Respiratory Tract Diseases
Conditions
Keywords
Acute respiratory disease prevention, Adenovirus
Brief summary
This is a multicenter, double-blind, randomized, placebo-controlled study to evaluate the safety and efficacy of oral DR-5001 in reducing the attack rate of febrile acute respiratory disease caused by type-4 and type-7 adenovirus as well as determine its immunogenicity.
Detailed description
The study will be conducted at two sites and will include a minimum of 4 visits. The overall study duration for participants will be approximately 8 weeks. Study participants will undergo acute respiratory disease evaluation that will include a throat swab and a blood draw. Each participant will also be contacted in six months for follow-up information.
Interventions
BIOLOGICALDR-5001
All randomized subjects received a single tablet of both Type-4 and Type-7 ADV vaccines on Day 0. Both vaccine tablets were administered orally, kept in the mouth as briefly as possible and swallowed whole with water. Chewing the tablets was not permitted.
OTHERPlacebo
All randomized subjects received a single tablet each of the placebos matching Type-4 and Type-7 ADV vaccines on Day 0. Both placebo tablets were administered orally, kept in the mouth as briefly as possible and swallowed whole with water. Chewing the tablets was not permitted.
Sponsors
Duramed Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
17 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Military recruit in training * Male or female; if female, must be of non-childbearing potential or with a documented negative pregnancy test \</= 72 hours prior to study medication administration and agree not to become pregnant
Exclusion criteria
* Female nursing an infant or planning on nursing during the study * Immunosuppressed for any reason, including past (within last 6 months) or current treatment with immunosuppressive therapy * Known allergy to any component of the vaccines and/or placebo tablets * Immunocompromised sexual partner or immunocompromised individuals in home
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Wild Type-4 Febrile Adenovirus (ADV) Acute Respiratory Disease (ARD) -- ITT Cohort | Day 0 - Day 56 | For the oral Type-4 vaccine, the primary outcome is the number of cases of ADV-4 febrile acute respiratory disease (ARD), defined as a subject with one or more clinical signs and symptoms of ARD and an oral temperature ≥ 100.5°F (38.06°C) and throat culture positive for wild ADV Type-4 infection. This outcome used the intent-to-treat cohort. |
| Number of Participants With Wild Type-4 Febrile Adenovirus (ADV) Acute Respiratory Disease (ARD) -- PP Cohort | Day 0 - Day 56 | For the oral Type-4 vaccine, the primary outcome is the number of cases of ADV-4 febrile acute respiratory disease (ARD), defined as a subject with one or more clinical signs and symptoms of ARD and an oral temperature ≥ 100.5°F (38.06°C) and throat culture positive for wild ADV Type-4 infection. This outcome used the per protocol cohort. |
| Number of Participants With Wild Type-4 Febrile Adenovirus (ADV) Acute Respiratory Disease (ARD) -- ITT Cohort --- Day 11-56 | Day 11 - Day 56 | For the oral Type-4 vaccine, the primary outcome is the number of cases of ADV-4 febrile acute respiratory disease (ARD), defined as a subject with one or more clinical signs and symptoms of ARD and an oral temperature ≥ 100.5°F (38.06°C) and throat culture positive for wild ADV Type-4 infection. This outcome used the intent-to-treat cohort; further, this outcome omitted ARD cases from Day 0-Day 10 because the protective effect of the vaccine was unlikely to take place during that time period. |
| Percentage of Participants Showing ADV-7 Seroconversion at Week 4 | Week 4 | ADV-7 seroconversion was defined as the development of ADV Type-7 neutralizing antibody at Week 4 (Day 26) after study medication that represented at least a fourfold increase in titer from baseline (visit 0) in a subject whose baseline Type-7 titer was \<1:4. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Wild Type-7 Adenovirus (ADV) Acute Respiratory Disease (ARD) -- ITT Cohort | Day 0 - Day 56 | For the oral Type-7 vaccine, the number of cases of ADV-7 acute respiratory disease (ARD) regardless of whether the participant was febrile or not. Therefore includes participants with one or more clinical signs and symptoms of ARD and throat culture positive for wild ADV Type-7 infection. This outcome used the intent-to-treat cohort. |
| Percentage of Participants Showing ADV-4 Seroconversion at Week 4 | Week 4 | ADV-4 seroconversion was defined as the development of ADV Type-4 neutralizing antibody at Week 4 (Day 26) after study medication that represented at least a fourfold increase in titer from baseline (visit 0) in a subject whose baseline Type-4 titer was \<1:4. |
