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Clinical Trial Results:
A Multicenter, Randomized, Double-Blind, Double-Dummy, Phase 3 Study of the Safety and Efficacy of Ritonavir-Boosted Elvitegravir (EVG/r) Versus Raltegravir (RAL) Each Administered With a Background Regimen in HIV-1 Infected, Antiretroviral Treatment-Experienced Adults

Summary
EudraCT number	2007-004225-26
Trial protocol	DE GB NL BE ES IT PT FR
Global end of trial date	22 Apr 2015

Results information
Results version number	v1(current)
This version publication date	07 May 2016
First version publication date	07 May 2016
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-183-0145

ISRCTN number

US NCT number

NCT00708162

WHO universal trial number (UTN)

Sponsor organisation name

Gilead Sciences

Sponsor organisation address

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

Public contact

Clinical Trial Mailbox, Gilead Sciences International Ltd , ClinicalTrialDisclosures@gilead.com

Scientific contact

Clinical Trial Mailbox, Gilead Sciences International Ltd , ClinicalTrialDisclosures@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

22 Apr 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

22 Apr 2015

Was the trial ended prematurely?

Main objective of the trial

The purpose of this study was to compare the safety, tolerability and efficacy of a regimen containing once-daily elvitegravir (EVG) versus twice-daily raltegravir (RAL) added to a background regimen (1 fully-active ritonavir (RTV)-boosted protease inhibitor (PI) plus 1 or 2 additional antiretroviral (ARV) agents) in HIV-1 infected, ARV treatment-experienced adults who had documented resistance, or at least six months experience prior to screening with two or more different classes of ARV agents. Participants were randomized in a 1:1 ratio to receive EVG plus background regimen (Elvitegravir group), or raltegravir plus background regimen (Raltegravir group). Due to known drug interactions, participants in the Elvitegravir group who received RTV-boosted atazanavir (ATV) or RTV-boosted lopinavir (LPV) as part of their background regimen received elvitegravir at a lower dose (85 mg).

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

The background regimen was constructed by the investigator based on viral resistance testing. The fully active PI was defined by phenotypic resistance analysis. For phenotypic susceptibility, fully active was defined as being below the lower clinical or biological cutoff. Participants were required to take their RTV dose based on the dosing schedule indicated in the prescribing information for the PI; no additional ritonavir was required to be taken with EVG. No other marketed PIs were allowed as part of the background regimen due to unknown drug interactions. The second agent could have been one nucleoside or nucleotide reverse transcriptase inhibitor (NRTI), etravirine, maraviroc, or T-20. However, the second agent must not have included an integrase inhibitor; the nonnucleoside reverse transcriptase inhibitors efavirenz, nevirapine, or delavirdine (due to unknown drug interactions); or the fixed-dose combination therapies Atripla® or Trizivir® (abacavir sulfate/lamivudine/zidovudine). The second agent may or may not have been fully active (except in Spain, where participants have to receive a fully active second agent, as requested by the Spanish regulatory agency). If the M184V/I reverse transcriptase (RT) mutation was present on the screening genotype report and an NRTI was used as the second agent, then either FTC or LAM may have been added as a third agent in the background regimen to maintain the M184V/I mutation. In this situation only, the fixed-dose combination therapies Combivir®, Truvada®, or Epzicom/Kivexa® may have been prescribed as the combined second and third agents of the background regimen. After Week 96, participants continued to take their blinded study drug and attended visits until treatment assignments were unblinded, at which point they were given the option to participate in an open-label EVG extension phase of the study.

Evidence for comparator

Actual start date of recruitment

19 Jun 2008

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 2

Country: Number of subjects enrolled

Portugal: 21

Country: Number of subjects enrolled

Spain: 34

Country: Number of subjects enrolled

United Kingdom: 11

Country: Number of subjects enrolled

Belgium: 11

Country: Number of subjects enrolled

France: 25

Country: Number of subjects enrolled

Germany: 14

Country: Number of subjects enrolled

Italy: 17

Country: Number of subjects enrolled

United States: 453

Country: Number of subjects enrolled

Mexico: 51

Country: Number of subjects enrolled

Canada: 34

Country: Number of subjects enrolled

Australia: 29

Country: Number of subjects enrolled

Puerto Rico: 22

Worldwide total number of subjects

724

EEA total number of subjects

135

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)

709

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants were enrolled in a total of 161 study sites in Australia, Europe, and North America. The first participant was screened on 19 June 2008. The last study visit occurred on 22 April 2015.

Screening details

1335 participants were screened.

Period 1 title

Randomized Phase

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Assessor

Are arms mutually exclusive

Yes

Elvitegravir

Arm description

EVG plus RAL placebo plus background regimen in the Randomized Phase, followed by EVG plus background regimen in the Open-Label Phase.

Arm type

Experimental

Investigational medicinal product name

Elvitegravir

Investigational medicinal product code

Other name

Vitekta®, GS-9137

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

EVG 150 mg tablet administered orally once daily with food (85 mg if receiving RTV-boosted ATV or RTV-boosted LPV as part of the background regimen)

Investigational medicinal product name

Raltegravir placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

RAL placebo tablet administered twice daily

Raltegravir

Arm description

EVG plus RAL placebo plus background regimen in the Randomized Phase, followed by EVG plus background regimen in the Open-Label Phase.

Arm type

Active comparator

Investigational medicinal product name

Raltegravir

Investigational medicinal product code

Other name

Isentress®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

RAL 400 tablet administered twice daily

Investigational medicinal product name

Elvitegravir placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

EVG placebo tablet administered orally once daily with food

Number of subjects in period 1 ^[1]	Elvitegravir	Raltegravir
Started	354	358
Completed	205	209
Not completed	149	149
Protocol violation	10	11
Adverse event, non-fatal	8	12
Death	2	9
Pregnancy	3	-
Lost to follow-up	34	34
Withdrew consent	31	22
Investigator's discretion	7	10
Participant noncompliance	40	32
Lack of efficacy	14	19

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: 7 participants in the Elvitegravir group and 5 participants in the Raltegravir group who were randomized but not treated are not included in the subject disposition table.

Period 2 title

Open-Label Phase

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Elvitegravir

Arm description

EVG plus RAL placebo plus background regimen in the Randomized Phase, followed by EVG plus background regimen in the Open-Label Phase.

