Human Papilloma Virus (HPV) Vaccine Efficacy Trial Against Cervical Pre-cancer in Young Adults With GlaxoSmithKline (GSK) Biologicals HPV-16/18

This study has been completed.

Sponsor:

Information provided by:

GlaxoSmithKline

ClinicalTrials.gov Identifier:

NCT00122681

First received: July 20, 2005

Last updated: February 23, 2012

Last verified: February 2012

History of Changes

Results First Received: November 30, 2009

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Investigator); Primary Purpose: Prevention
Conditions:	Human Papillomavirus (HPV) Infection Cervical Neoplasia
Interventions:	Biological: Cervarix™ Biological: Havrix™-based investigational formulation

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups

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

Participant Flow: Overall Study

	Havrix Group	Cervarix Group
STARTED	9325	9319
COMPLETED	7811	7798
NOT COMPLETED	1514	1521
Adverse Event	20	16
Lost to Follow-up	1080	1097
Protocol Violation	7	10
Withdrawal by Subject	257	251
Personal reasons	150	147

Baseline Characteristics

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Reporting Groups

	Description
Havrix Group	Subjects received 3 doses of GSK Biologicals' hepatitis A vaccine [HAV] (Havrix™-based investigational formulation) at Months 0, 1 and 6.
Cervarix Group	Subjects received 3 doses of Cervarix™ (GSK Biologicals' human papillomavirus [HPV] vaccine) at Months 0, 1 and 6.
Total	Total of all reporting groups

Baseline Measures

	Havrix Group	Cervarix Group	Total
Number of Participants [units: participants]	9325	9319	18644
Age [units: years] Mean ± Standard Deviation	20.0 ± 3.12	20.0 ± 3.10	20.0 ± 3.11
Gender [units: subjects]
Female	9325	9319	18644
Male	0	0	0

Outcome Measures

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1. Primary:

Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With HPV-16 and/or -18 Cervical Infection [ Time Frame: 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 ]

Show Outcome Measure 1

2. Primary:

Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With HPV-16 and/or -18 Cervical Infection [ Time Frame: at Month 48 ]

Show Outcome Measure 2

3. Secondary:

Number of Subjects Reporting Solicited Local and General Symptoms [ Time Frame: Within 7 days after any vaccination ]

Hide Outcome Measure 3

Measure Type	Secondary
Measure Title	Number of Subjects Reporting Solicited Local and General Symptoms
Measure 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.
Time Frame	Within 7 days after any vaccination
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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-).

Reporting Groups

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

Measured Values

	Havrix Group	Cervarix Group
Number of Participants Analyzed [units: participants]	3081	3078
Number of Subjects Reporting Solicited Local and General Symptoms [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 analysis provided for Number of Subjects Reporting Solicited Local and General Symptoms

4. Secondary:

Number of Subjects Reporting Unsolicited Adverse Events [ Time Frame: Within 30 days after any vaccination ]

Show Outcome Measure 4

5. Secondary:

Number of Subjects Reporting Serious Adverse Events (SAEs) [ Time Frame: Throughout the entire study period (Month 0 to Month 48) ]

Show Outcome Measure 5

6. Secondary:

Number of Subjects Reporting New Onset of Chronic Disease (NOCDs) [ Time Frame: Throughout the entire study (Month 0 to 48) ]

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7. Secondary:

Number of Subjects Reporting Medically Significant Conditions [ Time Frame: Throughout entire study period (Month 0 to Month 48) ]

Show Outcome Measure 7

8. 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 [ Time Frame: Throughout the entire study period (Month 0 to Month 48) ]

Show Outcome Measure 8

9. Secondary:

Number of Subjects With Persistent Infection (6-month Definition) With HPV-16 or HPV-18 [ Time Frame: 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 ]

Show Outcome Measure 9

10. Secondary:

Number of Subjects With Persistent Infection (6-month Definition) With HPV-16 or HPV-18 [ Time Frame: at Month 48 ]

Show Outcome Measure 10

11. Secondary:

Number of Subjects With Persistent Infection (6-month Definition) With Oncogenic HPV Types [ Time Frame: 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 ]

Show Outcome Measure 11

12. Secondary:

Number of Subjects With Persistent Infection (6-month Definition) With Oncogenic HPV Types [ Time Frame: at Month 48 ]

Show Outcome Measure 12

13. 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 [ Time Frame: 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 ]

Show Outcome Measure 13

14. Secondary:

Show Outcome Measure 14

15. Secondary:

Number of Subjects Reporting Persistent Infection (12-month Definition) With HPV-16 or HPV-18 [ Time Frame: 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 ]

Show Outcome Measure 15

16. Secondary:

Number of Subjects Reporting Persistent Infection (12-month Definition) With HPV-16 or HPV-18 [ Time Frame: at Month 48 ]

Show Outcome Measure 16

17. 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 [ Time Frame: 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 ]

Show Outcome Measure 17

18. Secondary:

Show Outcome Measure 18

19. 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 [ Time Frame: 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 ]