| Percentage of Participants Showing ADV Type-7 Booster at Week 4 | Baseline, Week 4 | ADV-7 booster effect is defined as the development of ADV Type-7 neutralizing antibody at Week 4 (Day 26) that represented at least a fourfold increase in titer from baseline (Visit 0) in a participant whose baseline Type-7 titer is ≥1:4. |
| Number of Participants With Wild Type-4 Adenovirus (ADV) Acute Respiratory Disease (ARD) -- ITT Cohort | Day 0 - Day 56 | For the oral Type-4 vaccine, the number of cases of ADV-4 acute respiratory disease (ARD) regardless of whether the participant was febrile or not. Therefore includes participants with one or more clinical signs and symptoms of ARD and throat culture positive for wild ADV Type-4 infection. This outcome used the intent-to-treat cohort. |
| Percentage of Participants Showing ADV Type-4 Booster at Week 4 | Baseline, Week 4 | ADV-4 booster effect is defined as the development of ADV Type-4 neutralizing antibody at Week 4 (Day 26) that represented at least a fourfold increase in titer from baseline (Visit 0) in a participant whose baseline Type-4 titer is ≥1:4. |
| Number of Participants With Wild Type-7 Febrile Adenovirus (ADV) Acute Respiratory Disease (ARD) -- ITT Cohort | Day 0 - Day 56 | For the oral Type-7 vaccine, a secondary outcome is the number of cases of ADV-7 febrile acute respiratory disease (ARD), defined as a subject with one or more clinical signs and symptoms of ARD and an oral temperature ≥ 100.5°F (38.06°C) and throat culture positive for wild ADV Type-7 infection. This outcome used the intent-to-treat cohort. |
Countries
United States
Participant flow
Recruitment details
The study was conducted in subjects undergoing military basic training.
Pre-assignment details
Participants were randomized to either the vaccine group or the matching placebo group in a 3:1 ratio.
Participants by arm
| Arm | Count |
|---|---|
| Vaccine Participants received a single tablet of both Type-4 and Type-7 adenovirus vaccines at study visit 1 (Day 0). | 3,031 |
| Placebo Participants received a single tablet of both placebos that matched the Type-4 and Type-7 adenovirus vaccines at study visit 1 (Day 0). | 1,009 |
| Total | 4,040 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Did not meet protocol requirement | 3 | 3 |
| Overall Study | Lost to Follow-up | 19 | 8 |
| Overall Study | Other | 100 | 35 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Pregnancy | 2 | 0 |
| Overall Study | Protocol Violation | 2 | 2 |
| Overall Study | Withdrawal by Subject | 17 | 6 |
Baseline characteristics
| Characteristic | Total | Vaccine | Placebo |
|---|---|---|---|
| Age, Continuous | 21.2 years STANDARD_DEVIATION 4 | 21.3 years STANDARD_DEVIATION 4 | 21.1 years STANDARD_DEVIATION 4.1 |
| Age, Customized | 19.8 years | 19.8 years | 19.7 years |
| Race/Ethnicity, Customized African-American | 740 participants | 554 participants | 186 participants |
| Race/Ethnicity, Customized Asian | 123 participants | 94 participants | 29 participants |
| Race/Ethnicity, Customized Caucasian | 2513 participants | 1871 participants | 642 participants |
| Race/Ethnicity, Customized Hispanic | 429 participants | 326 participants | 103 participants |
| Race/Ethnicity, Customized Other | 235 participants | 186 participants | 49 participants |
| Region of Enrollment United States | 4040 participants | 3031 participants | 1009 participants |
| Sex: Female, Male Female | 1488 Participants | 1121 Participants | 367 Participants |
| Sex: Female, Male Male | 2552 Participants | 1910 Participants | 642 Participants |
| Type-4 Titer Negative | 2584 participants | 1906 participants | 678 participants |
| Type-4 Titer Positive | 1454 participants | 1123 participants | 331 participants |
| Type-4 Titer Unknown | 2 participants | 2 participants | 0 participants |
| Type-7 Titer Negative | 1536 participants | 1159 participants | 377 participants |
| Type-7 Titer Positive | 2502 participants | 1870 participants | 632 participants |
| Type-7 Titer Unknown | 2 participants | 2 participants | 0 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 916 / 1,009 | 2,673 / 3,031 |
| serious Total, serious adverse events | 12 / 1,009 | 35 / 3,031 |
Outcome results
Primary
Number of Participants With Wild Type-4 Febrile Adenovirus (ADV) Acute Respiratory Disease (ARD) -- ITT Cohort
For the oral Type-4 vaccine, the primary outcome is the number of cases of ADV-4 febrile acute respiratory disease (ARD), defined as a subject with one or more clinical signs and symptoms of ARD and an oral temperature ≥ 100.5°F (38.06°C) and throat culture positive for wild ADV Type-4 infection. This outcome used the intent-to-treat cohort.