Arm type

Experimental

Investigational medicinal product name

Elvitegravir

Investigational medicinal product code

Other name

Vitekta®, GS-9137

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

EVG 150 mg tablet administered orally once daily with food (85 mg if receiving RTV-boosted ATV or RTV-boosted LPV as part of the background regimen)

Investigational medicinal product name

Raltegravir placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

RAL placebo tablet administered twice daily

Raltegravir

Arm description

RAL plus EVG placebo plus background regimen in the Randomized Phase, followed by EVG plus background regimen in the Open-Label Phase.

Arm type

Active comparator

Investigational medicinal product name

Raltegravir

Investigational medicinal product code

Other name

Isentress®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

RAL 400 tablet administered twice daily

Investigational medicinal product name

Elvitegravir placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

EVG placebo tablet administered orally once daily with food

Number of subjects in period 2 ^[2]	Elvitegravir	Raltegravir
Started	196	151
Completed	152	121
Not completed	44	30
Adverse event, non-fatal	1	2
Death	3	1
Unknown	1	-
Lost to follow-up	10	8
Withdrew consent	12	6
Investigator's discretion	3	2
Participant noncompliance	7	7
Lack of efficacy	7	4

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: 9 participants in the Elvitegravir group and 58 participants in the Raltegravir group who completed the Randomized Phase did not continue to the Open-Label Phase.

Baseline characteristics

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Reporting group title

Elvitegravir

Reporting group description

EVG plus RAL placebo plus background regimen in the Randomized Phase, followed by EVG plus background regimen in the Open-Label Phase.

Reporting group title

Raltegravir

Reporting group description

EVG plus RAL placebo plus background regimen in the Randomized Phase, followed by EVG plus background regimen in the Open-Label Phase.

Reporting group values	Elvitegravir	Raltegravir	Total
Number of subjects	354	358	712
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	44 ( 9 )	45 ( 9.1 )	-
Gender categorical
Units: Subjects
Female	60	67	127
Male	294	291	585
Ethnicity
Units: Subjects
Hispanic or Latino	81	74	155
Not Hispanic or Latino	272	283	555
Unknown or Not Reported	1	1	2
Race
Units: Subjects
White	210	227	437
Black or African American	128	119	247
Asian	9	5	14
American Indian or Alaska Native	3	3	6
Native Hawaiian or Other Pacific Islander	1	0	1
Other	3	4	7
HIV-1 RNA category
Units: Subjects
≤ 100,000 copies/mL	263	267	530
> 100,000 copies/mL	91	91	182
HIV Disease Status
Units: Subjects
Asymptomatic	172	175	347
Symptomatic HIV Infections	52	54	106
AIDS	126	125	251
Unknown	4	4	8
Type of PI in Background Regimen (Excluding Ritonavir)
One participant in the Raltegravir group switched from darunavir to fosamprenavir at Day 5, and is counted only in the number receiving darunavir at baseline.
Units: Subjects
atazanavir	64	53	117
darunavir	202	206	408
fosamprenavir	14	20	34
lopinavir	68	72	140
tipranavir	6	7	13
Type of NRTI in Background Regimen
Only participants who had an nucleoside reverse transcriptase inhibitor (NRTI) in their background regimen were reported.
Units: Subjects
tenofovir disoproxil fumarate	163	171	334
emtricitabine/tenofovir disoproxil fumarate	91	66	157
lamivudine	13	13	26
abacavir	6	15	21
abacavir/lamivudine	4	8	12
lamivudine/zidovudine	6	5	11
zidovudine	3	6	9
didanosine	1	7	8
emtricitabine	2	3	5
no NRTI in background regimen	65	64	129
Enfuvirtide (T-20) in background regimen
Units: Subjects
No	352	357	709
Yes	2	1	3
Etravirine in background regimen
Units: Subjects
No	309	303	612
Yes	45	55	100
Maraviroc in background regimen
Units: Subjects
No	330	340	670
Yes	24	18	42
Phenotypic Sensitivity Score
Phenotypic sensitivity score (PSS) was calculated by summing up drug susceptibility values (1=sensitive; 0.5=partially sensitive; 0=resistance or reduced susceptibility) on all drugs in the baseline background regimen. For subjects naive to enfuvirtide (or maraviroc), a score of 1 was assigned for enfuvirtide (or maraviroc). Higher scores correspond to increased sensitivity.
Units: Subjects
1.0	5	4	9
1.5	23	28	51
2.0	309	313	622
2.5	2	1	3
3.0	14	10	24
3.5	0	1	1
No baseline PSS score	1	1	2
Chronic Hepatitis B (HBV) Infection Status
Units: Subjects
Indeterminant	1	0	1
Negative	333	342	675
Positive	17	13	30
No baseline HBV measurement	3	3	6
Chronic Hepatitis C (HCV) Infection Status
Units: Subjects
Indeterminant	2	2	4
Negative	305	298	603
Positive	44	55	99
No baseline HCV measurement	3	3	6
HIV-1 RNA
Units: log10 copies/mL
arithmetic mean (standard deviation)	4.26 ( 0.969 )	4.27 ( 0.943 )	-
Cluster of differentiation (CD4) Cell Count
Units: cells/mm^3
arithmetic mean (standard deviation)	257.9 ( 204.31 )	265.3 ( 207.04 )	-

End points

Top of page

Reporting group title

Elvitegravir

Reporting group description

EVG plus RAL placebo plus background regimen in the Randomized Phase, followed by EVG plus background regimen in the Open-Label Phase.

Reporting group title

Raltegravir

Reporting group description

EVG plus RAL placebo plus background regimen in the Randomized Phase, followed by EVG plus background regimen in the Open-Label Phase.

Reporting group title

Elvitegravir

Reporting group description

EVG plus RAL placebo plus background regimen in the Randomized Phase, followed by EVG plus background regimen in the Open-Label Phase.

Reporting group title

Raltegravir

Reporting group description

RAL plus EVG placebo plus background regimen in the Randomized Phase, followed by EVG plus background regimen in the Open-Label Phase.

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

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End point title

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

End point description

The percentage of participants achieving and maintaining confirmed HIV-1 RNA < 50 copies/mL at Week 48 was analyzed using the FDA-defined Time to Loss of Virologic Response (TLOVR) algorithm, which takes into account a patient's longitudinal viral load up to the predefined time point by considering patterns of suppression and rebounding.

End point type

Primary

End point timeframe

Week 48

End point values	Elvitegravir	Raltegravir
Number of subjects analysed	351	351
Units: percentage of participants
number (not applicable)	59	57.8

Difference in percentages

Statistical analysis description

The planned sample size of 700 HIV-1 infected participants, (350 in each group) was estimated to provide at least 85% power to establish noninferiority in the percentage of participants achieving and maintaining confirmed HIV-1 RNA < 50 copies/mL through Week 48. For sample size and power computation, it was assumed that both elvitegravir and raltegravir arms have a response rate of 0.74, that a noninferiority margin was 0.10, and that the significance level of the test was 1-sided 0.025 level.

Comparison groups

Elvitegravir v Raltegravir

Number of subjects included in analysis

702

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[1]

Method

Parameter type

Difference in percentages

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-6

upper limit

8.2

Notes
[1] - Null hypothesis: the EVG group was at least 10% worse than the RAL group with respect to percentage of participants achieving and maintaining HIV-1 RNA < 50 copies/mL through Week 48; alternative hypothesis: the EVG group was less than 10% worse than the RAL group. The difference in percentages and its 95% confidence interval (CI) were based on stratum-adjusted HIV-1 RNA level and the class of second agent (NRTI or other classes) using Mantel-Haenszel (MH) proportions and normal approximation.

Secondary: Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 50 Copies/mL at Week 96

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End point title

Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 50 Copies/mL at Week 96

End point description

The percentage of participants achieving and maintaining confirmed HIV-1 RNA < 50 copies/mL at Week 96 was analyzed using the FDA-defined TLOVR algorithm, which takes into account a patient's longitudinal viral load up to the predefined time point by considering patterns of suppression and rebounding.

End point type

Secondary

End point timeframe

Week 96

End point values	Elvitegravir	Raltegravir
Number of subjects analysed	351	351
Units: percentage of participants
number (not applicable)	47.6	45

Difference in percentages

Statistical analysis description

Null hypothesis: the EVG group was at least 10% worse than the RAL group with respect to percentage of participants achieving and maintaining HIV-1 RNA < 50 copies/mL through Week 48; alternative hypothesis: the EVG group was less than 10% worse than the RAL group. The difference in percentages and its 95% CI were based on stratum-adjusted HIV-1 RNA level and the class of second agent (NRTI or other classes) using MH proportions and normal approximation.

Comparison groups

Elvitegravir v Raltegravir

Number of subjects included in analysis

702

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

Difference in percentages

Point estimate

2.6

Confidence interval

level

95%

sides

2-sided

lower limit

-4.6

upper limit

9.9

Secondary: Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 400 Copies/mL at Week 48

Top of page

End point title

Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 400 Copies/mL at Week 48

End point description

The percentage of participants achieving and maintaining confirmed HIV-1 RNA < 400 copies/mL at Week 48 was analyzed using the FDA-defined TLOVR algorithm, which takes into account a patient's longitudinal viral load up to the predefined time point by considering patterns of suppression and rebounding.

End point type

Secondary

End point timeframe

Week 48

End point values	Elvitegravir	Raltegravir
Number of subjects analysed	351	351
Units: percentage of participants
number (not applicable)	68.1	67.2

Difference in percentages

Statistical analysis description

The difference in percentages and its 95% CI were based on stratum-adjusted HIV-1 RNA level and the class of second agent (NRTI or other classes) using MH proportions and normal approximation.

Comparison groups

Elvitegravir v Raltegravir

Number of subjects included in analysis

702

Analysis specification

Pre-specified

Analysis type

other ^[2]

Method

Parameter type

The difference in percentages and its 95

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-6

upper limit

7.7

Notes
[2] - Comparative analysis

Secondary: Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 400 Copies/mL at Week 96

Top of page

End point title

Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 400 Copies/mL at Week 96

End point description

The percentage of participants achieving and maintaining confirmed HIV-1 RNA < 400 copies/mL at Week 96 was analyzed using the FDA-defined TLOVR algorithm, which takes into account a patient's longitudinal viral load up to the predefined time point by considering patterns of suppression and rebounding.

End point type

Secondary

End point timeframe

Week 96

End point values	Elvitegravir	Raltegravir
Number of subjects analysed	351	351
Units: percentage of participants
number (not applicable)	57	56.1

Difference in percentages

Statistical analysis description

The difference in percentages and its 95% CI were based on stratum-adjusted HIV-1 RNA level and the class of second agent (NRTI or other classes) using MH proportions and normal approximation.

Comparison groups

Elvitegravir v Raltegravir

Number of subjects included in analysis

702

Analysis specification

Pre-specified

Analysis type

other ^[3]

Method

Parameter type

Difference in percentages

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-6.4

upper limit

8.2

Notes
[3] - Comparative analysis

Secondary: Virologic Response at Week 48 (HIV-1 RNA < 50 Copies/mL)

Top of page

End point title

Virologic Response at Week 48 (HIV-1 RNA < 50 Copies/mL)

End point description

Virologic response at Week 48 (percentage of participants with HIV-1 RNA < 50 copies/mL) was analyzed using the FDA-defined Snapshot algorithm, which defines a patient's virologic response status using the viral load along with study drug discontinuation status at the predefined time point within an allowed window of time.

End point type

Secondary

End point timeframe

Week 48

End point values	Elvitegravir	Raltegravir
Number of subjects analysed	351	351
Units: percentage of participants
number (not applicable)	59.8	57.5

Difference in percentages

Statistical analysis description

The difference in percentages and its 95% CI were based on stratum-adjusted HIV-1 RNA level and the class of second agent (NRTI or other classes) using MH proportions and normal approximation.

