Dose-Ranging Study of Quadrivalent Human Papillomavirus (HPV) (Types 6,11,16,18) L1 Virus-Like Particle (VLP) Vaccine - Study Results

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:	Papillomavirus Infections Genital Diseases, Female
Interventions:	Biological: Quadrivalent HPV (Types 6,11,16,18) L1 VLP Vaccine 20/40/40/20 Biological: Quadrivalent HPV (Types 6,11,16,18) L1 VLP Vaccine 40/40/40/40 Biological: Quadrivalent HPV (Types 6,11,16,18) L1 VLP Vaccine 80/80/40/80 Biological: Placebo (mcg) (Aluminum Adjuvant)225 Biological: Placebo (mcg) (Aluminum Adjuvant) 450

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups

	Description
Quadrivalent HPV (Types 6,11,16,18) L1 VLP Vaccine 20/40/40/20	The Vaccination Period for the Base Study encompassed Day 1 through Month 7, during which time subjects in Group 1 received a 20/40/40/20 formulation of quadrivalent human papillomavirus (qHPV) (Types 6, 11, 16, 18) L1 Virus-Like Particle (VLP) vaccine at Day 1, Month 2, and Month 6. The Follow-up Period for the Base Study encompassed the follow-up of subjects who had received the HPV 16 VLP Vaccine or placebo from completion of the Vaccination Period at Month 7 through Month 36.
Quadrivalent HPV (Types 6,11,16,18) L1 VLP Vaccine 40/40/40/40	The Vaccination Period for the Base Study encompassed Day 1 through Month 7, during which time subjects in Group 2 received a 40/40/40/40 formulation of quadrivalent human papillomavirus (HPV) (Types 6, 11, 16, 18) L1 Virus-Like Particle (VLP) vaccine at Day 1, Month 2, and Month 6. The Follow-up Period for the Base Study encompassed the follow-up of subjects who had received the HPV 16 VLP Vaccine or placebo from completion of the Vaccination Period at Month 7 through Month 36.
Quadrivalent HPV (Types 6,11,16,18) L1 VLP Vaccine 80/80/40/80	The Vaccination Period for the Base Study encompassed Day 1 through Month 7, during which time subjects in Group 3 received a 80/80/40/80 formulation of quadrivalent human papillomavirus (qHPV) (Types 6, 11, 16, 18) L1 Virus-Like Particle (VLP) vaccine at Day 1, Month 2, and Month 6. The Follow-up Period for the Base Study encompassed the follow-up of subjects who had received the qHPV 16 VLP Vaccine or placebo from completion of the Vaccination Period at Month 7 through Month 36.
Placebo (Mcg) (Aluminum Adjuvant) 225	The Vaccination Period for the Base Study encompassed Day 1 through Month 7, during which time subjects in Group 4 received placebo containing 225 mcg of aluminum adjuvant per dose at Day 1, Month 2, and Month 6. The Follow-up Period for the Base Study encompassed the follow-up of subjects who had received the qHPV 16 VLP Vaccine or placebo from completion of the Vaccination Period at Month 7 through Month 36.
Placebo (Mcg) (Aluminum Adjuvant) 450	The Vaccination Period for the Base Study encompassed Day 1 through Month 7, during which time subjects in Group 5 received placebo containing 450 mcg of aluminum adjuvant per dose at Day 1, Month 2, and Month 6. The Follow-up Period for the Base Study encompassed the follow-up of subjects who had received the qHPV 16 VLP Vaccine or placebo from completion of the Vaccination Period at Month 7 through Month 36.
Extension 1	This group includes 241 international subjects, who either: (1) received placebo during the base study and continued in the Extension to receive a dose of GARDASIL (20/40/40/20 mcg formulation of qHPV vaccine) at Month 60 (plus 2 and 3 at Months 62 and 66, respectively, (2) received 3 doses of GARDASIL during the Base study and continued into the Extension to receive a fourth dose of GARDASIL at Month 60 for the purposes of investigating whether a fourth dose of vaccine (administered ~4.5 years following completion of a 3-dose primary regimen) induces HPV 6, 11, 16, and 18 antibody responses that characterize immune therapy.
Extension 2	This group includes 17 subjects from the United States, who received placebo during the base study and received 3 doses of qHPV vaccine during the Extension, or received less than 3 doses of the qHPV Vaccine during the base study and completed the dose regimen during the Extension.

