Cervical Intraepithelial Neoplasm (CIN)-Warts Efficacy Trial in Women (Gardasil)(V501-013)(COMPLETED)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT00092521
First received: September 23, 2004
Last updated: August 26, 2014
Last verified: August 2014
Results First Received: August 3, 2009  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Prevention
Conditions: Cervical Cancer
Genital Warts
Interventions: Biological: V501
Biological: Comparator: Placebo
Biological: Human Papillomavirus (HPV) 16 Monovalent

  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
The study Protocol 013 (NCT00092521) (N =5759 total randomized) was comprised 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): the final participant visit took place on 19 January 2009.

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
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 Human papillomavirus (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 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 1:   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     Group 4 - Quadrivalent Human Papillomavirus Vaccine Extension  
STARTED     2723     304     2732     0  
COMPLETED     2583     290     2586     0  
NOT COMPLETED     140     14     146     0  
Randomized Not Vaccinated                 6                 0                 7                 0  
Adverse Event                 1                 0                 7                 0  
Death                 0                 0                 1                 0  
Lost to Follow-up                 51                 6                 44                 0  
Pregnancy                 5                 0                 7                 0  
Withdrawal by Subject                 59                 7                 62                 0  
Moved                 14                 1                 18                 0  
Unblinded                 2                 0                 0                 0  
New Medical History (Not AE)                 2                 0                 0                 0  

Period 2:   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     Group 4 - Quadrivalent Human Papillomavirus Vaccine Extension  
STARTED     2599 [1]   291 [1]   2607 [1]   0  
COMPLETED     2353     155     1959     0  
NOT COMPLETED     246     136     648     0  
Subjects Continuing                 34                 4                 35                 0  
Subjects in Extension                 13                 109                 412                 0  
Adverse Event                 1                 0                 0                 0  
Death                 2                 0                 1                 0  
Lost to Follow-up                 113                 14                 108                 0  
Protocol Violation                 1                 1                 5                 0  
Withdrawal by Subject                 40                 6                 51                 0  
Moved                 32                 2                 28                 0  
Site Terminated                 3                 0                 3                 0  
Travel                 2                 0                 0                 0  
Visits Compressed                 5                 0                 5                 0  
[1] Includes subjects who did not receive 3 doses of vaccine/placebo but continued into the follow-up

Period 3:   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  
Initiated Extension Study     0     0     0     829  
Received >=1 Dose in Extension Study     0     0     0     801  
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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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
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.

Total Total of all reporting groups

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  
[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 )  
Age, Customized [1]
[units: Participants]
       
16 to 24 Years of Age     2723     304     2732     5759  
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
  Show All Outcome Measures

1.  Primary:   Incidence of HPV 6/11/16/18-related Cervical Intraepithelial Neoplasia (CIN)(Any Grade), Adenocarcinoma In Situ (AIS) or Cervical Cancer   [ Time Frame: Follow-up through end of study (4 years) ]

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]   [ Time Frame: Follow-up through end of study (4 years) ]


  Serious Adverse Events


  Other Adverse Events
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Time Frame No text entered.
Additional Description Number of subjects at risk included randomized subjects who had follow-up. For Group 4 (Extension), number of subjects at risk included those who received >=1 vaccination in the extension study. Both serious and Other AEs were collected in the base period and only serious AEs were collected in the extension period.

Frequency Threshold
Threshold above which other adverse events are reported   1%  

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.

Group 4 - Quadrivalent Human Papillomavirus Vaccine Extension This group includes 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.

