Clinical Trial Results:
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Efficacy of GEN-004, a Pneumococcal Protein Subunit Vaccine, on Colonization Following Intranasal Challenge with S. pneumoniae
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Summary
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EudraCT number |
2014-000944-13 |
Trial protocol |
GB |
Global end of trial date |
19 Jul 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
07 Jul 2017
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First version publication date |
07 Jul 2017
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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 |
GEN-004-002
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02116998 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Genocea Biosciences, Inc.
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Sponsor organisation address |
100 Acorn Park Drive, 5th Floor, Cambridge, United States, MA 02140
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Public contact |
Director of Regulatory Sciences, TMC Pharma Services, 44 01252842255, Allison.Gillespie@TMCPharma.com
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Scientific contact |
Director of Regulatory Sciences, TMC Pharma Services, 44 01252842255, Allison.Gillespie@TMCPharma.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? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
19 Jul 2016
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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 |
19 Jul 2016
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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 |
The primary objective of this trial is to evaluate the efficacy of intramuscular GEN-004 (a recombinant S. pneumoniae protein subunit vaccine) with aluminum hydroxide as adjuvant compared with a placebo control. Efficacy was assessed in healthy adult subjects by evaluating the reduction in nasopharyngeal colonisation following intranasal inoculation with S. pneumoniae serotype 6B, as measured by the proportion of colonised subjects at 2, 7, and 14 days post-inoculation.
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Protection of trial subjects |
Two weeks after the third dose of study treatment, subjects were inoculated intranasally with S. pneumoniae serotype 6B (c. 80,000 CFU/100 μl per nostril). If a suspected pneumococcal infection occurred during the 14 days after inoculation, subjects were to be treated with antibiotics.
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Background therapy |
Not applicable | ||
Evidence for comparator |
This was a placebo-controlled trial. The challenge model (intranasal inoculation with S.pneumoniae after 3 doses of study treatment, with a placebo control) permits demonstration of biologic activity of the test article, GEN-004, measured by prevention of acquisition or colonisation. | ||
Actual start date of recruitment |
21 Aug 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
United Kingdom: 96
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Worldwide total number of subjects |
96
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EEA total number of subjects |
96
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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) |
96
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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 |
All subjects were recruited at a single centre in the United Kingdom between 18 Aug 2014 and 16 Apr 2016. | ||||||||||||||||||
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Pre-assignment
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Screening details |
Screening took place from -28 to -1 days before randomisation, when safety checks were undertaken: safety laboratory parameters (haematology, biochemistry, urinalysis, serology), physical examination, pregnancy test, and a review of medical history and concomitant medications. All screened subjects participated in the trial. | ||||||||||||||||||
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Period 1
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Period 1 title |
Treatment period (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, Data analyst | ||||||||||||||||||
Blinding implementation details |
An unblinded pharmacist (or other appropriately trained individual) at each site prepared each dose. This individual had no contact with the subjects and minimised contact with other study site personnel.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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GEN-004 | ||||||||||||||||||
Arm description |
Each subject was to receive 3 doses at 4 week (28 ±3 days) intervals of 100 μg GEN-004 with 350 μg of aluminium hydroxide (Days 1, 29, and 57). On Day 71, each subject was challenged with an intranasal inoculation of S. pneumoniae. Nasal washes were performed on Days 73, 78, and 85 to evaluate colonisation. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
GEN-004
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Investigational medicinal product code |
GEN-004
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
Three doses of 100 μg GEN-004 with 350 μg of aluminum hydroxide administered as an intramuscular injection at 4-week intervals.
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Arm title
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Placebo | ||||||||||||||||||
Arm description |
Each subject was to receive 3 doses at 4 week (28 ±3 days) intervals of placebo (0.9% saline) (Days 1, 29, and 57). On Day 71, each subject was challenged with an intranasal inoculation of S.pneumoniae. Nasal washes were performed on Days 73, 78, and 85 to evaluate colonisation. | ||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
Placebo
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
Three doses of placebo (0.9% saline) administered as an intramuscular injection at 4-week intervals.
