Cervical Intraepithelial Neoplasm (CIN)-Warts Efficacy Trial in Women (Gardasil) - Study Results

Study Type:	Interventional
Study Design:	Randomized, Double Blind (Subject, Investigator), Placebo Control, Parallel Assignment
Conditions:	Cervical Cancer Genital Warts
Interventions:	Biological: V501 Biological: Comparator: Placebo Biological: HPV 16 Monovalent

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
The study Protocol 013 (NCT00092521) (N =5759 total randomized) was compromised of two sub-studies: Protocol 011 (NCT00517309) (N=1877 total randomized) and Protocol 012 (NCT00092482) (N=3882 total randomized). Final safety data are presented in the results for Protocol 013 (NCT00092521).

Pre-Assignment Details

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

	Description
Group 1 - Base Study Quadrivalent Human Papillomavirus Vaccine	The Vaccination Period for the base study encompassed Day 1 through Month 7, during which time study subjects in Group 1 were vaccinated (at Day 1, Month 2 and Month 6) with the Quadrivalent HPV vaccine. The Follow-up Period for the Base Study encompassed the follow-up of subjects who had received the Quadrivalent HPV vaccine; from completion of the Vaccination Period at Month 7 through Month 48 of the study.
Group 2 - Base Study Monovalent HPV (Type 16) Vaccine	The Vaccination Period for the base study encompassed Day 1 through Month 7, during which time study subjects in Group 2 were vaccinated (at Day 1, Month 2 and Month 6) with the Monovalent (HPV 16) HPV vaccine. The Follow-up Period for the Base Study encompassed the follow-up of subjects who had received the Monovalent (HPV 16) HPV vaccine; from completion of the Vaccination Period at Month 7 through Month 48 of the study. Group 2 Base Study Monovalent HPV (Type 16) Vaccine was not part of the pre-specified efficacy analysis population.
Group 3 - Base Study Placebo	The Vaccination Period for the base study encompassed Day 1 through Month 7, during which time study subjects in Group 3 were vaccinated (at Day 1, Month 2 and Month 6) with placebo. The Follow-up Period for the Base Study encompassed the follow-up of subjects who had received placebo; from completion of the Vaccination Period at Month 7 through Month 48 of the study.
Group 4 - Quadrivalent Human Papillomavirus Vaccine Extension	This group includes 844 subjects who entered the extension including subjects who in the base study received fewer than the full three doses of Quadrivalent HPV vaccine during the base study (i.e., subjects who received placebo in the base study; subjects who received monovalent [type 16] HPV vaccine in the base study, or subjects who received ≥ 2 doses of quadrivalent HPV vaccine in the base study). Subjects who discontinued the base portion of the study could enter the extension portion of the study. In the extension period subjects designated as "Completed Period" are those who received three doses of quadrivalent HPV vaccine and completed all required follow-up visits. Subjects designated as "Not Completed" are those who: a) Received all three vaccinations, but did not complete follow-up; b) Did not receive all vaccinations, but completed follow-up, or c) Did not receive all vaccinations, and did not complete follow-up).

Participant Flow for 3 periods

Period: Vaccination (Day 1 Through Month 7)

	Group 1 - Base Study Quadrivalent Human Papillomavirus Vaccine	Group 2 - Base Study Monovalent HPV (Type 16) Vaccine	Group 3 - Base Study Placebo
STARTED	2723	304	2732
COMPLETED	2582	290	2587
NOT COMPLETED	141	14	145
Randomized Not Vaccinated	6	0	7
Adverse Event	1	0	7
Death	1	0	0
Lost to Follow-up	51	6	44
Pregnancy	5	0	7
Withdrawal by Subject	59	7	62
Moved	14	1	18
Unblinded	2	0	0
New Medical History (Not AE)	2	0	0

Period: Follow-Up (After Month 7)

	Group 1 - Base Study Quadrivalent Human Papillomavirus Vaccine	Group 2 - Base Study Monovalent HPV (Type 16) Vaccine	Group 3 - Base Study Placebo
STARTED	2599^[1]	291^[2]	2607^[3]
COMPLETED	2354	155	1959
NOT COMPLETED	245	136	648
Subjects Continuing	34	4	35
Subjects in Extension	13	109	412
Adverse Event	1	0	0
Death	1	0	1
Lost to Follow-up	113	14	108
Protocol Violation	1	1	5
Withdrawal by Subject	40	6	51
Moved	32	2	28
Site Terminated	3	0	3
Travel	2	0	0
Visits Compressed	5	0	5

[1]	Includes subjects who did not receive 3 doses of vaccine/placebo but continued into the follow-up
[2]	Includes subjects who did not receive 3 doses of vaccine/placebo but continued into the follow-up
[3]	Includes subjects who did not receive 3 doses of vaccine/placebo but continued into the follow-up