Other Adverse Events
    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  
Total, other (not including serious) adverse events          
# participants affected / at risk     2458/2673     276/299     2331/2672     0/0  
Gastrointestinal disorders          
Abdominal pain * 1        
# participants affected / at risk     88/2673 (3.29%)     8/299 (2.68%)     81/2672 (3.03%)     0/0 (0.00%)  
Abdominal pain upper * 1        
# participants affected / at risk     82/2673 (3.07%)     5/299 (1.67%)     87/2672 (3.26%)     0/0 (0.00%)  
Diarrhea * 1        
# participants affected / at risk     105/2673 (3.93%)     9/299 (3.01%)     96/2672 (3.59%)     0/0 (0.00%)  
Dyspepsia * 1        
# participants affected / at risk     17/2673 (0.64%)     5/299 (1.67%)     16/2672 (0.60%)     0/0 (0.00%)  
Gastritis * 1        
# participants affected / at risk     22/2673 (0.82%)     4/299 (1.34%)     13/2672 (0.49%)     0/0 (0.00%)  
Nausea * 1        
# participants affected / at risk     210/2673 (7.86%)     23/299 (7.69%)     174/2672 (6.51%)     0/0 (0.00%)  
Toothache * 1        
# participants affected / at risk     48/2673 (1.80%)     4/299 (1.34%)     40/2672 (1.50%)     0/0 (0.00%)  
Vomiting * 1        
# participants affected / at risk     62/2673 (2.32%)     9/299 (3.01%)     56/2672 (2.10%)     0/0 (0.00%)  
General disorders          
Asthenia * 1        
# participants affected / at risk     29/2673 (1.08%)     7/299 (2.34%)     25/2672 (0.94%)     0/0 (0.00%)  
Fatigue * 1        
# participants affected / at risk     73/2673 (2.73%)     12/299 (4.01%)     102/2672 (3.82%)     0/0 (0.00%)  
Malaise * 1        
# participants affected / at risk     47/2673 (1.76%)     3/299 (1.00%)     40/2672 (1.50%)     0/0 (0.00%)  
Pain * 1        
# participants affected / at risk     19/2673 (0.71%)     3/299 (1.00%)     26/2672 (0.97%)     0/0 (0.00%)  
Pyrexia * 1        
# participants affected / at risk     436/2673 (16.31%)     33/299 (11.04%)     348/2672 (13.02%)     0/0 (0.00%)  
Injection site erythema † 1        
# participants affected / at risk     659/2673 (24.65%)     84/299 (28.09%)     450/2672 (16.84%)     0/0 (0.00%)  
Injection site haematoma † 1        
# participants affected / at risk     94/2673 (3.52%)     6/299 (2.01%)     97/2672 (3.63%)     0/0 (0.00%)  
Injection site hypersensitivity † 1        
# participants affected / at risk     27/2673 (1.01%)     9/299 (3.01%)     22/2672 (0.82%)     0/0 (0.00%)  
Injection site pain † 1        
# participants affected / at risk     2281/2673 (85.33%)     242/299 (80.94%)     2014/2672 (75.37%)     0/0 (0.00%)  
Injection site pruritus † 1        
# participants affected / at risk     109/2673 (4.08%)     12/299 (4.01%)     80/2672 (2.99%)     0/0 (0.00%)  
Injection site reaction † 1        
# participants affected / at risk     22/2673 (0.82%)     4/299 (1.34%)     17/2672 (0.64%)     0/0 (0.00%)  
Injection site swelling † 1        
# participants affected / at risk     694/2673 (25.96%)     70/299 (23.41%)     413/2672 (15.46%)     0/0 (0.00%)  
Infections and infestations          
Gastroenteritis * 1        
# participants affected / at risk     17/2673 (0.64%)     3/299 (1.00%)     18/2672 (0.67%)     0/0 (0.00%)  
Influenza * 1        
# participants affected / at risk     124/2673 (4.64%)     18/299 (6.02%)     113/2672 (4.23%)     0/0 (0.00%)  
Nasopharyngitis * 1        
# participants affected / at risk     185/2673 (6.92%)     22/299 (7.36%)     166/2672 (6.21%)     0/0 (0.00%)  
Pharyngitis * 1        
