Cholera
Conditions
Brief summary
Demonstrate that the vaccine offers protection based on antibody levels in older adults and is similar to antibody levels in adults aged 18-45 following vaccination with PXVX0200.
Detailed description
Demonstrate that seroconversion by classical Inaba vibriocidal antibody at Day 11 in older adults ages 46-64 years (inclusive) was non inferior to seroconversion at Day 11 in younger adults ages 18-45 years following vaccination with PXVX0200.
Interventions
BIOLOGICALPXVX0200
BIOLOGICALPlacebo
Sponsors
Emergent BioSolutions
Bavarian Nordic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
46 Years to 64 Years
Healthy volunteers
Yes
Inclusion criteria
1. Able to understand the study and give written consent. 2. Healthy male and female adults, age 46-64 years (inclusive) without significant medical history, physical, or abnormal screening laboratory test results at screening. 3. Women of childbearing potential must have had a negative urine pregnancy test at screening, prior to vaccination. Female subjects must be of non-childbearing potential (as defined as surgically sterile or postmenopausal for more than 1 year), or if of childbearing potential must be practicing abstinence or using an effective licensed method of birth control (eg, use hormonal or barrier birth control such as implants, injectables, combined oral contraceptives, intrauterine devices \[IUDs\], cervical sponges, diaphragms, condoms with spermicidal agents; or must have a vasectomized partner) within 2 months of vaccination and must agree to continue such precautions during the study. 4. Willing and able to comply with the study requirements and procedures.
Exclusion criteria
1. Currently active unstable or undiagnosed medical conditions including immunodeficiency, cardiovascular disease, respiratory disease, endocrine disorder, liver disease, renal disease, gastrointestinal disease, neurologic illness, psychiatric disorder requiring hospitalization, current drug or alcohol abuse. Examples of unstable or undiagnosed medical conditions including unstable angina pectoris, shortness of breath on exertion without clear etiology and chronic renal failure requiring dialysis. Examples of conditions that do not meet
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Seroconversion Rate at Day 11 | Day 11 | The seroconversion rate is defined as the percentage of subjects with a 4-fold or greater rise over baseline Day 1 Serum Vibriocidal Antibody (SVA) titer against the classical Inaba biotype of V. cholerae at Day 11 following one dose of Vaxchora vaccine. The hypothesis was that the seroconversion rate would be non-inferior to the seroconversion rate at Day 11 in adults between the ages of 18 and 45 years. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Geometric Mean Titer (GMT) | Day 11 | The Day 11 vibriocidal GMTs were compared between older and younger adults. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Mean Fold Change in Vibriocidal Antibody Titer Between Day 1 and Day 11 | Day 11 | The mean log2 fold change between Day 1 and Day 11 in classical Inaba vibriocidal antibody titer attained by older adults was compared to the younger adults aged 18 - 45 yrs. |
| Cumulative Seroconversion Through Day 29 Compared to Day 11 for Younger Adults | Day 29 | The cumulative seroconversion through Day 29 for older adults was compared to the Day 11 seroconversion for the younger adults aged 18 - 45 yrs. Seroconversion is defined as a 4-fold rise in antibody titer relative to baseline values. |
| Seroconversion Against Other V. Cholerae Biotypes/Serotypes | Day 11 | Seroconversion of the vibriocidal antibody response against 4 V. cholerae biotypes/serotypes - classical Inaba, El Tor Inaba, classical Ogawa and El Tor Ogawa was assessed. |
| Anti-CT Antibody Response in Older Adults | Day 11 | The seroconversion of anti-Cholera Toxin (CT) antibody response in older adults was assessed. Seroconversion is defined as a 4-fold rise in anti-CT antibody titer relative to baseline values. |
Countries
United States
Participant flow
Recruitment details
This study included healthy volunteers (46 - 64 years) who were not previously immunized against cholera. A total of 398 subjects randomized, of which 299 received study treatment and 99 received placebo. A total of 36 subjects from the treatment group continued in the Immune Sub-study population.
Pre-assignment details
This study included healthy volunteers (46 - 64 years) who were not previously immunized against cholera. A total of 398 subjects randomized, of which 299 received study treatment and 99 received placebo. A total of 36 subjects from the treatment group continued in the Immune Sub-study population. The historical control subjects are not included in the protocol enrollment number for PXVX-VC-200-005. They are solely a comparator population.
