 / 141 (1.42%)	1 / 119 (0.84%)
occurrences all number	28	35	2	1
Urinary tract infection
subjects affected / exposed	17 / 431 (3.94%)	31 / 435 (7.13%)	1 / 141 (0.71%)	2 / 119 (1.68%)
occurrences all number	27	42	1	2
Folliculitis
subjects affected / exposed	19 / 431 (4.41%)	26 / 435 (5.98%)	2 / 141 (1.42%)	0 / 119 (0.00%)
occurrences all number	24	30	2	0
Gonorrhoea
subjects affected / exposed	26 / 431 (6.03%)	20 / 435 (4.60%)	1 / 141 (0.71%)	0 / 119 (0.00%)
occurrences all number	31	27	1	0
Pharyngitis
subjects affected / exposed	22 / 431 (5.10%)	25 / 435 (5.75%)	0 / 141 (0.00%)	0 / 119 (0.00%)
occurrences all number	24	28	0	0
Gastroenteritis
subjects affected / exposed	23 / 431 (5.34%)	21 / 435 (4.83%)	0 / 141 (0.00%)	2 / 119 (1.68%)
occurrences all number	26	22	0	2
Influenza
subjects affected / exposed	25 / 431 (5.80%)	18 / 435 (4.14%)	1 / 141 (0.71%)	2 / 119 (1.68%)
occurrences all number	28	20	1	2
Chlamydial infection
subjects affected / exposed	24 / 431 (5.57%)	20 / 435 (4.60%)	1 / 141 (0.71%)	0 / 119 (0.00%)
occurrences all number	30	23	1	0

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Were there any global substantial amendments to the protocol? Yes

10 Dec 2013

● Management of HIV-1 genotype/phenotype resistance testing was clarified and the dual-energy x-ray absorptiometry (DXA) window at the early study drug discontinuation (ESDD) visit was corrected. ● The prior and concomitant medication table was updated based on the current company core data sheets for elvitegravir (EVG), cobicistat (COBI), and Stribild® (STB). ● Guidance for management of potential posterior uveitis cases was added. ● Appendix 6 of the protocol with the most current Resistance Mutations by Antiretroviral Class table was updated. ● Renamed secondary endpoints as key secondary endpoints and tertiary endpoints as other secondary endpoints ● Added spine BMD as a secondary objective and key secondary endpoint ● Added treatment-emergent proteinuria as a key secondary endpoint ● Added urine retinol binding protein (RBP) to creatinine ratio and urine beta-2-microglobulin to creatinine ratio as other secondary endpoints ● Removed the proportion of participants with HIV-1 RNA < 200 copies/mL at Weeks 48 and 96 as defined by the US Food and Drug Administration (FDA)-defined snapshot algorithm from secondary efficacy endpoints ● Updated the statistical analysis method to improve statistical power, and added imputation method for missing data ● Updated safety analysis section and added treatment-emergent proteinuria and urine RBP to creatinine ratio and urine beta-2-microglobulin to creatinine ratio ● Updated the statistical testing procedures

18 Dec 2014

•Extending the blinded phase of the study from 96 weeks of treatment to 144 weeks of treatment. •Updated Region participating in the GS-US-292-0111 study to remove Brazil •Addition of language from Country Specific Addendum for UK to incorporate country specific end of study information into protocol. •Revision of end of study language to align with E/C/F/TAF Program. •Removal of EQ-5D Questionnaire post Week 96 Study and ESDD Visits. •Revised HIV-1 RNA stratification to > 100,000 copies/mL for 95% confidence interval construction to match SAP •Concomitant Medication Table updated based on current company core data sheet for E/C/F/TAF. •Addition of FRAX (Fracture Risk Assessment Tool) at Baseline per Administrative Letter #3 •Removal of blood collected for bone biomarkers post Week 96 Study and ESDD Visits to minimize subject burden. •Updated criteria for Plasma Storage Sample used for future testing to match Appendix 2 Study Procedures Table

Were there any global interruptions to the trial? No

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

None reported

http://www.ncbi.nlm.nih.gov/pubmed/29627709
http://www.ncbi.nlm.nih.gov/pubmed/28282300
http://www.ncbi.nlm.nih.gov/pubmed/28076335
http://www.ncbi.nlm.nih.gov/pubmed/26892863
http://www.ncbi.nlm.nih.gov/pubmed/27742226
http://www.ncbi.nlm.nih.gov/pubmed/26829661
http://www.ncbi.nlm.nih.gov/pubmed/25890673

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Clinical trials

Clinical Trial Results: A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Versus Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate in HIV-1 Positive, Antiretroviral Treatment- Naïve Adults

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Week 48

Primary: Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Week 48

Secondary: Percentage of participants with HIV-1 RNA < 50 copies/mL at Week 96

Secondary: Percentage of participants with HIV-1 RNA < 50 copies/mL at Week 96

Secondary: Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Weeks 48 and 96

Secondary: Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Weeks 48 and 96

Secondary: Change From Baseline in CD4+ Cell Count at Week 48

Secondary: Change From Baseline in CD4+ Cell Count at Week 48

Secondary: Change From Baseline in CD4+ Cell Count at Week 96

Secondary: Change From Baseline in CD4+ Cell Count at Week 96

Secondary: Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 48

Secondary: Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 48

Secondary: Percent Change From Baseline in Hip BMD at Week 96

Secondary: Percent Change From Baseline in Hip BMD at Week 96

Secondary: Percent Change From Baseline in Spine BMD at Week 48

Secondary: Percent Change From Baseline in Spine BMD at Week 48

Secondary: Percent Change From Baseline in Spine BMD at Week 96

Secondary: Percent Change From Baseline in Spine BMD at Week 96

Secondary: Change From Baseline in Serum Creatinine at Week 48

Secondary: Change From Baseline in Serum Creatinine at Week 48

Secondary: Change From Baseline in Serum Creatinine at Week 96

Secondary: Change From Baseline in Serum Creatinine at Week 96

Secondary: Percentage of Participants With Treatment-emergent Proteinuria Through Week 48

Secondary: Percentage of Participants With Treatment-emergent Proteinuria Through Week 48

Secondary: Percentage of Participants With Treatment-emergent Proteinuria Through Week 96

Secondary: Percentage of Participants With Treatment-emergent Proteinuria Through Week 96

Secondary: Percent Change From Baseline in Urine Retinol Binding Protein (RBP) to Creatinine Ratio at Week 48

Secondary: Percent Change From Baseline in Urine Retinol Binding Protein (RBP) to Creatinine Ratio at Week 48

Secondary: Percent Change From Baseline in Urine RBP to Creatinine Ratio at Week 96

Secondary: Percent Change From Baseline in Urine RBP to Creatinine Ratio at Week 96

Secondary: Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio at Week 48

Secondary: Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio at Week 48

Secondary: Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio at Week 96

Secondary: Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio at Week 96

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Versus Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate in HIV-1 Positive, Antiretroviral Treatment- Naïve Adults