Show Outcome Measure 19

20. Secondary:

Show Outcome Measure 20

21. 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 [ Time Frame: At Months 6, 7, 12, 24, 36 & 48 ]

Show Outcome Measure 21

22. Secondary:

Anti-HPV-16 and Anti-HPV-18 ELISA Titers in the Immunogenicity Subset [ Time Frame: At Months 6, 7, 12, 24, 36 and 48 ]

Show Outcome Measure 22

23. Secondary:

HPV-16 and HPV-18 Seroconversion (V5/J4 Monoclonal Inhibition Test) [ Time Frame: Month 0, 7, 12 and 24 ]

Show Outcome Measure 23

24. Secondary:

HPV-16 and HPV-18 Geometric Mean Titers (GMT) (V5/J4 Monoclonal Inhibition Test) [ Time Frame: Month 0, 7, 12, 24 ]

Show Outcome Measure 24

25. Secondary:

Number of Subjects Seropositive for Anti-HPV-16 and Anti-HPV-18 Antibodies Using Pseudovirion Based Neutralizing Assay (PBNA) [ Time Frame: At Month 0, 7, 12, 24, 36 and 48 ]

Show Outcome Measure 25

26. Secondary:

Titers for Anti-HPV-16 and Anti-HPV-18 Antibodies Using Pseudovirion Based Neutralizing Assay (PBNA) [ Time Frame: At month 0, 7, 12, 24, 36 and 48 ]

Show Outcome Measure 26

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact:

Name/Title: GSK Response Center
Organization: GlaxoSmithKline
phone: 866-435-7343

Publications:

Romanowski B et al. Clinical benefit of the AS04-adjuvanted human papillomavirus 16/18 vaccine against CIN2+ related to the 5 most common oncogenic HPV types: PATRICIA trial. Abstract presented at IDSA. Philadelphia, USA, 29 October-1 November, 2009.

Naud P et al. Cross-protective efficacy of the ASO4-adjuvanted HPV-16/18 vaccine against oncogenic HPV-31, -33 and - 45. Abstract presented at European Research Organization on Genital Infection and Neoplasia 2010 (EUROGIN). Monte Carlo, Monaco, 17-20 February 2010.

Skinner R. S et al. Cross-protective efficacy of Cervarix™ against oncogenic HPV types beyond HPV-16/18. Abstract presented at International Papillomavirus Conference and Clinical Workshop (IPvC). Malmo, Sweden, 8-14 May 2009.

Kitchener H et al. Cross-protective efficacy of the AS04-adjuvanted HPV-16/18 vaccine in oncogenic HPV infection-naïve women: results from a double-blind, randomised, Phase III trial (PATRICIA). Abstract presented at the 16th International Meeting of European Society of Gynaecological Oncology. Belgrade, Serbia, 11-14 October 2009.

Paavonen J, Naud P, Salmerón J, Wheeler CM, Chow SN, Apter D, Kitchener H, Castellsague X, Teixeira JC, Skinner SR, Hedrick J, Jaisamrarn U, Limson G, Garland S, Szarewski A, Romanowski B, Aoki FY, Schwarz TF, Poppe WA, Bosch FX, Jenkins D, Hardt K, Zahaf T, Descamps D, Struyf F, Lehtinen M, Dubin G; HPV PATRICIA Study Group; Greenacre M. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet. 2009 Jul 25;374(9686):301-14. Epub 2009 Jul 6.

Descamps D et al. (2009) Safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine for cervical cancer prevention: A pooled analysis of 11 clinical trials. Hum Vaccin. 5(5):51-59.

Wacholder S et al. (2010) Risk of miscarriage with bivalent vaccine against human papillomavirus (HPV) types 16 and 18: pooled analysis of two randomised controlled trials. BMJ. 340:c712

Szarewski A et al. Cross-protective efficacy of CervarixTM against oncogenic types beyond HPV-16/18 : analysis of the According-to-Protocol (ATP) cohort in a double blind, randomized controlled Phase III efficacy trial. Abstract presented at FIGO 2009 - 19th World Congress of Gynecology & Obstetrics. Cape Town, South Africa, 4-9 October, 2009.

Paavonen J, Jenkins D, Bosch FX, Naud P, Salmeron J, Wheeler CM, Chow SN, Apter DL, Kitchener HC, Castellsague X, de Carvalho NS, Skinner SR, Harper DM, Hedrick JA, Jaisamrarn U, Limson GA, Dionne M, Quint W, Spiessens B, Peeters P, Struyf F, Wieting SL, Lehtinen MO, Dubin G; HPV PATRICIA study group. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet. 2007 Jun 30;369(9580):2161-70.

Verstraeten T, Descamps D, David MP, Zahaf T, Hardt K, Izurieta P, Dubin G, Breuer T. Analysis of adverse events of potential autoimmune aetiology in a large integrated safety database of AS04 adjuvanted vaccines. Vaccine. 2008 Dec 2;26(51):6630-8.

