Rabies
Conditions
Brief summary
This is an exploratory trial to evaluate the effect of antimalarial drugs on the immune response generated by rabies vaccine when administered for post-exposure prophylaxis. This study will use the FDA approved post-exposure prophylaxis vaccine regimen (without rabies immune globulin) in the presence or absence of an FDA-approved malaria chemoprophylaxis regimen.
Detailed description
Rabies is present on all continents where U.S. military personnel deploy, including countries where malaria is also endemic and where U.S. military personnel are required to take malaria prophylaxis. Rabies post-exposure prophylaxis in unvaccinated individuals who are not on malaria prophylaxis consists of four, 1.0-mL intramuscular (IM) injections of the purified chick embryo cell (PCECV) rabies vaccine on days 0, 3, 7, and 14. The current Advisory Committee on Immunization Practices (ACIP) guidelines recommend that exposed persons who are taking malaria prophylaxis should receive a fifth dose of rabies vaccine 28 days after the exposure. These guidelines do not differentiate between drugs used for malaria prophylaxis This study will administer the post-exposure regimen to volunteers from a US population of military age who are taking one of three malaria prophylaxis regimens or no malaria prophylaxis. The goal of this study is to asses if individuals on malaria prophylaxis achieve the required rabies titer after completion of the four dose regimen. Obtaining rabies vaccine and rabies immune globulin in a deployed setting can be challenging. A full understanding of the requirements for protecting exposed individuals is necessary for appropriate decision making in a resource-constrained environment.
Interventions
DRUGChloroquine
FDA approve dosing schedule
DRUGAtovaquone and Proguanil
FDA approve dosing schedule
DRUGDoxycycline
FDA approve dosing schedule
BIOLOGICALRabies Vaccine
FDA approve dosing schedule
Sponsors
Walter Reed Army Institute of Research (WRAIR)
Kansas State University
State University of New York - Upstate Medical University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
1. Provide signed and dated informed consent form. 2. Willing to comply with all study procedures and be available for the duration of the study. 3. Male or female, aged ≥ 18 to ≤ 60 years on day of inclusion. 4. In good general health based on medical history and physical exam
Exclusion criteria
1. Subject is pregnant, or lactating, or of childbearing potential (to be considered of non-childbearing potential, a female must be post-menopausal for at least 1 year, surgically sterile, or using an effective method of contraception or abstinence from at least 4 weeks prior to the first vaccination and until at least 4 weeks after the last vaccination. 2. Participation in the 4 weeks preceding the first trial vaccination, or planned participation during the present trial period, in another clinical trial investigating a vaccine, drug, medical device, or medical procedure. 3. Previous history of receiving the rabies vaccine. 4. Previous history of receiving rabies immune globulin. 5. Any major psychiatric disorder, such as severe depression, severe anxiety disorder, psychosis, schizophrenia, other major psychiatric disorders, or seizures. History of mild depression or anxiety disorder that are well controlled are not
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Geometric Mean Titer (GMT) 14 Days Post Fourth Dose Post Exposure Prophylaxis (PEP) With Purified Chick Embryo Cell Vaccine (PCECV) in Each Malaria Prophylaxis Group Compared to Control to Determine if a Fifth Dose of PEP Would Add Value | 6 weeks for Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Groups and at 4 weeks for Rabies Group | Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Groups received antimalarial up to day 14 and rabies vaccinations on day 14, 17, 21, and 28 (dose 4). Rabies Group received the rabies vaccination on days 0, 3,7 and 14 (dose 4). Rabies virus-specific serum antibody neutralization assay was used to measure rabies virus antibodies, using the rapid fluorescent foci inhibition test (RFFIT). A titer of \>0.5 IU/ml against rabies virus as protective. Descriptive analyses were based on samples taken 14 days after dose 4, (e.g., at 6 weeks for Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Arms and at 4 weeks for Rabies Arm). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| GMT Over Protective Titer Prior to Third Dose of PCECV | 21 days for Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Groups and 7 days for Rabies Arm | Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Groups received antimalarial up to day 14 and rabies vaccinations on day 14, 17, 21 (dose 3), and 28 (dose 4). Rabies Group received the rabies vaccination on days 0, 3, 7 (dose 3) and 14 (dose 4). For Chloroquine, Malarone and Doxycycline Groups, samples were taken on days 0, 21, 28 and 56. For Rabies Group, samples were taken on days 0, 7, 14 and 42. Rabies virus-specific serum antibody neutralization assay was used to measure rabies virus antibodies, using the rapid fluorescent foci inhibition test (RFFIT). A titer of \>0.5 IU/ml against rabies virus as protective. |
