Cholera
Conditions
Brief summary
The purpose of the study is to determine if PXVX0200 is safe and effective in preventing cholera infection
Detailed description
A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Efficacy Trial of a Single Dose of Live Oral Cholera Vaccine Candidate, PXVX0200 CVD 103-HgR Strain, in Preventing Cholera following Challenge with Vibrio cholerae O1 El Tor Inaba 10 Days or 3 Months after Vaccination in volunteers aged 18-45 years
Interventions
BIOLOGICALPXVX0200
Single dose; liquid suspension after reconstitution with buffer; 5x10\^8
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
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* healthy men or women, * age 18 to 45 years inclusive; * normal medical history and physical examination; and * no clinically significant abnormalities from: * urine dipstick for glucose, protein, and blood * complete blood count, * serum hepatic transaminases, * total bilirubin (direct if abnormal), * creatinine, * electrolytes, * albumin, or * electrocardiogram. * Women must have a negative pregnancy test.
Exclusion criteria
* travel to a cholera endemic area in the previous 5 years; * abnormal stool pattern or regular use of laxatives; * history of eating disorders (such as bulimia), anal or rectal disorders, allergy to tetracycline and/or ciprofloxacin; * history of cholera or enterotoxigenic E. coli challenge or infection; * current or recent antibiotic use; * pregnancy or nursing; * positive serology for HIV, hepatitis B antigen, or hepatitis C; * any immunosuppressive medical condition; * history of hospitalization for psychiatric illness or use of specific psychiatric drugs.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| % of Participants With Moderate to Severe Diarrhea | Ten days after vaccination | Determine whether a single dose of PXVX0200 provides significantly greater protection than placebo against a challenge with virulent V. cholerae O1 El Tor Inaba at 10 days after vaccination. The primary endpoint was the occurrence of moderate or severe (\>/= 3 liters) diarrhea. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Weight of Diarrheal Stools Following the 90 Day Cholera Challenge | Through 10 Days following challenge | Total weight (converted to volume) per subject of diarrheal stools measured from subjects with diarrhea following the 90 day cholera challenge. |
| % of Participants With Diarrhea of Any Severity Following a 10 Day Cholera Challenge | Through 10 Days following challenge | Incidence of mild or worse (any severity) diarrhea following the 10 day cholera challenge. |
| % of Participants With Diarrhea of Any Severity Following a 90 Day Challenge | Through 10 Days following challenge | Incidence of mild or worse (any severity) diarrhea following the 90 day cholera challenge. |
| % of Participants With Fever Following the 10 Day Cholera Challenge | Through 10 Days following challenge | Incidence of mild or worse fever following the 10 day cholera challenge. |
| % of Participants With Fever Following the 90 Day Cholera Challenge | Through 10 Days following challenge | Incidence of mild or worse fever following the 90 day cholera challenge. |
| Total Weight of Diarrheal Stools Following the 10 Day Cholera Challenge | Through 10 Days following challenge | Total weight (converted to volume) per subject of diarrheal stools measured from subjects with diarrhea following the 10 day cholera challenge. |
| Number of Days With Fecal Shedding Following 90 Day Challenge | Through 10 days following challenge | Number of days of fecal shedding of wild type V. cholerae following 90 Day Challenge |
| # of Days With Positive Stool Culture Following 10 Day Cholera Challenge | Through 10 Days following challenge | Total number of days with a positive stool culture following the 10 Day Cholera challenge. |
| # of Days With Positive Stool Culture Following 90 Day Cholera Challenge | Through 10 Days following challenge | Total number of days with a positive stool culture following 90 Day Cholera Challenge |
| % of Participants With Reactogenicity, Diarrhea, Fever or Unsolicited Adverse Events Following Vaccination | Following vaccination (Days 1 - 8) and to Day 29 | Incidence and severity of signs and symptoms of reactogenicity such as diarrhea, and fever following vaccination (through Day 8). Incidence and severity of unsolicited adverse events following vaccination (through Day 29). |
