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Clinical Trial Results:
A phase III, double-blind, randomized, controlled study to evaluate the efficacy of GlaxoSmithKline Biologicals’ HPV-16/18 VLP/AS04 vaccine compared to hepatitis A vaccines as control in prevention of persistent HPV-16 or HPV-18 cervical infection and cervical neoplasia, administered intramuscularly according to a 0, 1, 6 month schedule in healthy female subjects aged 15 – 25 years or age.

Summary
EudraCT number	2004-001325-14
Trial protocol	ES
Global end of trial date	26 Nov 2009

Results information
Results version number	v3(current)
This version publication date	17 Mar 2023
First version publication date	25 Oct 2014
Other versions	v1 , v2
Version creation reason	Correction of full data set Results have been amended to account for consistency with other registries.

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

580299/008

ISRCTN number

US NCT number

NCT00122681

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline Biologicals

Sponsor organisation address

Rue de l'Institut 89, Rixensart, Belgium,

Public contact

Clinical Trials Call Center , GlaxoSmithKline Biologicals , 044 2089904466, GSKClinicalSupportHD@gsk.com

Scientific contact

Clinical Trials Call Center , GlaxoSmithKline Biologicals , 044 2089904466, GSKClinicalSupportHD@gsk.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

07 Sep 2010

Is this the analysis of the primary completion data?

Yes

Primary completion date

03 Nov 2006

Global end of trial reached?

Yes

Global end of trial date

26 Nov 2009

Was the trial ended prematurely?

Main objective of the trial

Primary objectives: - To demonstrate efficacy of the candidate vaccine compared with control in the prevention of histopathologically confirmed CIN2+ associated with HPV-16 or HPV-18 cervical infection detected in the preceding cytological specimen (by PCR) post dose 3 (after Month 6 to Month 48) in adolescent and young adult women who are negative for HPV DNA (by PCR) at Months 0 and 6 for the corresponding HPV type The principal analysis will be performed on subjects who are seronegative (by ELISA) prior to vaccination for the corresponding HPV type present in the sample.

Protection of trial subjects

As with all injectable vaccines, appropriate medical treatment was always readily available in case of anaphylactic reactions following the administration of the vaccine. For this reason, the vaccinee remained under medical supervision for 30 minutes after vaccination.

Background therapy

Evidence for comparator

Actual start date of recruitment

06 May 2004

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 548

Country: Number of subjects enrolled

Brazil: 1803

Country: Number of subjects enrolled

Mexico: 971

Country: Number of subjects enrolled

Philippines: 2467

Country: Number of subjects enrolled

Taiwan: 1485

Country: Number of subjects enrolled

Finland: 4808

Country: Number of subjects enrolled

Germany: 772

Country: Number of subjects enrolled

Belgium: 173

Country: Number of subjects enrolled

Canada: 506

Country: Number of subjects enrolled

Italy: 37

Country: Number of subjects enrolled

Spain: 387

Country: Number of subjects enrolled

Thailand: 1852

Country: Number of subjects enrolled

United Kingdom: 271

Country: Number of subjects enrolled

United States: 2564

Worldwide total number of subjects

18644

EEA total number of subjects

6448

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)

18644

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Of the 18729 subjects enrolled in the study, 64 subjects were not vaccinated. Within the 18665 subjects vaccinated, 21 subjects from 1 center were excluded from all analyses because of potential data discrepancies identified at this center. As a result, a total of 18644 subjects are reported as started in the participant flow.

Period 1 title

Overall Trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Havrix Group

Arm description

Subjects received 3 doses of GSK Biologicals' hepatitis A vaccine [HAV] (Havrix-based investigational formulation) at Months 0, 1 and 6.

Arm type

Experimental

Investigational medicinal product name

Cervarix

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

Intramuscular injection, 3 doses.

Cervarix Group

Arm description

Subjects received 3 doses of Cervarix (GSK Biologicals' human papillomavirus [HPV] vaccine) at Months 0, 1 and 6.

Arm type

Active comparator

Investigational medicinal product name

Havrix-based investigational formulation

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

Intramuscular injection, 3 doses.

Number of subjects in period 1	Havrix Group	Cervarix Group
Started	9325	9319
Completed	7811	7798
Not completed	1514	1521
Consent withdrawn by subject	257	251
Personal reasons	150	147
Adverse event, non-fatal	20	16
Lost to follow-up	1080	1097
Protocol deviation	7	10

Baseline characteristics

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Reporting group title

Havrix Group

Reporting group description

Subjects received 3 doses of GSK Biologicals' hepatitis A vaccine [HAV] (Havrix-based investigational formulation) at Months 0, 1 and 6.

Reporting group title

Cervarix Group

Reporting group description

Subjects received 3 doses of Cervarix (GSK Biologicals' human papillomavirus [HPV] vaccine) at Months 0, 1 and 6.

Reporting group values	Havrix Group	Cervarix Group	Total
Number of subjects	9325	9319	18644
Age categorical
Units: Subjects
In utero			0
Preterm newborn infants (gestational age < 37 wks)			0
Newborns (0-27 days)			0
Infants and toddlers (28 days-23 months)			0
Children (2-11 years)			0
Adolescents (12-17 years)			0
Adults (18-64 years)			0
From 65-84 years			0
85 years and over			0
Age continuous
Units: years
median (standard deviation)	20 ( 3.12 )	20 ( 3.1 )	-
Gender categorical
Units: Subjects
Female	9325	9319	18644
Male	0	0	0

End points

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Reporting group title

Havrix Group

Reporting group description

Subjects received 3 doses of GSK Biologicals' hepatitis A vaccine [HAV] (Havrix-based investigational formulation) at Months 0, 1 and 6.

Reporting group title

Cervarix Group

Reporting group description

Subjects received 3 doses of Cervarix (GSK Biologicals' human papillomavirus [HPV] vaccine) at Months 0, 1 and 6.

Primary: Number of subjects with histopathologically-confirmed cervical intraepithelial neoplasia (CIN)2+ associated with HPV-16 and/or -18 cervical infection in subjects HPV DNA negative and seronegative at baseline or overall (any serostatus at baseline)

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End point title

Number of subjects with histopathologically-confirmed cervical intraepithelial neoplasia (CIN)2+ associated with HPV-16 and/or -18 cervical infection in subjects HPV DNA negative and seronegative at baseline or overall (any serostatus at baseline)

End point description

CIN2+ was defined as CIN grades 2 and 3, endocervical adenocarcinoma in situ (AIS) and invasive cervical cancer. Detection was done in: 1. DNA- and sero-: subjects HPV deoxyribonucleic acid (DNA) negative (DNA-) at Month 0 and Month 6 for the corresponding HPV-type and seronegative (sero-) for HPV-16 and/or HPV-18 by Enzyme-linked Immunosorbent Assay (ELISA) at baseline (Month 0). 2. Overall: subjects DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline. Analysis was performed on the According-to-Protocol (ATP) cohort for efficacy, which included all evaluable subjects who had received 3 doses of study vaccine, who had a normal or low-grade cytology (i.e. negative or Atypical Squamous Cells of Undetermined Significance (ASC-US) or Low-grade Squamous Intraepithelial Lesion (LSIL)) at Month 0.

End point type

Primary

End point timeframe

Up to the moment when 36 cases of CIN2+ lesions associated with HPV-16 or HPV-18 infection had been detected, including at least 15 cases of CIN2+ associated with HPV-18 infection. Mean follow-up was 34.9 months post-dose 3

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	7767	7814
Units: Subjests
HPV-16/18, DNA- & sero- subjects (n= 7312, 7344)	56	4
HPV-16, DNA- & sero- subjects (n= 6165, 6303)	46	2
HPV-18, DNA- & sero- subjects (n= 6746, 6794)	15	2
HPV-16/18, overall (n= 7767, 7814)	65	6
HPV-16, overall (n= 7276, 7372)	54	4
HPV-18, overall (n= 7583, 7645)	16	2

Vaccine efficacy against CIN2+ analysis 1

Statistical analysis description

Vaccine efficacy against CIN2+ associated with HPV-16 or HPV-18 (by PCR) in HPV DNA negative and seronegative subjects at baseline, using conditional exact method. The VE was defined as follows: VE = 1-Rate Ratio (RR), where RR = incidence rate in HPV Group (vaccine)/ incidence rate in HAV Group (control); Incidence rate = n/T(per 100); n= number of subjects reporting at least one event in each group and T(years) = sum of follow-up period (censored at the first occurrence of an event) expressed.

Comparison groups

Havrix Group v Cervarix Group

Number of subjects included in analysis

15581

Analysis specification

Pre-specified

Analysis type

other ^[1]

Method

Parameter type

1-Rate Ratio

Point estimate

92.9

Confidence interval

level

95%

sides

2-sided

lower limit

79.9

upper limit

98.3

Notes
[1] - Efficacy

Vaccine efficacy against CIN2+ analysis 2

Statistical analysis description

Vaccine efficacy against CIN2+ associated with HPV-16 (by PCR) in HPV DNA negative and seronegative subjects at baseline, using conditional exact method. The VE was defined as follows: VE = 1-Rate Ratio (RR), where RR = incidence rate in HPV Group (vaccine)/ incidence rate in HAV Group (control); Incidence rate = n/T(per 100); n= number of subjects reporting at least one event in each group and T(years) = sum of follow-up period (censored at the first occurrence of an event) expressed.

Comparison groups

Havrix Group v Cervarix Group

Number of subjects included in analysis

15581

Analysis specification

Pre-specified

Analysis type

other ^[2]

Method

Parameter type

1-Rate Ratio

Point estimate

95.7

Confidence interval

level

95%

sides

2-sided

lower limit

82.9

upper limit

99.6

Notes
[2] - Efficacy

Vaccine efficacy against CIN2+ analysis 3

Statistical analysis description

Vaccine efficacy against CIN2+ associated with HPV-18 (by PCR) in HPV DNA negative and seronegative subjects at baseline, using conditional exact method. The VE was defined as follows: VE = 1-Rate Ratio (RR), where RR = incidence rate in HPV Group (vaccine)/ incidence rate in HAV Group (control); Incidence rate = n/T(per 100); n= number of subjects reporting at least one event in each group and T(years) = sum of follow-up period (censored at the first occurrence of an event) expressed.

Comparison groups

Cervarix Group v Havrix Group

Number of subjects included in analysis

15581

Analysis specification

Pre-specified

Analysis type

other ^[3]

Method

Parameter type

1-Rate Ratio

Point estimate

86.7

Confidence interval

level

95%

sides

2-sided

lower limit

39.7

upper limit

98.7

Notes
[3] - Efficacy

Vaccine efficacy against CIN2+ analysis 4

Statistical analysis description

Vaccine efficacy against CIN2+ for HPV-16 or HPV-18 (by PCR) in HPV DNA negative subjects at baseline, regardless of initial serostatus, using conditional exact method. The VE was defined as follows: VE = 1-Rate Ratio (RR), where RR = incidence rate in HPV Group (vaccine)/ incidence rate in HAV Group (control); Incidence rate = n/T(per 100); n= number of subjects reporting at least one event in each group and T(years) = sum of follow-up period (censored at the first occurrence of an event).

Comparison groups

Havrix Group v Cervarix Group

Number of subjects included in analysis

15581

Analysis specification

Pre-specified

Analysis type

other ^[4]

Method

Parameter type

1-Rate Ratio

Point estimate

90.8

Confidence interval

level

95%

sides

2-sided

lower limit

78.1

upper limit

96.9

Notes
[4] - Efficacy

Vaccine efficacy against CIN2+ analysis 5

Statistical analysis description

Vaccine efficacy against CIN2+ for HPV-16 (by PCR) in HPV DNA negative subjects at baseline, regardless of initial serostatus, using conditional exact method. The VE was defined as follows: VE = 1-Rate Ratio (RR), where RR = incidence rate in HPV Group (vaccine)/ incidence rate in HAV Group (control); Incidence rate = n/T(per 100); n= number of subjects reporting at least one event in each group and T(years) = sum of follow-up period (censored at the first occurrence of an event).

Comparison groups

Havrix Group v Cervarix Group

Number of subjects included in analysis

15581

Analysis specification

Pre-specified

Analysis type

other ^[5]

Method

Parameter type

1-Rate Ratio

Point estimate

92.7

Confidence interval

level

95%

sides

2-sided

lower limit

79.3

upper limit

98.2

Notes
[5] - Efficacy

Vaccine efficacy against CIN2+ analysis 6

Statistical analysis description

Vaccine efficacy against CIN2+ for HPV-18 (by PCR) in HPV DNA negative subjects at baseline, regardless of initial serostatus, using conditional exact method. The VE was defined as follows: VE = 1-Rate Ratio (RR), where RR = incidence rate in HPV Group (vaccine)/ incidence rate in HAV Group (control); Incidence rate = n/T(per 100); n= number of subjects reporting at least one event in each group and T(years) = sum of follow-up period (censored at the first occurrence of an event).

Comparison groups

Havrix Group v Cervarix Group

Number of subjects included in analysis

15581

Analysis specification

Pre-specified

Analysis type

other ^[6]

Method

Parameter type

1-Rate Ratio

Point estimate

87.6

Confidence interval

level

95%

sides

2-sided

lower limit

44.1

upper limit

98.8

Notes
[6] - Efficacy

Primary: Number of subjects with histopathologically-confirmed cervical intraepithelial neoplasia (CIN)2+ associated with HPV-16 and/or -18 cervical infection in subjects HPV DNA negative and seronegative at baseline or overall (any serostatus at baseline)

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End point title

End point description

CIN2+ was defined as CIN grades 2 and 3, endocervical adenocarcinoma in situ (AIS) and invasive cervical cancer. Detection was done in subjects: 1. DNA- and sero-: HPV deoxyribonucleic acid (DNA) negative (DNA-) at Month 0 and Month 6 for the corresponding HPV-type and seronegative (sero-) for HPV-16 and/or HPV-18 by Enzyme-linked Immunosorbent Assay (ELISA) at baseline (Month 0) 2. Overall: subjects HPV DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline. Analysis was performed on the According-to-Protocol (ATP) cohort for efficacy, which included all evaluable subjects who had received 3 doses of study vaccine, who had a normal or low-grade cytology (i.e. negative or Atypical Squamous Cells of Undetermined Significance (ASC-US) or Low-grade Squamous Intraepithelial Lesion (LSIL)) at Month 0.

