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A Study of Gardasil (V501) in Preadolescents and Adolescents (V501-018)

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ClinicalTrials.gov Identifier: NCT00092547
Recruitment Status : Completed
First Posted : September 28, 2004
Results First Posted : May 4, 2010
Last Update Posted : February 20, 2018
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
Conditions: Human
Papillomavirus Infections
Interventions: Biological: V501
Biological: Comparator: Placebo

  Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
1781 participants were randomized to receive qHPV or Placebo in the Base Study. At month 30, participants who received Placebo in the Base Study were eligible to receive qHPV, and formed the Extension Group. Participants were to be followed for safety and efficacy for up to 10 years.

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
qHPV Vaccine in Base Study Represents participants who were randomized into the qHPV Group, who received three 0.5 mL intramuscular injections of V501 (qHPV) at Day 1, Month 2, and Month 6.
Placebo in Base Study Represents participants who were randomized into the Placebo Group, who received three 0.5 mL intramuscular injections of placebo at Day 1, Month 2, and Month 6.
qHPV Vaccine in Extension Study Represent participants originally enrolled into the Placebo Group who continued in the study to receive 0.5 mL intramuscular injections of V501 (qHPV) at Month 30, Month 32, and Month 36.

Participant Flow for 8 periods

Period 1:   Base Vaccine Phase (Day 1 to Month 7)
    qHPV Vaccine in Base Study   Placebo in Base Study   qHPV Vaccine in Extension Study
STARTED   1184   597   0 
Vaccinated   1179   596   0 
COMPLETED   1121   561   0 
NOT COMPLETED   63   36   0 
Not Vaccinated                5                1                0 
Adverse Event                4                1                0 
Lost to Follow-up                18                7                0 
Withdrawal by Subject                28                21                0 
Moved                3                1                0 
per sponsor request: (noncompliant)                0                1                0 
Did not meet local regulations                0                1                0 
Refused Vaccination                5                3                0 

Period 2:   Base Follow-up Phase (Month 7 to 18)
    qHPV Vaccine in Base Study   Placebo in Base Study   qHPV Vaccine in Extension Study
STARTED   1128 [1]   565 [1]   0 
COMPLETED   1108   551   0 
NOT COMPLETED   20   14   0 
Subject moved                1                5                0 
Withdrawal by Subject                4                2                0 
Lost to Follow-up                13                7                0 
Protocol Violation                1                0                0 
Physician Decision                1                0                0 
[1] Includes participants continuing and who previously discontinued who re-entered the study

Period 3:   Base Follow-up Phase (Month 18 to 30)
    qHPV Vaccine in Base Study   Placebo in Base Study   qHPV Vaccine in Extension Study
STARTED   964 [1]   490 [1]   0 
COMPLETED   956   485   0 
NOT COMPLETED   8   5   0 
Subject moved                4                2                0 
Withdrawal by Subject                1                3                0 
Lost to Follow-up                2                0                0 
Protocol Violation                1                0                0 
[1] Includes participants continuing and who previously discontinued who re-entered the study

Period 4:   Extension Vaccine Phase (Month 30 to 37)
    qHPV Vaccine in Base Study   Placebo in Base Study   qHPV Vaccine in Extension Study
STARTED   956 [1]   0   485 [1] 
Vaccinated in Extension Study   0   0   482 
COMPLETED   933   0   469 
NOT COMPLETED   23   0   16 
Subject moved                3                0                0 
Withdrawal by Subject                6                0                9 
Lost to Follow-up                14                0                7 
[1] Includes participants continuing and who previously discontinued who re-entered the study

Period 5:   Long-term Follow-up (Month 42 Visit)
    qHPV Vaccine in Base Study   Placebo in Base Study   qHPV Vaccine in Extension Study
STARTED   612 [1]   0   308 [1] 
COMPLETED   611   0   308 
NOT COMPLETED   1   0   0 
Adverse Event                1                0                0 
[1] Includes participants continuing and who previously discontinued who re-entered the study

Period 6:   Long-term Follow-up (Month 72 Visit)
    qHPV Vaccine in Base Study   Placebo in Base Study   qHPV Vaccine in Extension Study
STARTED   550 [1]   0   276 [1] 
COMPLETED   550   0   276 
NOT COMPLETED   0   0   0 
[1] Includes participants continuing and who previously discontinued who re-entered the study

Period 7:   Long-term Follow-up (Month 96 Visit)
    qHPV Vaccine in Base Study   Placebo in Base Study   qHPV Vaccine in Extension Study
STARTED   508 [1]   0   267 [1] 
COMPLETED   508   0   267 
NOT COMPLETED   0   0   0 
[1] Includes participants continuing and who previously discontinued who re-entered the study

Period 8:   Long-term Follow-up (Month 126 Visit)
    qHPV Vaccine in Base Study   Placebo in Base Study   qHPV Vaccine in Extension Study
STARTED   454   0   211 
COMPLETED   454   0   211 
NOT COMPLETED   0   0   0 



  Baseline Characteristics

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.
No text entered.

