Dose-Ranging Study of Quadrivalent Human Papillomavirus (HPV) (Types 6,11,16,18) L1 Virus-Like Particle (VLP) Vaccine (V501-007)(COMPLETED)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT00365716
First received: August 16, 2006
Last updated: May 5, 2014
Last verified: May 2014
Results First Received: May 19, 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
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
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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
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     Extension 1     Extension 2  
STARTED     290     284     292     146     146     0     0  
COMPLETED     269     260     271     136     139     0     0  
NOT COMPLETED     21     24     21     10     7     0     0  
Randomized Not Vaccinated                 1                 2                 0                 0                 0                 0                 0  
Adverse Event                 0                 2                 0                 0                 1                 0                 0  
Lost to Follow-up                 4                 6                 6                 4                 0                 0                 0  
Unspecified                 0                 1                 0                 0                 0                 0                 0  
Pregnancy                 3                 2                 3                 1                 1                 0                 0  
Protocol Violation                 1                 2                 0                 1                 2                 0                 0  
Withdrawal by Subject                 12                 9                 12                 4                 3                 0                 0  

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     Extension 1     Extension 2  
STARTED     269     260     271     136     139     0     0  
COMPLETED     137     245     251     57     57     0     0  
NOT COMPLETED     132     15     20     79     82     0     0  
Proceeded to Extension 1                 114                 0                 0                 69                 75                 0                 0  
Lost to Follow-up                 6                 8                 5                 4                 3                 0                 0  
Moved                 3                 2                 1                 2                 0                 0                 0  
Unspecified                 2                 0                 0                 0                 1                 0                 0  
Protocol Violation                 0                 1                 1                 0                 0                 0                 0  
Withdrawal by Subject                 7                 4                 13                 4                 3                 0                 0  

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
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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.
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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.

Total Total of all reporting groups

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

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 ]


  Serious Adverse Events
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Time Frame Adverse events (AEs) were collected from Day 1 until Month 7. AEs were collected on the subject’s vaccination report card daily for 14 days after each injection.
Additional Description Subjects were observed for 30 minutes after each vaccination. Temperatures were recorded for 5 days after each injection (4 hours after injection and daily for the next 4 days). At Months 2, 3, 6, and 7, subjects were solicited for any gynecological health concerns and any SAEs that had occurred.

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.

  • There was one subject randomized to the quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine 20/40/40/20 mcg group who received the 225 mcg aluminum adjuvant placebo at the third vaccination visit. This subject was not included in the counts reported in the Adverse Event tables. No SAEs were reported for this subject.
  • There was 1 patient that was randomized, but never vaccinated. As such, that patient is not included in this table.
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.

  • There were 2 patients from the 40/40/40/40 group that were randomized, but were never vaccinated. As such, these 2 patients are not included in this table.
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.

Extensions

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.

  • Serious Adverse Events (SAEs) were collected during Extension 1 and Extension 2. Note that the N includes only the 241 subjects vaccinated during the Extension Periods; of the 258 subjects that entered either Extension, 17 subjects discontinued before being vaccinated and therefore are not included in this table.

Serious Adverse Events
    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     Extensions  
Total, serious adverse events              
# participants affected / at risk     3/288 (1.04%)     0/282 (0.00%)     2/292 (0.68%)     0/146 (0.00%)     3/146 (2.05%)     1/241 (0.41%)  
Gastrointestinal disorders              
Appendicitis † 1            
# participants affected / at risk     0/288 (0.00%)     0/282 (0.00%)     0/292 (0.00%)     0/146 (0.00%)     1/146 (0.68%)     0/241 (0.00%)  
Kidney infection † 1            
# participants affected / at risk     0/288 (0.00%)     0/282 (0.00%)     0/292 (0.00%)     0/146 (0.00%)     1/146 (0.68%)     0/241 (0.00%)  
Pyelonephritis † 1            
# participants affected / at risk     0/288 (0.00%)     0/282 (0.00%)     1/292 (0.34%)     0/146 (0.00%)     0/146 (0.00%)     0/241 (0.00%)  
Injury, poisoning and procedural complications              
Drug toxicity † 1            
# participants affected / at risk     0/288 (0.00%)     0/282 (0.00%)     0/292 (0.00%)     0/146 (0.00%)     0/146 (0.00%)     1/241 (0.41%)  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)              
Pancreatic carcinoma † 1            
# participants affected / at risk     1/288 (0.35%)     0/282 (0.00%)     0/292 (0.00%)     0/146 (0.00%)     0/146 (0.00%)     0/241 (0.00%)  
Psychiatric disorders              
Depression † 1            
# participants affected / at risk     1/288 (0.35%)     0/282 (0.00%)     1/292 (0.34%)     0/146 (0.00%)     0/146 (0.00%)     0/241 (0.00%)  
Renal and urinary disorders              
Renal colic † 1            
# participants affected / at risk     1/288 (0.35%)     0/282 (0.00%)     0/292 (0.00%)     0/146 (0.00%)     0/146 (0.00%)     0/241 (0.00%)  
Reproductive system and breast disorders              
Cervix haemorrhage uterine † 1            
# participants affected / at risk     0/288 (0.00%)     0/282 (0.00%)     0/292 (0.00%)     0/146 (0.00%)     1/146 (0.68%)     0/241 (0.00%)  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA 12.0




  Other Adverse Events


  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
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