End point type

Primary

End point timeframe

at Month 48

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	7767	7806
Units: Subjects
HPV-16/18, DNA- & sero- subjects (n= 7305, 7338)	97	5
HPV-16, DNA- & sero- subjects (n= 6160, 6296)	81	2
HPV-18, DNA- & sero- subjects (n= 6739, 6789)	23	3
HPV-16/18, overall (n= 7760, 7806)	108	7
HPV-16, overall (n= 7267, 7364)	91	4
HPV-18, overall (n= 7577, 7638)	24	3

Vaccine efficacy against CIN2+ analysis 1

Statistical analysis description

Comparison groups

Cervarix Group v Havrix Group

Number of subjects included in analysis

15573

Analysis specification

Pre-specified

Analysis type

other ^[7]

Method

Parameter type

1-Rate Ratio

Point estimate

94.9

Confidence interval

level

95%

sides

2-sided

lower limit

87.7

upper limit

98.4

Notes
[7] - Efficacy

Vaccine efficacy against CIN2+ analysis 2

Statistical analysis description

Comparison groups

Havrix Group v Cervarix Group

Number of subjects included in analysis

15573

Analysis specification

Pre-specified

Analysis type

other ^[8]

Method

Parameter type

1-Rate Ratio

Point estimate

97.6

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

99.7

Notes
[8] - Efficacy

Vaccine efficacy against CIN2+ analysis 3

Statistical analysis description

Comparison groups

Havrix Group v Cervarix Group

Number of subjects included in analysis

15573

Analysis specification

Pre-specified

Analysis type

other ^[9]

Method

Parameter type

1-Rate Ratio

Point estimate

87.1

Confidence interval

level

95%

sides

2-sided

lower limit

57.2

upper limit

97.5

Notes
[9] - Efficacy

Vaccine efficacy against CIN2+ analysis 4

Statistical analysis description

Comparison groups

Havrix Group v Cervarix Group

Number of subjects included in analysis

15573

Analysis specification

Pre-specified

Analysis type

other ^[10]

Method

Parameter type

1-Rate Ratio

Point estimate

93.6

Confidence interval

level

95%

sides

2-sided

lower limit

86.3

upper limit

97.5

Notes
[10] - Efficacy

Vaccine efficacy against CIN2+ analysis 5

Statistical analysis description

Comparison groups

Cervarix Group v Havrix Group

Number of subjects included in analysis

15573

Analysis specification

Pre-specified

Analysis type

other ^[11]

Method

Parameter type

1-Rate Ratio

Point estimate

95.7

Confidence interval

level

95%

sides

2-sided

lower limit

88.5

upper limit

98.9

Notes
[11] - Efficacy

Vaccine efficacy against CIN2+ analysis 6

Statistical analysis description

Comparison groups

Cervarix Group v Havrix Group

Number of subjects included in analysis

15573

Analysis specification

Pre-specified

Analysis type

other ^[12]

Method

Parameter type

1-Rate Ratio

Point estimate

87.6

Confidence interval

level

95%

sides

2-sided

lower limit

59.2

upper limit

97.6

Notes
[12] - Efficacy

Secondary: Number of subjects reporting solicited local and general symptoms

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End point title

Number of subjects reporting solicited local and general symptoms

End point description

Solicited local symptoms assessed include pain, redness and swelling. Solicited general symptoms assessed include arthralgia, fatigue, fever (measured in degree celsius (°C) by axillary route), gastrointestinal symptoms, headache, myalgia, rash and urticaria. Data are presented across the 3 doses. Analysis was performed on a safety subset of the Total vaccinated cohort, which included vaccinated subjects from certain sites. Data are presented for the total subset (total), then stratified subject HPV-16/18 DNA & serostatus at baseline: DNA positive (DNA+) or negative (DNA-), ELISA seropositive (sero+) or seronegative (sero-).

End point type

Secondary

End point timeframe

Within 7 days after any vaccination

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	3081	3078
Units: Subjects
Pain, total (n= 3080, 3078)	2403	2787
Pain, sero+ or DNA+ (n= 827, 830)	622	743
Pain, sero- & DNA- (n=2219,2211)	1758	2013
Pain, DNA+ (n= 212, 236)	166	219
Redness, total (n= 3080, 3078)	851	1349
Redness, sero+ or DNA+ (n= 827, 830)	211	335
Redness, sero- & DNA- (n=2219,2211)	630	1005
Redness, DNA+ (n= 212, 236)	56	96
Swelling, total (n= 3080, 3078)	609	1293
Swelling, sero+ or DNA+ (n= 827, 830)	145	325
Swelling, sero- & DNA- (n=2219,2211)	454	959
Swelling, DNA+ (n= 212, 236)	27	93
Arthralgia, total (n=3081, 3078)	551	633
Arthralgia, sero+ or DNA+ (n= 828, 830)	160	149
Arthralgia, sero- & DNA- (n=2219,2211)	384	480
Arthralgia, DNA+ (n= 212, 236)	39	58
Fatigue, total (n=3081, 3078)	1652	1771
Fatigue, sero+ or DNA+ (n= 828, 830)	415	443
Fatigue, sero- & DNA- (n=2219,2211)	1215	1311
Fatigue, DNA+ (n= 212, 236)	116	123
Fever ≥ 37.5°C, total (n=3081, 3078)	342	385
Fever ≥ 37.5°C, sero+ or DNA+ (n= 828, 830)	103	126
Fever ≥ 37.5°C, sero- & DNA- (n=2219,2211)	236	254
Fever ≥ 37.5°C, DNA+ (n= 212, 236)	23	37
Gastro-intestinal symptoms, total (n=3081,3078)	847	856
Gastro-intestinal,sero+ or DNA+ (n= 828, 830)	241	248
Gastro-intestinal,sero- & DNA- (n=2219,221)	595	601
Gastro-intestinal symptoms, DNA+ (n= 212, 236)	64	72
Headache, total (n= 3081, 3078)	1583	1668
Headache, sero+ or DNA+ (n= 828, 830)	423	425
Headache, sero- & DNA- (n=2219,2211)	1141	1223
Headache, DNA+ (n= 212, 236)	112	125
Myalgia, total (n= 3081, 3078)	1381	1607
Myalgia, sero+ or DNA+ (n= 828, 830)	347	392
Myalgia, sero- & DNA- (n=2219, 2211)	1019	1200
Myalgia, DNA+ (n= 212, 236)	85	119
Rash, total (n= 3081, 3078)	258	314
Rash, sero+ or DNA+ (n= 828, 830)	72	91
Rash, sero- & DNA- (n=2219, 2211)	182	221
Rash, DNA+ (n= 212, 236)	19	29
Urticaria, total (n= 3081, 3078)	244	300
Urticaria, sero+ or DNA+ (n= 828, 830)	73	90
Urticaria, sero- & DNA- (n=2219, 2211)	169	206
Urticaria, DNA+ (n= 212, 236)	14	25

No statistical analyses for this end point

Secondary: Number of subjects reporting unsolicited adverse events

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End point title

Number of subjects reporting unsolicited adverse events

End point description

Unsolicited adverse event (AE) covers any AE reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Analysis was performed on the Safety Subset of the Total Vaccinated Cohort and stratified according to initial (Month 0) HPV-16/18 DNA Status and According to HPV-16 or -18 Serostatus.

End point type

Secondary

End point timeframe

Within 30 days after any vaccination

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	3187	3184
Units: Subjects
total (n=3187, 3184)	1466	1448
sero+ DNA+ (n=858, 854)	400	386
sero- DNA- (n=2289, 2290)	1048	1049
DNA+ (n=222, 243)	111	122

No statistical analyses for this end point

Secondary: Number of subjects reporting serious adverse events (SAEs)

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End point title

Number of subjects reporting serious adverse events (SAEs)

End point description

SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject. Analysis was performed on the Total Vaccinated Cohort. The data are presented stratified by initial (Month 0) HPV-16/18 DNA status and according to HPV-16 or 18 serostatus (by ELISA).

End point type

Secondary

End point timeframe

Throughout the entire study period (Month 0 to Month 48)

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	9325	9319
Units: Subjects
Total (n=9325, 9319)	829	835
Sero + and DNA + (n=2419, 2409)	239	251
Sero- and DNA- (n=6789, 6804)	587	576
DNA+ (n=649, 690)	69	82

No statistical analyses for this end point

Secondary: Number of subjects reporting new onset of chronic disease (NOCDs)

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End point title

Number of subjects reporting new onset of chronic disease (NOCDs)

End point description

NOCDs include autoimmune disorders, asthma, type I diabetes, allergies. Analysis was performed on the Total Vaccinated Cohort and stratified according to initial (Month 0) HPV-16/18 DNA Status and According to HPV-16 or -18 Serostatus.

End point type

Secondary

End point timeframe

Throughout the entire study (Month 0 to 48)

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	9325	9319
Units: Subjects
Total (n= 9325, 9319)	307	285
sero+ and DNA+ (n= 2419, 2409)	79	79
sero- and DNA- (n= 6789, 6804)	225	201
DNA+ (n= 649, 690)	21	24

No statistical analyses for this end point

Secondary: Number of subjects reporting medically significant conditions

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End point title

Number of subjects reporting medically significant conditions

End point description

Medically significant conditions include adverse events (AEs) prompting emergency room or physician visits that are not related to common diseases or routine visits for physical examination or vaccination, or serious adverse events (SAEs) that are not related to common diseases. Common diseases include upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervico-vaginal yeast infections, menstrual cycle abnormalities and injury. Analysis was performed on the Total Vaccinated Cohort and stratified according to initial (Month 0) HPV-16/18 DNA Status and According to HPV-16 or -18 Serostatus.

End point type

Secondary

End point timeframe

Throughout entire study period (Month 0 to Month 48)

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	9325	9319
Units: Subjects
Total (n=9325, 9319)	3378	3298
sero+ DNA+ (n= 2419, 2409)	957	958
sero- DNA- (n= 6789, 6804)	2378	2303
DNA+ (n= 649, 690)	285	296

No statistical analyses for this end point

Secondary: Number of subjects with outcome of pregnancies, overall and stratified by initial (Month 0) HPV-16/18 DNA status and according to HPV-16 or -18 serostatus

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End point title

Number of subjects with outcome of pregnancies, overall and stratified by initial (Month 0) HPV-16/18 DNA status and according to HPV-16 or -18 serostatus

End point description

Pregnancy outcomes are normal infant, premature infant, abnormal infant, elective termination, therapeutic abortion, ectopic pregnancy, spontaneous abortion, still birth, lost to follow-up, no pregnancy/molar pregnancy, pregnancy ongoing. Analysis was performed on the Total Vaccinated Cohort and stratified according to initial (Month 0) HPV-16/18 DNA Status and According to HPV-16 or -18 Serostatus.

End point type

Secondary

End point timeframe

Throughout the entire study period (Month 0 to Month 48)

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	2257	2257
Units: Subjects
total (n=2257, 2257), normal infant	1671	1642
total, premature birth	66	77
total, abnormal infant	22	26
total, elective termination	228	212
total, therapeutic abortion	1	2
total, ectopic pregnancy	9	20
total, spontaneous abortion	195	205
total, still birth	11	16
total, lost to follow-up	42	41
total, no pregnancy, molar pregnancy	1	4
total, pregnancy ongoing	11	12
sero- DNA- (n=1553, 1540), normal infant	1164	1159
sero- DNA-, premature birth	42	37
sero- DNA-, abnormal infant	15	18
sero- DNA-, elective termination	162	138
sero- DNA-, therapeutic abortion	0	1
sero- DNA-, ectopic pregnancy	7	13
sero- DNA-, spontaneous abortion	125	134
sero- DNA -, still birth	8	10
sero- DNA-, lost to follow-up	21	21
sero- DNA-, no pregnancy, molar pregnancy	1	3
sero- DNA-, pregnancy ongoing	8	6
sero+ DNA+ (n=676, 685), normal infant	486	464
sero+ DNA+, premature birth	24	39
sero+ DNA+, abnormal infant	6	8
sero+ DNA+, elective termination	62	67
sero+ DNA+, therapeutic abortion	1	1
sero+ DNA+, ectopic pregnancy	2	7
sero+ DNA+, spontaneous abortion	68	67
sero+ DNA+, still birth	3	6
sero+ DNA+, lost to follow-up	21	19
sero+ DNA+, no pregnancy, molar pregnancy	0	1
sero+ DNA+, pregnancy ongoing	3	6
DNA+(n=162, 199), normal infant	110	131
DNA+, premature infant	5	19
DNA+, abnormal infant	0	0
DNA+, elective termination	21	18
DNA+, therapeutic abortion	0	1
DNA+, ectopic pregnancy	0	2
DNA+, spontaneous abortion	18	21
DNA+, still birth	0	1
DNA+, lost to follow-up	7	5
DNA+, no pregnancy, molar pregnancy	0	0
DNA+, pregnancy ongoing	1	1

No statistical analyses for this end point

Secondary: Number of subjects with persistent infection (6-month definition) with HPV-16 or HPV-18

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End point title

Number of subjects with persistent infection (6-month definition) with HPV-16 or HPV-18

End point description

Persistent cervical HPV infection (6-month definition) was defined as the detection of the same HPV type by polymerase chain reaction (PCR) in cervical samples at 2 consecutive evaluations over approximately a 6-month interval. Detection was done in subjects: 1. DNA- and sero-: subjects HPV DNA- at Month 0 and Month 6 for the corresponding HPV-type and sero- for HPV-16 and/or HPV-18 by Enzyme-linked Immunosorbent Assay (ELISA) at baseline (Month 0) 2. Overall: subjects HPV DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline. Analysis was performed on the According-to-Protocol (ATP) cohort for efficacy, which included all evaluable subjects, who had received 3 doses of study vaccine and who had a normal or low-grade cytology (i.e. negative or ASC-US or LSIL) at Month 0. All subjects had at least 5 months of follow-up after Month 12.

