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Study of Human Papillomavirus (HPV) 16 Vaccine in the Prevention of HPV 16 Infection in 16- to 23-Year-Old Females (V501-005)

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ClinicalTrials.gov Identifier: NCT00365378
Recruitment Status : Completed
First Posted : August 17, 2006
Results First Posted : April 9, 2010
Last Update Posted : October 23, 2015
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Prevention
Condition HPV 16 Infection
Interventions Biological: Comparator: HPV 16 L1 Vaccine
Biological: Comparator: Placebo
Enrollment 2409
Recruitment Details  
Pre-assignment Details  
Arm/Group Title HPV 16 L1 VLP (Group 1) Placebo (Group 2) Extension
Hide Arm/Group Description

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.)

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.)

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.
Period Title: Vaccination (Day 1 to Month 7)
Started 1204 1205 0
Entered Vaccination Period 1193 1198 0
Completed 993 1038 0
Not Completed 211 167 0
Reason Not Completed
Randomized Not Vaccinated             11             7             0
Adverse Event             4             5             0
Lost to Follow-up             88             75             0
Pregnancy             19             14             0
Protocol Violation             22             13             0
Withdrawal by Subject             50             44             0
Other             17             9             0
Period Title: Follow-up (Month 7 Though Month 48)
Started 993 1038 0
Completed 835 836 0
Not Completed 158 202 0
Reason Not Completed
Moved             6             5             0
Lost to Follow-up             67             69             0
Pregnancy             0             1             0
Protocol Violation             1             2             0
Withdrawal by Subject             73             104             0
Other             11             21             0
Period Title: Extension
Started 0 0 400
Completed 0 0 203
Not Completed 0 0 197
Reason Not Completed
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
Other             0             0             31
Arm/Group Title HPV 16 L1 VLP (Group 1) Placebo (Group 2) Total
Hide Arm/Group Description

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 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 of all reporting groups
Overall Number of Baseline Participants 1204 1205 2409
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Full Range)
Unit of measure:  Years
Number Analyzed 1204 participants 1205 participants 2409 participants
20.0
(16 to 25)
20.1
(16 to 23)
20.1
(16 to 25)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1204 participants 1205 participants 2409 participants
Female
1204
 100.0%
1205
 100.0%
2409
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 1204 participants 1205 participants 2409 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
1.Primary Outcome
Title Incidence of Persistent HPV 16 Infection
Hide Description Cases of persistent infection were those with detection of HPV 16 by PCR (Polymerase chain reaction) on at least 2 consecutive visits at least 4 months apart; or detection of HPV 16 in a cervical biopsy specimen showing pathologic evidence of CIN1 (Cervical intraepithelial neoplasia), CIN2 or CIN3 together with HPV 16 detected at the visit immediately before or after the biopsy; or detection of HPV 16 on a subject's last visit.
Time Frame Through Month 48
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol population: subjects must have no major protocol violations, must be seronegative to HPV 16 at Day 1 and PCR (Polymerase chain reaction) negative to HPV 16 through Month 7, and must provide follow-up data after Month 7
Arm/Group Title HPV 16 L1 VLP (Group 1) Placebo (Group 2)
Hide Arm/Group Description:

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 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.

Overall Number of Participants Analyzed 755 750
Measure Type: Number
Unit of Measure: Incidence per 100 person-years
0.3 4.9
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection HPV 16 L1 VLP (Group 1), Placebo (Group 2)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Vaccine Efficacy
Estimated Value 94.3
Confidence Interval 95%
87.8 to 97.7
Estimation Comments

Vaccine Efficacy (% relative risk reduction)

Confidence Interval based on binomial tail probabilities and not from a dispersion parameter.

2.Primary Outcome
Title Incidence of HPV 16-related CIN1, CIN2 or C1N3
Hide Description Cases of HPV 16-related CIN1, CIN2 or CIN3 are those with detection of HPV 16 in a cervical biopsy specimen showing pathologic evidence of CIN1, CIN2 or CIN3 together with HPV 16 detected at the visit immediately before or after the biopsy.
Time Frame Through Month 48
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol population: subjects must have no major protocol violations, must be seronegative to HPV 16 at Day 1 and PCR negative to HPV 16 through Month 7, and must provide follow-up data after Month 7
Arm/Group Title HPV 16 L1 VLP (Group 1) Placebo (Group 2)
Hide Arm/Group Description:

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 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.

