Clinical Trial Results:
A phase III, double-blind, randomized, controlled study to evaluate the immunogenicity and safety of GlaxoSmithKline (GSK) Biologicals’ HPV-16/18 L1 VLP AS04 vaccine administered intramuscularly according to a 0, 1, 6-month schedule in healthy Chinese female subjects aged 9-17 years.
Summary
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EudraCT number |
2012-003025-25 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
08 Dec 2012
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Results information
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Results version number |
v1 |
This version publication date |
11 May 2016
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First version publication date |
12 Jul 2015
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Other versions |
v2 |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
112022
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
GlaxoSmithKline Biologicals
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Sponsor organisation address |
Rue de l'Institut 89, Rixensart, Belgium, B-1330
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Public contact |
Clinical Disclosure Advisor, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com
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Scientific contact |
Clinical Disclosure Advisor, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
08 Mar 2012
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
08 Dec 2012
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
•To demonstrate the non-inferiority of HPV immune response at one month post-dose 3 in Chinese female subjects aged 9-17 years from the current study versus Chinese women aged 18-25 years enrolled in the HPV-039 study (eTrack No. 107638).
Criteria for non-inferiority (one month after the third vaccine dose):
-The objective will be reached if for each HPV antigen (anti-HPV-16 and anti-HPV-18), the upper limit of the 95% confidence interval (CI) for the GMT ratio [GMTs in subjects aged 18-25 years with immunogenicity results at Month 7 who receive HPV-16/18 L1 VLP AS04 vaccine in the HPV-039 study divided by the GMTs of subjects aged 9-17 years who receive HPV-16/18 L1 VLP AS04 vaccine in the HPV-058 study] is below 2.
-This objective will be evaluated in the according-to-protocol (ATP) cohort for immunogenicity
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Protection of trial subjects |
As with all injectable vaccines, appropriate medical treatment was always readily available in case of anaphylactic reactions following the administration of the vaccine. For this reason, the vaccine remained under medical supervision for 30 minutes after vaccination.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
24 Oct 2009
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
China: 750
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Worldwide total number of subjects |
750
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
750
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | |||||||||||||||||||||
Pre-assignment
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Screening details |
A total number of 750 subjects were enrolled in this study. | |||||||||||||||||||||
Period 1
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Period 1 title |
Owerall Study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor | |||||||||||||||||||||
Blinding implementation details |
Blinding was maintained for all subjects and investigators and their study staff participating in this study with regard to the individual subject treatment (vaccine or control) assignments allocated in this study. GSK personnel directly involved in the conduct of this study (e.g. site monitors, medical monitors, laboratory personnel, etc.) was also blinded to the subject’s treatment assignments.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Cervarix Group | |||||||||||||||||||||
Arm description |
Subjects received 3 doses of Cervarix vaccine. Cervarix vaccine was administered intramuscularly into the deltoid muscle of the non-dominant arm according to a 0, 1, 6-month schedule. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Cervarix
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Investigational medicinal product code |
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Other name |
CervarixTM
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Pharmaceutical forms |
Injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
Subjects will receive three doses of the Cervarix vaccine intramuscularly according to a 0, 1, 6-month schedule.
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Arm title
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Placebo Group | |||||||||||||||||||||
Arm description |
Subjects received 3 doses of placebo. Placebo vaccine was administered intramuscularly into the deltoid muscle of the non-dominant arm according to a 0, 1, 6-month schedule. | |||||||||||||||||||||
Arm type |
Control | |||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
Placebo
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Pharmaceutical forms |
Injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
Subjects will receive three doses of control intramuscularly according to a 0, 1, 6-month schedule.