End point type

Secondary

End point timeframe

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	7556	7619
Units: Subjects
HPV-16/18, DNA- & sero- (n= 7122, 7177)	488	29
HPV-16, DNA- & sero- (n= 6018, 6163)	337	22
HPV-18, DNA- & sero- (n= 6567, 6642)	184	7
HPV-16/18, overall (n= 7556, 7619)	540	37
HPV-16, overall (n= 7085, 7196)	380	29
HPV-18, overall (n= 7377, 7457)	195	8

No statistical analyses for this end point

Secondary: Number of subjects with persistent infection (6-month definition) with HPV-16 or HPV-18

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End point title

Number of subjects with persistent infection (6-month definition) with HPV-16 or HPV-18

End point description

Persistent cervical HPV infection (6-month definition) was defined as the detection of the same HPV type by polymerase chain reaction (PCR) in cervical samples at 2 consecutive evaluations over approximately a 6-month interval. Detection was done in subjects: 1. DNA- and sero-: subjects HPV DNA- at Month 0 and Month 6 for the corresponding HPV-type and sero- for HPV-16 and/or HPV-18 by Enzyme-linked Immunosorbent Assay (ELISA) at baseline (Month 0) 2. Overall: subjects HPV DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline. Analysis was performed on the According-to-Protocol (ATP) cohort for efficacy, which included all evaluable subjects, who had received 3 doses of study vaccine, who had a normal or low-grade cytology (i.e. negative or ASC-US or LSIL) at Month 0. All subjects had at least 5 months of follow-up after Month 12.

End point type

Secondary

End point timeframe

at Month 48

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	7572	7626
Units: Subjects
HPV-16/18, DNA- & sero- (n= 7137, 7182)	588	35
HPV-16, DNA- & sero- (n= 6029, 6165)	418	24
HPV-18, DNA- & sero- (n= 6581, 6649)	212	11
HPV-16/18, overall (n= 7572, 7626)	654	45
HPV-16, overall (n= 7099, 7202)	437	31
HPV-18, overall (n= 7394, 7465)	227	14

No statistical analyses for this end point

Secondary: Number of subjects with persistent infection (6-month definition) with oncogenic HPV types

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End point title

Number of subjects with persistent infection (6-month definition) with oncogenic HPV types

End point description

Oncogenic types included HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68. Detection was done in subjects who were HPV DNA negative at baseline regardless of initial serostatus. HRW-HPV= All high-risk (oncogenic) HPV types excluding HPV-16 and HPV-18 HR-HPV= High-risk (oncogenic) HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68. Analysis was performed on the According-to-Protocol (ATP) cohort for efficacy, which included all evaluable subjects, who had received 3 doses of study vaccine and who had a normal or low-grade cytology (i.e. negative or ASC-US or LSIL) at Month 0. All subjects had at least 5 months of follow-up after Month 12.

End point type

Secondary

End point timeframe

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	7553	7587
Units: Subjects
HPV-16 (n= 7085, 7196)	380	29
HPV-18 (n= 7377, 7457)	195	8
HPV-31 (n= 7398, 7394)	199	45
HPV-33 (n= 7496, 7527)	100	55
HPV-35 (n= 7553, 7572)	43	55
HPV- 39 (n= 7411, 7423)	149	147
HPV-45 (n= 7540, 7587)	79	19
HPV-51 (n= 7152, 7188)	354	304
HPV-52 (n= 7221, 7280)	315	293
HPV-56 (n= 7435, 7460)	174	182
HPV-58 (n= 7494, 7512)	101	111
HPV-59 (n= 7514, 7528)	59	56
HPV-66 (n= 7358, 7405)	178	168
HPV-68 (n= 7409, 7441)	134	138
HRW-HPV (n= 7640, 7665)	1351	1207
HR-HPV (n= 7640, 7665)	1607	1233

No statistical analyses for this end point

Secondary: Number of Subjects With Persistent Infection (6-month Definition) With Oncogenic HPV Types

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End point title

Number of Subjects With Persistent Infection (6-month Definition) With Oncogenic HPV Types

End point description

Oncogenic types included HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68. Detection was done in subjects who were HPV DNA negative at baseline regardless of initial serostatus. HRW-HPV = All high-risk (oncogenic) HPV types excluding HPV-16 and HPV-18 HR-HPV = High-risk (oncogenic) HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68. Analysis was performed on the According-to-Protocol (ATP) cohort for efficacy, which included all evaluable subjects, who had received 3 doses of study vaccine and who had a normal or low-grade cytology (i.e. negative or ASC-US or LSIL) at Month 0. All subjects had at least 5 months of follow-up after Month 12.

End point type

Secondary

End point timeframe

at Month 48

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	7569	7594
Units: Subjects
HPV-16 (n= 7099, 7202)	473	31
HPV-18 (n= 7394, 7465)	227	14
HPV-31 (n= 7414, 7400)	247	58
HPV-33 (n= 7513, 7534)	117	65
HPV-35 (n= 7569, 7579)	56	67
HPV-39 (n= 7428, 7429)	184	175
HPV-45 (n= 7556, 7594)	90	24
HPV-51 (n= 7165, 7190)	416	349
HPV-52 (n= 7237, 7289)	374	346
HPV-56 (n= 7451, 7467)	215	226
HPV-58 (n= 7511, 7518)	122	144
HPV-59 (n= 7530, 7536)	68	73
HPV-66 (n= 7375, 7412)	215	211
HPV-68 (n= 7424, 7450)	169	165
HRW-HPV (n= 7656, 7672)	1556	1399
HR-HPV (n= 7656, 7672)	1837	1424

No statistical analyses for this end point

Secondary: Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 or HPV-18 Detected Within the Lesional Component of the Cervical Tissue Specimen

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End point title

Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 or HPV-18 Detected Within the Lesional Component of the Cervical Tissue Specimen

End point description

CIN1+ was defined as histopathologically-confirmed lesions including cervical intraepithelial neoplasia of grade 1 (CIN1), grade 2 (CIN2), grade 3 (CIN3), AIS and invasive cervical cancer. Detection was done in subjects: 1. DNA- and sero-: subjects HPV DNA- at Month 0 and Month 6 for the corresponding HPV-type and sero- for HPV-16 and/or HPV-18 by Enzyme-linked Immunosorbent Assay (ELISA) at baseline (Month 0) 2. Overall: subjects HPV DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline. Analysis was performed on the According-to-Protocol (ATP) cohort for efficacy, which included all evaluable subjects who had a normal or low-grade cytology (i.e. negative or ASC-US or LSIL) at Month 0.

End point type

Secondary

End point timeframe

at Month 48

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	7760	7806
Units: Subjects
HPV-16/18, DNA- & sero- (n= 7305, 7338)	165	12
HPV-16, DNA- & sero- (n= 6160, 6296)	124	6
HPV-18, DNA- & sero- (n= 6739, 6789)	52	6
HPV-16/18, overall (n= 7760, 7806)	182	16
HPV-16, overall (n= 7267, 7364)	140	10
HPV-18, overall (n= 7577, 7638)	53	6

No statistical analyses for this end point

Secondary: Number of subjects with histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ associated with HPV-16 or HPV-18 detected within the lesional component of the cervical tissue specimen

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End point title

Number of subjects with histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ associated with HPV-16 or HPV-18 detected within the lesional component of the cervical tissue specimen

End point description

CIN1+ was defined as histopathologically-confirmed lesions including cervical intraepithelial neoplasia of grade 1 (CIN1), grade 2 (CIN2), grade 3 (CIN3), AIS and invasive cervical cancer. Detection was done in subjects: 1. DNA- and sero-: subjects HPV DNA- at Month 0 and Month 6 for the corresponding HPV-type and sero- for HPV-16 and/or HPV-18 by Enzyme-linked Immunosorbent Assay (ELISA) at baseline (Month 0) 2. Overall: subjects HPV DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline. Analysis was performed on the According-to-Protocol (ATP) cohort for efficacy, which included all evaluable subjects, who had received 3 doses of study vaccine and who had a normal or low-grade cytology (i.e. negative or ASC-US or LSIL) at Month 0.

End point type

Secondary

End point timeframe

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	7767	7814
Units: Subjects
HPV-16/18, DNA- & sero- (n= 7312, 7344)	96	8
HPV-16, DNA- & sero- (n= 6165, 6303)	70	5
HPV-18, DNA- & sero- (n= 6746, 6794)	31	3
HPV-16/18, overall (n= 7767, 7814)	111	12
HPV-16, overall (n= 7276, 7372)	84	9
HPV-18, overall (n= 7583, 7645)	32	3

No statistical analyses for this end point

Secondary: Number of subjects reporting persistent infection (12-month definition) with HPV-16 or HPV-18

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End point title

Number of subjects reporting persistent infection (12-month definition) with HPV-16 or HPV-18

End point description

Persistent cervical HPV infection (12-month definition) was defined as the detection of the same HPV type (by PCR) over a 12-month interval (evaluations were planned at approximately 6-month intervals). Detection was done in subjects: 1. DNA- and sero-: subjects HPV DNA- at Month 0 and Month 6 for the corresponding HPV-type and sero- for HPV-16 and/or HPV-18 by Enzyme-linked Immunosorbent Assay (ELISA) at baseline (Month 0) 2. Overall: subjects HPV DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline. Analysis was performed on the According-to-Protocol (ATP) cohort for efficacy, which included all evaluable subjects, who had received 3 doses of study vaccine and who had a normal or low-grade cytology (i.e. negative or ASC-US or LSIL) at Month 0. All subjects had at least 10 months of follow-up after Month 12.

End point type

Secondary

End point timeframe

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	7404	7466
Units: Subjects
HPV-16/18, DNA- & sero- (n= 6984, 7035)	227	20
HPV-16, DNA- & sero- (n= 5903, 6052)	171	17
HPV-18, DNA- & sero- (n= 6440, 6508)	66	3
HPV-16/18, overall (n= 7404, 7466)	252	21
HPV-16, overall (n= 6941, 7057)	192	18
HPV-18, overall (n= 7231, 7307)	70	3

No statistical analyses for this end point

Secondary: Number of Subjects Reporting Persistent Infection (12-month Definition) With HPV-16 or HPV-18

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End point title

Number of Subjects Reporting Persistent Infection (12-month Definition) With HPV-16 or HPV-18

End point description

End point type

Secondary

End point timeframe

at Month 48

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	7461	7517
Units: Subjects
HPV-16/18, DNA- & sero- (n= 7038, 7082)	354	26
HPV-16, DNA- & sero- (n= 5949, 6089)	269	19
HPV-18, DNA- & sero- (n= 6490, 6552)	98	7
HPV-16/18, overall (n= 7461, 7517)	388	28
HPV-16, overall (n= 6996, 7103)	300	20
HPV-18, overall (n= 7288, 7356)	103	8

No statistical analyses for this end point

Secondary: Number of subjects with histopathologically confirmed Cervical Intraepithelial Neoplasia (CIN)1+ associated with oncogenic HPV types detected within the lesional component of the cervical tissue specimen

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End point title

Number of subjects with histopathologically confirmed Cervical Intraepithelial Neoplasia (CIN)1+ associated with oncogenic HPV types detected within the lesional component of the cervical tissue specimen

End point description

Oncogenic HPV types assessed included HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68. Detection was done in subjects who were HPV DNA negative at baseline regardless of initial serostatus. Analysis was performed on the According-to-Protocol (ATP) cohort for efficacy, which included all evaluable subjects, who had received 3 doses of study vaccine and who had a normal or low-grade cytology (i.e. negative or ASC-US or LSIL) at Month 0.

End point type

Secondary

End point timeframe

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	7764	7782
Units: Subjects
HPV-16 (n= 7276, 7372)	84	9
HPV-18 (n= 7583, 7645)	32	3
HPV-31 (n= 7599, 7583)	49	6
HPV-33 (n= 7706, 7720)	34	21
HPV-35 (n= 7764, 7768)	13	4
HPV-39 (n= 7614, 7609)	29	18
HPV-45 (n= 7745, 7782)	12	1
HPV-51 (n= 7352, 7363)	57	42
HPV-52 (n= 7414, 7461)	44	29
HPV-56 (n= 7638, 7646)	26	23
HPV-58 (n= 7702, 7709)	34	11
HPV-59 (n=7723, 7720)	12	8
HPV-66 (n= 7564, 7592)	24	15
HPV-68 (n= 7614, 7633)	22	11

No statistical analyses for this end point

Secondary: Number of Subjects With Histopathologically Confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With Oncogenic HPV Types Detected Within the Lesional Component of the Cervical Tissue Specimen

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End point title

Number of Subjects With Histopathologically Confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With Oncogenic HPV Types Detected Within the Lesional Component of the Cervical Tissue Specimen

End point description

End point type

Secondary

End point timeframe

at Month 48

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	7757	7774
Units: Subjects
HPV-16 (n= 7267, 7364)	140	10
HPV-18 (n= 7577, 7638)	53	6
HPV-31 (n= 7592, 7575)	79	11
HPV-33 (n= 7700, 7712)	66	23
HPV-35 (n= 7757, 7760)	18	7
HPV-39 (n= 7608, 7602)	48	26
HPV-45 (n= 7738, 7774)	25	3
HPV-51 (n= 7341, 7356)	96	61
HPV-52 (n= 7409, 7455)	81	51
HPV-56 (n= 7631, 7638)	45	36
HPV-58 (n= 7696, 7701)	42	25
HPV-59 (n=7716, 7713)	20	13
HPV-66 (n= 7559, 7583)	44	30
HPV-68 (n= 7606, 7626)	43	28

No statistical analyses for this end point

Secondary: Number of subjects with histopathologically confirmed Cervical Intraepithelial Neoplasia (CIN)2+ associated with oncogenic HPV types detected within the lesional component of the cervical tissue specimen

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End point title

Number of subjects with histopathologically confirmed Cervical Intraepithelial Neoplasia (CIN)2+ associated with oncogenic HPV types detected within the lesional component of the cervical tissue specimen

End point description

CIN2+ was defined as histopathologically-confirmed lesions including cervical intraepithelial neoplasia of grade 2 (CIN2), grade 3 (CIN3), AIS and invasive cervical cancer. Oncogenic types detected included HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68. Detection was done in subjects who were HPV DNA negative at baseline, regardless of initial serostatus. Analysis was performed on the According-to-Protocol (ATP) cohort for efficacy, which included all evaluable subjects, who had received 3 doses of study vaccine and who had a normal or low-grade cytology (i.e. negative or ASC-US or LSIL) at Month 0.