Reporting Groups
  Description
qHPV Vaccine in Base Study Represents participants who were randomized into the qHPV Group, who received three 0.5 mL intramuscular injections of V501 (qHPV) at Day 1, Month 2, and Month 6
Placebo in Base Study Represents participants who were randomized into the Placebo Group, who received three 0.5 mL intramuscular injections of placebo at Day 1, Month 2, and Month 6
Total Total of all reporting groups

Baseline Measures
   qHPV Vaccine in Base Study   Placebo in Base Study   Total 
Overall Participants Analyzed 
[Units: Participants]
 1184   597   1781 
Age 
[Units: Years]
Mean (Standard Deviation)
 11.9  (1.9)   11.8  (1.9)   11.9  (1.9) 
Age, Customized 
[Units: Participants]
     
8 Years of Age and Under   0   0   0 
9 to 16 Years of Age   1184   597   1781 
17 Years of Age and Over   0   0   0 
Sex: Female, Male 
[Units: Participants]
Count of Participants
     
Female      616  52.0%      322  53.9%      938  52.7% 
Male      568  48.0%      275  46.1%      843  47.3% 
Race/Ethnicity, Customized 
[Units: Participants]
     
Asian   149   70   219 
Black   50   21   71 
Hispanic American   260   130   390 
Native American   0   1   1 
White   716   369   1085 
Other   9   6   15 


  Outcome Measures

1.  Primary:   Number of Participants Reporting Serious Adverse Experiences (SAEs) Through Month 18   [ Time Frame: Up to Month 18 ]

2.  Primary:   Number of Participants Reporting SAEs From Month 18 Through Month 37   [ Time Frame: Month 18 to Month 37 ]

3.  Primary:   Number of Participants Reporting Other (Non-serious) AEs Through Month 18   [ Time Frame: Up to Month 18: Injection site AEs were collected from Days 1-5 and other non-serious AEs from Days 1-15 after any vaccination ]

4.  Primary:   Percentage of Participants Who Are Seropositive for HPV Types 6, 11, 16, and 18 at Month 72   [ Time Frame: Month 72 (66 Months Post-dose 3 for the Original qHPV Vaccine Cohort and 36 months Post-dose 3 for the Extension Group) ]

5.  Primary:   Geometric Mean Titers (GMTs) for Anti-HPV 6, 11, 16, and 18 at Month 72   [ Time Frame: Month 72 (66 Months Post-dose 3 for the Original qHPV Vaccine Cohort and 36 months Post-dose 3 for the Extension Group) ]

6.  Primary:   Geometric Mean Titers for Anti-HPV 6, 11, 16, and 18 at Month 96   [ Time Frame: Month 96 (90 Months Post-dose 3 for Original qHPV Vaccine Group and 60 Months Post-dose 3 for Extension Group) ]

7.  Primary:   Percentage of Participants Who Are Seropositive for HPV Types 6, 11, 16, and 18 at Month 96   [ Time Frame: Month 96 (90 Months Post-dose 3 for Original qHPV Vaccine Cohort and 60 Months Post-dose 3 for Extension Group) ]

8.  Primary:   Geometric Mean Titers for Anti-HPV 6, 11, 16, and 18 at Month 126   [ Time Frame: Month 126 (120 Months Post-dose 3 for Original qHPV Vaccine Cohort and 90 Months Post-dose 3 for Extension Group) ]

9.  Primary:   Percentage of Participants Who Are Seropositive for HPV Types 6, 11, 16, and 18 at Month 126   [ Time Frame: Month 126 (120 Months Post-dose 3 for Original qHPV Vaccine Cohort and 90 Months Post-dose 3 for Extension Group) ]

10.  Primary:   Number of Participants Reporting SAEs Related to Study Vaccine or to a Study Procedure in the Long-term Follow-up   [ Time Frame: Month 37 to Month 126 ]