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Baseline characteristics reporting groups
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Reporting group title |
Cervarix Group
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Reporting group description |
Subjects received 3 doses of Cervarix vaccine. Cervarix vaccine was administered intramuscularly into the deltoid muscle of the non-dominant arm according to a 0, 1, 6-month schedule. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo Group
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Reporting group description |
Subjects received 3 doses of placebo. Placebo vaccine was administered intramuscularly into the deltoid muscle of the non-dominant arm according to a 0, 1, 6-month schedule. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Cervarix Group
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Reporting group description |
Subjects received 3 doses of Cervarix vaccine. Cervarix vaccine was administered intramuscularly into the deltoid muscle of the non-dominant arm according to a 0, 1, 6-month schedule. | ||
Reporting group title |
Placebo Group
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Reporting group description |
Subjects received 3 doses of placebo. Placebo vaccine was administered intramuscularly into the deltoid muscle of the non-dominant arm according to a 0, 1, 6-month schedule. |
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End point title |
Geometric mean titers (GMTs) for antibodies against Human Papillomavirus (HPV)-16/18 antigens | ||||||||||||||||||
End point description |
Titers were given as geometric mean titers and were measured by Enzyme-linked Immunosorbent Assay (ELISA) and expressed as Enzyme-linked Immunosorbent Assay Units Per Milliliter (EL.U/mL).
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End point type |
Primary
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End point timeframe |
One month after the third dose (at Month 7)
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Statistical analysis title |
Anti-HPV-016 immune response | ||||||||||||||||||
Comparison groups |
Cervarix Group v Placebo Group
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Number of subjects included in analysis |
725
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||||||||
P-value |
< 2 | ||||||||||||||||||
Method |
t-test, 2-sided | ||||||||||||||||||
Parameter type |
GMT ratio | ||||||||||||||||||
Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
0.32 | ||||||||||||||||||
upper limit |
0.43 | ||||||||||||||||||
Variability estimate |
Standard deviation
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Dispersion value |
0.37
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Statistical analysis title |
Anti-HPV-018 immune response | ||||||||||||||||||
Comparison groups |
Cervarix Group v Placebo Group
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Number of subjects included in analysis |
725
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||||||||
P-value |
< 2 | ||||||||||||||||||
Method |
GMT ratio | ||||||||||||||||||
Parameter type |
GMT ratio | ||||||||||||||||||
Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
0.36 | ||||||||||||||||||
upper limit |
0.49 | ||||||||||||||||||
Variability estimate |
Standard deviation
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Dispersion value |
0.42
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End point title |
Number of subjects seroconverted for Anti-HPV-16 and Anti-HPV-18 antibodies | |||||||||||||||
End point description |
Seroconversion is defined as the appearance of anti-HPV-16 and/or anti- HPV-18 antibodies (i.e. antibody titer ≥ cut-off value) in the sera of subjects seronegative before vaccination. Cut-off values were 8 enzyme-linked immunosorbent assay units per milliliter (EL.U/mL) for anti-HPV-16 antibodies and 7 EL.U/mL for anti- HPV-18 antibodies.
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End point type |
Secondary
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End point timeframe |
At Month 7
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No statistical analyses for this end point |
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End point title |
Number of subjects reporting any and grade 3 solicited local symptoms | |||||||||||||||||||||||||||
End point description |
Solicited local symptoms assessed were pain, redness and swelling. Any was defined as any solicited local symptom reported irrespective of intensity. Grade 3 pain was defined as pain that prevented normal activity. Grade 3 redness and swelling were defined as redness/swelling above 50 millimeter (mm).
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End point type |
Secondary
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End point timeframe |
During the 7 days (Days 0 – 6) following each vaccination
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No statistical analyses for this end point |
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End point title |
Number of subjects reporting any, grade 3 and related solicited general symptoms | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Solicited general symptoms assessed were arthralgia, fatigue, gastrointestinal, headache, myalgia, rash, urticaria and fever (= axillary temperature above 37.0 degrees Celsius (°C). Grade 3 fever = axillary temperature above 39.0°C. Grade 3 urticaria = urticaria distributed on at least 4 body areas. For other symptoms, any = occurrence of any general symptom regardless of intensity grade or relation to vaccination and grade 3 = a general symptom that prevented normal activity. Related was a general symptom assessed by the investigator as causally related to the study vaccination.
