Clinical Trial Results:
Boostability for rabies in last-minute travelers: One Day Rabies Pre-exposure Intradermal Vaccination followed by one day Postexposure Intradermal Vaccination
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Summary
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EudraCT number |
2014-001836-12 |
Trial protocol |
BE |
Global end of trial date |
27 Mar 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
05 Jun 2019
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First version publication date |
05 Jun 2019
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Other versions |
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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 |
ITMC0414
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Institute of Tropical Medicine
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Sponsor organisation address |
Nationalestraat 155, Antwerpen, Belgium, 2000
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Public contact |
Clinical Trials Unit, Institute of Tropical Medicine, 0032 32476625, yvanherrewege@itg.be
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Scientific contact |
Clinical Trials Unit, Institute of Tropical Medicine, 0032 32476625, yvanherrewege@itg.be
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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? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
26 Sep 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
27 Mar 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
27 Mar 2017
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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 determine if a 2 x 0,1 ml priming dose results in an acceptable boostability (% of subjects that have boostable rabies antibodies) after 1 year.
- To determine the lowest booster dose (4 x 0,1 ml, or 2 x 0,1 ml) after a 2 x 0,1 ml priming dose needed to induce an acceptable boostability after 1 year.
- A vaccination regimen is considered to have an acceptable boostability if at least 90% of vaccinated subjects would reach a rabies titre of > 0.5 IU/mL 7 days after booster vaccination. This will be assessed by comparing the one-sided 95% confidence interval for the % of boostable subjects with the target value of 90%. If the one-sided 95% confidence interval excludes 90%, an acceptable boostability is considered to be established.
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Protection of trial subjects |
This is a low risk clinical trial, investigating only registered vaccines. The main expected adverse reactions are the following common AE’s;
• local reactions at the injection site, such as pain, erythema, swelling, or itching.
• mild systemic reactions, such as headache, nausea, abdominal pain, muscle aches, and dizziness.
• an immune complex-like reaction characterized by urticaria, pruritus, and malaise.
Serious Adverse Events, such as death or life threatening features, like anaphylactic shock, angioedema or hypovolemic shock (described in the literature as vaccine-related side effects) might occur as well.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
23 Oct 2014
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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 |
Belgium: 303
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Worldwide total number of subjects |
303
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EEA total number of subjects |
303
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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) |
0
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Adults (18-64 years) |
303
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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 |
Recruitment started on 23 October 2014 and was completed on 25 June 2015. 303 subjects were recruited in total. | ||||||||||||||||
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Pre-assignment
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Screening details |
Inclusion: - ICF - Rabies seronegative - Belgian soldiers or military students not deployable to high-risk areas - Prepared to follow study schedule Exclusion: - Previous rabies vaccination - Intake of mefloquine - Planned deployment to overseas areas within 28 days - Planned deployment to high rabies risk area within 2 years | ||||||||||||||||
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Period 1
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Period 1 title |
Primary Vaccination Period
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Is this the baseline period? |
No | ||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||
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Arms
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Arm title
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Primary vaccination period | ||||||||||||||||
Arm description |
- | ||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||
Investigational medicinal product name |
Rabipur
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder and solution for solution for injection
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Routes of administration |
Intradermal use
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Dosage and administration details |
Simulated Intradermal Post-exposure schedule with 2 x 1 injection (2 x 0,1
ml) (two sites) on day 0
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Period 2
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Period 2 title |
Post-Exposure Prophylaxis
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Is this the baseline period? |
Yes [1] | ||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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4 doses | ||||||||||||||||
Arm description |
Simulated Intradermal Post-exposure schedule with 4 x 1 injection (4 x 0,1 ml) (two sites) on day 365 | ||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||
Investigational medicinal product name |
Rabipur
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder and solution for solution for injection
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Routes of administration |
Intradermal use
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Dosage and administration details |
Simulated Intradermal Post-exposure schedule with 4 x 1 injection (4 x 0,1
ml) (two sites) on day 365
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Arm title
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2 doses | ||||||||||||||||
Arm description |
Simulated Intradermal Post-exposure schedule with 2 x 1 injection (2 x 0,1 ml) (two sites) on day 365 | ||||||||||||||||
Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
Rabipur
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder and solution for solution for injection
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Routes of administration |
Intradermal use
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Dosage and administration details |
Simulated Intradermal Post-exposure schedule with 2 x 1 injection (2 x 0,1
ml) (two sites) on day 365
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| Notes [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period. Justification: The primary vaccination period is not the main study period, so not considered the baseline. |
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| Notes [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: The primary vaccination period is not the main study period, so not considered the baseline. |
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Baseline characteristics reporting groups
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Reporting group title |
4 doses
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Reporting group description |
Simulated Intradermal Post-exposure schedule with 4 x 1 injection (4 x 0,1 ml) (two sites) on day 365 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
2 doses
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Reporting group description |
Simulated Intradermal Post-exposure schedule with 2 x 1 injection (2 x 0,1 ml) (two sites) on day 365 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Primary vaccination period
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Reporting group description |
- | ||
Reporting group title |
4 doses
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Reporting group description |
Simulated Intradermal Post-exposure schedule with 4 x 1 injection (4 x 0,1 ml) (two sites) on day 365 | ||
Reporting group title |
2 doses
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Reporting group description |
Simulated Intradermal Post-exposure schedule with 2 x 1 injection (2 x 0,1 ml) (two sites) on day 365 | ||
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End point title |
Acceptable boostability of the rabies antibodies (more than 0.5 IU/ml) on day 7 after booster vaccination | |||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Assessed on day 7 after booster vaccination at 1 year after the initial vaccination.
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Statistical analysis title |
Efficacy analysis | |||||||||
Statistical analysis description |
The proportion of subjects with serology results above 0.5 IU/mL was calculated and the one-sided confidence interval using the Wilson's score method was constructed. Acceptable boostability was inferred if the lower bound of the confidence interval was above 90%.
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Comparison groups |
4 doses v 2 doses
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Number of subjects included in analysis |
271
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | |||||||||
Method |
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Parameter type |
Wilson's confidence interval | |||||||||
Point estimate |
99.3
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Confidence interval |
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level |
95% | |||||||||
sides |
1-sided
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lower limit |
96.7 | |||||||||
upper limit |
- | |||||||||
Statistical analysis title |
Efficacy analysis | |||||||||
Statistical analysis description |
The proportion of subjects with serology results above 0.5 IU/mL was calculated and the one-sided confidence interval using the Wilson's score method was constructed. Acceptable boostability was inferred if the lower bound of the confidence interval was above 90%.
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Comparison groups |
2 doses v 4 doses
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Number of subjects included in analysis |
271
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | |||||||||
Method |
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Parameter type |
Wilson's confidence interval | |||||||||
Point estimate |
99.3
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Confidence interval |
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level |
95% | |||||||||
sides |
1-sided
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lower limit |
96.8 | |||||||||
upper limit |
- | |||||||||
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End point title |
Rabies serology more than 3 IU/ml after primary vaccination | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Assessed at day 14 after primary vaccination.
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Statistical analysis title |
Efficacy analysis | |||||||||
Statistical analysis description |
All secondary and tertiary endpoints are binary endpoints similar to the primary endpoint. They will be analyzed similarly to the primary. No target values for the secondary endpoints are predefined, but the CIs will be interpreted in terms of clinical relevance of possible differences rather than statistical significance.
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Comparison groups |
4 doses v 2 doses
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Number of subjects included in analysis |
271
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Analysis specification |
Post-hoc
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Analysis type |
other | |||||||||
Method |
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Parameter type |
Proportion above 3IU/mL | |||||||||
Point estimate |
1.3
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Confidence interval |
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level |
95% | |||||||||
sides |
1-sided
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lower limit |
0.6 | |||||||||
upper limit |
- | |||||||||
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End point title |
Rabies serology more than 3 IU/ml after booster vaccination | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Assessed on day 7 after booster vaccination
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Statistical analysis title |
Efficacy analysis | |||||||||
Statistical analysis description |
All secondary and tertiary endpoints are binary endpoints similar to the primary endpoint. They will be analyzed similarly to the primary. No target values for the secondary endpoints are predefined, but the CIs will be interpreted in terms of clinical relevance of possible differences rather than statistical significance.
