Clinical Trial Results:
Immunogenicity and Safety of the Purified Vero Rabies Vaccine - Serum Free in Comparison with the Reference Purified Vero Rabies Vaccine in Post-exposure Use in Healthy Subjects in China
Summary
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EudraCT number |
2015-005194-20 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
10 Mar 2012
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Results information
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Results version number |
v1(current) |
This version publication date |
20 Apr 2016
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First version publication date |
20 Apr 2016
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Other versions |
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 |
VRV08
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01339312 | ||
WHO universal trial number (UTN) |
U1111-1117-7193 | ||
Sponsors
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Sponsor organisation name |
Sanofi Pasteur SA
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Sponsor organisation address |
2, avenue Pont Pasteur, Lyon Cedex 07, France, F-69367
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Public contact |
Director, Clinical Development, Sanofi Pasteur SA, 33 4 37 37 54 76, ada-maria.minutello@sanofipasteur.com
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Scientific contact |
Director, Clinical Development, Sanofi Pasteur SA, 33 4 37 37 54 76, ada-maria.minutello@sanofipasteur.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 |
15 Aug 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 |
10 Mar 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 that VRVg is at least as immunogenic as the reference vaccine, Verorab vaccine, in terms of proportion of subjects with a rabies virus neutralizing antibody (RVNA) titer ≥ 0.5 international units (IU)/mL at Day 14, i.e. before the fourth injection, in subjects aged 10 to 17 years and in subjects aged 18 years and over.
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Protection of trial subjects |
Only subjects that met all the study inclusion and none of the exclusion criteria were randomized and vaccinated in the study. Vaccinations were performed by qualified and trained study personnel. Subjects with allergy to any of the vaccine components were not vaccinated. After vaccination, subjects were also kept under clinical observation for 30 minutes to ensure their safety. Appropriate medical equipment was also available on site in case of any immediate allergic reactions.
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Background therapy |
Not applicable | ||
Evidence for comparator |
Not applicable | ||
Actual start date of recruitment |
17 Apr 2011
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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: 816
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Worldwide total number of subjects |
816
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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) |
176
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Adolescents (12-17 years) |
232
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Adults (18-64 years) |
408
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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 |
The study subjects were enrolled from 17 April 2011 to 07 August 2011 at 1 clinic center in China. | ||||||||||||||||||
Pre-assignment
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Screening details |
A total of 816 subjects who met all of the inclusion and none of the exclusion criteria were randomized and vaccinated in this study. Two subjects randomized to receive VRVg received Verorab for the 1st injection and were therefore included in the Verorab group for safety analysis. | ||||||||||||||||||
Period 1
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Period 1 title |
Overall trial (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, Assessor | ||||||||||||||||||
Blinding implementation details |
This was an observer-blind study. Subjects were blinded to which vaccine was administered. Only the person who prepared and administered the vaccine remained unblinded. To maintain the blind, the person who administered the vaccine was different from the person who assessed safety to avoid bias in safety collection. In the event of an emergency (i.e., serious adverse event) the code could be broken as explained in the code-breakding procedures by the Investigator.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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VRVg | ||||||||||||||||||
Arm description |
Subjects received a total of 5 Purified Vero Rabies Vaccine - Serum Free (VRVg) vaccine injections. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Purified Vero Rabies Vaccine - Serum Free (VRVg)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder and solvent for suspension for injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
0.5 mL, intramuscular (alternating between the left and right deltoid for each injection, starting with the left deltoid for the first injection), 1 injection each on Day 0, 3, 7, 14, and 28 (for a total of 5 injections)
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Arm title
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Verorab | ||||||||||||||||||
Arm description |
Subjects received a total of 5 Purified Vero Rabies Vaccine (Verorab) vaccine injections. | ||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||
Investigational medicinal product name |
Purified Vero Rabies Vaccine (Verorab Vaccine)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder and solvent for suspension for injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
0.5 mL, intramuscular (alternating between the left and right deltoid for each injection, starting with the left deltoid for the first injection), 1 injection each on Day 0, 3, 7, 14, and 28 (for a total of 5 injections)
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Baseline characteristics reporting groups
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Reporting group title |
VRVg
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Reporting group description |
Subjects received a total of 5 Purified Vero Rabies Vaccine - Serum Free (VRVg) vaccine injections. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Verorab
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Reporting group description |
Subjects received a total of 5 Purified Vero Rabies Vaccine (Verorab) vaccine injections. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
VRVg
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Reporting group description |
Subjects received a total of 5 Purified Vero Rabies Vaccine - Serum Free (VRVg) vaccine injections. | ||
Reporting group title |
Verorab
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Reporting group description |
Subjects received a total of 5 Purified Vero Rabies Vaccine (Verorab) vaccine injections. |
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End point title |
Percentage of Healthy Subjects 10 to 17 Years Achieving Rabies Virus Neutralizing Antibodies (RVNA) Titer ≥ 0.5 IU/mL After Three Vaccinations with Either Purified Vero Rabies Vaccine – Serum Free or the Reference Purified Vero Rabies Vaccine | |||||||||||||||
End point description |
Antibody titers to each vaccine were assessed using the rapid fluorescent focus inhibition test (RFFIT) method. Seroconversion was defined as rabies virus neutralizing antibody (RVNA) titers ≥0.5 IU/mL.