Participant Flow for 4 periods

Period 1: Base Study (Day 1 to Month 7)

	Quadrivalent HPV (Types 6,11,16,18) L1 VLP Vaccine 20/40/40/20	Quadrivalent HPV (Types 6,11,16,18) L1 VLP Vaccine 40/40/40/40	Quadrivalent HPV (Types 6,11,16,18) L1 VLP Vaccine 80/80/40/80	Placebo (Mcg) (Aluminum Adjuvant) 225	Placebo (Mcg) (Aluminum Adjuvant) 450
STARTED	290	284	292	146	146
COMPLETED	269	260	271	136	139
NOT COMPLETED	21	24	21	10	7
Randomized Not Vaccinated	1	2	0	0	0
Adverse Event	0	2	0	0	1
Lost to Follow-up	4	6	6	4	0
Unspecified	0	1	0	0	0
Pregnancy	3	2	3	1	1
Protocol Violation	1	2	0	1	2
Withdrawal by Subject	12	9	12	4	3

Period 2: Long Term Follow-up (Month 7 toMonth 36)

	Quadrivalent HPV (Types 6,11,16,18) L1 VLP Vaccine 20/40/40/20	Quadrivalent HPV (Types 6,11,16,18) L1 VLP Vaccine 40/40/40/40	Quadrivalent HPV (Types 6,11,16,18) L1 VLP Vaccine 80/80/40/80	Placebo (Mcg) (Aluminum Adjuvant) 225	Placebo (Mcg) (Aluminum Adjuvant) 450
STARTED	269	260	271	136	139
COMPLETED	137	245	251	57	57
NOT COMPLETED	132	15	20	79	82
Proceeded to Extension 1	114	0	0	69	75
Lost to Follow-up	6	8	5	4	3
Moved	3	2	1	2	0
Unspecified	2	0	0	0	1
Protocol Violation	0	1	1	0	0
Withdrawal by Subject	7	4	13	4	3

Period 3: Extension 1

	Quadrivalent HPV (Types 6,11,16,18) L1 VLP Vaccine 20/40/40/20	Quadrivalent HPV (Types 6,11,16,18) L1 VLP Vaccine 40/40/40/40	Quadrivalent HPV (Types 6,11,16,18) L1 VLP Vaccine 80/80/40/80	Placebo (Mcg) (Aluminum Adjuvant) 225	Placebo (Mcg) (Aluminum Adjuvant) 450	Extension 1	Extension 2
STARTED	0	0	0	0	0	241	0
COMPLETED	0	0	0	0	0	219	0
NOT COMPLETED	0	0	0	0	0	22	0
Lost to Follow-up	0	0	0	0	0	1	0
Unspecified	0	0	0	0	0	9	0
Moved	0	0	0	0	0	4	0
Withdrawal by Subject	0	0	0	0	0	3	0
Pregnancy	0	0	0	0	0	4	0
Protocol Violation	0	0	0	0	0	1	0

Period 4: Extension 2

	Quadrivalent HPV (Types 6,11,16,18) L1 VLP Vaccine 20/40/40/20	Quadrivalent HPV (Types 6,11,16,18) L1 VLP Vaccine 40/40/40/40	Quadrivalent HPV (Types 6,11,16,18) L1 VLP Vaccine 80/80/40/80	Placebo (Mcg) (Aluminum Adjuvant) 225	Placebo (Mcg) (Aluminum Adjuvant) 450	Extension 1	Extension 2
STARTED	0	0	0	0	0	0	17 ^[1]
COMPLETED	0	0	0	0	0	0	7
NOT COMPLETED	0	0	0	0	0	0	10
Lost to Follow-up	0	0	0	0	0	0	2
Unspecified	0	0	0	0	0	0	3
Withdrawal by Subject	0	0	0	0	0	0	5