11.  Secondary:   Percentage of Original qHPV Vaccine Participants Who Are Seropositive for HPV Types 6, 11, 16, and 18 at Month 1 Postdose 3 (Month 7)   [ Time Frame: Month 7 (1 Month Postdose 3) ]

12.  Secondary:   Percentage of Original qHPV Vaccine Participants Who Are Seropositive for HPV Types 6, 11, 16, and 18 at Month 12 Postdose 3 (Month 18).   [ Time Frame: Month 18 (12 Months Post-dose 3) ]

13.  Secondary:   Percentage of Original qHPV Vaccine Participants Who Are Seropositive for HPV Types 6, 11, 16, and 18 at Month 18 Postdose 3 (Month 24)   [ Time Frame: Month 24 (18 Months Post-dose 3) ]

14.  Secondary:   Percentage of Original qHPV Vaccine Participants Who Are Seropositive for HPV Types 6, 11, 16, and 18 at Month 24 Postdose 3 (Month 30)   [ Time Frame: Month 30 (24 Months Post-dose 3) ]

15.  Secondary:   Percentage of Original qHPV Vaccine Participants Who Are Seropositive for HPV Types 6, 11, 16, and 18 at Month 31 Postdose 3 (Month 37).   [ Time Frame: Month 37 (31 Months Post-dose 3) ]

16.  Secondary:   Percentage of Participants in the Extension Group Who Are Seropositive for HPV Types 6, 11, 16, and 18 at Month 1 Postdose 3 of qHPV (Month 37)   [ Time Frame: Month 37 (1 Month Post-dose 3 of qHPV) ]

17.  Secondary:   Geometric Mean Titers of Original qHPV Vaccine Cohort for Anti-HPV 6, 11, 16, and 18 at Month 1 Postdose 3 of qHPV Vaccine (Month 7)   [ Time Frame: Month 7 (1 Month Post-dose 3) ]

18.  Secondary:   Geometric Mean Titers of Original qHPV Vaccine Cohort for Anti-HPV 6, 11, 16, and 18 at Month 12 Postdose 3 of qHPV Vaccine (Month 18)   [ Time Frame: Month 18 (Month 12 Post-dose 3) ]

19.  Secondary:   Geometric Mean Titers of Original qHPV Vaccine Cohort for Anti-HPV 6, 11, 16, and 18 at Month 18 Postdose 3 of qHPV Vaccine (Month 24)   [ Time Frame: Month 24 (18 Months Post-dose 3) ]

20.  Secondary:   Geometric Mean Titers of Original qHPV Vaccine Cohort for Anti-HPV 6, 11, 16, and 18 at Month 24 Postdose 3 of qHPV Vaccine (Month 30)   [ Time Frame: Month 30 (24 Months Post-dose 3) ]

21.  Secondary:   Geometric Mean Titers of Original qHPV Vaccine Cohort for Anti-HPV 6, 11, 16, and 18 at Month 31 Postdose 3 of qHPV Vaccine (Month 37)   [ Time Frame: Month 37 (31 Months Post-dose 3) ]

22.  Secondary:   Geometric Mean Titers in the Extension Group for Anti-HPV 6, 11, 16, and 18 at Month 1 Postdose 3 of qHPV Vaccine (Month 37)   [ Time Frame: Month 37 (1 Month Post-dose 3 of qHPV) ]

23.  Secondary:   Combined Incidence of HPV 6/11/16/18-related Persistent Infection and HPV 6/11/16/18-related CIN, AIS, VIN, VaIN, Genital Warts, and Cervical/Vaginal/Vulvar Cancer in Females   [ Time Frame: Up to Month 126 ]

24.  Secondary:   Combined Incidence of HPV 6/11/16/18-related Persistent Infection and HPV 6/11/16/18-related PIN, Genital Warts, and Penile/Perineal/Perianal Cancer in Males   [ Time Frame: Up to Month 126 ]


  Serious Adverse Events

Time Frame Day 1 to Month 30 and Month 30 to Month 126
Additional Description Day 1 to Month 30: All adverse events were collected up to Day 15 after any vaccination. Month 30 to Month 126: Nonserious AEs were not collected. Deaths and related SAEs were collected throughout the study. Non-serious AEs were not solicited during the Extension Study; any reported non-serious AEs were unsolicited and not systematically assessed.