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End point type |
Secondary
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End point timeframe |
During the 7 days (Days 0 – 6) following each vaccination
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No statistical analyses for this end point |
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End point title |
Number of subjects reporting medically significant conditions (MSCs) | ||||||||||||
End point description |
Medically significant conditions (MSCs) are defined as: adverse events (AEs) prompting emergency room or physician visits that are not (1) related to common diseases or (2) routine visits for physical examination or vaccination, or serious adverse events (SAEs) that are not related to common diseases. Common diseases include: upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervicovaginal yeast infections, menstrual cycle abnormalities and injury. MSCs were collected regardless of causal relationship to vaccination and intensity.
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End point type |
Secondary
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End point timeframe |
Throughout the study period (from Day 0 up to Month 12)
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No statistical analyses for this end point |
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End point title |
Number of subjects reporting pregnancies and pregnancy outcomes | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Throughout the study period (from Day 0 up to Month 12)
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No statistical analyses for this end point |
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End point title |
Number of subjects reporting any, grade 3 and related unsolicited adverse events (AEs) | ||||||||||||||||||
End point description |
Unsolicited AE covers any AE reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as occurrence of any unsolicited symptom regardless of intensity grade or relation to vaccination. Grade 3 was an event that prevented normal activities and related was defined as an unsolicited AE assessed by the investigator to be causally related to the study vaccination.
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End point type |
Secondary
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End point timeframe |
Within 30 days (Days 0 – 29) after any vaccination
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No statistical analyses for this end point |
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End point title |
Number of subjects reporting any and related serious adverse events (SAEs) | |||||||||||||||
End point description |
SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject. Any was defined as occurrence of any symptom regardless of intensity grade or relation to vaccination and related was an event assessed by the investigator as causally related to the study vaccination.
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End point type |
Secondary
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End point timeframe |
Throughout the study period (from Day 0 up to Month 12)
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Serious adverse events were assessed from Day 0 up to Month 12. Systematically assessed frequent adverse events (AEs) and non-systematically assessed frequent AEs were assessed during 7 days and 30 days post vaccination period respectively.
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Adverse event reporting additional description |
For the systematically assessed other (non-serious) adverse events, the total participants at risk in Cervarix Group included those from Total Vaccinated cohort who had the symptom sheet completed and with at least one documented dose.
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Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
12.1
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Reporting groups
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Reporting group title |
Cervarix Group
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Reporting group description |
Subjects received 3 doses of Cervarix vaccine. Cervarix vaccine was administered intramuscularly into the deltoid muscle of the non-dominant arm according to a 0, 1, 6-month schedule. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo Group
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Reporting group description |
Subjects received 3 doses of placebo. Placebo vaccine was administered intramuscularly into the deltoid muscle of the non-dominant arm according to a 0, 1, 6-month schedule. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Notes [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: The analysis was performed on the Total Vaccinated cohort, only on subjects with their symptom sheets completed. [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: The analysis was performed on the Total Vaccinated cohort, only on subjects with their symptom sheets completed. [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: The analysis was performed on the Total Vaccinated cohort, only on subjects with their symptom sheets completed. [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: The analysis was performed on the Total Vaccinated cohort, only on subjects with their symptom sheets completed. [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: The analysis was performed on the Total Vaccinated cohort, only on subjects with their symptom sheets completed. [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: The analysis was performed on the Total Vaccinated cohort, only on subjects with their symptom sheets completed. [7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: The analysis was performed on the Total Vaccinated cohort, only on subjects with their symptom sheets completed. [8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: The analysis was performed on the Total Vaccinated cohort, only on subjects with their symptom sheets completed. [9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: The analysis was performed on the Total Vaccinated cohort, only on subjects with their symptom sheets completed. |
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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03 Nov 2010 |
Amendment 1
• Due to a delay in the availability of the Month 7 serology data to be generated at the National Institute for Control of Pharmaceutical and Biological Products (NICPBP), the initial planned final analysis (for immunogenicity and safety data up to Month 7) and the annex analysis (for safety data collected during the 5-month extended safety follow-up (EFSU) period up to Month 12) will be conducted as one final analysis and will include all data up to Month 12. A clinical study report will be written to present the final analysis data.
• The name of the coordinating authors and contributing authors have been updated in the title page. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |