Clinical Trial Results:
Verorab® immunogenicity and safety after a one week, 4-site, intradermal (ID) post-exposure prophylaxis regimen (4-4-4-0-0) followed by a one visit, 4-site, ID booster at five years.
Summary
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EudraCT number |
2018-004707-40 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
14 Nov 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
24 Jul 2019
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First version publication date |
24 Jul 2019
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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 |
RAB40
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01622062 | ||
WHO universal trial number (UTN) |
U1111-1117-7193 | ||
Sponsors
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Sponsor organisation name |
Sanofi Pasteur
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Sponsor organisation address |
14 Espace Henry Vallée, Lyon, France, 69007
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Public contact |
Trial Transparency Team, Sanofi Pasteur, Contact-US@sanofi.com
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Scientific contact |
Trial Transparency Team, Sanofi Pasteur, Contact-US@sanofi.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 |
12 Jun 2019
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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 |
14 Nov 2018
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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 post-exposure prophylaxis (PEP) using the "one-week, 4-site" (4-4-4-0-0) intradermal (ID) vaccination regimen is non-inferior to PEP using the updated Thai Red Cross (TRC) (2-2-2-0-2) ID vaccination regimen in terms of seroconversion rate at Day 14 (Group 1 versus Group 3, and Group 2 versus Group 3).
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Protection of trial subjects |
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 were also available on site in case of any immediate allergic reactions.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
29 Jun 2012
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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 |
Philippines: 600
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Worldwide total number of subjects |
600
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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) |
17
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Children (2-11 years) |
237
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Adolescents (12-17 years) |
65
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Adults (18-64 years) |
281
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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 |
Study was conducted at Philippines from 29 June 2012 to 14 November 2018. | ||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
A total of 600 subjects who met all of the inclusion criteria and none of the exclusion criteria were enrolled and randomised in the study. | ||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Group 1 | ||||||||||||||||||||||||||||||||
Arm description |
Subjects with World Health Organization (WHO) Category II exposure received PEP with Purified Vero cell Rabies Vaccine (PVRV) using "one-week, 4-site" (4-4-4-0-0) ID vaccination regimen on Day 0, Day 3 and Day 7, and a "single-visit, 4-site" booster vaccination with PVRV 5 years later. | ||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Purified Vero cell Rabies Vaccine
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Investigational medicinal product code |
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Other name |
VERORAB®
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Pharmaceutical forms |
Powder and solvent for suspension for injection
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Routes of administration |
Intradermal use
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Dosage and administration details |
Subjects received 0.1 milliliter (mL) of vaccine administered intradermally in 4 site 'one week' (4-4-4-0-0) regimen at both deltoids and both anterior thighs.
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Arm title
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Group 2 | ||||||||||||||||||||||||||||||||
Arm description |
Subjects with WHO Category III exposure received PEP with PVRV using "one-week, 4-site" (4-4-4-0-0) ID vaccination regimen on Day 0, Day 3 and Day 7 and purified Equine Rabies Immunoglobulin (pERIG) Favirab® on Day 0, and a "single-visit, 4-site" booster vaccination with PVRV 5 years later. | ||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Purified Vero cell Rabies Vaccine
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Investigational medicinal product code |
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Other name |
VERORAB®
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Pharmaceutical forms |
Powder and solvent for suspension for injection
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Routes of administration |
Intradermal use
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Dosage and administration details |
Subjects received 0.1 mL of vaccine administered intradermally in 4 site 'one week' (4-4-4-0-0) regimen at both deltoids and both anterior thighs.
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Investigational medicinal product name |
Purified Equine Rabies Immunoglobulin
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Investigational medicinal product code |
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Other name |
FAVIRAB®
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intradermal use
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Dosage and administration details |
The dose was calculated according to the weight of the subject. The recommended dose was same for children and adults: 40 international units per kilogram (IU/kg) of body weight.
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Arm title
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Group 3 | ||||||||||||||||||||||||||||||||
Arm description |
Subjects with WHO Category III exposure receive PEP with PVRV using the updated 2-site TRC (2-2-2-0-2) ID vaccination regimen on Day 0, Day 3, Day 7 and Day 28 and pERIG Favirab® on Day 0, and a "single-visit, 4-site" booster vaccination with PVRV 5 years later. | ||||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Purified Vero cell Rabies Vaccine
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Investigational medicinal product code |
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Other name |
VERORAB®
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Pharmaceutical forms |
Powder and solvent for suspension for injection
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Routes of administration |
Intradermal use
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Dosage and administration details |
Subjects received 0.1 mL of vaccine administered intradermally in 2-site TRC (2-2-2-0-2) regimen at both deltoids.
