Study of Human Papillomavirus (HPV) 16 Vaccine in the Prevention of HPV 16 Infection in 16- to 23-Year-Old Females

This study has been completed.

Sponsor:

Information provided by:

Merck

ClinicalTrials.gov Identifier:

NCT00365378

First received: August 16, 2006

Last updated: April 20, 2010

Last verified: April 2010

History of Changes

Results First Received: March 22, 2010

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Investigator); Primary Purpose: Prevention
Condition:	HPV 16 Infection
Interventions:	Biological: Comparator: HPV 16 L1 Vaccine Biological: Comparator: Placebo

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
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Reporting Groups

	Description
HPV 16 L1 VLP (Group 1)	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 HPV (Human Papillomavirus) 16 Virus-Like Particle (VLP) Vaccine. The Follow-up Period for the Base Study encompassed the follow-up of subjects who had received the HPV 16 VLP Vaccine from completion of the Vaccination Period at Month 7 through Month 48. (The Month 7 visit was to be scheduled to occur no earlier than 3 weeks and no later than 7 weeks following the Month 6 visit.)
Placebo (Group 2)	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 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. (The Month 7 visit was to be scheduled to occur no earlier than 3 weeks and no later than 7 weeks following the Month 6 visit.)
Extension	This group includes 400 subjects who received Monovalent HPV 16 L1 VLP vaccine or placebo during the base study. This includes subjects who previously discontinued from the study.

Description

HPV 16 L1 VLP (Group 1)

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 HPV (Human Papillomavirus) 16 Virus-Like Particle (VLP) Vaccine.

The Follow-up Period for the Base Study encompassed the follow-up of subjects who had received the HPV 16 VLP Vaccine from completion of the Vaccination Period at Month 7 through Month 48. (The Month 7 visit was to be scheduled to occur no earlier than 3 weeks and no later than 7 weeks following the Month 6 visit.)

Placebo (Group 2)

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 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. (The Month 7 visit was to be scheduled to occur no earlier than 3 weeks and no later than 7 weeks following the Month 6 visit.)

Extension

This group includes 400 subjects who received Monovalent HPV 16 L1 VLP vaccine or placebo during the base study. This includes subjects who previously discontinued from the study.

Participant Flow for 3 periods

Period 1: Vaccination (Day 1 to Month 7)

	HPV 16 L1 VLP (Group 1)	Placebo (Group 2)
STARTED	1204	1205
Entered Vaccination Period	1193	1198
COMPLETED	993	1038
NOT COMPLETED	211	167
Randomized Not Vaccinated	11	7
Adverse Event	4	5
Lost to Follow-up	88	75
Pregnancy	19	14
Protocol Violation	22	13
Withdrawal by Subject	50	44
Unspecified	17	9

Period 2: Follow-up (Month 7 Though Month 48)

	HPV 16 L1 VLP (Group 1)	Placebo (Group 2)
STARTED	993	1038
COMPLETED	835	836
NOT COMPLETED	158	202
Moved	6	5
Lost to Follow-up	67	69
Pregnancy	0	1
Protocol Violation	1	2
Withdrawal by Subject	73	104
Unspecified	11	21

Period 3: Extension

	HPV 16 L1 VLP (Group 1)	Placebo (Group 2)	Extension
STARTED	0	0	400
COMPLETED	0	0	203
NOT COMPLETED	0	0	197
Adverse Event	0	0	1
Moved	0	0	8
Lost to Follow-up	0	0	57
Protocol Violation	0	0	2
Withdrawal by Subject	0	0	98
Unspecified	0	0	31

Baseline Characteristics

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Reporting Groups

	Description
HPV 16 L1 VLP (Group 1)	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 HPV (Human Papillomavirus) 16 Virus-Like Particle (VLP) Vaccine. The Follow-up Period for the Base Study encompassed the follow-up of subjects who had received the HPV 16 VLP Vaccine from completion of the Vaccination Period at Month 7 through Month 48.
Placebo (Group 2)	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 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.
Total	Total of all reporting groups

Description

HPV 16 L1 VLP (Group 1)

The Follow-up Period for the Base Study encompassed the follow-up of subjects who had received the HPV 16 VLP Vaccine from completion of the Vaccination Period at Month 7 through Month 48.