Participants by arm
| Arm | Count |
|---|---|
| PXVX0200 in Older Adults PXVX0200 is a live-attenuated cholera vaccine for single-dose oral administration. Subjects will be randomly assigned 3:1 to receive PXVX0200 (300) or placebo (100). Each subject will have at least 4 visits composed of a screening visit, a vaccination visit (Day 1), and post-vaccination visits at Day 11, and Day 29 telephone contacts will be made on Day 91 and 181. | 299 |
| Placebo in Older Adults The placebo consisted of 100 mL of physiological saline administered orally. Physiological saline was sourced by the clinical sites. Subjects will be randomly assigned 3:1 to receive PXVX0200 (300) or placebo (100). Each subject will have at least 4 visits composed of a screening visit, a vaccination visit (Day 1), and post-vaccination visits at Day 11, and Day 29 telephone contacts will be made on Day 91 and 181. | 99 |
| Historical Control: Adults Aged 18-45 This arm consists of historical data from Vaxchora vaccine subjects from study PXVX-VC-200-004. The data was included in study PXVX-VC-200-005 as a comparator bridging population for the Day 11 seroconversion. NCT02094586, PubMed ID: 29317118 | 2,688 |
| Total | 3,086 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | 3 subjects randomized to treatment unable to receive vaccine as product not available, | 3 | 0 | 0 |
| Overall Study | Lost to Follow-up | 3 | 4 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | PXVX0200 in Older Adults | Placebo in Older Adults | Historical Control: Adults Aged 18-45 |
|---|---|---|---|---|
| Age, Categorical Between 46-64 years (inclusive) <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 46-64 years (inclusive) >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 46-64 years (inclusive) Between 18 and 65 years | 3086 Participants | 299 Participants | 99 Participants | 2688 Participants |
| Age, Continuous | 33.1 years | 53.8 years STANDARD_DEVIATION 4.99 | 54.1 years STANDARD_DEVIATION 5.2 | 30.0 years STANDARD_DEVIATION 7.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 18 Participants | 6 Participants | 1 Participants | 11 Participants |
| Race (NIH/OMB) Asian | 58 Participants | 0 Participants | 2 Participants | 56 Participants |
| Race (NIH/OMB) Black or African American | 758 Participants | 68 Participants | 19 Participants | 671 Participants |
| Race (NIH/OMB) More than one race | 52 Participants | 2 Participants | 0 Participants | 50 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 9 Participants | 1 Participants | 0 Participants | 8 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 38 Participants | 1 Participants | 0 Participants | 37 Participants |
| Race (NIH/OMB) White | 2153 Participants | 221 Participants | 77 Participants | 1855 Participants |
| Region of Enrollment Australia | 347 participants | 0 participants | 0 participants | 347 participants |
| Region of Enrollment United States | 2739 participants | 299 participants | 99 participants | 2341 participants |
| Sex: Female, Male Female | 1698 Participants | 164 Participants | 52 Participants | 1482 Participants |
| Sex: Female, Male Male | 1388 Participants | 135 Participants | 47 Participants | 1206 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 296 | 0 / 99 |
| other Total, other adverse events | 37 / 296 | 11 / 99 |
| serious Total, serious adverse events | 3 / 296 | 0 / 99 |
Outcome results
Primary
Seroconversion Rate at Day 11
The seroconversion rate is defined as the percentage of subjects with a 4-fold or greater rise over baseline Day 1 Serum Vibriocidal Antibody (SVA) titer against the classical Inaba biotype of V. cholerae at Day 11 following one dose of Vaxchora vaccine. The hypothesis was that the seroconversion rate would be non-inferior to the seroconversion rate at Day 11 in adults between the ages of 18 and 45 years.
Time frame: Day 11
Population: Immunogenicity Evaluable Population (IEP)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PXVX0200 in Older Adults | Seroconversion Rate at Day 11 | 90.4 % of participants |
| Historical Control: Adults Aged 18-45 | Seroconversion Rate at Day 11 | 93.5 % of participants |
95% CI: [-6.7, 0.4]
Secondary
Geometric Mean Titer (GMT)
The Day 11 vibriocidal GMTs were compared between older and younger adults.