Reporting Groups
  Description
qHPV Vaccine in Base: Vaccine Phase and Follow-up Participants who were randomized into the qHPV Group, who received three 0.5 mL intramuscular injections of qHPV at Day 1, Month 2, and Month 6, and had safety follow-up. Adverse events are reported for this group from Day 1 to Month 30.
Placebo in Base: Vaccine Phase and Follow-up

Participants who were randomized into the Placebo Group, who received three 0.5 mL intramuscular injections of placebo vaccine at Day 1, Month 2, and Month 6, and had safety followup.

Adverse events are reported for this group from Day 1 to Month 30.

qHPV Vaccine in Base: Extension and Long-term Follow-up Participants who received qHPV in the Base Study. No study treatment was administered after Month 6 for these participants. Adverse events are reported for this group from Month 30 to Month 126. Non-serious AEs were not solicited.
qHPV Vaccine in Extension: Extension and Long-term Follow-up Participants who received placebo in the Base Study and three 0.5 mL intramuscular injections of V501 (qHPV) at Month 30, Month 32, and Month 36 in the Extension Study. Adverse events are reported for this group from Month 30 to Month 126. Non-serious AEs were not solicited.

Serious Adverse Events
    qHPV Vaccine in Base: Vaccine Phase and Follow-up   Placebo in Base: Vaccine Phase and Follow-up   qHPV Vaccine in Base: Extension and Long-term Follow-up   qHPV Vaccine in Extension: Extension and Long-term Follow-up
Total, Serious Adverse Events         
# participants affected / at risk   6/1165 (0.52%)   0/584 (0.00%)   2/932 (0.21%)   3/481 (0.62%) 
Blood and lymphatic system disorders         
Haemorrhagic anaemia * 1         
# participants affected / at risk   1/1165 (0.09%)   0/584 (0.00%)   0/932 (0.00%)   0/481 (0.00%) 
# events   1   0   0   0 
Gastrointestinal disorders         
Colitis ulcerative * 1         
# participants affected / at risk   1/1165 (0.09%)   0/584 (0.00%)   0/932 (0.00%)   0/481 (0.00%) 
# events   1   0   0   0 
General disorders         
Chest pain * 1         
# participants affected / at risk   0/1165 (0.00%)   0/584 (0.00%)   0/932 (0.00%)   1/481 (0.21%) 
# events   0   0   0   1 
Infections and infestations         
Appendicitis * 1         
# participants affected / at risk   1/1165 (0.09%)   0/584 (0.00%)   0/932 (0.00%)   0/481 (0.00%) 
# events   1   0   0   0 
Localised infection * 1         
# participants affected / at risk   1/1165 (0.09%)   0/584 (0.00%)   0/932 (0.00%)   0/481 (0.00%) 
# events   1   0   0   0 
Injury, poisoning and procedural complications         
Meniscus injury * 1         
# participants affected / at risk   0/1165 (0.00%)   0/584 (0.00%)   0/932 (0.00%)   1/481 (0.21%) 
# events   0   0   0   1 
Road traffic accident * 1         
# participants affected / at risk   0/1165 (0.00%)   0/584 (0.00%)   1/932 (0.11%)   0/481 (0.00%) 
# events   0   0   1   0 
Metabolism and nutrition disorders         
Type 1 diabetes mellitus * 1         
# participants affected / at risk   1/1165 (0.09%)   0/584 (0.00%)   0/932 (0.00%)   0/481 (0.00%) 
# events   1   0   0   0 
Musculoskeletal and connective tissue disorders         
Pain in extremity * 1         
# participants affected / at risk   1/1165 (0.09%)   0/584 (0.00%)   0/932 (0.00%)   0/481 (0.00%) 
# events   1   0   0   0 
Nervous system disorders         
VIIth nerve paralysis * 1         
# participants affected / at risk   0/1165 (0.00%)   0/584 (0.00%)   0/932 (0.00%)   1/481 (0.21%) 
# events   0   0   0   1 
Tonic clonic movements * 1         
# participants affected / at risk   0/1165 (0.00%)   0/584 (0.00%)   1/932 (0.11%)   0/481 (0.00%) 
# events   0   0   1   0 
Renal and urinary disorders         
Acute kidney injury * 1         
# participants affected / at risk   1/1165 (0.09%)   0/584 (0.00%)   0/932 (0.00%)   0/481 (0.00%) 
# events   1   0   0   0 
Reproductive system and breast disorders         
Dysfunctional uterine bleeding * 1         
# participants affected / at risk   1/1165 (0.09%)   0/584 (0.00%)   0/932 (0.00%)   0/481 (0.00%) 
# events   1   0   0   0 
* Events were collected by non-systematic assessment
1 Term from vocabulary, MedDRA 11.0




  Other Adverse Events

Time Frame Day 1 to Month 30 and Month 30 to Month 126
Additional Description Day 1 to Month 30: All adverse events were collected up to Day 15 after any vaccination. Month 30 to Month 126: Nonserious AEs were not collected. Deaths and related SAEs were collected throughout the study. Non-serious AEs were not solicited during the Extension Study; any reported non-serious AEs were unsolicited and not systematically assessed.