Comparison groups

Elvitegravir v Raltegravir

Number of subjects included in analysis

702

Analysis specification

Pre-specified

Analysis type

other ^[4]

Method

Parameter type

Difference in percentages

Point estimate

2.2

Confidence interval

level

95%

sides

2-sided

lower limit

-5

upper limit

9.3

Notes
[4] - Comparative analysis

Secondary: Virologic Response at Week 96 (HIV-1 RNA < 50 Copies/mL)

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End point title

Virologic Response at Week 96 (HIV-1 RNA < 50 Copies/mL)

End point description

Virologic response at Week 96 (percentage of participants with HIV-1 RNA < 50 copies/mL) was analyzed using the FDA-defined Snapshot algorithm, which defines a patient's virologic response status using the viral load along with study drug discontinuation status at the predefined time point within an allowed window of time.

End point type

Secondary

End point timeframe

Week 96

End point values	Elvitegravir	Raltegravir
Number of subjects analysed	351	351
Units: percentage of participants
number (not applicable)	52.4	53

Difference in percentages

Statistical analysis description

The difference in percentages and its 95% CI were based on stratum-adjusted HIV-1 RNA level and the class of second agent (NRTI or other classes) using MH proportions and normal approximation.

Comparison groups

Elvitegravir v Raltegravir

Number of subjects included in analysis

702

Analysis specification

Pre-specified

Analysis type

other ^[5]

Method

Parameter type

Difference in percentages

Point estimate

-0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-7.9

upper limit

6.8

Notes
[5] - Comparative analysis

Secondary: Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 50 Copies/mL) up to Week 48

Top of page

End point title

Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 50 Copies/mL) up to Week 48

End point description

The percentage of participants with pure virologic failure (HIV-1 RNA cutoff at 50 copies/mL) up to Week 48 was estimated using the Kaplan-Meier method in the time to event analysis.

End point type

Secondary

End point timeframe

Baseline to Week 48

End point values	Elvitegravir	Raltegravir
Number of subjects analysed	351	351
Units: percentage of participants
number (confidence interval 95%)	35 (29.8 to 39.8)	35 (29.8 to 39.8)

No statistical analyses for this end point

Secondary: Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 50 Copies/mL) up to Week 96

Top of page

End point title

Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 50 Copies/mL) up to Week 96

End point description

The percentage of participants with pure virologic failure (HIV-1 RNA cutoff at 50 copies/mL) up to Week 96 was estimated using the Kaplan-Meier method in the time to event analysis.

End point type

Secondary

End point timeframe

Baseline to Week 96

End point values	Elvitegravir	Raltegravir
Number of subjects analysed	351	351
Units: percentage of participants
number (confidence interval 95%)	45 (39.3 to 49.9)	46 (41.1 to 51.9)

No statistical analyses for this end point

Secondary: Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 400 Copies/mL) up to Week 48

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End point title

Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 400 Copies/mL) up to Week 48

End point description

The percentage of participants with pure virologic failure (HIV-1 RNA cutoff at 400 copies/mL) up to Week 48 was estimated using the Kaplan-Meier method in the time to event analysis.

End point type

Secondary

End point timeframe

Baseline to Week 48

End point values	Elvitegravir	Raltegravir
Number of subjects analysed	351	351
Units: percentage of participants
number (confidence interval 95%)	24 (19.5 to 28.5)	24 (19.7 to 28.9)

No statistical analyses for this end point

Secondary: Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 400 Copies/mL) up to Week 96

Top of page

End point title

Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 400 Copies/mL) up to Week 96

End point description

The percentage of participants with pure virologic failure (HIV-1 RNA cutoff at 400 copies/mL) up to Week 96 was estimated using the Kaplan-Meier method in the time to event analysis.

End point type

Secondary

End point timeframe

Baseline to Week 96

End point values	Elvitegravir	Raltegravir
Number of subjects analysed	351	351
Units: percentage of participants
number (confidence interval 95%)	32 (26.7 to 36.7)	31 (26.1 to 36.1)

No statistical analyses for this end point

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

Top of page

End point title

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

End point description

The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 48 was analyzed using the missing = failure method, where participants with missing data were considered as having failed to meet the criteria for evaluation.

End point type

Secondary

End point timeframe

Week 48

End point values	Elvitegravir	Raltegravir
Number of subjects analysed	351	351
Units: percentage of participants
number (not applicable)	61	60.7

Difference in percentages

Statistical analysis description

The difference in percentages and its 95% CI were based on stratum-adjusted HIV-1 RNA level and the class of second agent (NRTI or other classes) using MH proportions and normal approximation.

Comparison groups

Elvitegravir v Raltegravir

Number of subjects included in analysis

702

Analysis specification

Pre-specified

Analysis type

other ^[6]

Method

Parameter type

Difference in percentages

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-6.9

upper limit

7.3

Notes
[6] - Comparative analysis

Secondary: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 96

Top of page

End point title

Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 96

End point description

The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 96 was analyzed using the missing = failure method.

End point type

Secondary

End point timeframe

Week 96

End point values	Elvitegravir	Raltegravir
Number of subjects analysed	351	351
Units: percentage of participants
number (not applicable)	53.6	56.4

Difference in percentages

Statistical analysis description

The difference in percentages and its 95% CI were based on stratum-adjusted HIV-1 RNA level and the class of second agent (NRTI or other classes) using MH proportions and normal approximation.

Comparison groups

Elvitegravir v Raltegravir

Number of subjects included in analysis

702

Analysis specification

Pre-specified

Analysis type

other ^[7]

Method

Parameter type

Difference in percentages

Point estimate

-2.9

Confidence interval

level

95%

sides

2-sided

lower limit

-10.2

upper limit

4.4

Notes
[7] - Comparative analysis

Secondary: Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Week 48

Top of page

End point title

Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Week 48

End point description

The percentage of participants with HIV-1 RNA < 400 copies/mL at Week 48 was analyzed using the missing = failure method.

End point type

Secondary

End point timeframe

Week 48

End point values	Elvitegravir	Raltegravir
Number of subjects analysed	351	351
Units: percentage of participants
number (not applicable)	70.1	72.1

Difference in percentages

Statistical analysis description

The difference in percentages and its 95% CI were based on stratum-adjusted HIV-1 RNA level and the class of second agent (NRTI or other classes) using MH proportions and normal approximation.

Comparison groups

Elvitegravir v Raltegravir

Number of subjects included in analysis

702

Analysis specification

Pre-specified

Analysis type

other ^[8]

Method

Parameter type

Difference in percentages

Point estimate

-2

Confidence interval

level

95%

sides

2-sided

lower limit

-8.6

upper limit

4.7

Notes
[8] - Comparative analysis

Secondary: Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Week 96

Top of page

End point title

Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Week 96

End point description

The percentage of participants with HIV-1 RNA < 400 copies/mL at Week 96 was analyzed using the missing = failure method.

End point type

Secondary

End point timeframe

Week 96

End point values	Elvitegravir	Raltegravir
Number of subjects analysed	351	351
Units: percentage of participants
number (not applicable)	61.3	63

Difference in percentages

Statistical analysis description

The difference in percentages and its 95% CI were based on stratum-adjusted HIV-1 RNA level and the class of second agent (NRTI or other classes) using MH proportions and normal approximation.

Comparison groups

Elvitegravir v Raltegravir

Number of subjects included in analysis

702

Analysis specification

Pre-specified

Analysis type

other ^[9]

Method

Parameter type

Difference in percentages

Point estimate

-1.7

Confidence interval

level

95%

sides

2-sided

lower limit

-8.8

upper limit

5.5

Notes
[9] - Comparative analysis

Secondary: Change From Baseline in HIV-1 RNA at Week 48

Top of page

End point title

Change From Baseline in HIV-1 RNA at Week 48

End point description

The change from baseline in log10 HIV-1 RNA (copies/mL) at Week 48 was analyzed. Participants with evaluable change data at Week 48 were analyzed.

End point type

Secondary

End point timeframe

Baseline to Week 48

End point values	Elvitegravir	Raltegravir
Number of subjects analysed	280	291
Units: log10 copies/mL
arithmetic mean (standard deviation)	-2.17 ( 1.162 )	-2.18 ( 1.178 )

Difference in log10 copies/mL

Statistical analysis description

The difference in least squares means (LSM) and its 95% CI were obtained using an analysis of variance model (ANOVA) adjusting for baseline HIV-1 RNA level and class of the second agent (NRTI or other classes).

Comparison groups

Elvitegravir v Raltegravir

Number of subjects included in analysis

571

Analysis specification

Pre-specified

Analysis type

other ^[10]

Method

Parameter type

Difference in log10 copies/mL

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.16

upper limit

0.19

Notes
[10] - Comparative analysis

Secondary: Change From Baseline in HIV-1 RNA at Week 96

Top of page

End point title

Change From Baseline in HIV-1 RNA at Week 96

End point description

The change from baseline in log10 HIV-1 RNA (copies/mL) at Week 96 was analyzed. Participants with evaluable change data at Week 96 were analyzed.

End point type

Secondary

End point timeframe

Baseline to Week 96

End point values	Elvitegravir	Raltegravir
Number of subjects analysed	238	238
Units: log10 copies/mL
arithmetic mean (standard deviation)	-2.26 ( 1.078 )	-2.31 ( 1.068 )

Difference in log10 copies/mL

Statistical analysis description

The difference in LSM and its 95% CI were obtained using ANOVA adjusting for baseline HIV-1 RNA level and class of the second agent (NRTI or other classes).

Comparison groups

Elvitegravir v Raltegravir

Number of subjects included in analysis

476

Analysis specification

Pre-specified

Analysis type

other ^[11]

Method

Parameter type

Difference in log10 copies/mL

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-0.12

upper limit

0.22

Notes
[11] - Comparative analysis

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

Top of page

End point title

Change From Baseline in CD4 Cell Count at Week 48

End point description

The change from baseline in CD4 cell count (cells/mm^3) at Week 48 was analyzed. Participants with evaluable change data at Week 48 were analyzed.

End point type

Secondary

End point timeframe

Baseline to Week 48

End point values	Elvitegravir	Raltegravir
Number of subjects analysed	267	282
Units: cells/mm^3
arithmetic mean (standard deviation)	138 ( 141.4 )	147 ( 148.9 )

Difference in cells/mm^3

Statistical analysis description

The difference in LSM and its 95% CI were obtained using ANOVA adjusting for baseline HIV-1 RNA level and class of the second agent (NRTI or other classes).

Comparison groups

Elvitegravir v Raltegravir

Number of subjects included in analysis

549

Analysis specification

Pre-specified

Analysis type

other ^[12]

Method

Parameter type

Difference in cells/mm^3

Point estimate

-9

Confidence interval

level

95%

sides

2-sided

lower limit

-33

upper limit

Notes
[12] - Comparative analysis

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

Top of page

End point title

Change From Baseline in CD4 Cell Count at Week 96

End point description

The change from baseline in CD4 cell count (cells/mm^3) at Week 96 was analyzed. Participants with evaluable change data at Week 96 were analyzed.

End point type

Secondary

End point timeframe

Baseline to Week 96

End point values	Elvitegravir	Raltegravir
Number of subjects analysed	231	233
Units: cells/mm^3
arithmetic mean (standard deviation)	205 ( 191.5 )	198 ( 162.2 )

Difference in cells/mm^3

Statistical analysis description

The difference in LSM and its 95% CI were obtained using ANOVA adjusting for baseline HIV-1 RNA level and class of the second agent (NRTI or other classes).

Comparison groups

Elvitegravir v Raltegravir

Number of subjects included in analysis

464

Analysis specification

Pre-specified

Analysis type

other ^[13]

Method

Parameter type

Difference in cells/mm^3

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-25

upper limit

Notes
[13] - Comparative analysis

Adverse events

Top of page

Timeframe for reporting adverse events

Baseline through end of study drug treatment (average exposure: 100 weeks) plus 30 days

Adverse event reporting additional description

Safety Analysis Set: participants who were randomized and received at least one dose of study drug

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

Elvitegravir

Reporting group description

Adverse events in this reporting group are those experienced by participants in the Elvitegravir group during the Randomized Phase.

Reporting group title

Raltegravir

Reporting group description

Adverse events in this reporting group are those experienced by participants in the Raltegravir group during the Randomized Phase.

Reporting group title

All Elvitegravir

Reporting group description

Adverse events in this reporting group are those experienced by participants in the Elvitegravir group during both the Randomized Phase and Open-Label Phase, and those experienced by participants in the Raltegravir group following switch to EVG in the Open-Label Phase only.