End point type

Secondary

End point timeframe

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	7764	7782
Units: Subjects
HPV-16 (n= 7276, 7372)	54	4
HPV-18 (n= 7583, 7645)	16	2
HPV-31 (n= 7599, 7583)	25	2
HPV-33 (n= 7706, 7720)	25	12
HPV-35 (n= 7764, 7768)	6	1
HPV-39 (n= 7614, 7609)	10	3
HPV-45 (n= 7745, 7782)	4	0
HPV-51 (n= 7352, 7363)	27	10
HPV-52 (n= 7414, 7461)	14	12
HPV-56 (n= 7638, 7646)	10	4
HPV-58 (n=7702, 7709)	17	6
HPV-59 (n= 7723, 7720)	4	1
HPV-66 (n= 7564, 7592)	10	4
HPV-68 (n= 7614, 7633)	11	5

No statistical analyses for this end point

Secondary: Number of subjects with histopathologically confirmed Cervical Intraepithelial Neoplasia (CIN)2+ associated with oncogenic HPV types detected within the lesional component of the cervical tissue specimen

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End point title

End point description

End point type

Secondary

End point timeframe

at Month 48

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	7757	7774
Units: Subjects
HPV-16 (n= 7267, 7364)	91	4
HPV-18 (n= 7577, 7638)	24	3
HPV-31 (n= 7592, 7575)	40	5
HPV-33 (n= 7700, 7712)	41	13
HPV-35 (n= 7757, 7760)	8	3
HPV-39 (n= 7608, 7602)	16	4
HPV-45 (n= 7738, 7774)	11	2
HPV-51 (n= 7341, 7356)	46	21
HPV-52 (n= 7409, 7455)	33	24
HPV-56 (n= 7631, 7638)	13	7
HPV-58 (n=7696, 7701)	21	15
HPV-59 (n= 7716, 7713)	5	1
HPV-66 (n= 7559, 7583)	16	7
HPV-68 (n= 7606, 7626)	15	11

No statistical analyses for this end point

Secondary: Number of seropositive subjects for anti-HPV-16 and anti-HPV-18 antibody titers by ELISA in the immunogenicity subset, according to initial (Month 0) HPV-16 or HPV-18 serostatus

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End point title

Number of seropositive subjects for anti-HPV-16 and anti-HPV-18 antibody titers by ELISA in the immunogenicity subset, according to initial (Month 0) HPV-16 or HPV-18 serostatus

End point description

Cut-off values assessed for seropositivity include 8 enzyme-linked immunosorbent assay units per milliliter (EL.U/mL) for anti-HPV-16 antibodies and 7 EL.U/mL for anti-HPV-18 antibodies. Results are presented for the total group and stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus by ELISA - seronegative (sero-) or seropositive (sero+). The analyses were performed on the ATP cohort for immunogenicity on evaluable subjects for whom immunogenicity data were available.

End point type

Secondary

End point timeframe

At Months 6, 7, 12, 24, 36 & 48

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	898	1036
Units: Subjects
HPV-16, sero-, pre-vaccination (n= 750, 872)	0	0
HPV-16, sero-, Month 6 (n= 738, 865)	41	864
HPV-16, sero-, Month 7 (n= 740, 865)	34	861
HPV-16, sero-, Month 12 (n= 719, 839)	30	837
HPV-16, sero-, Month 24 (n= 672, 797)	33	796
HPV-16, sero-, Month 36 (n= 664, 784)	35	784
HPV-16, sero-, Month 48 (n= 603, 746)	47	746
HPV-16, sero+, pre-vaccination (n= 147, 164)	147	164
HPV-16, sero+, Month 6 (n= 139, 162)	119	161
HPV-16, sero+, Month 7 (n= 139, 163)	106	162
HPV-16, sero+, Month 12 (n= 134, 154)	101	154
HPV-16, sero+, Month 24 (n= 138, 146)	96	146
HPV-16, sero+, Month 36 (n= 127, 142)	88	142
HPV-16, sero+, Month 48 (n= 118, 145)	85	145
HPV-16, total, pre-vaccination (n= 897, 1036)	147	164
HPV-16, total, Month 6 (n= 877, 1027)	160	1025
HPV-16, total, Month 7 (n= 879, 1028)	140	1023
HPV-16, total, Month 12 (n= 853, 993)	131	991
HPV-16, total, Month 24 (n= 810, 943)	129	942
HPV-16, total, Month 36 (n= 791, 926)	123	926
HPV-16, total, Month 48 (n= 721, 891)	132	891
HPV-18, sero-, pre-vaccination (n= 790,939)	0	0
HPV-18, sero-, Month 6 (n= 771, 930)	29	927
HPV-18, sero-, Month 7 (n= 772, 930)	32	925
HPV-18, sero-, Month 12 (n= 748, 901)	36	901
HPV-18, sero-, Month 24 (n= 698, 854)	37	853
HPV-18, sero-, Month 36 (n= 691, 841)	31	841
HPV-18, sero-, Month 48 (n= 633, 806)	32	804
HPV-18, sero+, pre-vaccination (n= 108, 97)	108	97
HPV-18, sero+, Month 6 (n= 105, 97)	90	96
HPV-18, sero+, Month 7 (n= 105, 97)	90	97
HPV-18, sero+, Month 12 (n= 106, 92)	89	92
HPV-18, sero+, Month 24 (n= 102, 89)	84	89
HPV-18, sero+, Month 36 (n= 98, 86)	73	86
HPV-18, sero+, Month 48 (n= 91, 86)	70	86
HPV-18, total, pre-vaccination (n= 898, 1036)	108	97
HPV-18, total, Month 6 (n= 876, 1027)	119	1023
HPV-18, total, Month 7 (n= 877, 1027)	122	1022
HPV-18, total, Month 12 (n= 854, 993)	125	993
HPV-18, total, Month 24 (n= 800, 943)	121	942
HPV-18, total, Month 36 (n= 789, 927)	104	927
HPV-18, total, Month 48 (n= 724, 892)	102	890

No statistical analyses for this end point

Secondary: Anti-HPV-16 and anti-HPV-18 ELISA titers in the immunogenicity subset

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End point title

Anti-HPV-16 and anti-HPV-18 ELISA titers in the immunogenicity subset

End point description

Titers are given as Geometric Mean Titers (GMTs) expressed as ELISA Units per milliliter (EL.U/mL). GMTs are presented for the total group and also stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus by ELISA [seronegative (sero-) or seropositive (sero+)]. The analyses were performed on the ATP cohort for immunogenicity for whom immunogenicity data were available.

End point type

Secondary

End point timeframe

At Months 6, 7, 12, 24, 36 and 48

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	898	1036
Units: EL.U/mL
geometric mean (confidence interval 95%)
Anti-HPV-16, sero-, pre-vaccination (n= 750, 872)	4 (4 to 4)	4 (4 to 4)
Anti-HPV-16, sero-, Month 6 (n= 738, 865)	4.4 (4.2 to 4.5)	630.7 (591.6 to 672.4)
Anti-HPV-16, sero-, Month 7 (n= 740, 865)	4.4 (4.2 to 4.6)	9206.5 (8609.4 to 9845.1)
Anti-HPV-16, sero-, Month 12 (n= 719, 839)	4.3 (4.2 to 4.4)	3281.1 (3064.5 to 3513)
Anti-HPV-16, sero-, Month 24 (n= 672, 797)	4.4 (4.2 to 4.5)	1592 (1491.6 to 1699.2)
Anti-HPV-16, sero-, Month 36 (n= 664, 784)	4.4 (4.2 to 4.5)	1265.1 (1184.8 to 1350.8)
Anti-HPV-16, sero-, Month 48 (n= 603, 746)	4.6 (4.4 to 4.8)	1174.3 (1096.1 to 1258)
Anti-HPV-16, sero+, pre-vaccination (n= 147, 164)	29.7 (25 to 35.4)	28.9 (24.7 to 33.8)
Anti-HPV-16, sero+, Month 6 (n= 139, 162)	24.4 (19.9 to 29.8)	1256.9 (1030.1 to 1533.7)
Anti-HPV-16, sero+, Month 7 (n= 139, 163)	21.7 (17.4 to 27)	6423.1 (5486.3 to 7520)
Anti-HPV-16, sero+, Month 12 (n= 134, 154)	20.2 (16.3 to 25.1)	2909.6 (2504.3 to 3380.4)
Anti-HPV-16, sero+, Month 24 (n= 138, 146)	18.7 (15 to 23.2)	1573.2 (1356.7 to 1824.2)
Anti-HPV-16, sero+, Month 36 (n= 127, 142)	17.7 (14 to 22.2)	1244.3 (1068.9 to 1448.4)
Anti-HPV-16, sero+, Month 48 (n= 118, 145)	18.3 (14.5 to 23)	1115.9 (959.6 to 1297.7)
Anti-HPV-16, total, pre-vaccination (n= 897, 1036)	5.6 (5.3 to 5.9)	5.5 (5.2 to 5.8)
Anti-HPV-16, total, Month 6 (n= 877, 1027)	5.7 (5.4 to 6.1)	703.2 (659.5 to 749.7)
Anti-HPV-16, total, Month 7 (n= 879, 1028)	5.6 (5.3 to 6)	8695.7 (8171.9 to 9253.1)
Anti-HPV-16, total, Month 12 (n= 853, 993)	5.5 (5.2 to 5.8)	3220.5 (3026.4 to 3427.1)
Anti-HPV-16, total, Month 24 (n= 810, 943)	5.6 (5.3 to 5.9)	1589.1 (1497.2 to 1686.6)
Anti-HPV-16, total, Month 36 (n=791, 926)	5.4 (5.1 to 5.8)	1261.9 (1188.3 to 1340)
Anti-HPV-16, total, Month 48 (n=721, 891)	5.7 (5.4 to 6.1)	1164.6 (1093.9 to 1239.8)
Anti-HPV-18, sero-, pre-vaccination (n=790, 939)	3.5 (3.5 to 3.5)	3.5 (3.5 to 3.5)
Anti-HPV-18, sero-, Month 6 (n=771, 930)	3.7 (3.6 to 3.8)	542.7 (510.2 to 577.2)
Anti-HPV-18, sero-, Month 7 (n= 772, 930)	3.8 (3.6 to 3.9)	4741.3 (4452.2 to 5049.1)
Anti-HPV-18, sero-, Month 12 (n= 748, 901)	3.8 (3.7 to 3.9)	1521.7 (1431 to 1618.1)
Anti-HPV-18, sero-, Month 24 (n= 698, 854)	3.8 (3.7 to 3.9)	704.4 (658.4 to 753.8)
Anti-HPV-18, sero-, Month 36 (n= 691, 841)	3.7 (3.6 to 3.8)	534.3 (498.9 to 572.1)
Anti-HPV-18, sero-, Month 48 (n= 633, 806)	3.8 (3.7 to 3.9)	476.2 (443.2 to 511.6)
Anti-HPV-18, sero+, pre-vaccination (n= 108, 97)	23.4 (18.9 to 29.1)	24.8 (20.1 to 30.6)
Anti-HPV-18, sero+, Month 6 (n= 105, 97)	19.6 (15.2 to 25.4)	903.8 (714 to 1144.2)
Anti-HPV-18, sero+, Month 7 (n= 105, 97)	20.8 (16.2 to 26.8)	4135.7 (3548.6 to 4819.9)
Anti-HPV-18, sero+, Month 12 (n= 106, 92)	19.9 (15.5 to 25.5)	1509.5 (1271.3 to 1792.3)
Anti-HPV-18, sero+, Month 24 (n= 102, 89)	18.9 (14.6 to 24.4)	745.6 (620.1 to 896.6)
Anti-HPV-18, sero+, Month 36 (n= 98, 86)	16.8 (12.8 to 22.1)	580.9 (475 to 710.4)
Anti-HPV-18, sero+, Month 48 (n= 91, 86)	16.5 (12.6 to 21.6)	510.6 (415.7 to 627.2)
Anti-HPV-18, total, pre-vaccination (n= 898, 1036)	4.4 (4.2 to 4.6)	4.2 (4 to 4.4)
Anti-HPV-18, total, Month 6 (n= 876, 1027)	4.5 (4.3 to 4.8)	569.5 (536 to 605.1)
Anti-HPV-18, total, Month 7 (n= 877, 1027)	4.6 (4.4 to 4.9)	4680.5 (4413.4 to 4963.7)
Anti-HPV-18, total, Month 12 (n= 854, 993)	4.6 (4.4 to 4.9)	1520.5 (1435 to 1611.2)
Anti-HPV-18, total, Month 24 (n= 800, 943)	4.7 (4.4 to 4.9)	708.2 (664.6 to 754.8)
Anti-HPV-18, total, Month 36 (n=789, 927)	4.5 (4.3 to 4.8)	538.5 (504.7 to 574.5)
Anti-HPV-18, total, Month 48 (n=724, 892)	4.6 (4.3 to 4.8)	479.4 (448 to 513)

No statistical analyses for this end point

Secondary: HPV-16 and HPV-18 seroconversion (V5/J4 monoclonal inhibition test)

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End point title

HPV-16 and HPV-18 seroconversion (V5/J4 monoclonal inhibition test)

End point description

HPV-16 V5 cut-off was defined as greater than or equal to 41 ELU/mL. Only seronegative subjects were analysed. Seronegative subjects are subjects who had an antibody titer of less than 41 ELU/mL before vaccination. HPV-18 J4 cut-off was defined as greater than or equal to 110 EL.U/mL. Both seropositive and seronegative subjects were included in the analysis. Seropositive subjects were subjects with an antibody titer of greater than or equal to 110 EL.U/mL. Seronegative subjects were subjects with an antibody titer less than 110 EL.U/mL. Analyses was performed on the Total Vaccinated Cohort on subjects with available results.