Wheeler C et al. Cross-protective efficacy of the AS04-adjuvanted human papillomavirus (HPV)-16/18 vaccine against cervical intraepithelial neoplasia 2+ in a Phase III, double-blind, randomised trial (PATRICIA). Abstract presented at the 16th International Meeting of European Society of Gynaecological Oncology. Belgrade, Serbia, 11-14 October 2009.

Chow SN et al. Efficacy of the HPV-16/18 AS04-adjuvanted vaccine against abnormal cytology and reduction in colposcopy referrals and cervical excisions in an HPV-negative population. Abstract presented at the 16th International Meeting of European Society of Gynaecological Oncology. Belgrade, Serbia, 11-14 October 2009.

Poppe W et al. Vaccine efficacy in women with evidence of prior HPV-16/18 infection and incomplete protection by natural immunity: analysis from a Phase III, double blind, randomised trial of the AS04-adjuvanted HPV-16/18 vaccine. Abstract presented at the 16th International Meeting of European Society of Gynaecological Oncology. Belgrade, Serbia, 11-14 October 2009.

Tjalma W et al. Efficacy of the HPV-16/18 AS04-adjuvanted vaccine against abnormal cytology and low-grade histopathological lesions in an oncogenic HPV-naïve population. Abstract presented at the 16th International Meeting of European Society of Gynaecological Oncology. Belgrade, Serbia, 11-14 October 2009.

Publications automatically indexed to this study:

Roset Bahmanyar E, Paavonen J, Naud P, Salmerón J, Chow SN, Apter D, Kitchener H, Castellsagué X, Teixeira JC, Skinner SR, Jaisamrarn U, Limson GA, Garland SM, Szarewski A, Romanowski B, Aoki F, Schwarz TF, Poppe WA, De Carvalho NS, Harper DM, Bosch FX, Raillard A, Descamps D, Struyf F, Lehtinen M, Dubin G; HPV PATRICIA Study Group. Prevalence and risk factors for cervical HPV infection and abnormalities in young adult women at enrolment in the multinational PATRICIA trial. Gynecol Oncol. 2012 Dec;127(3):440-50. doi: 10.1016/j.ygyno.2012.08.033. Epub 2012 Aug 30.

Lehtinen M, Paavonen J, Wheeler CM, Jaisamrarn U, Garland SM, Castellsagué X, Skinner SR, Apter D, Naud P, Salmerón J, Chow SN, Kitchener H, Teixeira JC, Hedrick J, Limson G, Szarewski A, Romanowski B, Aoki FY, Schwarz TF, Poppe WA, De Carvalho NS, Germar MJ, Peters K, Mindel A, De Sutter P, Bosch FX, David MP, Descamps D, Struyf F, Dubin G; HPV PATRICIA Study Group. Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol. 2012 Jan;13(1):89-99. Epub 2011 Nov 8.

Wheeler CM, Castellsagué X, Garland SM, Szarewski A, Paavonen J, Naud P, Salmerón J, Chow SN, Apter D, Kitchener H, Teixeira JC, Skinner SR, Jaisamrarn U, Limson G, Romanowski B, Aoki FY, Schwarz TF, Poppe WA, Bosch FX, Harper DM, Huh W, Hardt K, Zahaf T, Descamps D, Struyf F, Dubin G, Lehtinen M; HPV PATRICIA Study Group. Cross-protective efficacy of HPV-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by non-vaccine oncogenic HPV types: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol. 2012 Jan;13(1):100-10. Epub 2011 Nov 8.

Szarewski A, Poppe WA, Skinner SR, Wheeler CM, Paavonen J, Naud P, Salmeron J, Chow SN, Apter D, Kitchener H, Castellsagué X, Teixeira JC, Hedrick J, Jaisamrarn U, Limson G, Garland S, Romanowski B, Aoki FY, Schwarz TF, Bosch FX, Harper DM, Hardt K, Zahaf T, Descamps D, Struyf F, Lehtinen M, Dubin G; HPV PATRICIA Study Group. Efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in women aged 15-25 years with and without serological evidence of previous exposure to HPV-16/18. Int J Cancer. 2012 Jul 1;131(1):106-16. doi: 10.1002/ijc.26362. Epub 2011 Oct 23.

Wacholder S, Chen BE, Wilcox A, Macones G, Gonzalez P, Befano B, Hildesheim A, Rodríguez AC, Solomon D, Herrero R, Schiffman M; CVT group. Risk of miscarriage with bivalent vaccine against human papillomavirus (HPV) types 16 and 18: pooled analysis of two randomised controlled trials. BMJ. 2010 Mar 2;340:c712.

Responsible Party:	Cheri Hudson; Clinical Disclosure Advisor, GSK Clinical Disclosure
ClinicalTrials.gov Identifier:	NCT00122681 History of Changes
Other Study ID Numbers:	580299/008
Study First Received:	July 20, 2005
Results First Received:	November 30, 2009
Last Updated:	February 23, 2012
Health Authority:	United States: Food and Drug Administration

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