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Investigational medicinal product name |
Purified Equine Rabies Immunoglobulin
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Investigational medicinal product code |
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Other name |
FAVIRAB®
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intradermal use
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Dosage and administration details |
The dose was calculated according to the weight of the subject. The recommended dose was same for children and adults: 40 IU/kg of body weight.
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Baseline characteristics reporting groups
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Reporting group title |
Group 1
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Reporting group description |
Subjects with World Health Organization (WHO) Category II exposure received PEP with Purified Vero cell Rabies Vaccine (PVRV) using "one-week, 4-site" (4-4-4-0-0) ID vaccination regimen on Day 0, Day 3 and Day 7, and a "single-visit, 4-site" booster vaccination with PVRV 5 years later. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group 2
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Reporting group description |
Subjects with WHO Category III exposure received PEP with PVRV using "one-week, 4-site" (4-4-4-0-0) ID vaccination regimen on Day 0, Day 3 and Day 7 and purified Equine Rabies Immunoglobulin (pERIG) Favirab® on Day 0, and a "single-visit, 4-site" booster vaccination with PVRV 5 years later. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group 3
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Reporting group description |
Subjects with WHO Category III exposure receive PEP with PVRV using the updated 2-site TRC (2-2-2-0-2) ID vaccination regimen on Day 0, Day 3, Day 7 and Day 28 and pERIG Favirab® on Day 0, and a "single-visit, 4-site" booster vaccination with PVRV 5 years later. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Group 1
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Reporting group description |
Subjects with World Health Organization (WHO) Category II exposure received PEP with Purified Vero cell Rabies Vaccine (PVRV) using "one-week, 4-site" (4-4-4-0-0) ID vaccination regimen on Day 0, Day 3 and Day 7, and a "single-visit, 4-site" booster vaccination with PVRV 5 years later. | ||
Reporting group title |
Group 2
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Reporting group description |
Subjects with WHO Category III exposure received PEP with PVRV using "one-week, 4-site" (4-4-4-0-0) ID vaccination regimen on Day 0, Day 3 and Day 7 and purified Equine Rabies Immunoglobulin (pERIG) Favirab® on Day 0, and a "single-visit, 4-site" booster vaccination with PVRV 5 years later. | ||
Reporting group title |
Group 3
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Reporting group description |
Subjects with WHO Category III exposure receive PEP with PVRV using the updated 2-site TRC (2-2-2-0-2) ID vaccination regimen on Day 0, Day 3, Day 7 and Day 28 and pERIG Favirab® on Day 0, and a "single-visit, 4-site" booster vaccination with PVRV 5 years later. |
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End point title |
Percentage of Subjects With Seroconversion on Day 14 | ||||||||||||||||
End point description |
Seroconversion was defined as a rabies virus-neutralizing antibody titer >= 0.5 IU/mL. Analysis was performed on Per Protocol Analysis Set (PPAS) which included all subjects who received at least one dose of the study vaccine during the Primary Vaccination Phase, and had a post-vaccination blood sample at Day 14 or Day 90. Subjects with following protocol deviations were excluded from PPAS: subject did not meet all protocol-specified inclusion criteria or met at least one of the protocol specified exclusion criteria, subject did not complete the vaccination schedule at visits (V) 01, V02, and V03, subject received a vaccine other than the one that he / she was randomised to receive, subjects received a protocol-restricted therapy / medication / vaccine between V01 and V04, subjects with rabies virus-neutralizing antibodies (≥ 0.2 IU/mL or missing value) at baseline; sample collection not done at Day 14 or sample at V04 did not produced a valid test result.
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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 |
Group 1 versus (vs) Group 3 | ||||||||||||||||
Comparison groups |
Group 1 v Group 3
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Number of subjects included in analysis |
347
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | ||||||||||||||||
Method |
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Parameter type |
Percentage difference | ||||||||||||||||
Point estimate |
1.16
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-1.145 | ||||||||||||||||
upper limit |
4.14 | ||||||||||||||||
Notes [1] - Non-inferiority was concluded if the limit of the two-sided 95% Confidence Interval (CI) of the difference is above delta. |
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Statistical analysis title |
Group 2 vs Group 3 | ||||||||||||||||
Comparison groups |
Group 2 v Group 3
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Number of subjects included in analysis |
334
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [2] | ||||||||||||||||
Method |
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Parameter type |
Percentage difference | ||||||||||||||||
Point estimate |
0.55
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-2.375 | ||||||||||||||||
upper limit |
3.566 | ||||||||||||||||
Notes [2] - Non-inferiority was concluded if the limit of the two-sided 95% CI of the difference is above delta. |
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End point title |
Percentage of Subjects With Seroconversion Before and After Primary Vaccination | ||||||||||||||||||||||||||||
End point description |
Seroconversion was defined as rabies virus neutralizing antibody titers >= 0.5 IU/mL. Analysis was performed on PPAS. Here, ‘n’ = subjects with available data for each specified category.