End point type

Secondary

End point timeframe

Month 0, 7, 12 and 24

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	17	17
Units: Subjects
pre-vaccination V5 HPV-16 (n= 17,17)	0	0
Month 7 V5 HPV-16 (n= 17,17)	0	17
Month 12 V5 HPV-16 (n= 5, 2)	0	2
Month 24 V5 HPV-16 (n=17, 17)	0	17
pre-vaccination J4 HPV-18 (n= 17, 17)	0	1
Month 7 J4 HPV-18 (n= 17,17)	0	17
Month 12 J4 HPV-18 (n= 5, 2)	1	1
Month 24 V5 HPV-18 (n=17, 17)	1	11

No statistical analyses for this end point

Secondary: HPV-16 and HPV-18 Geometric Mean Titers (GMT) (V5/J4 monoclonal inhibition test)

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End point title

HPV-16 and HPV-18 Geometric Mean Titers (GMT) (V5/J4 monoclonal inhibition test)

End point description

Titers were expressed as GMTs in ELISA units per milliliter (EL.U/mL). The analyses was performed on the Total Vaccinated cohort on subjects with available results.

End point type

Secondary

End point timeframe

Month 0, 7, 12, 24

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	17	17
Units: U/mL
geometric mean (confidence interval 95%)
pre-vaccination V5 HPV-16 (n= 17,17)	20.5 (20.5 to 20.5)	20.5 (20.5 to 20.5)
Month 7 V5 HPV-16 (n= 17,17)	20.5 (20.5 to 20.5)	816.7 (472.5 to 1411.4)
Month 12 V5 HPV-16 (n= 5, 2)	20.5 (20.5 to 20.5)	173.5 (25.1 to 1199.3)
Month 24 V5 HPV-16 (n=17, 17)	20.5 (20.5 to 20.5)	163.3 (104 to 256.6)
pre-vaccination J4 HPV-18 (n= 17, 17)	55 (55 to 55)	57.7 (52.1 to 63.8)
Month 7 J4 HPV-18 (n= 17,17)	55 (55 to 55)	679.2 (423.6 to 1088.9)
Month 12 J4 HPV-18 (n= 5, 2)	71 (35 to 144.2)	83.6 (0.4 to 17024)
Month 24 V5 HPV-18 (n=17, 17)	58.1 (51.7 to 65.2)	139.5 (90.5 to 215.1)

No statistical analyses for this end point

Secondary: Number of subjects seropositive for anti-HPV-16 and anti-HPV-18 antibodies using pseudovirion based neutralizing assay (PBNA)

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End point title

Number of subjects seropositive for anti-HPV-16 and anti-HPV-18 antibodies using pseudovirion based neutralizing assay (PBNA)

End point description

Seropositivity was defined as subjects with a titer equal to or greater than 40. Subjects with an antibody titer smaller than 40 prior to vaccination were seronegative prior to vaccination and subjects with a titer equal to or greater than 40 were seropositive prior to vaccination.

End point type

Secondary

End point timeframe

At Month 0, 7, 12, 24, 36 and 48

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	47	48
Units: Subjects
pre-vaccination HPV-16 (n= 44, 46)	0	0
Month 7 HPV-16 (n= 44, 46)	0	46
Month 12 HPV-16 (n= 43, 45)	0	45
Month 24 HPV-16 (n= 40, 46)	0	46
Month 36 HPV-16 (n= 33, 41)	0	41
Month 48 HPV-16 (n= 33, 41)	0	40
pre-vaccination HPV-18 (n= 47, 48)	0	0
Month 7 HPV-18 (n= 44, 46)	0	46
Month 12 HPV-18 (n= 43, 45)	0	44
Month 24 HPV-18 (n= 40, 46)	0	46
Month 36 HPV-18 (n= 33, 41)	0	41
Month 48 HPV-18 (n= 33, 41)	2	39

No statistical analyses for this end point

Secondary: Titers for anti-HPV-16 and anti-HPV-18 antibodies using pseudovirion based neutralizing assay (PBNA)

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End point title

Titers for anti-HPV-16 and anti-HPV-18 antibodies using pseudovirion based neutralizing assay (PBNA)

End point description

Titers were expressed as GMTs. The analyses were performed on the ATP cohort for immunogenicity which included subjects for whom immunogenicity data were available.

End point type

Secondary

End point timeframe

At month 0, 7, 12, 24, 36 and 48

End point values	Havrix Group	Cervarix Group
Number of subjects analysed	47	48
Units: Titer
geometric mean (confidence interval 95%)
pre-vaccination HPV-16 (n= 44, 46)	20 (20 to 20)	20 (20 to 20)
Month 7 HPV-16 (n= 44, 46)	20 (20 to 20)	27364.8 (19780.1 to 37857.9)
Month 12 HPV-16 (n= 43, 45)	20 (20 to 20)	8385.9 (5857.3 to 12006)
Month 24 HPV-16 (n= 40, 46)	20 (20 to 20)	3647.4 (2586.5 to 5143.4)
Month 36 HPV-16 (n= 33, 41)	20 (20 to 20)	2245.1 (1616.6 to 3117.9)
Month 48 HPV-16 (n= 33, 41)	20 (20 to 20)	1931.1 (1294.4 to 2880.8)
pre-vaccination HPV-18 (n= 47, 48)	20 (20 to 20)	20 (20 to 20)
Month 7 HPV-18 (n= 44, 46)	20 (20 to 20)	9052.7 (6851.8 to 11960.5)
Month 12 HPV-18 (n= 43, 45)	20 (20 to 20)	1889.9 (1316 to 2714.1)
Month 24 HPV-18 (n= 40, 46)	20 (20 to 20)	1695.6 (1200.7 to 2394.4)
Month 36 HPV-18 (n= 33, 41)	20 (20 to 20)	1326.9 (948 to 1857.3)
Month 48 HPV-18 (n= 33, 41)	23.8 (18.6 to 30.4)	1078.1 (714.9 to 1625.6)

No statistical analyses for this end point

Secondary: Geometric mean titers of anti-HPV-16 in subjects without and with 6-month persistent infection

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End point title

Geometric mean titers of anti-HPV-16 in subjects without and with 6-month persistent infection ^[13]

End point description

GMT for anti-HPV-16 antibodies by ELISA in subjects with breakthrough persistent infections 6-month definition, were compared to those in a matched set of subjects without breakthrough persistent infections. The analysis was based on the Total Vaccinated Cohort, which included all vaccinated subjects for whom data were available, only on subjects HPV-16 DNA negative and seronegative at baseline.

End point type

Secondary

End point timeframe

At Month 7

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting values for the Cervarix Group.

End point values	Cervarix Group
Number of subjects analysed	1123
Units: EL.U/mL
geometric mean (confidence interval 95%)
Subjects without 6 Month persistent infection	7667.34 (7212.13 to 8151.29)
Subjects with 6 Month persistent infection	6986.3 (5692.83 to 8573.66)

No statistical analyses for this end point

Secondary: Number of seroconverted subjects for anti-HPV-16 without and with 6-month persistent infection

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End point title

Number of seroconverted subjects for anti-HPV-16 without and with 6-month persistent infection ^[14]

End point description

Seroconversion rates for anti-HPV-16 antibodies by ELISA in subjects with breakthrough persistent infections 6-month definition, were compared to those in a matched set of subjects without breakthrough persistent infections. The analysis was based on the Total Vaccinated Cohort, which included all vaccinated subjects for whom data were available, only on subjects HPV-16 DNA negative and seronegative at baseline.

End point type

Secondary

End point timeframe

At Month 7

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting values for the Cervarix Group.

End point values	Cervarix Group
Number of subjects analysed	1123
Units: Subjects
Subjects without 6 Month persistent infection	1118
Subjects with 6 Month persistent infection	45

No statistical analyses for this end point

Secondary: Geometric mean titers of anti-HPV-16 in subjects without and with 12-month persistent infection

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End point title

Geometric mean titers of anti-HPV-16 in subjects without and with 12-month persistent infection ^[15]

End point description

GMTs for anti-HPV-16 antibodies by ELISA in subjects with breakthrough persistent infections 12-month definition, were compared to those in a matched set of subjects without breakthrough persistent infections. The analysis was based on the Total Vaccinated Cohort, which included all vaccinated subjects for whom data were available, only on subjects HPV-16 DNA negative and seronegative at baseline.

End point type

Secondary

End point timeframe

At Month 7

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting values for the Cervarix Group.

End point values	Cervarix Group
Number of subjects analysed	1120
Units: EL.U/mL
geometric mean (confidence interval 95%)
Subjects without 12 Month persistent infection	7683.56 (7229.22 to 8166.44)
Subjects with 12 Month persistent infection	6839.71 (5362.44 to 8723.96)

No statistical analyses for this end point

Secondary: Number of seroconverted subjects for anti-HPV-16 without and with 12-month persistent infection

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End point title

Number of seroconverted subjects for anti-HPV-16 without and with 12-month persistent infection ^[16]

End point description

Seroconversion rates for anti-HPV-16 antibodies by ELISA in subjects with breakthrough persistent infections 12-month definition, were compared to those in a matched set of subjects without breakthrough persistent infections. The analysis was based on the Total Vaccinated Cohort, which included all vaccinated subjects for whom data were available, only on subjects HPV-16 DNA negative and seronegative at baseline.

End point type

Secondary

End point timeframe

At Month 7

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting values for the Cervarix Group.

End point values	Cervarix Group
Number of subjects analysed	1120
Units: Subjects
Subjects without 12 Month persistent infection	1115
Subjects with 12 Month persistent infection	37

No statistical analyses for this end point

Secondary: Geometric mean titers of anti-HPV-18 in subjects without and with 6-month persistent infection

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End point title

Geometric mean titers of anti-HPV-18 in subjects without and with 6-month persistent infection ^[17]

End point description

GMTs for anti-HPV-18 antibodies by ELISA in subjects with breakthrough persistent infections 6-month definition, were compared to those in a matched set of subjects without breakthrough persistent infections. The analysis was based on the Total Vaccinated Cohort, which included all vaccinated subjects for whom data were available, only on subjects HPV-18 DNA negative and seronegative at baseline.

End point type

Secondary

End point timeframe

At Month 7

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting values for the Cervarix Group.

End point values	Cervarix Group
Number of subjects analysed	1248
Units: EL.U/mL
geometric mean (confidence interval 95%)
Subjects without 6 Month persistent infection	3963.5 (3750.71 to 4188.37)
Subjects with 6 Month persistent infection	2945.69 (2271.74 to 3819.58)

No statistical analyses for this end point

Secondary: Number of seroconverted subjects for anti-HPV-18 without and with 6- month persistent infection

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End point title

Number of seroconverted subjects for anti-HPV-18 without and with 6- month persistent infection ^[18]

End point description

Seroconversion rates for anti-HPV-18 antibodies by ELISA in subjects with breakthrough persistent infections 6-month definition, were compared to those in a matched set of subjects without breakthrough persistent infections. The analysis was based on the Total Vaccinated Cohort, which included all vaccinated subjects for whom data were available, only on subjects HPV-18 DNA negative and seronegative at baseline.

End point type

Secondary

End point timeframe

At Month 7

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting values for the Cervarix Group.

End point values	Cervarix Group
Number of subjects analysed	1248
Units: Subjects
Subjects without 6 Month persistent infection	1242
Subjects with 6 Month persistent infection	28

No statistical analyses for this end point

Secondary: Geometric mean titers of anti-HPV-18 in subjects without and with 12-month persistent infection

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End point title

Geometric mean titers of anti-HPV-18 in subjects without and with 12-month persistent infection ^[19]

End point description

GMTs for anti-HPV-18 antibodies by ELISA in subjects with breakthrough persistent infections 12-month definition, were compared to those in a matched set of subjects without breakthrough persistent infections. The analysis was based on the Total Vaccinated Cohort, which included all vaccinated subjects for whom data were available, only on subjects HPV-18 DNA negative and seronegative at baseline.

End point type

Secondary

End point timeframe

At Month 7

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting values for the Cervarix Group.

End point values	Cervarix Group
Number of subjects analysed	1243
Units: EL.U/mL
geometric mean (confidence interval 95%)
Subjects without 12 Month persistent infection	3965.67 (3753.09 to 4190.29)
Subjects with 12 Month persistent infection	3063.23 (2261.65 to 4148.91)

No statistical analyses for this end point

Secondary: Number of seroconverted subjects for anti-HPV-18 without and with 12-month persistent infection

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End point title

Number of seroconverted subjects for anti-HPV-18 without and with 12-month persistent infection ^[20]

End point description

Seroconversion rates for anti-HPV-18 antibodies by ELISA in subjects with breakthrough persistent infections 12-month definition, were compared to those in a matched set of subjects without breakthrough persistent infections.

End point type

Secondary

End point timeframe

At Month 7

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting values for the Cervarix Group.

End point values	Cervarix Group
Number of subjects analysed	1243
Units: Subjects
Subjects without 12 Month persistent infection	1237
Subjects with 12 Month persistent infection	21

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Solicited symptoms: Days 0-6 post-vaccination; Unsolicited symptoms: Days 0-29 post-vaccination; Serious Adverse Events: Months 0-48 post-vaccination.

Adverse event reporting additional description

Results presented per group consist of a summary of the events (SAEs and AEs other than SAEs, respectively) reported, compiling overall number of subjects with events across the different periods of assessment.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

10.0

Reporting group title

Cervarix Group

Reporting group description

Subjects received 3 doses of Cervarix (GSK Biologicals' human papillomavirus [HPV] vaccine) at Months 0, 1 and 6.

Reporting group title

Havrix Group

Reporting group description

Subjects received 3 doses of GSK Biologicals' hepatitis A vaccine [HAV] (Havrix-based investigational formulation) at Months 0, 1 and 6.