| Number of Days With Fecal Shedding Following 10 Day Challenge | Through 10 Days post challenge | Number of days of fecal shedding of wild type V. cholerae following 10 Day Challenge. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PXVX0200 Biological: PXVX0200 Single dose; liquid suspension after reconstitution with buffer; 2x10\^8 to 2x10\^9 CFU in a liquid suspension | 95 |
| Placebo Biological: Placebo physiological saline | 102 |
| Total | 197 |
Baseline characteristics
| Characteristic | PXVX0200 | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 95 Participants | 102 Participants | 197 Participants |
| Age, Continuous | 31.5 years | 30.6 years | 31.0 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 4 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 89 Participants | 97 Participants | 186 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 64 Participants | 69 Participants | 133 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 26 Participants | 32 Participants | 58 Participants |
| Region of Enrollment United States | 95 participants | 102 participants | 197 participants |
| Sex: Female, Male Female | 27 Participants | 46 Participants | 73 Participants |
| Sex: Female, Male Male | 68 Participants | 56 Participants | 124 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 95 | 0 / 102 |
| other Total, other adverse events | 17 / 95 | 17 / 102 |
| serious Total, serious adverse events | 0 / 95 | 2 / 102 |
Outcome results
Primary
% of Participants With Moderate to Severe Diarrhea
Determine whether a single dose of PXVX0200 provides significantly greater protection than placebo against a challenge with virulent V. cholerae O1 El Tor Inaba at 10 days after vaccination. The primary endpoint was the occurrence of moderate or severe (\>/= 3 liters) diarrhea.
Time frame: Ten days after vaccination
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PXVX0200 | % of Participants With Moderate to Severe Diarrhea | 5.7 percentage of participants |
| Placebo | % of Participants With Moderate to Severe Diarrhea | 59.1 percentage of participants |
Comparison: 35 participants were challenged 10 days after receiving PXVX0200. 66 participants were challenged either 10 days or 90 days after receiving placebo.
Primary
% of Participants With Moderate to Severe Diarrhea
Determine whether a single dose of PXVX0200 provides significant greater protection than placebo against a challenge with virulent V. cholerae O1 El Tor Inaba at 3 months after vaccination. The primary endpoint was the occurrence of moderate or severe (\>/= 3 liters) of diarrhea.
Time frame: Ninety days after vaccination
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PXVX0200 | % of Participants With Moderate to Severe Diarrhea | 12.1 percentage of participants |
| Placebo | % of Participants With Moderate to Severe Diarrhea | 59.1 percentage of participants |
Comparison: 33 participants were challenged 90 days after receiving PXVX0200. 66 participants were challenged either 10 days or 90 days after receiving placebo.
Secondary
Number of Days With Fecal Shedding Following 10 Day Challenge
Number of days of fecal shedding of wild type V. cholerae following 10 Day Challenge.
Time frame: Through 10 Days post challenge
Population: Intent to treat (ITT) population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PXVX0200 | Number of Days With Fecal Shedding Following 10 Day Challenge | 0.0 Days |
| Placebo | Number of Days With Fecal Shedding Following 10 Day Challenge | 3.0 Days |
Comparison: 35 participants were challenged 10 days after receiving PXVX0200. 66 participants were challenged either 10 days or 90 days after receiving placebo.p-value: <0.0001Wilcoxon (Mann-Whitney)
Secondary
Number of Days With Fecal Shedding Following 90 Day Challenge
Number of days of fecal shedding of wild type V. cholerae following 90 Day Challenge
Time frame: Through 10 days following challenge
Population: Intent to treat (ITT) population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PXVX0200 | Number of Days With Fecal Shedding Following 90 Day Challenge | 2.0 Days |
| Placebo | Number of Days With Fecal Shedding Following 90 Day Challenge | 3.0 Days |
Comparison: 33 participants were challenged 90 days after receiving PXVX0200. 66 participants were challenged either 10 days or 90 days after receiving placebo.p-value: <0.0001Wilcoxon (Mann-Whitney)
Secondary
# of Days With Positive Stool Culture Following 10 Day Cholera Challenge
Total number of days with a positive stool culture following the 10 Day Cholera challenge.
Time frame: Through 10 Days following challenge
Population: Intent to treat (ITT) comprising all subjects who were randomized and received either PXVX0200 vaccine or placebo.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PXVX0200 | # of Days With Positive Stool Culture Following 10 Day Cholera Challenge | 0.9 Days | Standard Deviation 1.2 |
| Placebo | # of Days With Positive Stool Culture Following 10 Day Cholera Challenge | 3.3 Days | Standard Deviation 1.01 |
Comparison: 35 participants were challenged 10 days after receiving PXVX0200. 66 participants were challenged either 10 days or 90 days after receiving placebo.p-value: <0.0001Wilcoxon (Mann-Whitney)
Secondary
# of Days With Positive Stool Culture Following 90 Day Cholera Challenge
Total number of days with a positive stool culture following 90 Day Cholera Challenge
Time frame: Through 10 Days following challenge
Population: Intent to treat (ITT) comprising all subjects who were randomized and received either PXVX0200 vaccine or placebo.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PXVX0200 | # of Days With Positive Stool Culture Following 90 Day Cholera Challenge | 2.1 Days | Standard Deviation 1.41 |
| Placebo | # of Days With Positive Stool Culture Following 90 Day Cholera Challenge | 3.3 Days | Standard Deviation 1.01 |
Comparison: 33 participants were challenged 90 days after receiving PXVX0200. 66 participants were challenged either 10 days or 90 days after receiving placebo.p-value: <0.0001Wilcoxon (Mann-Whitney)
Secondary
% of Participants With Diarrhea of Any Severity Following a 10 Day Cholera Challenge
Incidence of mild or worse (any severity) diarrhea following the 10 day cholera challenge.
Time frame: Through 10 Days following challenge
Population: Intent to treat population comprising all subjects who were randomized and received either PXVX0200 vaccine or placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PXVX0200 | % of Participants With Diarrhea of Any Severity Following a 10 Day Cholera Challenge | 14.3 % of participants |
| Placebo | % of Participants With Diarrhea of Any Severity Following a 10 Day Cholera Challenge | 92.4 % of participants |
Comparison: 35 participants were challenged 10 days after receiving PXVX0200. 66 participants were challenged either 10 days or 90 days after receiving placebo.95% CI: [67, 100]
Secondary
% of Participants With Diarrhea of Any Severity Following a 90 Day Challenge
Incidence of mild or worse (any severity) diarrhea following the 90 day cholera challenge.
Time frame: Through 10 Days following challenge
Population: Intent to treat population comprising all subjects who were randomized and received either PXVX0200 vaccine or placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PXVX0200 | % of Participants With Diarrhea of Any Severity Following a 90 Day Challenge | 45.5 % of participants |
| Placebo | % of Participants With Diarrhea of Any Severity Following a 90 Day Challenge | 92.4 % of participants |
Comparison: 33 participants were challenged 90 days after receiving PXVX0200. 66 participants were challenged either 10 days or 90 days after receiving placebo.95% CI: [33.6, 66.8]
Secondary
% of Participants With Fever Following the 10 Day Cholera Challenge
Incidence of mild or worse fever following the 10 day cholera challenge.
Time frame: Through 10 Days following challenge
Population: Intent to treat population comprising all subjects who were randomized and received either PXVX0200 vaccine or placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PXVX0200 | % of Participants With Fever Following the 10 Day Cholera Challenge | 2.9 % of participants |
| Placebo | % of Participants With Fever Following the 10 Day Cholera Challenge | 27.3 % of participants |
Comparison: 35 participants were challenged 10 days after receiving PXVX0200. 66 participants were challenged either 10 days or 90 days after receiving placebo.p-value: 0.0025Fisher Exact
Secondary
% of Participants With Fever Following the 90 Day Cholera Challenge
Incidence of mild or worse fever following the 90 day cholera challenge.
Time frame: Through 10 Days following challenge
Population: Intent to treat population comprising all subjects who were randomized and received either PXVX0200 vaccine or placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PXVX0200 | % of Participants With Fever Following the 90 Day Cholera Challenge | 6.1 % of participants |
| Placebo | % of Participants With Fever Following the 90 Day Cholera Challenge | 27.3 % of participants |
Comparison: 33 participants were challenged 90 days after receiving PXVX0200. 66 participants were challenged either 10 days or 90 days after receiving placebo.p-value: 0.0159Fisher Exact
Secondary
% of Participants With Reactogenicity, Diarrhea, Fever or Unsolicited Adverse Events Following Vaccination
Incidence and severity of signs and symptoms of reactogenicity such as diarrhea, and fever following vaccination (through Day 8). Incidence and severity of unsolicited adverse events following vaccination (through Day 29).
Time frame: Following vaccination (Days 1 - 8) and to Day 29
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PXVX0200 | % of Participants With Reactogenicity, Diarrhea, Fever or Unsolicited Adverse Events Following Vaccination | % of Subjects with Reactogenicity | 49.5 % of participants |
| PXVX0200 | % of Participants With Reactogenicity, Diarrhea, Fever or Unsolicited Adverse Events Following Vaccination | % of Subjects with Diarrhea Symptoms | 1.1 % of participants |
| PXVX0200 | % of Participants With Reactogenicity, Diarrhea, Fever or Unsolicited Adverse Events Following Vaccination | % of Subjects with Unsolicited AEs | 17.9 % of participants |
| PXVX0200 | % of Participants With Reactogenicity, Diarrhea, Fever or Unsolicited Adverse Events Following Vaccination | % of Subjects with Fever Symptoms | 2.2 % of participants |
| Placebo | % of Participants With Reactogenicity, Diarrhea, Fever or Unsolicited Adverse Events Following Vaccination | % of Subjects with Unsolicited AEs | 16.7 % of participants |
| Placebo | % of Participants With Reactogenicity, Diarrhea, Fever or Unsolicited Adverse Events Following Vaccination | % of Subjects with Reactogenicity | 50.0 % of participants |
| Placebo | % of Participants With Reactogenicity, Diarrhea, Fever or Unsolicited Adverse Events Following Vaccination | % of Subjects with Diarrhea Symptoms | 3.0 % of participants |
| Placebo | % of Participants With Reactogenicity, Diarrhea, Fever or Unsolicited Adverse Events Following Vaccination | % of Subjects with Fever Symptoms | 1.0 % of participants |
Secondary
Total Weight of Diarrheal Stools Following the 10 Day Cholera Challenge
Total weight (converted to volume) per subject of diarrheal stools measured from subjects with diarrhea following the 10 day cholera challenge.
Time frame: Through 10 Days following challenge
Population: Intent to Treat population comprising all subjects who were randomized and received either PXVX0200 vaccine or placebo.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PXVX0200 | Total Weight of Diarrheal Stools Following the 10 Day Cholera Challenge | 309 mL |
| Placebo | Total Weight of Diarrheal Stools Following the 10 Day Cholera Challenge | 4524 mL |
Comparison: 35 participants were challenged 10 days after receiving PXVX0200. 66 participants were challenged either 10 days or 90 days after receiving placebo.p-value: 0.0073Wilcoxon (Mann-Whitney)
Secondary
Total Weight of Diarrheal Stools Following the 90 Day Cholera Challenge
Total weight (converted to volume) per subject of diarrheal stools measured from subjects with diarrhea following the 90 day cholera challenge.
Time frame: Through 10 Days following challenge
Population: Intent to Treat population comprising all subjects who were randomized and received either PXVX0200 vaccine or placebo.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PXVX0200 | Total Weight of Diarrheal Stools Following the 90 Day Cholera Challenge | 603 mL |
| Placebo | Total Weight of Diarrheal Stools Following the 90 Day Cholera Challenge | 4524 mL |
Comparison: 33 participants were challenge 90 days after receiving PXVX0200. 66 participants were challenged either 10 days or 90 days after receiving placebo.p-value: <0.0001Wilcoxon (Mann-Whitney)