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End point type |
Secondary
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End point timeframe |
Day 0, Day 14, Day 90
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects With Seroconversion After Primary Vaccination (Antibody Persistence) | ||||||||||||||||||||||||||||||||
End point description |
Seroconversion was defined as rabies virus neutralizing antibody titers >= 0.5 IU/mL. Analysis was performed on Full analysis set which included all randomised subjects who received at least one dose of the study vaccine during the Primary Vaccination Phase, and had a post-vaccination blood sample at Day 14 or Day 90. Here, ‘n’ = subjects with available data for each specified category.
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End point type |
Secondary
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End point timeframe |
Year 1 to Year 4
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects With Seroconversion After Booster Vaccination | ||||||||||||||||||||||||
End point description |
Seroconversion was defined as rabies virus neutralizing antibody titers >= 0.5 IU/mL. Analysis was performed on booster full analysis set which included randomised subjects who received the booster vaccine at V13, and had a post-vaccination blood sample at Day 11 post-V13.
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End point type |
Secondary
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End point timeframe |
Year 5 and Year 5 + 11 days
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No statistical analyses for this end point |
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End point title |
Geometric Mean Titers (GMTs) Ratio Against Rabies Virus Antibodies Before and After Primary Vaccination | ||||||||||||||||||||||||
End point description |
GMTs of rabies virus-neutralizing antibodies were assessed by the rapid fluorescent focus inhibition test. Analysis was performed on PPAS. Here, ‘n’ = subjects with available data for each specified category.
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End point type |
Secondary
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End point timeframe |
Day 0, Day 14, Day 90
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No statistical analyses for this end point |
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End point title |
GMT Ratio Against Rabies Virus Antibodies After Primary Vaccination (Antibody Persistence) | ||||||||||||||||||||||||||||||||
End point description |
GMT ratio of rabies virus-neutralizing antibodies was assessed by the rapid fluorescent focus inhibition test. Analysis was performed on Full analysis set. Here, ‘n’ = subjects with available data for each specified category.
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End point type |
Secondary
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End point timeframe |
Year 1, 2, 3, 4 and Day 90
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No statistical analyses for this end point |
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End point title |
GMTs Against Rabies Virus Antibodies After Booster Vaccination | ||||||||||||||||||||||||
End point description |
GMTs of rabies virus-neutralizing antibodies was assessed by the rapid fluorescent focus inhibition test. Analysis was performed on booster full analysis set.
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End point type |
Secondary
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End point timeframe |
Year 5, Year 5 + 11 days
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No statistical analyses for this end point |
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End point title |
Number of Subjects Reporting Immediate Unsolicited Adverse Events Following Primary and Booster Vaccination | ||||||||||||||||||||||||
End point description |
An unsolicited Adverse Event (AE) is an observed AE that does not fulfill the conditions prelisted in the case report form in terms of symptom and / or onset post-vaccination. Analysis was performed on safety analysis set which included subjects who received a dose of study or control vaccine. Here, ‘n’ = subjects with available data for each specified category.
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End point type |
Secondary
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End point timeframe |
Within 30 minutes after vaccination
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No statistical analyses for this end point |
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End point title |
Number of Subjects Reporting Solicited Injection Site Reactions Following Primary and Booster Vaccination | ||||||||||||||||||||||||||||||||||||||||
End point description |
Solicited Injection (Inj.) site reactions were tenderness (for subjects aged <= 23 months), pain (for subjects aged >= 2 years), erythema and swelling. Analysis was performed on safety analysis set. Here, ‘n’ = subjects with available data for each specified category.
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End point type |
Secondary
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End point timeframe |
Within 7 days after vaccination
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No statistical analyses for this end point |
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End point title |
Number of Subjects Reporting Solicited Systemic Reactions Following Primary and Booster Vaccination | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Solicited systemic reactions are Fever, Vomiting, Crying abnormal, Drowsiness, Appetite lost, and Irritability for subjects aged ≤ 23 months and Fever (Temperature), Headache, Malaise, and Myalgia for subjects aged ≥ 2 years. Analysis was performed on safety analysis set. Here, ‘n’ = subjects with available data for each specified category.
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End point type |
Secondary
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End point timeframe |
From Day 0 up to 7 days after injection 1, 2 and 3, and 7 days after subsequent injections
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No statistical analyses for this end point |
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End point title |
Number of Subjects Reporting Unsolicited Injection Site Reactions (Reac.) | ||||||||||||||||||||||||
End point description |
Analysis was performed on safety analysis set. Here, ‘n’ = subjects with available data for each specified category.