Serious adverse events	Cervarix Group	Havrix Group
Total subjects affected by serious adverse events
subjects affected / exposed	835 / 9319 (8.96%)	829 / 9325 (8.89%)
number of deaths (all causes)	10	13
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine leiomyoma
subjects affected / exposed	1 / 9319 (0.01%)	6 / 9325 (0.06%)
occurrences causally related to treatment / all	0 / 1	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Ovarian germ cell teratoma benign
subjects affected / exposed	3 / 9319 (0.03%)	3 / 9325 (0.03%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Teratoma
subjects affected / exposed	3 / 9319 (0.03%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Benign hydatidiform mole
subjects affected / exposed	3 / 9319 (0.03%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant melanoma
subjects affected / exposed	2 / 9319 (0.02%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ovarian adenoma
subjects affected / exposed	2 / 9319 (0.02%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fibroadenoma of breast
subjects affected / exposed	0 / 9319 (0.00%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Thyroid cancer
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Astrocytoma malignant
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Astrocytoma, low grade
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bone sarcoma
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Carcinoid tumour of the appendix
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gestational trophoblastic tumour
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Leiomyoma
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to lung
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Neoplasm
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ovarian neoplasm
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thyroid neoplasm
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vulval cancer
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	2 / 9319 (0.02%)	3 / 9325 (0.03%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 0
Circulatory collapse
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Jugular vein thrombosis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic venous thrombosis
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Varicose vein
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vasculitis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Venous thrombosis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Abortion induced
subjects affected / exposed	5 / 9319 (0.05%)	3 / 9325 (0.03%)
occurrences causally related to treatment / all	0 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Breech extraction
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nail operation
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous
subjects affected / exposed	70 / 9319 (0.75%)	59 / 9325 (0.63%)
occurrences causally related to treatment / all	2 / 70	1 / 59
deaths causally related to treatment / all	0 / 0	0 / 0
Abortion spontaneous incomplete
subjects affected / exposed	54 / 9319 (0.58%)	40 / 9325 (0.43%)
occurrences causally related to treatment / all	0 / 54	0 / 40
deaths causally related to treatment / all	0 / 0	0 / 0
Abortion spontaneous complete
subjects affected / exposed	43 / 9319 (0.46%)	46 / 9325 (0.49%)
occurrences causally related to treatment / all	0 / 43	0 / 46
deaths causally related to treatment / all	0 / 0	0 / 0
Abortion missed
subjects affected / exposed	20 / 9319 (0.21%)	27 / 9325 (0.29%)
occurrences causally related to treatment / all	0 / 20	1 / 27
deaths causally related to treatment / all	0 / 0	0 / 0
Premature labour
subjects affected / exposed	21 / 9319 (0.23%)	12 / 9325 (0.13%)
occurrences causally related to treatment / all	0 / 21	0 / 12
deaths causally related to treatment / all	0 / 0	0 / 0
Ectopic pregnancy
subjects affected / exposed	18 / 9319 (0.19%)	8 / 9325 (0.09%)
occurrences causally related to treatment / all	0 / 18	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Pre-eclampsia
subjects affected / exposed	10 / 9319 (0.11%)	11 / 9325 (0.12%)
occurrences causally related to treatment / all	0 / 10	0 / 11
deaths causally related to treatment / all	0 / 0	0 / 0
Blighted ovum
subjects affected / exposed	10 / 9319 (0.11%)	9 / 9325 (0.10%)
occurrences causally related to treatment / all	0 / 10	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Intra-uterine death
subjects affected / exposed	9 / 9319 (0.10%)	7 / 9325 (0.08%)
occurrences causally related to treatment / all	0 / 9	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Stillbirth
subjects affected / exposed	8 / 9319 (0.09%)	7 / 9325 (0.08%)
occurrences causally related to treatment / all	0 / 8	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperemesis gravidarum
subjects affected / exposed	5 / 9319 (0.05%)	4 / 9325 (0.04%)
occurrences causally related to treatment / all	0 / 5	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Premature rupture of membranes
subjects affected / exposed	6 / 9319 (0.06%)	3 / 9325 (0.03%)
occurrences causally related to treatment / all	0 / 6	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pregnancy induced hypertension
subjects affected / exposed	2 / 9319 (0.02%)	5 / 9325 (0.05%)
occurrences causally related to treatment / all	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Abortion threatened
subjects affected / exposed	3 / 9319 (0.03%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Premature baby
subjects affected / exposed	3 / 9319 (0.03%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Premature separation of placenta
subjects affected / exposed	4 / 9319 (0.04%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chorioamnionitis
subjects affected / exposed	3 / 9319 (0.03%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abortion incomplete
subjects affected / exposed	0 / 9319 (0.00%)	3 / 9325 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Eclampsia
subjects affected / exposed	1 / 9319 (0.01%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Retained products of conception
subjects affected / exposed	2 / 9319 (0.02%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ruptured ectopic pregnancy
subjects affected / exposed	2 / 9319 (0.02%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Threatened labour
subjects affected / exposed	0 / 9319 (0.00%)	3 / 9325 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Breech presentation
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Placenta praevia
subjects affected / exposed	0 / 9319 (0.00%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Retained placenta or membranes
subjects affected / exposed	2 / 9319 (0.02%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abortion complete
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Antepartum haemorrhage
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arrested labour
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cephalo-pelvic disproportion
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Face presentation
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
False labour
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Foetal distress syndrome
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Foetal growth retardation
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Imminent abortion
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Induced labour
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Obstructed labour
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oligohydramnios
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Placenta accreta
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Placenta praevia haemorrhage
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Postpartum uterine subinvolution
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Prolonged labour
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Small for dates baby
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Uterine inversion
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	9 / 9319 (0.10%)	11 / 9325 (0.12%)
occurrences causally related to treatment / all	0 / 9	0 / 11
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	2 / 9319 (0.02%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	1 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Adverse drug reaction
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chest pain
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cyst
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Drowning
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Fatigue
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Hypersensitivity
subjects affected / exposed	2 / 9319 (0.02%)	5 / 9325 (0.05%)
occurrences causally related to treatment / all	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Food allergy
subjects affected / exposed	2 / 9319 (0.02%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anaphylactic shock
subjects affected / exposed	2 / 9319 (0.02%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anaphylactic reaction
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Social circumstances
Homicide
subjects affected / exposed	1 / 9319 (0.01%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 2
Reproductive system and breast disorders
Ovarian cyst
subjects affected / exposed	11 / 9319 (0.12%)	10 / 9325 (0.11%)
occurrences causally related to treatment / all	0 / 11	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Ovarian cyst ruptured
subjects affected / exposed	4 / 9319 (0.04%)	11 / 9325 (0.12%)
occurrences causally related to treatment / all	0 / 4	0 / 11
deaths causally related to treatment / all	0 / 0	0 / 0
Endometriosis
subjects affected / exposed	2 / 9319 (0.02%)	6 / 9325 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Cervical dysplasia
subjects affected / exposed	4 / 9319 (0.04%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bartholinitis
subjects affected / exposed	2 / 9319 (0.02%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhagic ovarian cyst
subjects affected / exposed	3 / 9319 (0.03%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dysfunctional uterine bleeding
subjects affected / exposed	2 / 9319 (0.02%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fallopian tube cyst
subjects affected / exposed	3 / 9319 (0.03%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ovarian cyst torsion
subjects affected / exposed	1 / 9319 (0.01%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Dysmenorrhoea
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Parovarian cyst
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vaginal haemorrhage
subjects affected / exposed	0 / 9319 (0.00%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bartholin’s cyst
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspareunia
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ovarian adhesion
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ovarian torsion
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic pain
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Polycystic ovaries
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Uterine atony
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Uterine malposition
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Uterine polyp
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	8 / 9319 (0.09%)	8 / 9325 (0.09%)
occurrences causally related to treatment / all	0 / 8	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Nasal septum deviation
subjects affected / exposed	2 / 9319 (0.02%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	3 / 9319 (0.03%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tonsillar hypertrophy
subjects affected / exposed	1 / 9319 (0.01%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	2 / 9319 (0.02%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Apnoeic attack
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperventilation
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nasal turbinate hypertrophy
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary mass
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary thrombosis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rhinitis hypertrophic
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sleep apnoea syndrome
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Status asthmaticus
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	25 / 9319 (0.27%)	19 / 9325 (0.20%)
occurrences causally related to treatment / all	0 / 25	0 / 19
deaths causally related to treatment / all	0 / 0	0 / 0
Major depression
subjects affected / exposed	1 / 9319 (0.01%)	5 / 9325 (0.05%)
occurrences causally related to treatment / all	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Psychotic disorder
subjects affected / exposed	2 / 9319 (0.02%)	3 / 9325 (0.03%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Panic disorder
subjects affected / exposed	3 / 9319 (0.03%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anorexia nervosa
subjects affected / exposed	3 / 9319 (0.03%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Completed suicide
subjects affected / exposed	0 / 9319 (0.00%)	3 / 9325 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 3
Drug dependence
subjects affected / exposed	2 / 9319 (0.02%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Alcoholism
subjects affected / exposed	2 / 9319 (0.02%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anxiety
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bipolar disorder
subjects affected / exposed	4 / 9319 (0.04%)	4 / 9325 (0.04%)
occurrences causally related to treatment / all	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Conversion disorder
subjects affected / exposed	2 / 9319 (0.02%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eating disorder
subjects affected / exposed	0 / 9319 (0.00%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Abnormal behaviour
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Alcohol abuse
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bipolar II disorder
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bulimia nervosa
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Confusional state
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Depression suicidal
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dissociative disorder
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Drug abuse
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dysthymic disorder
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Emotional distress
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Generalized anxiety disorder
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Histrionic personality disorder
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intentional self-injury
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mania
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mental disorder
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Panic reaction
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Postpartum depression
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Schizophrenia
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	14 / 9319 (0.15%)	9 / 9325 (0.10%)
occurrences causally related to treatment / all	0 / 14	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	6 / 9319 (0.06%)	4 / 9325 (0.04%)
occurrences causally related to treatment / all	0 / 6	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	2 / 9319 (0.02%)	4 / 9325 (0.04%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Bile duct stone
subjects affected / exposed	2 / 9319 (0.02%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis chronic
subjects affected / exposed	3 / 9319 (0.03%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Biliary colic
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Biliary tract disorder
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gallbladder disorder
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gallbladder pain
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gallbladder polyp
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis alcoholic
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis cholestatic
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Liver disorder
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Weight increased
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Road traffic accident
subjects affected / exposed	9 / 9319 (0.10%)	10 / 9325 (0.11%)
occurrences causally related to treatment / all	0 / 9	0 / 10
deaths causally related to treatment / all	0 / 1	0 / 3
Concussion
subjects affected / exposed	7 / 9319 (0.08%)	6 / 9325 (0.06%)
occurrences causally related to treatment / all	0 / 7	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Ligament rupture
subjects affected / exposed	3 / 9319 (0.03%)	10 / 9325 (0.11%)
occurrences causally related to treatment / all	0 / 3	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	2 / 9319 (0.02%)	7 / 9325 (0.08%)
occurrences causally related to treatment / all	0 / 2	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	2 / 9319 (0.02%)	7 / 9325 (0.08%)
occurrences causally related to treatment / all	0 / 2	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	2 / 9319 (0.02%)	6 / 9325 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Head injury
subjects affected / exposed	3 / 9319 (0.03%)	4 / 9325 (0.04%)
occurrences causally related to treatment / all	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Clavicle fracture
subjects affected / exposed	4 / 9319 (0.04%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Overdose
subjects affected / exposed	3 / 9319 (0.03%)	3 / 9325 (0.03%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	2 / 9319 (0.02%)	3 / 9325 (0.03%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	3 / 9319 (0.03%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Limb injury
subjects affected / exposed	2 / 9319 (0.02%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple fractures
subjects affected / exposed	2 / 9319 (0.02%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	2 / 9319 (0.02%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hand fracture
subjects affected / exposed	1 / 9319 (0.01%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	0 / 9319 (0.00%)	3 / 9325 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Meniscus lesion
subjects affected / exposed	0 / 9319 (0.00%)	3 / 9325 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple injuries
subjects affected / exposed	3 / 9319 (0.03%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thermal burn
subjects affected / exposed	1 / 9319 (0.01%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	2 / 9319 (0.02%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abortion induced incomplete
subjects affected / exposed	0 / 9319 (0.00%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Accidental needle stick
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Accidental overdose
subjects affected / exposed	0 / 9319 (0.00%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Alcohol poisoning
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Brain contusion
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Excoriation
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Facial bones fracture
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fibula fracture
subjects affected / exposed	0 / 9319 (0.00%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gun shot wound
subjects affected / exposed	2 / 9319 (0.02%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Injury
subjects affected / exposed	2 / 9319 (0.02%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Jaw fracture
subjects affected / exposed	2 / 9319 (0.02%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Muscle strain
subjects affected / exposed	2 / 9319 (0.02%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic fracture
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin laceration
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ulna fracture
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abortion induced complete complicated
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Accident
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Animal bite
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arterial injury
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arthropod bite
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bone fissure
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Burns second degree
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cartilage injury
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colon injury
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device occlusion
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diaphragmatic injury
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fracture
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ilium fracture
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Joint injury
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Joint sprain
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Muscle injury
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nerve injury
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Poisoning
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Post lumbar puncture syndrome
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural haematoma
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Scapula fracture
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skeletal injury
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skull fracture
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Snake bite
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Soft tissue injury
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Splenic rupture
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tendon injury
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thoracic vertebral fracture
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Traumatic liver injury
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ulnar nerve injury
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Uterine perforation
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Uterine rupture
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Whiplash injury
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Congenital, familial and genetic disorders
Coarctation of the aorta
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dermoid cyst
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thyroglossal cyst
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular septal defect
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Sinus tachycardia
subjects affected / exposed	2 / 9319 (0.02%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	2 / 9319 (0.02%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	2 / 9319 (0.02%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	0 / 9319 (0.00%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Atrial fibrillation