Placebo (Group 2)

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 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.

Total

Total of all reporting groups

Baseline Measures

	HPV 16 L1 VLP (Group 1)	Placebo (Group 2)	Total
Number of Participants [units: participants]	1204	1205	2409
Age [units: years] Mean ( Full Range )	20.0 ( 16 to 25 )	20.1 ( 16 to 23 )	20.1 ( 16 to 25 )
Gender [units: participants]
Female	1204	1205	2409
Male	0	0	0
Race/Ethnicity, Customized [units: participants]
Asian	69	73	142
Black	94	114	208
Hispanic American	89	93	182
Native American	9	14	23
White	918	889	1807
Other	25	22	47

Outcome Measures

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1. Primary:

Incidence of Persistent HPV 16 Infection [ Time Frame: Through Month 48 ]

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2. Primary:

Incidence of HPV 16-related CIN1, CIN2 or C1N3 [ Time Frame: Through Month 48 ]

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3. Primary:

Serum Anti-HPV 16 Geometric Mean Titers [ Time Frame: Month 7 ]

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Serious Adverse Events

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Other Adverse Events

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Time Frame	Adverse events (AEs) were collected from Day 1 until Month 7. No non-serious AEs were collected and no Vaccination Report Card (VRCs) were used in the extension study, therefore no data is entered for that group in the Other Adverse Events table.
Additional Description	Subjects were observed for at least 20 minutes after each vaccination for any immediate reaction. Subjects were prompted to report temperatures and local (i.e., injection site) AEs for 5 days following each injection. Data on all other AEs were collected and recorded on the subject’s vaccine report card for 14 days after each vaccination visit.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
HPV 16 L1 VLP (Group 1)	The number of subjects who actually received the vaccine material corresponding to the indicated vaccination group. There was one subject randomized to the HPV 16 L1 VLP vaccine group who received placebo and then discontinued study participation. There was 1 subject randomized to the placebo group who received one vaccination of HPV 16 L1 VLP vaccine and then discontinued study participation. These 2 subjects were included in the counts reported in the Adverse Event tables. There were 2 subjects randomized to the HPV 16 L1 VLP vaccine group and 2 subjects randomized to the placebo group and who received mixed vaccine material. These 4 subjects were not included in the counts reported in this table. Therefore, this table reports N=1191 (1193 minus 2) subjects vaccinated with HPV 16 L1 VLP vaccine and N=1196 (1198 minus 2) subjects vaccinated with placebo.
Placebo (Group 2)	The number of subjects who actually received the vaccine material corresponding to the indicated vaccination group. There was one subject randomized to the HPV 16 L1 VLP vaccine group who received placebo and then discontinued study participation. There was 1 subject randomized to the placebo group who received one vaccination of HPV 16 L1 VLP vaccine and then discontinued study participation. These 2 subjects were included in the counts reported in the Adverse Event tables. There were 2 subjects randomized to the HPV 16 L1 VLP vaccine group and 2 subjects randomized to the placebo group and who received mixed vaccine material. These 4 subjects were not included in the counts reported in this table. Therefore, this table reports N=1191 (1193 minus 2) subjects vaccinated with HPV 16 L1 VLP vaccine and N=1196 (1198 minus 2) subjects vaccinated with placebo.
Extension	This group includes 400 subjects who received Monovalent HPV 16 L1 VLP vaccine or placebo during the base study. This includes subjects who previously discontinued from the study.