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Baseline characteristics reporting groups
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Reporting group title |
GEN-004
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Reporting group description |
Each subject was to receive 3 doses at 4 week (28 ±3 days) intervals of 100 μg GEN-004 with 350 μg of aluminium hydroxide (Days 1, 29, and 57). On Day 71, each subject was challenged with an intranasal inoculation of S. pneumoniae. Nasal washes were performed on Days 73, 78, and 85 to evaluate colonisation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Each subject was to receive 3 doses at 4 week (28 ±3 days) intervals of placebo (0.9% saline) (Days 1, 29, and 57). On Day 71, each subject was challenged with an intranasal inoculation of S.pneumoniae. Nasal washes were performed on Days 73, 78, and 85 to evaluate colonisation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
GEN-004
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Reporting group description |
Each subject was to receive 3 doses at 4 week (28 ±3 days) intervals of 100 μg GEN-004 with 350 μg of aluminium hydroxide (Days 1, 29, and 57). On Day 71, each subject was challenged with an intranasal inoculation of S. pneumoniae. Nasal washes were performed on Days 73, 78, and 85 to evaluate colonisation. | ||
Reporting group title |
Placebo
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Reporting group description |
Each subject was to receive 3 doses at 4 week (28 ±3 days) intervals of placebo (0.9% saline) (Days 1, 29, and 57). On Day 71, each subject was challenged with an intranasal inoculation of S.pneumoniae. Nasal washes were performed on Days 73, 78, and 85 to evaluate colonisation. | ||
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End point title |
S.pneumoniae colonisation 2 days post-inoculation measured by culture | |||||||||
End point description |
Subjects with intranasal colonisation as measured by culture
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End point type |
Primary
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End point timeframe |
2 days post-inoculation
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| Notes [1] - ITT population [2] - ITT population |
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Statistical analysis title |
Comparison of GEN-004 vs placebo | |||||||||
Statistical analysis description |
Fisher's exact test comparing proportions
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Comparison groups |
GEN-004 v Placebo
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Number of subjects included in analysis |
96
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | |||||||||
P-value |
= 0.5109 | |||||||||
Method |
Fisher exact | |||||||||
Confidence interval |
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| Notes [3] - Fisher's exact test comparing proportions of subjects with colonisation |
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End point title |
S.pneumoniae colonisation 7 days post-inoculation measured by culture | |||||||||
End point description |
Subjects with intranasal colonisation as measured by culture
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End point type |
Primary
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End point timeframe |
7 days post-inoculation
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| Notes [4] - ITT population [5] - ITT population |
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Statistical analysis title |
Comparison of GEN-004 vs placebo | |||||||||
Statistical analysis description |
Fisher's exact test comparing proportions of subjects with colonisation
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Comparison groups |
GEN-004 v Placebo
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Number of subjects included in analysis |
96
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
= 0.3644 | |||||||||
Method |
Fisher exact | |||||||||
Confidence interval |
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End point title |
S.pneumoniae colonisation 14 days post-inoculation measured by culture | |||||||||
End point description |
Subjects with intranasal colonisation as measured by culture
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End point type |
Primary
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End point timeframe |
14 days post-inoculation
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| Notes [6] - ITT population [7] - ITT population |
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Statistical analysis title |
Comparison of GEN-004 vs placebo | |||||||||
Comparison groups |
GEN-004 v Placebo
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Number of subjects included in analysis |
96
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Analysis specification |
Pre-specified
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Analysis type |
superiority [8] | |||||||||
P-value |
= 0.5111 | |||||||||
Method |
Fisher exact | |||||||||
Confidence interval |
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| Notes [8] - Fisher's exact test comparing proportions of subjects with colonisation |
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End point title |
S.pneumoniae colonisation at any time post-inoculation measured by culture | |||||||||
End point description |
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End point type |
Primary
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End point timeframe |
At any time post-inoculation
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| Notes [9] - ITT population [10] - ITT population |
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Statistical analysis title |
Comparison of GEN-004 vs placebo | |||||||||
Comparison groups |
Placebo v GEN-004
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Number of subjects included in analysis |
96
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Analysis specification |
Pre-specified
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Analysis type |
superiority [11] | |||||||||
P-value |
= 0.378 | |||||||||
Method |
Fisher exact | |||||||||
Confidence interval |
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| Notes [11] - Fisher's Exact Test comparing proportions |
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End point title |
S.pneumoniae colonisation 2 days post-inoculation measured by PCR | |||||||||
End point description |
Subjects with intranasal colonisation as measured by culture
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End point type |
Secondary
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End point timeframe |
2 days post-inoculation
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| Notes [12] - ITT population [13] - ITT population |
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Statistical analysis title |
Comparison of GEN-004 vs placebo | |||||||||
Comparison groups |
GEN-004 v Placebo
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Number of subjects included in analysis |
96
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Analysis specification |
Pre-specified
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Analysis type |
superiority [14] | |||||||||
P-value |
= 0.1866 | |||||||||
Method |
Fisher exact | |||||||||
Confidence interval |
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| Notes [14] - Fisher's Exact Test comparing proportions |
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End point title |
S.pneumoniae colonisation 7 days post-inoculation measured by PCR | |||||||||
End point description |
Subjects with intranasal colonisation as measured by PCR
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End point type |
Secondary