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiopulmonary failure
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Myocarditis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Pericarditis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular arrhythmia
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Wolff-parkinson-white syndrome
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Epilepsy
subjects affected / exposed	3 / 9319 (0.03%)	3 / 9325 (0.03%)
occurrences causally related to treatment / all	1 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Headache
subjects affected / exposed	5 / 9319 (0.05%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 5	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Migraine
subjects affected / exposed	4 / 9319 (0.04%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	1 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple sclerosis
subjects affected / exposed	3 / 9319 (0.03%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Optic neuritis
subjects affected / exposed	3 / 9319 (0.03%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	1 / 9319 (0.01%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Convulsion
subjects affected / exposed	3 / 9319 (0.03%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Facial palsy
subjects affected / exposed	2 / 9319 (0.02%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
subjects affected / exposed	2 / 9319 (0.02%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Grand mal convulsion
subjects affected / exposed	2 / 9319 (0.02%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Paraesthesia
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Syncope
subjects affected / exposed	0 / 9319 (0.00%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Anoxic encephalopathy
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aphasia
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Benign intracranial hypertension
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Brain injury
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cubital tunnel syndrome
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dystonia
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Facial paresis
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hydrocephalus
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Intracranial aneurysm
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intracranial venous sinus thrombosis
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Migraine with aura
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neuropathy peripheral
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peroneal nerve palsy
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pleocytosis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Polyneuropathy
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sciatica
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tension headache
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 9319 (0.01%)	3 / 9325 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphadenitis
subjects affected / exposed	3 / 9319 (0.03%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperchromic anaemia
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Idiopathic thrombocytopenic purpura
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Iron deficiency anaemia
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Deafness
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Deafness bilateral
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Meniere's disease
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tympanic membrane perforation
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vertigo
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Blindness unilateral
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Conjunctivitis
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dacryostenosis acquired
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Retinal detachment
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Strabismus
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vision blurred
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	16 / 9319 (0.17%)	15 / 9325 (0.16%)
occurrences causally related to treatment / all	0 / 16	0 / 15
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis
subjects affected / exposed	9 / 9319 (0.10%)	4 / 9325 (0.04%)
occurrences causally related to treatment / all	0 / 9	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain lower
subjects affected / exposed	4 / 9319 (0.04%)	4 / 9325 (0.04%)
occurrences causally related to treatment / all	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	3 / 9319 (0.03%)	5 / 9325 (0.05%)
occurrences causally related to treatment / all	0 / 3	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Crohn's disease
subjects affected / exposed	1 / 9319 (0.01%)	3 / 9325 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	1 / 9319 (0.01%)	3 / 9325 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	2 / 9319 (0.02%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 9319 (0.01%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	3 / 9319 (0.03%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 9319 (0.02%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Irritable bowel syndrome
subjects affected / exposed	2 / 9319 (0.02%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tooth impacted
subjects affected / exposed	2 / 9319 (0.02%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspepsia
subjects affected / exposed	0 / 9319 (0.00%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	2 / 9319 (0.02%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hiatus hernia
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	2 / 9319 (0.02%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Coeliac disease
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis ulcerative
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cyclic vomiting syndrome
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enteritis
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Faecaloma
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Faeces hard
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Food poisoning
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis erosive
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal inflammation
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ileitis
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Inflammatory bowel disease
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal mass
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal polyp
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Malocclusion
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mouth cyst
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal polyp
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Reflux gastritis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Reflux oesophagitis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tooth malformation
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Toothache
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Umbilical hernia
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Urticaria
subjects affected / exposed	1 / 9319 (0.01%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Henoch-schonlein purpura
subjects affected / exposed	2 / 9319 (0.02%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dermatitis atopic
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Erythema nodosum
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psoriasis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyoderma gangrenosum
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Skin disorder
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin necrosis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Stevens-johnson syndrome
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urticaria chronic
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	2 / 9319 (0.02%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Calculus bladder
subjects affected / exposed	2 / 9319 (0.02%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Calculus ureteric
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Calculus urinary
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Glomerulonephritis acute
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Glomerulonephritis membranoproliferative
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nephritis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrotic syndrome
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal colic
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Goitre
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Autoimmune thyroiditis
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Basedow’s disease
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	6 / 9319 (0.06%)	3 / 9325 (0.03%)
occurrences causally related to treatment / all	0 / 6	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	3 / 9319 (0.03%)	4 / 9325 (0.04%)
occurrences causally related to treatment / all	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Systemic lupus erythematosus
subjects affected / exposed	3 / 9319 (0.03%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Bone cyst
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Foot deformity
subjects affected / exposed	2 / 9319 (0.02%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rheumatoid arthritis
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arthritis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arthritis reactive
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arthropathy
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ligament disorder
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myofascial pain syndrome
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psoriatic arthropathy
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Synovitis
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	46 / 9319 (0.49%)	59 / 9325 (0.63%)
occurrences causally related to treatment / all	0 / 46	0 / 59
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	22 / 9319 (0.24%)	13 / 9325 (0.14%)
occurrences causally related to treatment / all	0 / 22	0 / 13
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	20 / 9319 (0.21%)	10 / 9325 (0.11%)
occurrences causally related to treatment / all	0 / 20	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	18 / 9319 (0.19%)	12 / 9325 (0.13%)
occurrences causally related to treatment / all	0 / 18	0 / 12
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	14 / 9319 (0.15%)	14 / 9325 (0.15%)
occurrences causally related to treatment / all	0 / 14	0 / 14
deaths causally related to treatment / all	0 / 0	0 / 0
tonsillitis
subjects affected / exposed	13 / 9319 (0.14%)	8 / 9325 (0.09%)
occurrences causally related to treatment / all	0 / 13	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	8 / 9319 (0.09%)	13 / 9325 (0.14%)
occurrences causally related to treatment / all	0 / 8	0 / 13
deaths causally related to treatment / all	0 / 0	0 / 0
Infectious mononucleosis
subjects affected / exposed	8 / 9319 (0.09%)	10 / 9325 (0.11%)
occurrences causally related to treatment / all	0 / 8	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic inflammatory disease
subjects affected / exposed	13 / 9319 (0.14%)	5 / 9325 (0.05%)
occurrences causally related to treatment / all	0 / 13	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonsillar abscess
subjects affected / exposed	8 / 9319 (0.09%)	8 / 9325 (0.09%)
occurrences causally related to treatment / all	0 / 8	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Acute tonsillitis
subjects affected / exposed	7 / 9319 (0.08%)	7 / 9325 (0.08%)
occurrences causally related to treatment / all	0 / 7	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	2 / 9319 (0.02%)	7 / 9325 (0.08%)
occurrences causally related to treatment / all	0 / 2	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic tonsillitis
subjects affected / exposed	2 / 9319 (0.02%)	6 / 9325 (0.06%)
occurrences causally related to treatment / all	0 / 2	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Dengue fever
subjects affected / exposed	3 / 9319 (0.03%)	3 / 9325 (0.03%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	3 / 9319 (0.03%)	3 / 9325 (0.03%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	2 / 9319 (0.02%)	3 / 9325 (0.03%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Endometritis decidual
subjects affected / exposed	1 / 9319 (0.01%)	4 / 9325 (0.04%)
occurrences causally related to treatment / all	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	3 / 9319 (0.03%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Meningitis viral
subjects affected / exposed	3 / 9319 (0.03%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis perforated
subjects affected / exposed	1 / 9319 (0.01%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	2 / 9319 (0.02%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Genital herpes
subjects affected / exposed	2 / 9319 (0.02%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
subjects affected / exposed	3 / 9319 (0.03%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Meningitis tuberculous
subjects affected / exposed	0 / 9319 (0.00%)	3 / 9325 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Peritonsillitis
subjects affected / exposed	1 / 9319 (0.01%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	2 / 9319 (0.02%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pilonidal cyst
subjects affected / exposed	1 / 9319 (0.01%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Post abortion infection
subjects affected / exposed	1 / 9319 (0.01%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural infection
subjects affected / exposed	1 / 9319 (0.01%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	1 / 9319 (0.01%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Viral infection
subjects affected / exposed	1 / 9319 (0.01%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Abortion infected
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial infection
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	0 / 9319 (0.00%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cervicitis
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic sinusitis
subjects affected / exposed	2 / 9319 (0.02%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ear infection
subjects affected / exposed	0 / 9319 (0.00%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Endometritis
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Epidemic nephropathy
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 9319 (0.00%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gynaecological chlamydia infection
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis a
subjects affected / exposed	2 / 9319 (0.02%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Kidney infection
subjects affected / exposed	2 / 9319 (0.02%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mastitis
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Parotitis
subjects affected / exposed	0 / 9319 (0.00%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia mycoplasmal
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Salmonellosis
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Salpingitis
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Salpingo-oophoritis
subjects affected / exposed	2 / 9319 (0.02%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tooth abscess
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tooth infection
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tubo-ovarian abscess
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Typhoid fever
subjects affected / exposed	2 / 9319 (0.02%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Varicella
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vulvitis
subjects affected / exposed	0 / 9319 (0.00%)	2 / 9325 (0.02%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Wound infection
subjects affected / exposed	2 / 9319 (0.02%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal wall abscess
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abscess
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abscess limb
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acquired immunodeficiency syndrome
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute sinusitis
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Appendiceal abscess
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial sepsis
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial toxaemia
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bartholin’s abscess
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Beta haemolytic streptococcal infection
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bone tuberculosis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Breast abscess
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Carbuncle
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral toxoplasmosis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cystitis
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cytomegalovirus infection
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enteritis infectious
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epiglottitis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Epstein-barr virus infection
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Extrapulmonary tuberculosis
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye infection toxoplasmal
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis bacterial
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal infection
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhagic fever
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis c
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes oesophagitis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hordeolum
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Induced abortion infection
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infected bites
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infection parasitic
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Laryngitis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lobar pneumonia
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Meningitis bacterial
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Meningitis pneumococcal
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neuroborreliosis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Otitis media acute
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ovarian abscess
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Parotid abscess
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Periorbital cellulitis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peritoneal tuberculosis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumococcal sepsis
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyoderma
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rhinitis
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Skin infection
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Streptococcal infection
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sweat gland infection
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tonsillitis streptococcal
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Trichomoniasis
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tuberculosis
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection bacterial
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vulval abscess
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	5 / 9319 (0.05%)	4 / 9325 (0.04%)
occurrences causally related to treatment / all	0 / 5	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Contusion
subjects affected / exposed	4 / 9319 (0.04%)	3 / 9325 (0.03%)
occurrences causally related to treatment / all	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	3 / 9319 (0.03%)	4 / 9325 (0.04%)
occurrences causally related to treatment / all	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	4 / 9319 (0.04%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gestational diabetes
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 9319 (0.01%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Hypoglycaemia
subjects affected / exposed	0 / 9319 (0.00%)	1 / 9325 (0.01%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
obesity
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Type 2 diabetes mellitus
subjects affected / exposed	1 / 9319 (0.01%)	0 / 9325 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Cervarix Group	Havrix Group
Total subjects affected by non serious adverse events
subjects affected / exposed	2869 / 9319 (30.79%)	2678 / 9325 (28.72%)
General disorders and administration site conditions
Pain at injection site
alternative assessment type: Systematic
subjects affected / exposed ^[1]	2787 / 3078 (90.55%)	2403 / 3080 (78.02%)
occurrences all number	2787	2403
Redness at injection site
alternative assessment type: Systematic
subjects affected / exposed ^[2]	1349 / 3078 (43.83%)	851 / 3080 (27.63%)
occurrences all number	1349	851
Swelling at injection site
alternative assessment type: Systematic
subjects affected / exposed ^[3]	1293 / 3078 (42.01%)	609 / 3080 (19.77%)
occurrences all number	1293	609
Arthralgia
alternative assessment type: Systematic
subjects affected / exposed ^[4]	633 / 3078 (20.57%)	551 / 3081 (17.88%)
occurrences all number	633	551
Fatigue
subjects affected / exposed ^[5]	1771 / 3078 (57.54%)	1652 / 3081 (53.62%)
occurrences all number	1771	1652
Fever ≥ 37.5 degrees Celsius
alternative assessment type: Systematic
subjects affected / exposed ^[6]	385 / 3078 (12.51%)	342 / 3081 (11.10%)
occurrences all number	385	342
Gastro-intestinal symptoms
alternative assessment type: Systematic
subjects affected / exposed ^[7]	856 / 3078 (27.81%)	847 / 3081 (27.49%)
occurrences all number	856	847
Headache
alternative assessment type: Systematic
subjects affected / exposed ^[8]	1668 / 3078 (54.19%)	1583 / 3081 (51.38%)
occurrences all number	1668	1583
Myalgia
alternative assessment type: Systematic
subjects affected / exposed ^[9]	1607 / 3078 (52.21%)	1381 / 3081 (44.82%)
occurrences all number	1607	1381
Rash
alternative assessment type: Systematic
subjects affected / exposed ^[10]	314 / 3078 (10.20%)	258 / 3081 (8.37%)
occurrences all number	314	258
Urticaria
alternative assessment type: Systematic
subjects affected / exposed ^[11]	300 / 3078 (9.75%)	244 / 3081 (7.92%)
occurrences all number	300	244
Infections and infestations
Influenza
subjects affected / exposed ^[12]	157 / 3184 (4.93%)	176 / 3187 (5.52%)
occurrences all number	157	176
Gynaecological Chlamydia infection
subjects affected / exposed	1035 / 9319 (11.11%)	1085 / 9325 (11.64%)
occurrences all number	1035	1085