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End point type |
Primary
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End point timeframe |
Day 14 post-vaccination
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Statistical analysis title |
Non-inferiority (VRVg-Verorab; Day 14) | |||||||||||||||
Statistical analysis description |
This was a non-inferiority analysis of the immunogenicity of VRVg vs Verorab, in terms of proportion of subjects with an RVNA titer ≥0.5 IU/mL.
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Comparison groups |
VRVg v Verorab
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Number of subjects included in analysis |
371
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | |||||||||||||||
Method |
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Parameter type |
Difference in proportions (VRVg-Verorab) | |||||||||||||||
Point estimate |
0
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
-1.54 | |||||||||||||||
upper limit |
2.96 | |||||||||||||||
Notes [1] - Non-inferiority was demonstrated if the lower limit of the 95% confidence interval of the difference VRVg - Verorab for proportion of subjects with RVNA titer ≥0.5 IU/mL is >-5.0%. VRG was non-inferior to Verorab. |
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End point title |
Percentage of Healthy Adult Subjects 18 Years and Older Achieving Rabies Virus Neutralizing Antibodies (RVNA) Titer ≥ 0.5 IU/mL After Three Vaccinations with Purified Vero Rabies Vaccine – Serum Free or Reference Purified Vero Rabies Vaccine | |||||||||||||||
End point description |
Antibody titers to each vaccine were assessed using the rapid fluorescent focus inhibition test (RFFIT) method. Seroconversion was defined as rabies virus neutralizing antibody (RVNA) titers ≥0.5 IU/mL.
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End point type |
Primary
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End point timeframe |
Day 14 post-vaccination
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Statistical analysis title |
Non-inferiority (VRVg-Verorab; Day 14) | |||||||||||||||
Statistical analysis description |
This was a non-inferiority analysis of the immunogenicity of VRVg vs Verorab, in terms of proportion of subjects with an RVNA titer ≥0.5 IU/mL.
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Comparison groups |
VRVg v Verorab
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Number of subjects included in analysis |
379
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [2] | |||||||||||||||
Method |
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Parameter type |
Difference in proportions (VRVg-Verorab) | |||||||||||||||
Point estimate |
0.4
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
-1.51 | |||||||||||||||
upper limit |
4.01 | |||||||||||||||
Notes [2] - Non-inferiority was demonstrated if the lower limit of the 95% confidence interval of the difference VRVg - Verorab for proportion of subjects with RVNA titer ≥0.5 IU/mL is >-5.0%. VRG was non-inferior to Verorab. |
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End point title |
Percentage of Healthy Subjects 10 to 17 Years Achieving Rabies Virus Neutralizing Antibodies (RVNA) Titer ≥ 0.5 IU/mL Before and Following Primary Series Vaccinations with Purified Vero Rabies Vaccine – Serum Free or Reference Purified Vero Rabies Vaccine | |||||||||||||||
End point description |
Antibody titers to each vaccine were assessed using the rapid fluorescent focus inhibition test (RFFIT) method. Seroconversion was defined as rabies virus neutralizing antibody (RVNA) titers ≥0.5 IU/mL.
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End point type |
Secondary
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End point timeframe |
Day 42 post-vaccination
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No statistical analyses for this end point |
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End point title |
Percentage of Healthy Adult Subjects 18 Years and Older Achieving Rabies Virus Neutralizing Antibodies (RVNA) Titer ≥ 0.5 IU/mL After Primary Series Vaccinations with Purified Vero Rabies Vaccine – Serum Free or Purified Vero Rabies Vaccine | |||||||||||||||
End point description |
Antibody titers to each vaccine were assessed using the rapid fluorescent focus inhibition test (RFFIT) method. Seroconversion was defined as rabies virus neutralizing antibody (RVNA) titers ≥0.5 IU/mL.
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End point type |
Secondary
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End point timeframe |
Day 42 post-vaccination
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No statistical analyses for this end point |
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End point title |
Geometric Mean Titers of Rabies Virus Neutralizing Antibodies (RVNA) Following Each Primary Series Vaccination with Purified Vero Rabies Vaccine – Serum Free or Purified Vero Rabies Vaccine in Pre-exposure Use in Healthy Subjects Aged 10 to 17 Years | |||||||||||||||||||||
End point description |
Antibody titers to each vaccine were assessed using the rapid fluorescent focus inhibition test (RFFIT) method.