Period: Extension Study (Group 4)

	Group 1 - Base Study Quadrivalent Human Papillomavirus Vaccine	Group 2 - Base Study Monovalent HPV (Type 16) Vaccine	Group 3 - Base Study Placebo	Group 4 - Quadrivalent Human Papillomavirus Vaccine Extension
STARTED	0	0	0	844
COMPLETED	0	0	0	635
NOT COMPLETED	0	0	0	209
Excluded ineligible for extension	0	0	0	23
Adverse Event	0	0	0	2
Lost to Follow-up	0	0	0	87
Pregnancy	0	0	0	4
Protocol Violation	0	0	0	2
Withdrawal by Subject	0	0	0	46
Moved	0	0	0	16
Site Terminated	0	0	0	4
Unable/unwilling to return	0	0	0	25

Baseline Characteristics

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Reporting Groups

Description

Group 1 - Base Study Quadrivalent Human Papillomavirus Vaccine

The Vaccination Period for the base study encompassed Day 1 through Month 7, during which time study subjects in Group 1 were vaccinated (at Day 1, Month 2 and Month 6) with the Quadrivalent HPV vaccine.

The Follow-up Period for the Base Study encompassed the follow-up of subjects who had received the Quadrivalent HPV vaccine; from completion of the Vaccination Period at Month 7 through Month 48 of the study.

Group 2 - Base Study Monovalent HPV (Type 16) Vaccine

The Vaccination Period for the base study encompassed Day 1 through Month 7, during which time study subjects in Group 2 were vaccinated (at Day 1, Month 2 and Month 6) with the Monovalent (HPV 16) HPV vaccine.

The Follow-up Period for the Base Study encompassed the follow-up of subjects who had received the Monovalent (HPV 16) HPV vaccine; from completion of the Vaccination Period at Month 7 through Month 48 of the study.

Group 3 - Base Study Placebo

The Vaccination Period for the base study encompassed Day 1 through Month 7, during which time study subjects in Group 3 were vaccinated (at Day 1, Month 2 and Month 6) with placebo.

The Follow-up Period for the Base Study encompassed the follow-up of subjects who had received placebo; from completion of the Vaccination Period at Month 7 through Month 48 of the study.

Baseline Measures

	Group 1 - Base Study Quadrivalent Human Papillomavirus Vaccine	Group 2 - Base Study Monovalent HPV (Type 16) Vaccine	Group 3 - Base Study Placebo	Total
Number of Participants [units: participants]	2723	304	2732	5759
Age, Customized^[1] [units: Participants]
16 to 24 Years of Age	2723	304	2732	5759
Age [units: years] Mean ± Standard Deviation	20.2 ± 1.8	20.2 ± 1.74	20.3 ± 1.8	20.3 ± 1.8
Age [units: Years] Median ( Full Range )	20 ( 16 to 24 )	20 ( 16 to 24 )	20 ( 16 to 24 )	20 ( 16 to 24 )
Gender [units: participants]
Female	2723	304	2732	5759
Male	0	0	0	0
Race/Ethnicity, Customized [units: participants]
Asian	151	27	165	343
Black	136	5	167	308
Hispanic American	567	93	566	1226
Native American	10	2	10	22
White	1600	171	1558	3329
Other - Unspecified	259	6	266	531

[1]	Although the upper age limit for this study was 23 years old, four subjects aged 24 were randomized into the study.

Outcome Measures

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1. Primary:

Incidence of HPV 6/11/16/18-related Cervical Intraepithelial Neoplasia (CIN)(Any Grade), Adenocarcinoma In Situ (AIS) or Cervical Cancer

Show Outcome Measure 1

2. Primary:

Incidence of HPV 6/11/16/18-related External Genital Lesions (EGL) [Genital Warts, Vulvar/Vaginal Intraepithelial Neoplasia (Any Grade), Vulvar/Vaginal Cancer]

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Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

All Principal Investigators ARE employed by the organization sponsoring the study.

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
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Results Point of Contact:

Name/Title: Executive Vice President, Clinical and Quantitative Sciences
Organization: Merck & Co., Inc.
phone: 1-800-672-6372

Publications:

Garland SM, Steben M, Sings HL, James M, Lu S, Railkar R, Barr E, Haupt RM, Joura EA. Natural History of Genital Warts: Analysis of the Placebo Arm of 2 Randomized Phase III Trials of a Quadrivalent Human Papillomavirus (Types 6, 11, 16, and 18) Vaccine. J Infect Dis. 2009 Jan 26; [Epub ahead of print]

Barr E, Gause CK, Bautista OM, Railkar RA, Lupinacci LC, Insinga RP, Sings HL, Haupt RM. Impact of a prophylactic quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 virus-like particle vaccine in a sexually active population of North American women. Am J Obstet Gynecol. 2008 Mar;198(3):261.e1-11.

Garland SM, Hernandez-Avila M, Wheeler CM, Perez G, Harper DM, Leodolter S, Tang GW, Ferris DG, Steben M, Bryan J, Taddeo FJ, Railkar R, Esser MT, Sings HL, Nelson M, Boslego J, Sattler C, Barr E, Koutsky LA; Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I Investigators. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med. 2007 May 10;356(19):1928-43.

Joura EA, Leodolter S, Hernandez-Avila M, Wheeler CM, Perez G, Koutsky LA, Garland SM, Harper DM, Tang GW, Ferris DG, Steben M, Jones RW, Bryan J, Taddeo FJ, Bautista OM, Esser MT, Sings HL, Nelson M, Boslego JW, Sattler C, Barr E, Paavonen J. Efficacy of a quadrivalent prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like-particle vaccine against high-grade vulval and vaginal lesions: a combined analysis of three randomised clinical trials. Lancet. 2007 May 19;369(9574):1693-702.

Insinga RP, Dasbach EJ, Allen SE, Carides GW, Myers ER. Reductions in Human Papillomavirus-Disease Resource Use and Costs with Quadrivalent Human Papillomavirus (Types 6, 11, 16, and 18) Recombinant Vaccination: The FUTURE Study Economic Evaluation. Value Health. 2008 May 16; [Epub ahead of print]

Perez G, Lazcano-Ponce E, Hernandez-Avila M, García PJ, Muñoz N, Villa LL, Bryan J, Taddeo FJ, Lu S, Esser MT, Vuocolo S, Sattler C, Barr E. Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 virus-like-particle vaccine in Latin American women. Int J Cancer. 2008 Mar 15;122(6):1311-8.

FUTURE II Study Group. Prophylactic efficacy of a quadrivalent human papillomavirus (HPV) vaccine in women with virological evidence of HPV infection. J Infect Dis. 2007 Nov 15;196(10):1438-46. Epub 2007 Oct 31.

Ault KA; Future II Study Group. Effect of prophylactic human papillomavirus L1 virus-like-particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in situ: a combined analysis of four randomised clinical trials. Lancet. 2007 Jun 2;369(9576):1861-8.

Giuliano AR, Lazcano-Ponce E, Villa L, Nolan T, Marchant C, Radley D, Golm G, McCarroll K, Yu J, Esser MT, Vuocolo SC, Barr E. Impact of baseline covariates on the immunogenicity of a quadrivalent (types 6, 11, 16, and 18) human papillomavirus virus-like-particle vaccine. J Infect Dis. 2007 Oct 15;196(8):1153-62. Epub 2007 Sep 17.

Garland SM, Insinga RP, Sings HL, Haupt RM, Joura EA. Human papillomavirus infections and vulvar disease development. Cancer Epidemiol Biomarkers Prev. 2009 Jun;18(6):1777-84.

Publications automatically indexed to this study:

Brown DR, Kjaer SK, Sigurdsson K, Iversen OE, Hernandez-Avila M, Wheeler CM, Perez G, Koutsky LA, Tay EH, Garcia P, Ault KA, Garland SM, Leodolter S, Olsson SE, Tang GW, Ferris DG, Paavonen J, Steben M, Bosch FX, Dillner J, Joura EA, Kurman RJ, Majewski S, Muñoz N, Myers ER, Villa LL, Taddeo FJ, Roberts C, Tadesse A, Bryan J, Lupinacci LC, Giacoletti KE, Sings HL, James M, Hesley TM, Barr E. The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in generally HPV-naive women aged 16-26 years. J Infect Dis. 2009 Apr 1;199(7):926-35.

Wheeler CM, Kjaer SK, Sigurdsson K, Iversen OE, Hernandez-Avila M, Perez G, Brown DR, Koutsky LA, Tay EH, García P, Ault KA, Garland SM, Leodolter S, Olsson SE, Tang GW, Ferris DG, Paavonen J, Steben M, Bosch FX, Dillner J, Joura EA, Kurman RJ, Majewski S, Muñoz N, Myers ER, Villa LL, Taddeo FJ, Roberts C, Tadesse A, Bryan J, Lupinacci LC, Giacoletti KE, James M, Vuocolo S, Hesley TM, Barr E. The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in sexually active women aged 16-26 years. J Infect Dis. 2009 Apr 1;199(7):936-44.

Responsible Party:	Merck & Co., Inc. ( Executive Vice President, Clinical and Quantitative Sciences )
Study ID Numbers:	2004_081, V501-013
Study First Received:	September 23, 2004
Results First Received:	August 3, 2009
Last Updated:	October 19, 2009
ClinicalTrials.gov Identifier:	NCT00092521 History of Changes
Health Authority:	United States: Food and Drug Administration