Frequency Threshold
Threshold above which other adverse events are reported   4%  

Reporting Groups
  Description
qHPV Vaccine in Base: Vaccine Phase and Follow-up Participants who were randomized into the qHPV Group, who received three 0.5 mL intramuscular injections of qHPV at Day 1, Month 2, and Month 6, and had safety follow-up. Adverse events are reported for this group from Day 1 to Month 30.
Placebo in Base: Vaccine Phase and Follow-up

Participants who were randomized into the Placebo Group, who received three 0.5 mL intramuscular injections of placebo vaccine at Day 1, Month 2, and Month 6, and had safety followup.

Adverse events are reported for this group from Day 1 to Month 30.

qHPV Vaccine in Base: Extension and Long-term Follow-up Participants who received qHPV in the Base Study. No study treatment was administered after Month 6 for these participants. Adverse events are reported for this group from Month 30 to Month 126. Non-serious AEs were not solicited.
qHPV Vaccine in Extension: Extension and Long-term Follow-up Participants who received placebo in the Base Study and three 0.5 mL intramuscular injections of V501 (qHPV) at Month 30, Month 32, and Month 36 in the Extension Study. Adverse events are reported for this group from Month 30 to Month 126. Non-serious AEs were not solicited.

Other Adverse Events
    qHPV Vaccine in Base: Vaccine Phase and Follow-up   Placebo in Base: Vaccine Phase and Follow-up   qHPV Vaccine in Base: Extension and Long-term Follow-up   qHPV Vaccine in Extension: Extension and Long-term Follow-up
Total, Other (not including serious) Adverse Events         
# participants affected / at risk   918/1165 (78.80%)   344/584 (58.90%)   0/932 (0.00%)   3/481 (0.62%) 
General disorders         
Injection site erythema * 1         
# participants affected / at risk   237/1165 (20.34%)   78/584 (13.36%)   0/932 (0.00%)   1/481 (0.21%) 
# events   323   109   0   1 
Injection site pain * 2         
# participants affected / at risk   853/1165 (73.22%)   268/584 (45.89%)   0/932 (0.00%)   3/481 (0.62%) 
# events   1705   434   0   3 
Injection site swelling * 2         
# participants affected / at risk   241/1165 (20.69%)   45/584 (7.71%)   0/932 (0.00%)   1/481 (0.21%) 
# events   336   63   0   1 
Pyrexia * 1         
# participants affected / at risk   100/1165 (8.58%)   44/584 (7.53%)   0/932 (0.00%)   0/481 (0.00%) 
# events   114   60   0   0 
Nervous system disorders         
Headache * 1         
# participants affected / at risk   221/1165 (18.97%)   111/584 (19.01%)   0/932 (0.00%)   0/481 (0.00%) 
# events   297   163   0   0 
Respiratory, thoracic and mediastinal disorders         
Oropharyngeal pain * 1         
# participants affected / at risk   52/1165 (4.46%)   24/584 (4.11%)   0/932 (0.00%)   0/481 (0.00%) 
# events   56   26   0   0 
* Events were collected by non-systematic assessment
1 Term from vocabulary, MedDRA 7.1
2 Term from vocabulary, MedDRA 11.0



  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
The difference between the prior and final data is a minor change in the definition of the per-protocol immunogenicity population, which was applied down to the base study. Also, protocol violators were identified and excluded from the analysis.


  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:
unchecked 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.
unchecked 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.


Results Point of Contact:  
Name/Title: Senior Vice President, Global Clinical Development
Organization: Merck Sharp & Dohme Corp.
phone: 1-800-672-6372
e-mail: ClinicalTrialsDisclosure@merck.com


Publications of Results:
Other Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT00092547     History of Changes
Other Study ID Numbers: V501-018
2004_084
First Submitted: September 23, 2004
First Posted: September 28, 2004
Results First Submitted: November 3, 2009
Results First Posted: May 4, 2010
Last Update Posted: February 20, 2018