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End point type |
Secondary
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End point timeframe |
Day 0 (pre-vaccination) and Day 14 and Day 42 post-vaccination
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No statistical analyses for this end point |
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End point title |
Geometric Mean Titers of Rabies Virus Neutralizing Antibodies (RVNA) After Each Primary Series Vaccination with Purified Vero Rabies Vaccine – Serum Free or Purified Vero Rabies Vaccine in Pre-exposure Use in Healthy Adult Subjects Aged 18 Years and Older | |||||||||||||||||||||
End point description |
Antibody titers to each vaccine were assessed using the rapid fluorescent focus inhibition test (RFFIT) method.
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End point type |
Secondary
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End point timeframe |
Day 0 (pre-vaccination) and Day 14 and Day 42 post-vaccination
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No statistical analyses for this end point |
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End point title |
Percentage of Healthy Subjects Reporting Solicited Injection-site or Systemic Reactions Following Any Vaccination with Either Purified Vero Rabies Vaccine – Serum Free (VRVg) or The Reference Purified Vero Rabies Vaccine | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Solicited injection site reactions: Pain, Erythema, and Swelling. Solicited systemic reactions: Fever, Headache, Malaise, and Myalgia.
Grade 3 Solicited injection site reactions (10 to 11 years): Pain, Incapacitating, unable to perform usual activities; Erythema and Swelling, > 30 mm. Grade 3 Solicited injection site reactions (12 years and older): Pain, Significant, prevents daily activity; Erythema and Swelling, > 30 mm. Grade 3 Solicited systemic reactions: Fever, ≥ 39.0°C; Headache, Malaise, and Myalgia, Significant, prevents daily activity.
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End point type |
Secondary
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End point timeframe |
Day 0 up to Day 7 post-vaccination
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No statistical analyses for this end point |
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End point title |
Percentage of Healthy Subjects Aged 10 to 17 Years Reporting Solicited Injection-site or Systemic Reactions Following Any Vaccination with Either Purified Vero Rabies Vaccine – Serum Free (VRVg) or The Reference Purified Vero Rabies Vaccine | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Solicited injection site reactions: Pain, Erythema, and Swelling. Solicited systemic reactions: Fever, Headache, Malaise, and Myalgia.
Grade 3 Solicited injection site reactions (10 to 11 years): Pain, Incapacitating, unable to perform usual activities; Erythema and Swelling, > 30 mm. Grade 3 Solicited injection site reactions (12 years and older): Pain, Significant, prevents daily activity; Erythema and Swelling, > 30 mm. Grade 3 Solicited systemic reactions: Fever, ≥ 39.0°C; Headache, Malaise, and Myalgia, Significant, prevents daily activity.
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End point type |
Secondary
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End point timeframe |
Day 0 up to Day 7 post-vaccination
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No statistical analyses for this end point |
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End point title |
Percentage of Healthy Subjects Aged 18 Year and Older Reporting Solicited Injection-site or Systemic Reactions Following Any Vaccination with Either Purified Vero Rabies Vaccine – Serum Free (VRVg) or The Reference Purified Vero Rabies Vaccine | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Solicited injection site reactions: Pain, Erythema, and Swelling. Solicited systemic reactions: Fever, Headache, Malaise, and Myalgia.
Grade 3 Solicited injection site reactions (10 to 11 years): Pain, Incapacitating, unable to perform usual activities; Erythema and Swelling, > 30 mm. Grade 3 Solicited injection site reactions (12 years and older): Pain, Significant, prevents daily activity; Erythema and Swelling, > 30 mm. Grade 3 Solicited systemic reactions: Fever, ≥ 39.0°C; Headache, Malaise, and Myalgia, Significant, prevents daily activity.
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End point type |
Secondary
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End point timeframe |
Day 0 up to Day 7 post-vaccination
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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 |
Adverse event data were collected from Day 0 up to Day 28 post-vaccination.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
13
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Reporting groups
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Reporting group title |
VRVg
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Reporting group description |
Subjects received a total of 5 Purified Vero Rabies Vaccine - Serum Free (VRVg) vaccine injections. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Verorab
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Reporting group description |
Subjects received a total of 5 Purified Vero Rabies Vaccine (Verorab) vaccine injections. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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21 Apr 2011 |
Exclusion criteria were modified and included clarification on non-inclusion of patients who self-reported seropositivity to hepatitis B, updated contraindications, and a more specific definition of bites by suspected rabid animals. |
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08 Jul 2011 |
The sample size was increased (due to an increase in the percentage of non-evaluable subjects) in order to appropriately assess the primary objective of the study. |
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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 | |||
Online references |
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http://www.ncbi.nlm.nih.gov/pubmed/24148575 |