Time frame: Day 0 - Day 56
Population: The intent-to-treat (ITT) cohort included all participants randomized and treated in the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vaccine | Number of Participants With Wild Type-4 Febrile Adenovirus (ADV) Acute Respiratory Disease (ARD) -- ITT Cohort | 1 participants |
| Placebo | Number of Participants With Wild Type-4 Febrile Adenovirus (ADV) Acute Respiratory Disease (ARD) -- ITT Cohort | 48 participants |
Comparison: The vaccine efficacy (VE) was defined as: VE = 1 - R, where R = P(vaccine)/P(placebo) was the relative risk of ARD attack in subjects who received vaccines compared to placebos (Blackwelder 1993). The 95% confidence interval of the VE was obtained by inverting the Chi Square method proposed by Koopman for the ratio of two binomial proportions (Koopman 1984). The goal of the analysis of efficacy was to demonstrate a VE of at least 80% with a lower 95% confidence bound at least 60%.95% CI: [96.02, 99.88]
Primary
Number of Participants With Wild Type-4 Febrile Adenovirus (ADV) Acute Respiratory Disease (ARD) -- ITT Cohort --- Day 11-56
For the oral Type-4 vaccine, the primary outcome is the number of cases of ADV-4 febrile acute respiratory disease (ARD), defined as a subject with one or more clinical signs and symptoms of ARD and an oral temperature ≥ 100.5°F (38.06°C) and throat culture positive for wild ADV Type-4 infection. This outcome used the intent-to-treat cohort; further, this outcome omitted ARD cases from Day 0-Day 10 because the protective effect of the vaccine was unlikely to take place during that time period.
Time frame: Day 11 - Day 56
Population: The intent-to-treat (ITT) cohort included all participants randomized and treated in the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vaccine | Number of Participants With Wild Type-4 Febrile Adenovirus (ADV) Acute Respiratory Disease (ARD) -- ITT Cohort --- Day 11-56 | 0 participants |
| Placebo | Number of Participants With Wild Type-4 Febrile Adenovirus (ADV) Acute Respiratory Disease (ARD) -- ITT Cohort --- Day 11-56 | 44 participants |
Primary
Number of Participants With Wild Type-4 Febrile Adenovirus (ADV) Acute Respiratory Disease (ARD) -- PP Cohort
For the oral Type-4 vaccine, the primary outcome is the number of cases of ADV-4 febrile acute respiratory disease (ARD), defined as a subject with one or more clinical signs and symptoms of ARD and an oral temperature ≥ 100.5°F (38.06°C) and throat culture positive for wild ADV Type-4 infection. This outcome used the per protocol cohort.
Time frame: Day 0 - Day 56
Population: The per-protocol (PP) cohort included all participants who met the eligibility criteria set forth in the protocol, did not have any significant violations or deviations from the protocol, and completed the final study visit (Day 56). Subjects who vomited within 24 hours after taking the study medication were excluded from the PP cohort.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vaccine | Number of Participants With Wild Type-4 Febrile Adenovirus (ADV) Acute Respiratory Disease (ARD) -- PP Cohort | 1 participants |
| Placebo | Number of Participants With Wild Type-4 Febrile Adenovirus (ADV) Acute Respiratory Disease (ARD) -- PP Cohort | 47 participants |
Primary
Percentage of Participants Showing ADV-7 Seroconversion at Week 4
ADV-7 seroconversion was defined as the development of ADV Type-7 neutralizing antibody at Week 4 (Day 26) after study medication that represented at least a fourfold increase in titer from baseline (visit 0) in a subject whose baseline Type-7 titer was \<1:4.
Time frame: Week 4
Population: Type-7 ADV Seroconversion Cohort: Included those subjects who had a negative Type-7 ADV serum neutralizing antibody status at baseline (\<1:4) and at least one titer value for ADV-7 at the subsequent visits following vaccination.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vaccine | Percentage of Participants Showing ADV-7 Seroconversion at Week 4 | 93.8 percentage of participants |
| Placebo | Percentage of Participants Showing ADV-7 Seroconversion at Week 4 | 5.3 percentage of participants |
Secondary
Number of Participants With Wild Type-4 Adenovirus (ADV) Acute Respiratory Disease (ARD) -- ITT Cohort
For the oral Type-4 vaccine, the number of cases of ADV-4 acute respiratory disease (ARD) regardless of whether the participant was febrile or not. Therefore includes participants with one or more clinical signs and symptoms of ARD and throat culture positive for wild ADV Type-4 infection. This outcome used the intent-to-treat cohort.