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End point timeframe |
7 days post-inoculation
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| Notes [15] - ITT population [16] - ITT population |
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Statistical analysis title |
Comparison of GEN-004 vs placebo | |||||||||
Comparison groups |
GEN-004 v Placebo
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Number of subjects included in analysis |
96
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Analysis specification |
Pre-specified
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Analysis type |
superiority [17] | |||||||||
P-value |
= 0.4952 | |||||||||
Method |
Fisher exact | |||||||||
Confidence interval |
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| Notes [17] - Fisher's Exact Test comparing proportions |
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End point title |
S.pneumoniae colonisation 14 days post-inoculation measured by PCR | |||||||||
End point description |
Subjects with intranasal colonisation as measured by PCR
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End point type |
Secondary
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End point timeframe |
14 days post-inoculation
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| Notes [18] - ITT population [19] - ITT population |
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Statistical analysis title |
Comparison of GEN-004 vs placebo | |||||||||
Statistical analysis description |
Fisher's Exact Test comparing proportions
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Comparison groups |
GEN-004 v Placebo
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Number of subjects included in analysis |
96
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
= 0.1258 | |||||||||
Method |
Fisher exact | |||||||||
Confidence interval |
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End point title |
S.pneumoniae colonisation any time post-inoculation measured by PCR | |||||||||
End point description |
Subjects with intranasal colonisation as measured by PCR
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End point type |
Secondary
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End point timeframe |
Any time post-inoculation
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| Notes [20] - ITT population [21] - ITT population |
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Statistical analysis title |
Comparison of GEN-004 vs placebo | |||||||||
Statistical analysis description |
Fisher's Exact Test comparing proportions
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Comparison groups |
GEN-004 v Placebo
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Number of subjects included in analysis |
96
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
= 0.8181 | |||||||||
Method |
Fisher exact | |||||||||
Confidence interval |
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End point title |
Time of maximum colonisation density based on culture - 2 days | |||||||||
End point description |
Microbiologic culture density was measured as the number of CFUs/mL of nasal wash.
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End point type |
Secondary
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End point timeframe |
2 days post-inoculation
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| Notes [22] - ITT population [23] - ITT population |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Time of maximum colonisation density based on culture - 7 days | |||||||||
End point description |
Microbiologic culture density was measured as the number of CFUs/mL of nasal wash.
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End point type |
Secondary
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End point timeframe |
7 days post-inoculation
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| Notes [24] - ITT population [25] - ITT population |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Time of maximum colonisation density based on culture - 14 days | |||||||||
End point description |
Microbiologic culture density was measured as the number of CFUs/mL of nasal wash.
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End point type |
Secondary
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End point timeframe |
14 days post-inoculation
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| Notes [26] - ITT population [27] - ITT population |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Time of maximum colonisation density based on PCR - 2 days | |||||||||
End point description |
qPCR density was measured as copies/mL of nasal wash.
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End point type |
Secondary
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End point timeframe |
2 days post-inoculation
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| Notes [28] - ITT population [29] - ITT population |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Time of maximum colonisation density based on PCR - 7 days | |||||||||
End point description |
qPCR density was measured as copies/mL of nasal wash.
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End point type |
Secondary
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End point timeframe |
7 days post-inoculation
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| Notes [30] - ITT population [31] - ITT population |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Time of maximum colonisation density based on PCR - 14 days | |||||||||
End point description |
qPCR density was measured as copies/mL of nasal wash.
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End point type |
Secondary
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End point timeframe |
14 days post-inoculation
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| Notes [32] - ITT population [33] - ITT population |
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| No statistical analyses for this end point | ||||||||||
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End point title |
AUC for colonisation density based on culture | ||||||||||||
End point description |
Area under the curve (AUC) for density of colonisation vs time post-inoculation was calculated for each subject, using the trapezoidal rule. AUC for colonisation density (based on culture) vs. post-inoculation time is presented by vaccine group for the ITT Population - all colonization (raw) data
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End point type |
Secondary
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End point timeframe |
All post-inoculation colonisation data
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| Notes [34] - Includes only subjects with all post-inoculation nasal wash samples [35] - Includes only subjects with all post-inoculation nasal wash samples |
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Statistical analysis title |
Comparison of GEN-004 vs placebo | ||||||||||||
Statistical analysis description |
Only subjects who had all post-inoculation nasal wash samples collected were included in the analysis. Comparability of vaccine groups was assessed using Wilcoxon’s rank sum test based on untransformed colonisation density data.
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Comparison groups |
GEN-004 v Placebo
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Number of subjects included in analysis |
80
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.6474 | ||||||||||||
Method |
Wilcoxon’s rank sum test | ||||||||||||
Confidence interval |
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End point title |
AUC for colonisation density based on PCR | ||||||||||||
End point description |
Microbiologic culture density was measured as PCR copy number/mL of nasal wash.
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End point type |
Secondary
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End point timeframe |
Anytime post-inoculation
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| Notes [36] - ITT population [37] - ITT population |
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Statistical analysis title |
Comparison of GEN-004 vs placebo | ||||||||||||
Statistical analysis description |
Only subjects who had all post-inoculation nasal wash samples collected were included in the analysis. Comparability of vaccine groups was assessed using Wilcoxon’s rank sum test based on untransformed colonisation density data.
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Comparison groups |
Placebo v GEN-004
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Number of subjects included in analysis |
96
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.8827 | ||||||||||||
Method |
Wilcoxon’s rank sum test | ||||||||||||
Confidence interval |
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End point title |
Duration of colonisation based on culture | ||||||||||||
End point description |
Only subjects who had all 3 nasal washes collected were included in this analysis.
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End point type |
Secondary
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End point timeframe |
Up to 14 days post-inoculation
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| Notes [38] - ITT population [39] - ITT population |
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Statistical analysis title |
Comparison of GEN-004 vs placebo | ||||||||||||
Comparison groups |
GEN-004 v Placebo
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Number of subjects included in analysis |
96
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.2682 | ||||||||||||
Method |
Wilcoxon’s rank sum test | ||||||||||||
Confidence interval |
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End point title |
Duration of colonisation based on PCR | ||||||||||||
End point description |
Only subjects who had all 3 nasal washes collected were included in this analysis.
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End point type |
Secondary
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End point timeframe |
Up to 14 days post-inoculation
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| Notes [40] - ITT population [41] - ITT population |
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Statistical analysis title |
Comparison of GEN-004 vs placebo | ||||||||||||
Comparison groups |
GEN-004 v Placebo
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Number of subjects included in analysis |
96
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.1824 | ||||||||||||
Method |
Wilcoxon’s rank sum test | ||||||||||||
Confidence interval |
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End point title |
Positive IgG responders to SP0148 antigen | |||||||||
End point description |
IgG titers (measured by enzyme-linked immunosorbent assay [ELISA]) against each GEN-004 antigen (SP0148, SP2108, and SP1912) were transformed using a log base 10, and summarised by vaccine group for each time of sampling. The fold rise in titre defined as the post-baseline result divided by the baseline result was calculated for the 3 antibody titers. A positive responder was defined as a ≥4-fold rise in IgG titre from baseline.
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End point type |
Secondary
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End point timeframe |
Up to 14 days post-baseline
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| Notes [42] - Subjects with available data are included in the denominator for this analysis [43] - Subjects with available data are included in the denominator for this analysis |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Positive IgG responders to SP1912 antigen | |||||||||
End point description |
IgG titers (measured by enzyme-linked immunosorbent assay [ELISA]) against each GEN-004 antigen (SP0148, SP2108, and SP1912) were transformed using a log base 10, and summarised by vaccine group for each time of sampling. The fold rise in titre defined as the post-baseline result divided by the baseline result was calculated for the 3 antibody titers. A positive responder was defined as a ≥4-fold rise in IgG titre from baseline.
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End point type |
Secondary
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End point timeframe |
Up to 14 days post-inoculation
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| Notes [44] - Subjects with available data are included in the denominator for this analysis [45] - Subjects with available data are included in the denominator for this analysis |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Positive IgG responders to SP2108 antigen | |||||||||
End point description |
IgG titers (measured by enzyme-linked immunosorbent assay [ELISA]) against each GEN-004 antigen (SP0148, SP2108, and SP1912) were transformed using a log base 10, and summarised by vaccine group for each time of sampling. The fold rise in titre defined as the post-baseline result divided by the baseline result was calculated for the 3 antibody titers. A positive responder was defined as a ≥4-fold rise in IgG titre from baseline.
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End point type |
Secondary
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End point timeframe |
Up to 14 days post-inoculation
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| Notes [46] - Subjects with available data are included in the denominator for this analysis [47] - Subjects with available data are included in the denominator for this analysis |
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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 |
From first dose of trial medication (Day 1) to 14 days post-inoculation with S.pneumoniae (Day 85) for all adverse events. From Day 1 to Day 383 for SAEs.
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Adverse event reporting additional description |
An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. The Investigator evaluated the intensity of each AE in accordance with the FDA Vaccine Toxicity Scale 7.
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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 |
17.0
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Reporting groups
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Reporting group title |
GEN-004
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Reporting group description |
Subjects treated with up to 3 intramuscular doses of GEN-004 vaccine with aluminium adjuvant, at 4-week intervals. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Subjects treated with up to 3 intramuscular doses of placebo, at 4-week intervals. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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? No | |||
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 | |||