[1]	17 Participants continued into Extension 2 from Extension 1

Baseline Characteristics

Hide Baseline Characteristics

Reporting Groups

	Description
Quadrivalent HPV (Types 6,11,16,18) L1 VLP Vaccine 20/40/40/20	The Vaccination Period for the Base Study encompassed Day 1 through Month 7, during which time subjects in Group 1 received a 20/40/40/20 formulation of quadrivalent human papillomavirus (HPV) (Types 6, 11, 16, 18) L1 Virus-Like Particle (VLP) vaccine at Day 1, Month 2, and Month 6. The Follow-up Period for the Base Study encompassed the follow-up of subjects who had received the HPV 16 VLP Vaccine or placebo from completion of the Vaccination Period at Month 7 through Month 36.
Quadrivalent HPV (Types 6,11,16,18) L1 VLP Vaccine 40/40/40/40	The Vaccination Period for the Base Study encompassed Day 1 through Month 7, during which time subjects in Group 2 received a 40/40/40/40 formulation of quadrivalent human papillomavirus (HPV) (Types 6, 11, 16, 18) L1 Virus-Like Particle (VLP) vaccine at Day 1, Month 2, and Month 6. The Follow-up Period for the Base Study encompassed the follow-up of subjects who had received the HPV 16 VLP Vaccine or placebo from completion of the Vaccination Period at Month 7 through Month 36.
Quadrivalent HPV (Types 6,11,16,18) L1 VLP Vaccine 80/80/40/80	The Vaccination Period for the Base Study encompassed Day 1 through Month 7, during which time subjects in Group 3 received a 80/80/40/80 formulation of quadrivalent human papillomavirus (qHPV) (Types 6, 11, 16, 18) L1 Virus-Like Particle (VLP) vaccine at Day 1, Month 2, and Month 6. The Follow-up Period for the Base Study encompassed the follow-up of subjects who had received the qHPV 16 VLP Vaccine or placebo from completion of the Vaccination Period at Month 7 through Month 36.
Placebo (Mcg) (Aluminum Adjuvant) 225	The Vaccination Period for the Base Study encompassed Day 1 through Month 7, during which time subjects in Group 4 received placebo containing 225 mcg of aluminum adjuvant per dose at Day 1, Month 2, and Month 6. The Follow-up Period for the Base Study encompassed the follow-up of subjects who had received the qHPV 16 VLP Vaccine or placebo from completion of the Vaccination Period at Month 7 through Month 36.
Placebo (Mcg) (Aluminum Adjuvant) 450	The Vaccination Period for the Base Study encompassed Day 1 through Month 7, during which time subjects in Group 5 received placebo containing 450 mcg of aluminum adjuvant per dose at Day 1, Month 2, and Month 6. The Follow-up Period for the Base Study encompassed the follow-up of subjects who had received the qHPV 16 VLP Vaccine or placebo from completion of the Vaccination Period at Month 7 through Month 36.

Baseline Measures

	Quadrivalent HPV (Types 6,11,16,18) L1 VLP Vaccine 20/40/40/20	Quadrivalent HPV (Types 6,11,16,18) L1 VLP Vaccine 40/40/40/40	Quadrivalent HPV (Types 6,11,16,18) L1 VLP Vaccine 80/80/40/80	Placebo (Mcg) (Aluminum Adjuvant) 225	Placebo (Mcg) (Aluminum Adjuvant) 450	Total
Number of Participants [units: participants]	290	284	292	146	146	1158
Age [units: years] Mean ( Full Range )	20.2 ( 16 to 23 )	20.0 ( 15 to 24 )	20.1 ( 16 to 23 )	20.0 ( 16 to 23 )	20.1 ( 13 to 23 )	20.0 ( 13 to 24 )
Gender [units: participants]
Female	290	284	292	146	146	1158
Male	0	0	0	0	0	0
Race/Ethnicity, Customized [units: participants]
Asian	7	11	5	6	5	34
Black	25	32	27	12	7	103
Hispanic American	15	15	10	10	11	61
Indian	0	0	2	0	0	2
Multi-racial	13	9	6	7	4	39
Native American	2	4	2	0	1	9
White	228	213	240	111	118	910