# participants affected / at risk     32/2673 (1.20%)     3/299 (1.00%)     31/2672 (1.16%)     0/0 (0.00%)  
Sinusitis * 1        
# participants affected / at risk     22/2673 (0.82%)     3/299 (1.00%)     18/2672 (0.67%)     0/0 (0.00%)  
Tonsillitis * 1        
# participants affected / at risk     26/2673 (0.97%)     2/299 (0.67%)     29/2672 (1.09%)     0/0 (0.00%)  
Upper respiratory tract infection * 1        
# participants affected / at risk     36/2673 (1.35%)     9/299 (3.01%)     42/2672 (1.57%)     0/0 (0.00%)  
Vulvovaginal candidiasis * 1        
# participants affected / at risk     10/2673 (0.37%)     4/299 (1.34%)     16/2672 (0.60%)     0/0 (0.00%)  
Injury, poisoning and procedural complications          
Procedural pain * 1        
# participants affected / at risk     4/2673 (0.15%)     3/299 (1.00%)     4/2672 (0.15%)     0/0 (0.00%)  
Musculoskeletal and connective tissue disorders          
Arthralgia * 1        
# participants affected / at risk     27/2673 (1.01%)     0/299 (0.00%)     25/2672 (0.94%)     0/0 (0.00%)  
Back Pain * 1        
# participants affected / at risk     68/2673 (2.54%)     10/299 (3.34%)     63/2672 (2.36%)     0/0 (0.00%)  
Muscle Spasms * 1        
# participants affected / at risk     14/2673 (0.52%)     3/299 (1.00%)     12/2672 (0.45%)     0/0 (0.00%)  
Myalgia * 1        
# participants affected / at risk     49/2673 (1.83%)     6/299 (2.01%)     54/2672 (2.02%)     0/0 (0.00%)  
Pain in Extremity * 1        
# participants affected / at risk     55/2673 (2.06%)     7/299 (2.34%)     57/2672 (2.13%)     0/0 (0.00%)  
Nervous system disorders          
Dizziness * 1        
# participants affected / at risk     123/2673 (4.60%)     18/299 (6.02%)     114/2672 (4.27%)     0/0 (0.00%)  
Headache * 1        
# participants affected / at risk     802/2673 (30.00%)     103/299 (34.45%)     76/2672 (2.84%)     0/0 (0.00%)  
Migraine * 1        
# participants affected / at risk     23/2673 (0.86%)     3/299 (1.00%)     15/2672 (0.56%)     0/0 (0.00%)  
Somnolence * 1        
# participants affected / at risk     30/2673 (1.12%)     0/299 (0.00%)     32/2672 (1.20%)     0/0 (0.00%)  
Psychiatric disorders          
Insomnia * 1        
# participants affected / at risk     35/2673 (1.31%)     2/299 (0.67%)     23/2672 (0.86%)     0/0 (0.00%)  
Reproductive system and breast disorders          
Dysmenorrhea * 1        
# participants affected / at risk     106/2673 (3.97%)     11/299 (3.68%)     100/2672 (3.74%)     0/0 (0.00%)  
Pelvic Pain * 1        
# participants affected / at risk     14/2673 (0.52%)     4/299 (1.34%)     22/2672 (0.82%)     0/0 (0.00%)  
Respiratory, thoracic and mediastinal disorders          
Cough * 1        
# participants affected / at risk     59/2673 (2.21%)     6/299 (2.01%)     40/2672 (1.50%)     0/0 (0.00%)  
Nasal congestion * 1        
# participants affected / at risk     26/2673 (0.97%)     3/299 (1.00%)     15/2672 (0.56%)     0/0 (0.00%)  
Oropharyngeal pain * 1        
# participants affected / at risk     109/2673 (4.08%)     14/299 (4.68%)     116/2672 (4.34%)     0/0 (0.00%)  
Skin and subcutaneous tissue disorders          
Dermatitis allergic * 1        
# participants affected / at risk     5/2673 (0.19%)     3/299 (1.00%)     10/2672 (0.37%)     0/0 (0.00%)  
Events were collected by systematic assessment
* Events were collected by non-systematic assessment
1 Term from vocabulary, MedDRA 11.1



  Limitations and Caveats
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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.


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