Overall Number of Participants Analyzed 755 750
Measure Type: Number
Unit of Measure: Incidence per 100 person-years
0.0 1.0
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection HPV 16 L1 VLP (Group 1), Placebo (Group 2)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Vaccine Efficacy
Estimated Value 100.0
Confidence Interval 95%
84.0 to 100.0
Estimation Comments

Vaccine Efficacy (% relative risk reduction)

Confidence Interval based on binomial tail probabilities and not from a dispersion parameter.

3.Primary Outcome
Title Serum Anti-HPV 16 Geometric Mean Titers
Hide Description The limit of detection of the assay was 6 mMU/ml. Samples with titer below the limit of detection were assigned a value of 3 for calculation of GMT and confidence interval. GMTs and confidence limits below the limit of detection are shown as "6.0".
Time Frame Month 7
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol population: subjects must have no major protocol violations, must be seronegative to HPV 16 at Day 1 and PCR negative to HPV 16 through Month 7, and must provide serology data at Month 7
Arm/Group Title HPV 16 L1 VLP (Group 1) Placebo (Group 2)
Hide Arm/Group Description:

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 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.

Overall Number of Participants Analyzed 684 680
Geometric Mean (95% Confidence Interval)
Unit of Measure: milliMerck units/ml (mMU/ml)
1518.8
(1385.5 to 1665.0)
6.0
(6.0 to 6.0)
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.
Adverse Event Reporting 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.
 