Notes
[1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Assessment for this event for this phase was performed solely on subjects with their symptom sheets completed.
[2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Assessment for this event for this phase was performed solely on subjects with their symptom sheets completed.
[3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Assessment for this event for this phase was performed solely on subjects with their symptom sheets completed.
[4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Assessment for this event for this phase was performed solely on subjects with their symptom sheets completed.
[5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Assessment for this event for this phase was performed solely on subjects with their symptom sheets completed.
[6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Assessment for this event for this phase was performed solely on subjects with their symptom sheets completed.
[7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Assessment for this event for this phase was performed solely on subjects with their symptom sheets completed.
[8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Assessment for this event for this phase was performed solely on subjects with their symptom sheets completed.
[9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Assessment for this event for this phase was performed solely on subjects with their symptom sheets completed.
[10] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Assessment for this event for this phase was performed solely on subjects with their symptom sheets completed.
[11] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Assessment for this event for this phase was performed solely on subjects with their symptom sheets completed.
[12] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
Justification: Assessment for this event for this phase was performed solely on subjects with their symptom sheets completed.

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Were there any global substantial amendments to the protocol? Yes

03 Dec 2004

In order to improve the robustness of the data on vaccine efficacy in the prevention of CIN2+ lesions, the final analysis will be performed when 36 cases of CIN2+ associated with HPV-16 and/or HPV-18 cervical infection in the ATP cohort are confirmed. This will allow the sponsor to perform the HPV-008 study as a stand alone trial (without the need of pooling with study HPV-009). Therefore, a total of 18,000 subjects will be enrolled (instead of 13,000) and the overall targeted recruitment period will be approximately 15 months. Further timings will be unchanged and there will be no impact on the recruitment strategy for immunogenicity and safety subsets. In order to strengthen the association of histopathologically confirmed CIN2+ with HPV-16 or HPV-18 cervical infection for the primary objective, PCR analysis will be performed on the lesional component of the tissue specimen (not on the preceding cytological specimen). Validation studies of this methodology have been performed. As the specificity of the Amplicor® screening test is not optimal for Neisseria gonorrhea (i.e. false positives since sensitivity of the test is high), a confirmatory test is offered (Aptima Combo 2 assay® by Gen-Probe Inc., San Diego, USA). In addition, this test (Aptima Combo 2 assay®) may be run on samples reported as “equivocal” or “inhibitory” for either Neisseria gonorrhea or Chlamydia trachomatis after Amplicor® testing. Data from the HPV-001 pilot efficacy study have been published in The Lancet medical journal. Reference to this publication has been made. A number of logistic procedures have been updated, i.e. contact addresses, the storage temperature of endocervical specimen and the type of endocervical brush to be used. The protocol has been reformatted to meet GSK Biologicals’ @standard requirements.

17 Aug 2005

As the total number of study subjects has increased to 18,000 (see amendment 1), CIN2+ efficacy data will be available at the time of the first interim analysis. Therefore, the analysis plan has been simplified: one interim analysis will be performed (to evaluate safety, efficacy and immunogenicity) when at least 23 cases of CIN2+ associated with HPV-16/18 infection have been detected. In addition, pooling with data from study HPV-009 is no longer required to provide a robust estimate of overall vaccine efficacy in the prevention of CIN2+ associated with HPV-16 or HPV-18 infection. Therefore, the protocol has been adapted accordingly. A prospective meta-analysis however may still be considered. The protocol has been updated to indicate that for solicited and unsolicited adverse events school or work absenteeism (as applicable) will be recorded besides occurrence, intensity and relationship to vaccination. In addition, we have clarified the post-vaccination time period for collecting unsolicited AEs which ends 30 days after each dose of study vaccine, meaning days 0-29. The clinical management algorithms have been updated to indicate that women with ASC-US/oncogenic HPV positive results or LSIL may be immediately referred for colposcopic evaluation. The protocol has been updated to take into account that in certain populations with very low prevalence of Neisseria gonorrhea infection, the benefits of screening for Neisseria gonorrhea infection in test subjects may not outweigh the risks and inconveniences associated with the false positive test results that would result from screening a low prevalence population. In such cases, investigators may decide to forgo testing for Neisseria gonorrhea in their study subjects. At Visit 1 (Month 0), concomitant medication/vaccination needs to be recorded.Anti-HPV-16/18 ELISA will be performed in all subjects at Month 0.

27 Jul 2006

Merck’'s HPV vaccine, Gardasil®, has been licensed and is now becoming commercially available in an increasing number of countries. Therefore, the study procedures have been revised to include questions at every visit to determine if subjects have received an HPV vaccine outside of the study. Data obtained after a subject has been found to have received an HPV vaccine outside of the study will be confounded, and therefore such subjects will be withdrawn from further participation in the study. Data from subjects who request information about their treatment group assignment (i.e., request unblinding) to determine if they will consider immunization with a licensed HPV vaccine outside of the study will be similarly confounded; therefore such subjects will be withdrawn from further participation in the study after they are unblinded. The analysis plan for vaccine efficacy against persistent infection with oncogenic HPV types has been slightly modified. Because of the limited number of persistent infections (12-month definition) expected at time of the interim analysis, persistent infection (6-month definition) will replace persistent infection (12-month definition) as a secondary endpoint. Consequently, vaccine efficacy against persistent infection (12-month definition) will be evaluated as exploratory endpoint. Additional exploratory objectives have been included as vaccine efficacy will also be evaluated against histopathologically confirmed vulval and vaginal intraepithelial neoplasia (VIN and VAIN). The analysis of safety has been further clarified for pregnancies, new onset chronic diseases and medically significant AEs (as detailed in the RAP). In case an autoimmune disease is diagnosed during the study, autoantibody testing may be performed on baseline sera collected at Month 0 and other sera samples collected during the study if agreed by the subject (see Section 8.1.1). Data from the HPV-007 long-term efficacy study have been published in The Lancet med.

17 Mar 2008

The aim of the current protocol amendment is to clarify the cross-over immunization procedure for subjects at their last study visit: • It was previously described that all subjects would be offered cross-over immunization after the trial was completed. Following the results of the interim analysis, it was recommended by the IDMC to provide the option of cross-over immunization after the database is frozen for final analysis. • Each subject will be informed of the possibility of requesting unblinding after completion of their end of study activities (Visit 10, Month 48) and of the procedure involved. • Exit colposcopy for women that have normal cytology and are high-risk HPV negative at the end of the study has been removed • For all histopathological outcomes, an exploratory analysis referred to as “HPV type assignment algorithm” will be assessed. In this analysis, the association with HPV types will be based not only on the detection of HPV DNA in the lesion, but also will consider the presence of HPV types in the two immediately preceding cytology samples in case more than one HPV type was found in the lesion. • The secondary endpoint for immunogenicity regarding vaccine breakthrough cases has been modified to state that inhibition and/or neutralisation assays may be performed in addition to ELISA assays on these samples. • Priority ranking for serology assays has been modified to place neutralization assays above inhibitions assays • Recent references regarding the HPV vaccine and results of the interim analysis of this study are included and the reference to the investigator brochure is updated. • Clarification of suspension of study related pelvic examinations during pregnancy, and guidance for collection of vaginal and vulval samples are added. • Reference to other vaccines containing MPL and licensure of Cervarix in some countries has been added. • Material Safety Data Sheets have been updated

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of subjects with histopathologically-confirmed cervical intraepithelial neoplasia (CIN)2+ associated with HPV-16 and/or -18 cervical infection in subjects HPV DNA negative and seronegative at baseline or overall (any serostatus at baseline)

Primary: Number of subjects with histopathologically-confirmed cervical intraepithelial neoplasia (CIN)2+ associated with HPV-16 and/or -18 cervical infection in subjects HPV DNA negative and seronegative at baseline or overall (any serostatus at baseline)

Primary: Number of subjects with histopathologically-confirmed cervical intraepithelial neoplasia (CIN)2+ associated with HPV-16 and/or -18 cervical infection in subjects HPV DNA negative and seronegative at baseline or overall (any serostatus at baseline)

Primary: Number of subjects with histopathologically-confirmed cervical intraepithelial neoplasia (CIN)2+ associated with HPV-16 and/or -18 cervical infection in subjects HPV DNA negative and seronegative at baseline or overall (any serostatus at baseline)

Secondary: Number of subjects reporting solicited local and general symptoms

Secondary: Number of subjects reporting solicited local and general symptoms

Secondary: Number of subjects reporting unsolicited adverse events

Secondary: Number of subjects reporting unsolicited adverse events

Secondary: Number of subjects reporting serious adverse events (SAEs)

Secondary: Number of subjects reporting serious adverse events (SAEs)

Secondary: Number of subjects reporting new onset of chronic disease (NOCDs)

Secondary: Number of subjects reporting new onset of chronic disease (NOCDs)

Secondary: Number of subjects reporting medically significant conditions

Secondary: Number of subjects reporting medically significant conditions

Secondary: Number of subjects with outcome of pregnancies, overall and stratified by initial (Month 0) HPV-16/18 DNA status and according to HPV-16 or -18 serostatus

Secondary: Number of subjects with outcome of pregnancies, overall and stratified by initial (Month 0) HPV-16/18 DNA status and according to HPV-16 or -18 serostatus

Secondary: Number of subjects with persistent infection (6-month definition) with HPV-16 or HPV-18

Secondary: Number of subjects with persistent infection (6-month definition) with HPV-16 or HPV-18

Secondary: Number of subjects with persistent infection (6-month definition) with HPV-16 or HPV-18

Secondary: Number of subjects with persistent infection (6-month definition) with HPV-16 or HPV-18

Secondary: Number of subjects with persistent infection (6-month definition) with oncogenic HPV types

Secondary: Number of subjects with persistent infection (6-month definition) with oncogenic HPV types

Secondary: Number of Subjects With Persistent Infection (6-month Definition) With Oncogenic HPV Types

Secondary: Number of Subjects With Persistent Infection (6-month Definition) With Oncogenic HPV Types

Secondary: Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 or HPV-18 Detected Within the Lesional Component of the Cervical Tissue Specimen

Secondary: Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 or HPV-18 Detected Within the Lesional Component of the Cervical Tissue Specimen

Secondary: Number of subjects with histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ associated with HPV-16 or HPV-18 detected within the lesional component of the cervical tissue specimen

Secondary: Number of subjects with histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ associated with HPV-16 or HPV-18 detected within the lesional component of the cervical tissue specimen

Secondary: Number of subjects reporting persistent infection (12-month definition) with HPV-16 or HPV-18

Secondary: Number of subjects reporting persistent infection (12-month definition) with HPV-16 or HPV-18

Secondary: Number of Subjects Reporting Persistent Infection (12-month Definition) With HPV-16 or HPV-18

Secondary: Number of Subjects Reporting Persistent Infection (12-month Definition) With HPV-16 or HPV-18

Secondary: Number of subjects with histopathologically confirmed Cervical Intraepithelial Neoplasia (CIN)1+ associated with oncogenic HPV types detected within the lesional component of the cervical tissue specimen

Secondary: Number of subjects with histopathologically confirmed Cervical Intraepithelial Neoplasia (CIN)1+ associated with oncogenic HPV types detected within the lesional component of the cervical tissue specimen

Secondary: Number of Subjects With Histopathologically Confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With Oncogenic HPV Types Detected Within the Lesional Component of the Cervical Tissue Specimen

Secondary: Number of Subjects With Histopathologically Confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With Oncogenic HPV Types Detected Within the Lesional Component of the Cervical Tissue Specimen

Secondary: Number of subjects with histopathologically confirmed Cervical Intraepithelial Neoplasia (CIN)2+ associated with oncogenic HPV types detected within the lesional component of the cervical tissue specimen

Secondary: Number of subjects with histopathologically confirmed Cervical Intraepithelial Neoplasia (CIN)2+ associated with oncogenic HPV types detected within the lesional component of the cervical tissue specimen

Secondary: Number of subjects with histopathologically confirmed Cervical Intraepithelial Neoplasia (CIN)2+ associated with oncogenic HPV types detected within the lesional component of the cervical tissue specimen

Secondary: Number of subjects with histopathologically confirmed Cervical Intraepithelial Neoplasia (CIN)2+ associated with oncogenic HPV types detected within the lesional component of the cervical tissue specimen

Secondary: Number of seropositive subjects for anti-HPV-16 and anti-HPV-18 antibody titers by ELISA in the immunogenicity subset, according to initial (Month 0) HPV-16 or HPV-18 serostatus

Secondary: Number of seropositive subjects for anti-HPV-16 and anti-HPV-18 antibody titers by ELISA in the immunogenicity subset, according to initial (Month 0) HPV-16 or HPV-18 serostatus

Secondary: Anti-HPV-16 and anti-HPV-18 ELISA titers in the immunogenicity subset

Secondary: Anti-HPV-16 and anti-HPV-18 ELISA titers in the immunogenicity subset

Secondary: HPV-16 and HPV-18 seroconversion (V5/J4 monoclonal inhibition test)

Secondary: HPV-16 and HPV-18 seroconversion (V5/J4 monoclonal inhibition test)

Secondary: HPV-16 and HPV-18 Geometric Mean Titers (GMT) (V5/J4 monoclonal inhibition test)

Secondary: HPV-16 and HPV-18 Geometric Mean Titers (GMT) (V5/J4 monoclonal inhibition test)

Secondary: Number of subjects seropositive for anti-HPV-16 and anti-HPV-18 antibodies using pseudovirion based neutralizing assay (PBNA)

Secondary: Number of subjects seropositive for anti-HPV-16 and anti-HPV-18 antibodies using pseudovirion based neutralizing assay (PBNA)

Secondary: Titers for anti-HPV-16 and anti-HPV-18 antibodies using pseudovirion based neutralizing assay (PBNA)

Secondary: Titers for anti-HPV-16 and anti-HPV-18 antibodies using pseudovirion based neutralizing assay (PBNA)

Secondary: Geometric mean titers of anti-HPV-16 in subjects without and with 6-month persistent infection

Secondary: Geometric mean titers of anti-HPV-16 in subjects without and with 6-month persistent infection

Secondary: Number of seroconverted subjects for anti-HPV-16 without and with 6-month persistent infection

Secondary: Number of seroconverted subjects for anti-HPV-16 without and with 6-month persistent infection

Secondary: Geometric mean titers of anti-HPV-16 in subjects without and with 12-month persistent infection

Secondary: Geometric mean titers of anti-HPV-16 in subjects without and with 12-month persistent infection

Secondary: Number of seroconverted subjects for anti-HPV-16 without and with 12-month persistent infection

Secondary: Number of seroconverted subjects for anti-HPV-16 without and with 12-month persistent infection

Secondary: Geometric mean titers of anti-HPV-18 in subjects without and with 6-month persistent infection

Secondary: Geometric mean titers of anti-HPV-18 in subjects without and with 6-month persistent infection

Secondary: Number of seroconverted subjects for anti-HPV-18 without and with 6- month persistent infection

Secondary: Number of seroconverted subjects for anti-HPV-18 without and with 6- month persistent infection

Secondary: Geometric mean titers of anti-HPV-18 in subjects without and with 12-month persistent infection

Secondary: Geometric mean titers of anti-HPV-18 in subjects without and with 12-month persistent infection

Secondary: Number of seroconverted subjects for anti-HPV-18 without and with 12-month persistent infection

Secondary: Number of seroconverted subjects for anti-HPV-18 without and with 12-month persistent infection

Adverse events

Adverse events

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