Serious adverse events	Elvitegravir	Raltegravir	All Elvitegravir
Total subjects affected by serious adverse events
subjects affected / exposed	73 / 354 (20.62%)	86 / 358 (24.02%)	127 / 505 (25.15%)
number of deaths (all causes)	5	10	9
number of deaths resulting from adverse events	0	3	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Anogenital warts
subjects affected / exposed	2 / 354 (0.56%)	1 / 358 (0.28%)	2 / 505 (0.40%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Kaposi's sarcoma
subjects affected / exposed	1 / 354 (0.28%)	1 / 358 (0.28%)	2 / 505 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anal cancer recurrent
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bowen's disease
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diffuse large B-cell lymphoma
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Lung cancer metastatic
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malignant neoplasm of unknown primary site
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Oral papilloma
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Salivary gland neoplasm
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anal cancer stage 0
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gallbladder adenocarcinoma
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hodgkin's disease stage IV
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Lung neoplasm malignant
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastases to liver
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Non-Hodgkin's lymphoma
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Primary effusion lymphoma
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Queyrat erythroplasia
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal adenocarcinoma
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal cancer
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
T-cell lymphoma
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Uterine leiomyoma
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Aortic stenosis
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemodynamic instability
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral artery thrombosis
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Shock
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	1 / 354 (0.28%)	4 / 358 (1.12%)	4 / 505 (0.79%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Drug withdrawal syndrome
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Immune reconstitution inflammatory syndrome
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	2 / 354 (0.56%)	1 / 358 (0.28%)	5 / 505 (0.99%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	2 / 354 (0.56%)	1 / 358 (0.28%)	2 / 505 (0.40%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 354 (0.28%)	1 / 358 (0.28%)	2 / 505 (0.40%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary cavitation
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute pulmonary oedema
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Choking
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Hypoxia
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung infiltration
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Suicidal ideation
subjects affected / exposed	3 / 354 (0.85%)	4 / 358 (1.12%)	4 / 505 (0.79%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	1 / 354 (0.28%)	1 / 358 (0.28%)	2 / 505 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Substance abuse
subjects affected / exposed	1 / 354 (0.28%)	1 / 358 (0.28%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anxiety
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Drug dependence
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hallucination, auditory
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Major depression
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute psychosis
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Alcohol abuse
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Alcohol withdrawal syndrome
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Confusional state
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychotic disorder
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Homicidal ideation
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Liver function test abnormal
subjects affected / exposed	0 / 354 (0.00%)	2 / 358 (0.56%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
Injury, poisoning and procedural complications
Overdose
subjects affected / exposed	2 / 354 (0.56%)	2 / 358 (0.56%)	3 / 505 (0.59%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	2 / 505 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Facial bones fracture
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	2 / 505 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	2 / 505 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	2 / 505 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Jaw fracture
subjects affected / exposed	0 / 354 (0.00%)	2 / 358 (0.56%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	0 / 354 (0.00%)	2 / 358 (0.56%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Thermal burn
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Alcohol poisoning
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chemical poisoning
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Contusion
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Craniocerebral injury
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fibula fracture
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Foreign body
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal stoma complication
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Head injury
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Limb traumatic amputation
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Perirenal haematoma
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skull fractured base
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Splenic injury
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Ulna fracture
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Phimosis
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemophilia
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	2 / 354 (0.56%)	0 / 358 (0.00%)	3 / 505 (0.59%)
occurrences causally related to treatment / all	0 / 2	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 354 (0.00%)	2 / 358 (0.56%)	3 / 505 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	2 / 505 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Atrial fibrillation
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	0 / 354 (0.00%)	2 / 358 (0.56%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mitral valve prolapse
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Pericardial effusion
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute coronary syndrome
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
Cardiac tamponade
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac ventricular thrombosis
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiogenic shock
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coronary artery stenosis
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sinus node dysfunction
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Syncope
subjects affected / exposed	2 / 354 (0.56%)	0 / 358 (0.00%)	7 / 505 (1.39%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 354 (0.28%)	2 / 358 (0.56%)	3 / 505 (0.59%)
occurrences causally related to treatment / all	0 / 1	2 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
Cerebrovascular accident
subjects affected / exposed	1 / 354 (0.28%)	2 / 358 (0.56%)	2 / 505 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	3 / 505 (0.59%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 354 (0.28%)	1 / 358 (0.28%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aphasia
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ataxia
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Carotid artery dissection
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Partial seizures
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Unresponsive to stimuli
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
Embolic stroke
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemolytic anaemia
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coombs positive haemolytic anaemia
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
Disseminated intravascular coagulation
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Eye disorders
Retinal detachment
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 354 (0.28%)	2 / 358 (0.56%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	1 / 354 (0.28%)	1 / 358 (0.28%)	2 / 505 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	1 / 354 (0.28%)	1 / 358 (0.28%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 354 (0.28%)	1 / 358 (0.28%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anal fistula
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Colitis
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 354 (0.00%)	2 / 358 (0.56%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Impaired gastric emptying
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Small intestinal obstruction
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal hernia