Arm/Group Title HPV 16 L1 VLP (Group 1) Placebo (Group 2) Extension
Hide Arm/Group Description 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. 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. 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.
All-Cause Mortality
HPV 16 L1 VLP (Group 1) Placebo (Group 2) Extension
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Hide Serious Adverse Events
HPV 16 L1 VLP (Group 1) Placebo (Group 2) Extension
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   19/1191 (1.60%)   20/1196 (1.67%)   1/400 (0.25%) 
Cardiac disorders       
Pericarditis * 1  0/1191 (0.00%)  1/1196 (0.08%)  0/400 (0.00%) 
Gastrointestinal disorders       
Abdominal discomfort * 1  1/1191 (0.08%)  1/1196 (0.08%)  0/400 (0.00%) 
Abdominal pain * 1  1/1191 (0.08%)  0/1196 (0.00%)  0/400 (0.00%) 
Nausea * 1  0/1191 (0.00%)  1/1196 (0.08%)  0/400 (0.00%) 
Hepatobiliary disorders       
Cholecystitis * 1  1/1191 (0.08%)  0/1196 (0.00%)  0/400 (0.00%) 
Infections and infestations       
Appendicitis * 1  0/1191 (0.00%)  1/1196 (0.08%)  0/400 (0.00%) 
Influenza * 1  0/1191 (0.00%)  1/1196 (0.08%)  0/400 (0.00%) 
Pneumonia * 1  0/1191 (0.00%)  1/1196 (0.08%)  0/400 (0.00%) 
Pyelonephritis * 1  1/1191 (0.08%)  1/1196 (0.08%)  0/400 (0.00%) 
Pyelonephritis acute * 1  0/1191 (0.00%)  1/1196 (0.08%)  0/400 (0.00%) 
Injury, poisoning and procedural complications       
Accidental overdose * 1  1/1191 (0.08%)  0/1196 (0.00%)  0/400 (0.00%) 
Alcohol poisoning * 1  0/1191 (0.00%)  1/1196 (0.08%)  0/400 (0.00%) 
Back injury * 1  0/1191 (0.00%)  2/1196 (0.17%)  0/400 (0.00%) 
Humerus fracture * 1  0/1191 (0.00%)  1/1196 (0.08%)  0/400 (0.00%) 
Joint dislocation * 1  1/1191 (0.08%)  1/1196 (0.08%)  0/400 (0.00%) 
Multiple injuries * 1  1/1191 (0.08%)  0/1196 (0.00%)  0/400 (0.00%) 
Nerve injury * 1  0/1191 (0.00%)  1/1196 (0.08%)  0/400 (0.00%) 
Overdose * 1  1/1191 (0.08%)  1/1196 (0.08%)  0/400 (0.00%) 
Pelvic fracture * 1  0/1191 (0.00%)  1/1196 (0.08%)  0/400 (0.00%) 
Radial nerve injury * 1  0/1191 (0.00%)  1/1196 (0.08%)  0/400 (0.00%) 
Road traffic accident * 1  0/1191 (0.00%)  2/1196 (0.17%)  0/400 (0.00%) 
Urinary bladder rupture * 1  0/1191 (0.00%)  1/1196 (0.08%)  0/400 (0.00%) 
Metabolism and nutrition disorders       
Dehydration * 1  1/1191 (0.08%)  0/1196 (0.00%)  0/400 (0.00%) 
Musculoskeletal and connective tissue disorders       
Arthropathy * 1  0/1191 (0.00%)  1/1196 (0.08%)  0/400 (0.00%) 
Intervertebral disc protrusion * 1  1/1191 (0.08%)  0/1196 (0.00%)  0/400 (0.00%) 
Limb deformity * 1  0/1191 (0.00%)  1/1196 (0.08%)  0/400 (0.00%) 
Nervous system disorders       
Headache * 1  0/1191 (0.00%)  0/1196 (0.00%)  1/400 (0.25%) 
Syncope * 1  1/1191 (0.08%)  0/1196 (0.00%)  0/400 (0.00%) 
Pregnancy, puerperium and perinatal conditions       
Ectopic pregnancy * 1  1/1191 (0.08%)  0/1196 (0.00%)  0/400 (0.00%) 
Psychiatric disorders       
Aggression * 1  0/1191 (0.00%)  1/1196 (0.08%)  0/400 (0.00%) 
Anxiety disorder * 1  0/1191 (0.00%)  1/1196 (0.08%)  0/400 (0.00%) 
Bulimia nervosa * 1  1/1191 (0.08%)  0/1196 (0.00%)  0/400 (0.00%) 
Completed suicide * 1  0/1191 (0.00%)  1/1196 (0.08%)  0/400 (0.00%) 
Depression * 1  0/1191 (0.00%)  2/1196 (0.17%)  0/400 (0.00%) 
Mania * 1  0/1191 (0.00%)  1/1196 (0.08%)  0/400 (0.00%) 
Suicide attempt * 1  0/1191 (0.00%)  2/1196 (0.17%)  0/400 (0.00%) 
Reproductive system and breast disorders       
Perineal laceration * 1  1/1191 (0.08%)  0/1196 (0.00%)  0/400 (0.00%) 
Dysfunctional uterine bleeding * 1  1/1191 (0.08%)  0/1196 (0.00%)  0/400 (0.00%) 
Ovarian cyst * 1  1/1191 (0.08%)  0/1196 (0.00%)  0/400 (0.00%) 
Ovarian cyst ruptured * 1  1/1191 (0.08%)  1/1196 (0.08%)  0/400 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Asthma * 1  2/1191 (0.17%)  1/1196 (0.08%)  0/400 (0.00%) 
Vascular disorders       
Haemorrhage * 1  1/1191 (0.08%)  1/1196 (0.08%)  0/400 (0.00%) 
Thrombosis * 1  1/1191 (0.08%)  0/1196 (0.00%)  0/400 (0.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 12.0
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
HPV 16 L1 VLP (Group 1) Placebo (Group 2) Extension
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1025/1191 (86.06%)   1013/1196 (84.70%)   0/0 
Gastrointestinal disorders       
Nausea * 1  91/1191 (7.64%)  95/1196 (7.94%)  0/0 
General disorders       
Fatigue * 1  59/1191 (4.95%)  64/1196 (5.35%)  0/0 
Injection Site Erythema * 1  335/1191 (28.13%)  286/1196 (23.91%)  0/0 
Injection Site Haematoma * 1  69/1191 (5.79%)  61/1196 (5.10%)  0/0 
Injection Site Pain * 1  951/1191 (79.85%)  924/1196 (77.26%)  0/0 
Injection Site Swelling * 1  288/1191 (24.18%)  211/1196 (17.64%)  0/0 
Infections and infestations       
Nasopharyngitis * 1  85/1191 (7.14%)  88/1196 (7.36%)  0/0 
Nervous system disorders       
Dizziness * 1  53/1191 (4.45%)  62/1196 (5.18%)  0/0 
Headache * 1  499/1191 (41.90%)  495/1196 (41.39%)  0/0 
Respiratory, thoracic and mediastinal disorders       
Oropharyngeal pain * 1  68/1191 (5.71%)  65/1196 (5.43%)  0/0 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 12.0
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.
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.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Senior Vice President, Global Clinical Development
Organization: Merck Sharp & Dohme Corp.
Phone: 1-800-672-6372
EMail: ClinicalTrialsDisclosure@merck.com
Publications:
Layout table for additonal information
Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT00365378    
Other Study ID Numbers: V501-005
2006_515
First Submitted: August 16, 2006
First Posted: August 17, 2006
Results First Submitted: March 22, 2010
Results First Posted: April 9, 2010
Last Update Posted: October 23, 2015