Outcome Measures

Show All Outcome Measures

1. Primary:

Number of Subjects With Injection Site Adverse Experiences [ Time Frame: Days 1-5 following any vaccination visit ]

Show Outcome Measure 1

2. Secondary:

Incidence of HPV 6-, 11-, 16- or 18-related Persistent Infection or Disease (Cervical Intraepithelial Neoplasia, Vulvar Intraepithelial Neoplasia, Vaginal Intraepithelial Neoplasia, Adenocarcinoma in Situ, Cervical Cancer, and Genital Warts) [ Time Frame: Through 36 Months ]

Show Outcome Measure 2

Serious Adverse Events

Show Serious Adverse Events

Other Adverse Events

Show Other Adverse Events

More Information

Hide More Information

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: Merck agreements may vary with individual investigators, but will not prohibit any investigator from publishing. Merck 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: Executive Vice President, Clinical and Quantitative Sciences
Organization: Merck Sharp & Dohme Corp
phone: 1-800-672-6372

Publications:

Villa LL, Costa RL, Petta CA, Andrade RP, Ault KA, Giuliano AR, Wheeler CM, Koutsky LA, Malm C, Lehtinen M, Skjeldestad FE, Olsson SE, Steinwall M, Brown DR, Kurman RJ, Ronnett BM, Stoler MH, Ferenczy A, Harper DM, Tamms GM, Yu J, Lupinacci L, Railkar R, Taddeo FJ, Jansen KU, Esser MT, Sings HL, Saah AJ, Barr E. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol. 2005 May;6(5):271-8.

Villa LL, Ault KA, Giuliano AR, Costa RL, Petta CA, Andrade RP, Brown DR, Ferenczy A, Harper DM, Koutsky LA, Kurman RJ, Lehtinen M, Malm C, Olsson SE, Ronnett BM, Skjeldestad FE, Steinwall M, Stoler MH, Wheeler CM, Taddeo FJ, Yu J, Lupinacci L, Railkar R, Marchese R, Esser MT, Bryan J, Jansen KU, Sings HL, Tamms GM, Saah AJ, Barr E. Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18. Vaccine. 2006 Jul 7;24(27-28):5571-83. Epub 2006 May 15.

Villa LL, Costa RL, Petta CA, Andrade RP, Paavonen J, Iversen OE, Olsson SE, Hoye J, Steinwall M, Riis-Johannessen G, Andersson-Ellstrom A, Elfgren K, Krogh G, Lehtinen M, Malm C, Tamms GM, Giacoletti K, Lupinacci L, Railkar R, Taddeo FJ, Bryan J, Esser MT, Sings HL, Saah AJ, Barr E. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up. Br J Cancer. 2006 Dec 4;95(11):1459-66. Epub 2006 Nov 21.

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.

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.

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.

Olsson SE, Villa LL, Costa RL, Petta CA, Andrade RP, Malm C, Iversen OE, Høye J, Steinwall M, Riis-Johannessen G, Andersson-Ellstrom A, Elfgren K, von Krogh G, Lehtinen M, Paavonen J, Tamms GM, Giacoletti K, Lupinacci L, Esser MT, Vuocolo SC, Saah AJ, Barr E. Induction of immune memory following administration of a prophylactic quadrivalent human papillomavirus (HPV) types 6/11/16/18 L1 virus-like particle (VLP) vaccine. Vaccine. 2007 Jun 21;25(26):4931-9. Epub 2007 Apr 20.

Smith JF, Brownlow M, Brown M, Kowalski R, Esser MT, Ruiz W, Barr E, Brown DR, Bryan JT. Antibodies from women immunized with Gardasil cross-neutralize HPV 45 pseudovirions. Hum Vaccin. 2007 Jul-Aug;3(4):109-15. Epub 2007 Feb 24.

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.

Responsible Party:	Executive Vice President, Clinical and Quantitative Sciences, Merck Sharp & Dohme Corp
ClinicalTrials.gov Identifier:	NCT00365716 History of Changes
Other Study ID Numbers:	2006_516, V501-007
Study First Received:	August 16, 2006
Results First Received:	May 19, 2010
Last Updated:	July 6, 2010
Health Authority:	United States: Food and Drug Administration