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anogenital dysplasia
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Odynophagia
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Chronic hepatic failure
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Hepatitis
subjects affected / exposed	0 / 354 (0.00%)	2 / 358 (0.56%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatitis cholestatic
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Drug-induced liver injury
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Skin ulcer
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dermatitis allergic
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	2 / 354 (0.56%)	1 / 358 (0.28%)	5 / 505 (0.99%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 354 (0.00%)	2 / 358 (0.56%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal tubular acidosis
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal vein thrombosis
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Calculus urinary
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Obstructive uropathy
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocrine disorders
Basedow's disease
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cushing's syndrome
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Osteoarthritis
subjects affected / exposed	1 / 354 (0.28%)	1 / 358 (0.28%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	2 / 505 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myopathy
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fasciitis
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myositis
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spondylolisthesis
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	12 / 354 (3.39%)	7 / 358 (1.96%)	15 / 505 (2.97%)
occurrences causally related to treatment / all	0 / 15	0 / 7	0 / 19
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 2
Cellulitis
subjects affected / exposed	5 / 354 (1.41%)	5 / 358 (1.40%)	8 / 505 (1.58%)
occurrences causally related to treatment / all	0 / 5	0 / 5	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	2 / 354 (0.56%)	4 / 358 (1.12%)	3 / 505 (0.59%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	2 / 354 (0.56%)	0 / 358 (0.00%)	3 / 505 (0.59%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	3 / 505 (0.59%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	3 / 505 (0.59%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	2 / 505 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	2 / 505 (0.40%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 2
Urosepsis
subjects affected / exposed	1 / 354 (0.28%)	1 / 358 (0.28%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	2 / 505 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abscess limb
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epididymitis
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Folliculitis
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Genital herpes
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Meningitis aseptic
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neurosyphilis
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oesophageal candidiasis
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ophthalmic herpes zoster
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Periorbital cellulitis
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin infection
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute hepatitis B
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arthritis infective
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Biliary sepsis
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Breast abscess
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Candida infection
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enterocolitis bacterial
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Extradural abscess
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bursitis infective
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatitis A
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Herpes simplex
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infectious colitis
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Muscle abscess
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Parotid abscess
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Perirectal abscess
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pharyngotonsillitis
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Spinal cord abscess
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Streptococcal sepsis
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	3 / 505 (0.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gout
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Type 1 diabetes mellitus
subjects affected / exposed	1 / 354 (0.28%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Electrolyte imbalance
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperosmolar hyperglycaemic state
subjects affected / exposed	0 / 354 (0.00%)	0 / 358 (0.00%)	1 / 505 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lactic acidosis
subjects affected / exposed	0 / 354 (0.00%)	1 / 358 (0.28%)	0 / 505 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Elvitegravir	Raltegravir	All Elvitegravir
Total subjects affected by non serious adverse events
subjects affected / exposed	279 / 354 (78.81%)	250 / 358 (69.83%)	294 / 505 (58.22%)
Vascular disorders
Hypertension
subjects affected / exposed	14 / 354 (3.95%)	26 / 358 (7.26%)	39 / 505 (7.72%)
occurrences all number	14	28	41
Nervous system disorders
Headache
subjects affected / exposed	49 / 354 (13.84%)	37 / 358 (10.34%)	63 / 505 (12.48%)
occurrences all number	58	49	87
General disorders and administration site conditions
Fatigue
subjects affected / exposed	39 / 354 (11.02%)	25 / 358 (6.98%)	55 / 505 (10.89%)
occurrences all number	47	31	68
Pyrexia
subjects affected / exposed	18 / 354 (5.08%)	19 / 358 (5.31%)	29 / 505 (5.74%)
occurrences all number	19	22	33
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	120 / 354 (33.90%)	77 / 358 (21.51%)	158 / 505 (31.29%)
occurrences all number	172	111	246
Nausea
subjects affected / exposed	45 / 354 (12.71%)	41 / 358 (11.45%)	61 / 505 (12.08%)
occurrences all number	53	53	74
Abdominal pain
subjects affected / exposed	24 / 354 (6.78%)	18 / 358 (5.03%)	40 / 505 (7.92%)
occurrences all number	28	21	45
Vomiting
subjects affected / exposed	22 / 354 (6.21%)	28 / 358 (7.82%)	30 / 505 (5.94%)
occurrences all number	24	30	35
Gastrooesophageal reflux disease
subjects affected / exposed	14 / 354 (3.95%)	9 / 358 (2.51%)	28 / 505 (5.54%)
occurrences all number	16	9	31
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	41 / 354 (11.58%)	47 / 358 (13.13%)	65 / 505 (12.87%)
occurrences all number	42	61	71
Oropharyngeal pain
subjects affected / exposed	18 / 354 (5.08%)	10 / 358 (2.79%)	24 / 505 (4.75%)
occurrences all number	18	10	27
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	28 / 354 (7.91%)	29 / 358 (8.10%)	40 / 505 (7.92%)
occurrences all number	31	38	46
Psychiatric disorders
Depression
subjects affected / exposed	33 / 354 (9.32%)	33 / 358 (9.22%)	49 / 505 (9.70%)
occurrences all number	37	34	56
Insomnia
subjects affected / exposed	26 / 354 (7.34%)	21 / 358 (5.87%)	42 / 505 (8.32%)
occurrences all number	28	23	47
Anxiety
subjects affected / exposed	16 / 354 (4.52%)	9 / 358 (2.51%)	33 / 505 (6.53%)
occurrences all number	18	9	37
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	42 / 354 (11.86%)	36 / 358 (10.06%)	68 / 505 (13.47%)
occurrences all number	47	47	78
Arthralgia
subjects affected / exposed	30 / 354 (8.47%)	28 / 358 (7.82%)	57 / 505 (11.29%)
occurrences all number	39	31	77
Pain in extremity
subjects affected / exposed	28 / 354 (7.91%)	25 / 358 (6.98%)	48 / 505 (9.50%)
occurrences all number	30	25	56
Muscle spasms
subjects affected / exposed	18 / 354 (5.08%)	13 / 358 (3.63%)	28 / 505 (5.54%)
occurrences all number	21	13	33
Myalgia
subjects affected / exposed	14 / 354 (3.95%)	11 / 358 (3.07%)	26 / 505 (5.15%)
occurrences all number	16	11	30
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	75 / 354 (21.19%)	59 / 358 (16.48%)	116 / 505 (22.97%)
occurrences all number	124	100	218
Nasopharyngitis
subjects affected / exposed	40 / 354 (11.30%)	32 / 358 (8.94%)	56 / 505 (11.09%)
occurrences all number	62	41	94
Bronchitis
subjects affected / exposed	34 / 354 (9.60%)	34 / 358 (9.50%)	57 / 505 (11.29%)
occurrences all number	41	45	68
Urinary tract infection
subjects affected / exposed	28 / 354 (7.91%)	35 / 358 (9.78%)	52 / 505 (10.30%)
occurrences all number	40	47	74
Sinusitis
subjects affected / exposed	28 / 354 (7.91%)	28 / 358 (7.82%)	48 / 505 (9.50%)
occurrences all number	34	34	59
Influenza
subjects affected / exposed	15 / 354 (4.24%)	10 / 358 (2.79%)	30 / 505 (5.94%)
occurrences all number	17	10	33
Folliculitis
subjects affected / exposed	18 / 354 (5.08%)	7 / 358 (1.96%)	25 / 505 (4.95%)
occurrences all number	22	7	32
Gastroenteritis
subjects affected / exposed	15 / 354 (4.24%)	7 / 358 (1.96%)	25 / 505 (4.95%)
occurrences all number	17	7	32
Oral herpes
subjects affected / exposed	15 / 354 (4.24%)	6 / 358 (1.68%)	26 / 505 (5.15%)
occurrences all number	27	6	43
Metabolism and nutrition disorders
Hypercholesterolaemia
subjects affected / exposed	12 / 354 (3.39%)	20 / 358 (5.59%)	26 / 505 (5.15%)
occurrences all number	15	27	44