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Comparison groups |
4 doses v 2 doses
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Number of subjects included in analysis |
271
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Analysis specification |
Post-hoc
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Analysis type |
other | |||||||||
Method |
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Parameter type |
Proportion above 3 IU/mL | |||||||||
Point estimate |
91.9
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Confidence interval |
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level |
95% | |||||||||
sides |
1-sided
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lower limit |
88.7 | |||||||||
upper limit |
- | |||||||||
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End point title |
Long-lasting protection after primary vaccination (rabies serology more than 10 IU/ml) | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Assessed on day 14 after primary vaccination
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Statistical analysis title |
Efficacy analysis | |||||||||
Statistical analysis description |
All secondary and tertiary endpoints are binary endpoints similar to the primary endpoint. They will be analyzed similarly to the primary. No target values for the secondary endpoints are predefined, but the CIs will be interpreted in terms of clinical relevance of possible differences rather than statistical significance.
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Comparison groups |
4 doses v 2 doses
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Number of subjects included in analysis |
271
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Analysis specification |
Post-hoc
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Analysis type |
other | |||||||||
Method |
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Parameter type |
Proportion above 10IU/mL | |||||||||
Point estimate |
19.5
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Confidence interval |
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level |
95% | |||||||||
sides |
1-sided
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lower limit |
16 | |||||||||
upper limit |
- | |||||||||
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End point title |
Long-lasting protection after booster vaccination (rabies serology more than 10 IU/ml) | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Assessed on day 7 after booster vaccination
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Statistical analysis title |
Efficacy analysis | |||||||||
Statistical analysis description |
All secondary and tertiary endpoints are binary endpoints similar to the primary endpoint. They will be analyzed similarly to the primary. No target values for the secondary endpoints are predefined, but the CIs will be interpreted in terms of clinical relevance of possible differences rather than statistical significance.
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Comparison groups |
4 doses v 2 doses
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Number of subjects included in analysis |
271
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Analysis specification |
Post-hoc
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Analysis type |
other | |||||||||
Method |
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Parameter type |
Proportion above 10 IU/mL | |||||||||
Point estimate |
74.5
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Confidence interval |
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level |
95% | |||||||||
sides |
1-sided
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lower limit |
70 | |||||||||
upper limit |
- | |||||||||
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End point title |
Rabies serology of 0.5 IU/ml or more after primary vaccination | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Assessed on day 14 after primary vaccination
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Statistical analysis title |
Efficacy analysis | |||||||||
Statistical analysis description |
All secondary and tertiary endpoints are binary endpoints similar to the primary endpoint. They will be analyzed similarly to the primary. No target values for the secondary endpoints are predefined, but the CIs will be interpreted in terms of clinical relevance of possible differences rather than statistical significance.
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Comparison groups |
4 doses v 2 doses
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Number of subjects included in analysis |
271
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Analysis specification |
Post-hoc
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Analysis type |
other | |||||||||
Method |
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Parameter type |
Proportion | |||||||||
Point estimate |
82.5
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Confidence interval |
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level |
95% | |||||||||
sides |
1-sided
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lower limit |
78.6 | |||||||||
upper limit |
- | |||||||||
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End point title |
Adverse Events and Serious Adverse Events | ||||||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
- Adverse events within 7 days after primary and booster vaccination
- Serious Adverse Events within 7 days after primary and booster 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 events are reported within 7 days of the vaccination.
Serious adverse events are reported within 14 days of the vaccination.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 |
All participants (Whole study period)
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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10 Mar 2016 |
The objective of this amendment was to carry out an interim analysis, including more data than foreseen in the initial protocol [v 2.0]. As mentioned in the protocol version 2.0 we will analyse serology data of day 0 and day 14 for all subjects (N=303), because they finished their primary vaccination. The proposed interim analysis would include boostability data (primary endpoint) of the first 53 participants who have completed their study procedures (by protocol) by the end of 2015. The interim analysis would thus concern the results of the serology tests performed at Day 365 and 372, are separately analysed for this 53 subjects, without waiting for the results (Day 365 and 372) of the whole group of 303 subjects. |
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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/30566636 |
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