Time frame: Day 0 - Day 56
Population: The intent-to-treat (ITT) cohort included all participants randomized and treated in the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vaccine | Number of Participants With Wild Type-4 Adenovirus (ADV) Acute Respiratory Disease (ARD) -- ITT Cohort | 3 participants |
| Placebo | Number of Participants With Wild Type-4 Adenovirus (ADV) Acute Respiratory Disease (ARD) -- ITT Cohort | 65 participants |
Comparison: The vaccine efficacy (VE) was defined as: VE = 1 - R, where R = P(vaccine)/P(placebo) was the relative risk of ARD attack in subjects who received vaccines compared to placebos (Blackwelder 1993). The 95% confidence interval of the VE was obtained by inverting the Chi Square method proposed by Koopman for the ratio of two binomial proportions (Koopman 1984). The goal of the analysis of efficacy was to demonstrate a VE of at least 80% with a lower 95% confidence bound at least 60%.95% CI: [95.39, 99.49]
Secondary
Number of Participants With Wild Type-7 Adenovirus (ADV) Acute Respiratory Disease (ARD) -- ITT Cohort
For the oral Type-7 vaccine, the number of cases of ADV-7 acute respiratory disease (ARD) regardless of whether the participant was febrile or not. Therefore includes participants with one or more clinical signs and symptoms of ARD and throat culture positive for wild ADV Type-7 infection. This outcome used the intent-to-treat cohort.
Time frame: Day 0 - Day 56
Population: The intent-to-treat (ITT) cohort included all participants randomized and treated in the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vaccine | Number of Participants With Wild Type-7 Adenovirus (ADV) Acute Respiratory Disease (ARD) -- ITT Cohort | 0 participants |
| Placebo | Number of Participants With Wild Type-7 Adenovirus (ADV) Acute Respiratory Disease (ARD) -- ITT Cohort | 0 participants |
Secondary
Number of Participants With Wild Type-7 Febrile Adenovirus (ADV) Acute Respiratory Disease (ARD) -- ITT Cohort
For the oral Type-7 vaccine, a secondary outcome is the number of cases of ADV-7 febrile acute respiratory disease (ARD), defined as a subject with one or more clinical signs and symptoms of ARD and an oral temperature ≥ 100.5°F (38.06°C) and throat culture positive for wild ADV Type-7 infection. This outcome used the intent-to-treat cohort.
Time frame: Day 0 - Day 56
Population: The intent-to-treat (ITT) cohort included all participants randomized and treated in the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vaccine | Number of Participants With Wild Type-7 Febrile Adenovirus (ADV) Acute Respiratory Disease (ARD) -- ITT Cohort | 0 participants |
| Placebo | Number of Participants With Wild Type-7 Febrile Adenovirus (ADV) Acute Respiratory Disease (ARD) -- ITT Cohort | 0 participants |
Secondary
Percentage of Participants Showing ADV-4 Seroconversion at Week 4
ADV-4 seroconversion was defined as the development of ADV Type-4 neutralizing antibody at Week 4 (Day 26) after study medication that represented at least a fourfold increase in titer from baseline (visit 0) in a subject whose baseline Type-4 titer was \<1:4.
Time frame: Week 4
Population: Type-4 ADV Seroconversion Cohort: Included those subjects who had a negative Type-4 ADV serum neutralizing antibody status at baseline (\<1:4) and at least one titer value for ADV-4 at the subsequent visits following vaccination.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vaccine | Percentage of Participants Showing ADV-4 Seroconversion at Week 4 | 94.5 percentage of participants |
| Placebo | Percentage of Participants Showing ADV-4 Seroconversion at Week 4 | 10.6 percentage of participants |
Secondary
Percentage of Participants Showing ADV Type-4 Booster at Week 4
ADV-4 booster effect is defined as the development of ADV Type-4 neutralizing antibody at Week 4 (Day 26) that represented at least a fourfold increase in titer from baseline (Visit 0) in a participant whose baseline Type-4 titer is ≥1:4.
Time frame: Baseline, Week 4
Population: Type-4 ADV Booster Cohort included subjects who had a positive Type-4 ADV serum neutralizing antibody status at baseline (≥ 1:4) and at least one titer value for ADV Type-4 at the subsequent visits following study medication administration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vaccine | Percentage of Participants Showing ADV Type-4 Booster at Week 4 | 50.3 percentage of participants |
| Placebo | Percentage of Participants Showing ADV Type-4 Booster at Week 4 | 0.6 percentage of participants |
Secondary
Percentage of Participants Showing ADV Type-7 Booster at Week 4
ADV-7 booster effect is defined as the development of ADV Type-7 neutralizing antibody at Week 4 (Day 26) that represented at least a fourfold increase in titer from baseline (Visit 0) in a participant whose baseline Type-7 titer is ≥1:4.
Time frame: Baseline, Week 4
Population: Type-7 ADV Booster Cohort included subjects who had a positive Type-7 ADV serum neutralizing antibody status at baseline (≥ 1:4) and at least one titer value for ADV Type-7 at the subsequent visits following study medication administration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vaccine | Percentage of Participants Showing ADV Type-7 Booster at Week 4 | 46.1 percentage of participants |
| Placebo | Percentage of Participants Showing ADV Type-7 Booster at Week 4 | 3.9 percentage of participants |