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Were there any global substantial amendments to the protocol? Yes

30 Jul 2008

All references to “second single agent” were changed to “second agent;” the protocol was updated to include Asia as a region for site participation and to include Mexico as a participating country in North America; if the M184V/I RT mutation was present on the screening genotype report and a NRTI was used as the second agent, FTC or 3TC may have been prescribed as a third agent, or one of the fixed-dose combination therapies Combivir®, Truvada®, or Epzicom®/Kivexa® may have been prescribed as the combined second and third agents; the addition of adverse event (AE) monitoring recommendations when EVG/r and rifabutin were administered together; change in inclusion criteria, including hepatic transaminases criteria and the deletion of the prothrombin time criterion. The inclusion criterion of the upper limit of normal (ULN) for hepatic transaminases aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels was changed from ≤ 2.5 to ≤ 5; the malignant exclusion criterion was modified to include exclusion of a history of or ongoing malignancy (including untreated carcinoma in-situ) other than cutaneous Kaposi sarcoma (KS), basal cell carcinoma, or resected, noninvasive cutaneous squamous carcinoma; the definition of virologic rebound was changed.

18 Feb 2009

The protocol was updated to reflect the unification of Studies GS-US-183-0144 and GS-US-183-0145; the inclusion criterion that subjects remain on their stable antiretroviral regimen until the baseline visit was modified to allow subjects to discontinue their regimen after screening and remain off therapy at the discretion of the investigator; the screening window was extended to 56 days; additional secondary efficacy endpoints were added; the malignancy exclusion criterion was further modified to clarify that subjects with a history of or ongoing malignancy, other than cutaneous KS, basal cell carcinoma, or resected, noninvasive cutaneous squamous carcinoma, were not eligible and that subjects with biopsy-confirmed cutaneous KS were eligible; however, they must not have received any systemic therapy for KS within 30 days of baseline and were not anticipated to require systemic therapy during the study.

05 Aug 2009

The HIV-1 RNA reference assay changed from the Roche COBAS® AmpliPrep/COBAS TaqMan® HIV-1 Test, version 1.0 (referred to as the Taqman 1.0 assay) to the Roche COBAS AmpliPrep/COBAS Amplicor HIV-1 Monitor Ultrasensitive Test version 1.5 (referred to as the Amplicor Assay). This change, which resulted in the retesting of samples obtained after screening, was based on published data (Lima V, et al, JAIDS 2009;51(1):3-6) demonstrating that the Taqman 1.0 assay did not correlate well with the Amplicor assay at the critical threshold of HIV-1 RNA < 50 copies/mL.

06 Jul 2010

The study was extended to include an optional 144-week open-label extension; updated GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities, Urinalysis section

04 Feb 2011

At the request of the FDA, the blinded study was extended to 96 weeks of double-blind treatment prior to the open-label extension to collect longer-term blinded comparative safety and effectiveness data; incorporated the clarifications to Amendment 4 referenced in the Administrative Letter dated 26 October 2010; these included a change in Gilead’s medical monitor, assessments for the Early Study Drugs Discontinuation Visit, and definition of HIV-related diseases.

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.

10 participants from a single study site were excluded from Intent-to-Treat (ITT) Analysis Set due to critical and multiple protocol violations (elvitegravir arm: n = 3; raltegravir arm: n = 7).

http://www.ncbi.nlm.nih.gov/pubmed/22015077

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Clinical trials

Clinical Trial Results: A Multicenter, Randomized, Double-Blind, Double-Dummy, Phase 3 Study of the Safety and Efficacy of Ritonavir-Boosted Elvitegravir (EVG/r) Versus Raltegravir (RAL) Each Administered With a Background Regimen in HIV-1 Infected, Antiretroviral Treatment-Experienced Adults

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

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

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

Secondary: Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 50 Copies/mL at Week 96

Secondary: Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 50 Copies/mL at Week 96

Secondary: Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 400 Copies/mL at Week 48

Secondary: Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 400 Copies/mL at Week 48

Secondary: Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 400 Copies/mL at Week 96

Secondary: Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 400 Copies/mL at Week 96

Secondary: Virologic Response at Week 48 (HIV-1 RNA < 50 Copies/mL)

Secondary: Virologic Response at Week 48 (HIV-1 RNA < 50 Copies/mL)

Secondary: Virologic Response at Week 96 (HIV-1 RNA < 50 Copies/mL)

Secondary: Virologic Response at Week 96 (HIV-1 RNA < 50 Copies/mL)

Secondary: Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 50 Copies/mL) up to Week 48

Secondary: Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 50 Copies/mL) up to Week 48

Secondary: Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 50 Copies/mL) up to Week 96

Secondary: Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 50 Copies/mL) up to Week 96

Secondary: Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 400 Copies/mL) up to Week 48

Secondary: Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 400 Copies/mL) up to Week 48

Secondary: Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 400 Copies/mL) up to Week 96

Secondary: Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 400 Copies/mL) up to Week 96

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

Secondary: Percentage of Participants With 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 < 400 Copies/mL at Week 48

Secondary: Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Week 48

Secondary: Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Week 96

Secondary: Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Week 96

Secondary: Change From Baseline in HIV-1 RNA at Week 48

Secondary: Change From Baseline in HIV-1 RNA at Week 48

Secondary: Change From Baseline in HIV-1 RNA at Week 96

Secondary: Change From Baseline in HIV-1 RNA at Week 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

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
A Multicenter, Randomized, Double-Blind, Double-Dummy, Phase 3 Study of the Safety and Efficacy of Ritonavir-Boosted Elvitegravir (EVG/r) Versus Raltegravir (RAL) Each Administered With a Background Regimen in HIV-1 Infected, Antiretroviral Treatment-Experienced Adults