Time frame: Day 11
Population: IEP
| Arm | Measure | Value (MEAN) |
|---|---|---|
| PXVX0200 in Older Adults | Geometric Mean Titer (GMT) | 4282 Geometric Mean Titer |
| Historical Control: Adults Aged 18-45 | Geometric Mean Titer (GMT) | 9688 Geometric Mean Titer |
| Placebo in Older Adults | Geometric Mean Titer (GMT) | 44 Geometric Mean Titer |
95% CI: [0.34, 0.57]
Other Pre-specified
Anti-CT Antibody Response in Older Adults
The seroconversion of anti-Cholera Toxin (CT) antibody response in older adults was assessed. Seroconversion is defined as a 4-fold rise in anti-CT antibody titer relative to baseline values.
Time frame: Day 11
Population: Immune Sub-Study Population. The Historical Control population is not included as anti-CT levels were not assessed in that study.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| PXVX0200 in Older Adults | Anti-CT Antibody Response in Older Adults | 55.6 % of participants |
| Historical Control: Adults Aged 18-45 | Anti-CT Antibody Response in Older Adults | 0 % of participants |
Other Pre-specified
Cumulative Seroconversion Through Day 29 Compared to Day 11 for Younger Adults
The cumulative seroconversion through Day 29 for older adults was compared to the Day 11 seroconversion for the younger adults aged 18 - 45 yrs. Seroconversion is defined as a 4-fold rise in antibody titer relative to baseline values.
Time frame: Day 29
Population: IEP
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PXVX0200 in Older Adults | Cumulative Seroconversion Through Day 29 Compared to Day 11 for Younger Adults | 94.2 % of participants |
| Historical Control: Adults Aged 18-45 | Cumulative Seroconversion Through Day 29 Compared to Day 11 for Younger Adults | 93.5 % of participants |
| Placebo in Older Adults | Cumulative Seroconversion Through Day 29 Compared to Day 11 for Younger Adults | 1.0 % of participants |
95% CI: [-2.2, 3.5]
Other Pre-specified
Mean Fold Change in Vibriocidal Antibody Titer Between Day 1 and Day 11
The mean log2 fold change between Day 1 and Day 11 in classical Inaba vibriocidal antibody titer attained by older adults was compared to the younger adults aged 18 - 45 yrs.
Time frame: Day 11
Population: IEP. Placebo was not included in this additional bridging analysis as increase in SVA titer from Day 1 to 11 is not applicable for placebo subjects.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| PXVX0200 in Older Adults | Mean Fold Change in Vibriocidal Antibody Titer Between Day 1 and Day 11 | 6.6 Fold Change in Titer from Day 1 |
| Historical Control: Adults Aged 18-45 | Mean Fold Change in Vibriocidal Antibody Titer Between Day 1 and Day 11 | 7.1 Fold Change in Titer from Day 1 |
p-value: 0.0062t-test, 2 sided
Other Pre-specified
Seroconversion Against Other V. Cholerae Biotypes/Serotypes
Seroconversion of the vibriocidal antibody response against 4 V. cholerae biotypes/serotypes - classical Inaba, El Tor Inaba, classical Ogawa and El Tor Ogawa was assessed.
Time frame: Day 11
Population: IEP. The Historical Control population is not included as testing against these other biotypes/serotypes was not included in that study.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| PXVX0200 in Older Adults | Seroconversion Against Other V. Cholerae Biotypes/Serotypes | Classical Inaba | 90.4 % of participants |
| PXVX0200 in Older Adults | Seroconversion Against Other V. Cholerae Biotypes/Serotypes | El Tor Inaba | 91.0 % of participants |
| PXVX0200 in Older Adults | Seroconversion Against Other V. Cholerae Biotypes/Serotypes | Classical Ogawa | 73.2 % of participants |
| PXVX0200 in Older Adults | Seroconversion Against Other V. Cholerae Biotypes/Serotypes | El Tor Ogawa | 71.4 % of participants |
| Historical Control: Adults Aged 18-45 | Seroconversion Against Other V. Cholerae Biotypes/Serotypes | El Tor Inaba | 5.1 % of participants |
| Historical Control: Adults Aged 18-45 | Seroconversion Against Other V. Cholerae Biotypes/Serotypes | El Tor Ogawa | 6.1 % of participants |
| Historical Control: Adults Aged 18-45 | Seroconversion Against Other V. Cholerae Biotypes/Serotypes | Classical Inaba | 0 % of participants |
| Historical Control: Adults Aged 18-45 | Seroconversion Against Other V. Cholerae Biotypes/Serotypes | Classical Ogawa | 2.0 % of participants |