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End point type |
Secondary
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End point timeframe |
Within 21 days after vaccination
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No statistical analyses for this end point |
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End point title |
Number of Subjects Reporting Unsolicited Systemic Adverse Events | ||||||||||||||||||||||||
End point description |
Unsolicited systemic adverse events were defined as any unfavorable and unintended sign, symptom or disease not meeting the definition of solicited event and not occurring at the injection site of the investigational medicinal product, whether or not considered related to the investigational medicinal product. Analysis was performed on safety analysis set. Here, ‘n’ = subjects with available data for each specified category.
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End point type |
Secondary
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End point timeframe |
Between the first and the second vaccination, between the second and the third vaccination, between the third and the fourth vaccination (for Group 3), and up to 28 days after the remaining vaccination
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No statistical analyses for this end point |
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End point title |
Number of Subjects Reporting Serious Adverse Events (SAE) | ||||||||||||||||||||||||||||||||
End point description |
An SAE is any untoward medical occurrence that at any dose (including overdose): results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect, is an important medical event, whether or not considered related to the investigational medical product. Only related or fatal serious adverse events were reported during the period ranging from Day 28 post primary vaccination to the booster vaccination at Year 5. Analysis was performed on safety analysis set. Here, ‘n’ = subjects with available data for each specified category.
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End point type |
Secondary
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End point timeframe |
Up to 28 days after primary vaccination and booster vaccination, during full study duration
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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 |
Solicited reaction (SR) within 7 days after vaccination, unsolicited injection site reaction within 21 days after vaccination, unsolicited AEs between vaccinations up to fourth vaccination, then up to 28 days after remaining vaccinations,SAEs during study
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Adverse event reporting additional description |
Safety Analysis Set. SR: AE prelisted(PL) in electronic case report form (eCRF),considered related to vaccination(adverse drug reaction). Unsolicited AE:observed AE not fulfilling conditions PL in eCRF in terms of symptom &/or onset post-vaccination. Only related/fatal SAEs reported from D28 post primary vaccination to booster vaccination at Year 5
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
14.0
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Reporting groups
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Reporting group title |
Group 1
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Reporting group description |
Subjects with WHO Category II exposure received PEP with PVRV using "one-week, 4-site" (4-4-4-0-0) ID vaccination regimen on Day 0, Day 3 and Day 7, and a "single-visit, 4-site" booster vaccination with PVRV 5 years later. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group 3
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Reporting group description |
Subjects with WHO Category III exposure receive PEP with PVRV using the updated 2-site TRC (2-2-2-0-2) ID vaccination regimen on Day 0, Day 3, Day 7 and Day 28 and pERIG Favirab® on Day 0, and a "single-visit, 4-site" booster vaccination with PVRV 5 years later. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group 2
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Reporting group description |
Subjects with WHO Category III exposure received PEP with PVRV using "one-week, 4-site" (4-4-4-0-0) ID vaccination regimen on Day 0, Day 3 and Day 7 and pERIG Favirab® on Day 0, and a "single-visit, 4-site" booster vaccination with PVRV 5 years later. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 Sep 2012 |
Following amendment changes were made: The wording in the primary objective, primary endpoint and secondary endpoints and other parts of the protocol was modified; mainly “seroprotection” was changed to “seroconversion”; women of childbearing potential and sexually active were required to use a medically acceptable and effective method of birth control during 1 month following booster vaccination. The wording was updated to reflect this; Favirab® was deleted from the primary study objective. Also it was clarified that Favirab® was a commercial product and not an investigational product; sentences were added to the primary objective to define the comparison between groups at Day 14. |
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01 Jul 2013 |
Following amendment changes were made: Originally, the countries planned to participate in the study were India, Pakistan and The Philippines. Due to organizational difficulties, India and Pakistan did not participate in the study. Therefore, all parts of the protocol related to the involvement of these 2 countries were deleted from the protocol; in order to avoid the drop out of the subjects in-between yearly visits, phone calls were given on a quarterly basis to the subjects to remind them to come back to the site for the next visits. The wording in the protocol was added to reflect this; clarification on the process to follow if re-exposure of subjects occurred during the study; clarification on collection of all SAEs during the study. |
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10 Apr 2014 |
Following amendment changes were made: Originally, two interim analyses (Day 90, Year 1) and corresponding interim reports were planned. The testing of the Day 90 blood samples at the laboratory was unexpectedly delayed and all Year 1 follow-up blood samples would be available before the Day 90 samples could be tested. Therefore it was decided by the Sponsor to test all Day 90 and Year 1 blood samples at the same time and delete the D90 interim analysis and interim report. The wording throughout the protocol was adapted accordingly; the timelines for different milestones of the study (eg, first visit of first patient) were updated. |
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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 |