Other Adverse Events

	HPV 16 L1 VLP (Group 1)	Placebo (Group 2)	Extension
Total, other (not including serious) adverse events
# participants affected / at risk	1025/1191	1013/1196	0/0
Gastrointestinal disorders
Nausea ^{* 1}
# participants affected / at risk	91/1191 (7.64%)	95/1196 (7.94%)	0/0 (0.00%)
General disorders
Fatigue ^{* 1}
# participants affected / at risk	59/1191 (4.95%)	64/1196 (5.35%)	0/0 (0.00%)
Injection Site Erythema ^{* 1}
# participants affected / at risk	335/1191 (28.13%)	286/1196 (23.91%)	0/0 (0.00%)
Injection Site Haematoma ^{* 1}
# participants affected / at risk	69/1191 (5.79%)	61/1196 (5.10%)	0/0 (0.00%)
Injection Site Pain ^{* 1}
# participants affected / at risk	951/1191 (79.85%)	924/1196 (77.26%)	0/0 (0.00%)
Injection Site Swelling ^{* 1}
# participants affected / at risk	288/1191 (24.18%)	211/1196 (17.64%)	0/0 (0.00%)
Infections and infestations
Nasopharyngitis ^{* 1}
# participants affected / at risk	85/1191 (7.14%)	88/1196 (7.36%)	0/0 (0.00%)
Nervous system disorders
Dizziness ^{* 1}
# participants affected / at risk	53/1191 (4.45%)	62/1196 (5.18%)	0/0 (0.00%)
Headache ^{* 1}
# participants affected / at risk	499/1191 (41.90%)	495/1196 (41.39%)	0/0 (0.00%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain ^{* 1}
# participants affected / at risk	68/1191 (5.71%)	65/1196 (5.43%)	0/0 (0.00%)

*	Events were collected by non-systematic assessment
1	Term from vocabulary, MedDRA 12.0

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: 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
Of note, the number of subjects reported in the results posting is slightly different than that specified in the publication by Koutsky, et al (2002). The data provided here is based on final data.

Results Point of Contact:

Name/Title: Executive Vice President, Clinical and Quantitative Sciences
Organization: Merck Sharp & Dohme Corp
phone: 1-800-672-6372

Publications:

Mao C, Koutsky LA, Ault KA, Wheeler CM, Brown DR, Wiley DJ, Alvarez FB, Bautista OM, Jansen KU, Barr E. Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial. Obstet Gynecol. 2006 Jan;107(1):18-27. Erratum in: Obstet Gynecol. 2006 Jun;107(6):1425.

Koutsky LA, Ault KA, Wheeler CM, Brown DR, Barr E, Alvarez FB, Chiacchierini LM, Jansen KU; Proof of Principle Study Investigators. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med. 2002 Nov 21;347(21):1645-51.

Paavonen J; Future II Study Group. Baseline demographic characteristics of subjects enrolled in international quadrivalent HPV (types 6/11/16/18) vaccine clinical trials. Curr Med Res Opin. 2008 Jun;24(6):1623-34. Epub 2008 Apr 23.

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.

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.

Fraser C, Tomassini JE, Xi L, Golm G, Watson M, Giuliano AR, Barr E, Ault KA. Modeling the long-term antibody response of a human papillomavirus (HPV) virus-like particle (VLP) type 16 prophylactic vaccine. Vaccine. 2007 May 22;25(21):4324-33. Epub 2007 Mar 12.

Publications automatically indexed to this study:

Wiley DJ, Masongsong EV, Lu S, Heather L S, Salem B, Giuliano AR, Ault KA, Haupt RM, Brown DR. Behavioral and sociodemographic risk factors for serological and DNA evidence of HPV6, 11, 16, 18 infections. Cancer Epidemiol. 2012 Jun;36(3):e183-9. Epub 2012 Jan 25.

Responsible Party:	Executive Vice President, Clinical and Quantitative Sciences, Merck Sharp & Dohme Corp
ClinicalTrials.gov Identifier:	NCT00365378 History of Changes
Other Study ID Numbers:	2006_515, V501-005
Study First Received:	August 16, 2006
Results First Received:	March 22, 2010
Last Updated:	April 20, 2010
Health Authority:	United States: Food and Drug Administration

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