| GMT Over Protective Titer Prior Fourth Dose of PCECV | 28 days for Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Groups and 14 days for Rabies Arm | Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Groups received antimalarial up to day 14 and rabies vaccinations on day 14, 17, 21 (dose 3), and 28 (dose 4). Rabies Group received the rabies vaccination on days 0, 3, 7 (dose 3) and 14 (dose 4). For Chloroquine, Malarone and Doxycycline Groups, samples were taken on days 0, 21, 28 and 56. For Rabies Group, samples were taken on days 0, 7, 14 and 42. Rabies virus-specific serum antibody neutralization assay was used to measure rabies virus antibodies, using the rapid fluorescent foci inhibition test (RFFIT). A titer of \>0.5 IU/ml against rabies virus as protective. |
| GMT Over Protective Titer 28 Days Post Fourth Dose of PCECV | Up to 8 weeks for Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Groups and up to 6 weeks for Rabies Arm | Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Groups received antimalarial up to day 14 and rabies vaccinations on day 14, 17, 21 (dose 3), and 28 (dose 4). Rabies Group received the rabies vaccination on days 0, 3,7 (dose 3) and 14 (dose 4). For Chloroquine, Malarone and Doxycycline Groups, samples were taken on days 0, 21, 28 and 56. For Rabies Group, samples were taken on days 0, 7, 14 and 42. Rabies virus-specific serum antibody neutralization assay was used to measure rabies virus antibodies, using the rapid fluorescent foci inhibition test (RFFIT). A titer of \>0.5 IU/ml against rabies virus as protective. |
Countries
United States
Participant flow
Recruitment details
Healthy adults aged 18 to 60 were recruited from 11-Nov-2016 to 07-Jun-2018 in and around the study site in Syracuse, New York
Participants by arm
| Arm | Count |
|---|---|
| Chloroquine Chloroquine Phosphate tablet for oral administration 500 mg chloroquine phosphate (equivalent to 300 mg base)
Chloroquine: FDA approve dosing schedule
Rabies Vaccine: FDA approve dosing schedule | 20 |
| Atovaquone and Proguanil (Malarone) Malarone tablet for oral administration 250 mg atovaquone and 100 mg proguanil hydrochloride.
RabAvert rabies vaccine, at least 2.5 IU of rabies antigen.
Atovaquone and Proguanil: FDA approve dosing schedule
Rabies Vaccine: FDA approve dosing schedule | 23 |
| Doxycycline Doxycycline hyclate tablet for oral administration, contains specially coated pellets of doxycycline hyclate equivalent to 100 mg of doxycycline.
RabAvert rabies vaccine, at least 2.5 IU of rabies antigen.
Doxycycline: FDA approve dosing schedule
Rabies Vaccine: FDA approve dosing schedule | 23 |
| Rabies RabAvert rabies vaccine, at least 2.5 IU of rabies antigen.
Rabies Vaccine: FDA approve dosing schedule | 25 |
| Total | 91 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 2 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 3 | 0 |
Baseline characteristics
| Characteristic | Chloroquine | Atovaquone and Proguanil (Malarone) | Doxycycline | Rabies | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants | 23 Participants | 22 Participants | 25 Participants | 89 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 2 Participants | 0 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 20 Participants | 21 Participants | 25 Participants | 85 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Participants with data available at both baseline and post baseline assessments | 20 participants | 23 participants | 23 participants | 25 participants | 91 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 1 Participants | 5 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 20 Participants | 22 Participants | 18 Participants | 78 Participants |
| Region of Enrollment United States | 20 Participants | 23 Participants | 23 Participants | 25 Participants | 91 Participants |
| Sex: Female, Male Female | 12 Participants | 16 Participants | 13 Participants | 11 Participants | 52 Participants |
| Sex: Female, Male Male | 8 Participants | 7 Participants | 10 Participants | 14 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 26 | 0 / 27 | 0 / 25 |
| other Total, other adverse events | 17 / 25 | 22 / 26 | 19 / 27 | 19 / 25 |
| serious Total, serious adverse events | 0 / 25 | 0 / 26 | 0 / 27 | 0 / 25 |
Outcome results
Primary
Geometric Mean Titer (GMT) 14 Days Post Fourth Dose Post Exposure Prophylaxis (PEP) With Purified Chick Embryo Cell Vaccine (PCECV) in Each Malaria Prophylaxis Group Compared to Control to Determine if a Fifth Dose of PEP Would Add Value
Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Groups received antimalarial up to day 14 and rabies vaccinations on day 14, 17, 21, and 28 (dose 4). Rabies Group received the rabies vaccination on days 0, 3,7 and 14 (dose 4). Rabies virus-specific serum antibody neutralization assay was used to measure rabies virus antibodies, using the rapid fluorescent foci inhibition test (RFFIT). A titer of \>0.5 IU/ml against rabies virus as protective. Descriptive analyses were based on samples taken 14 days after dose 4, (e.g., at 6 weeks for Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Arms and at 4 weeks for Rabies Arm).
Time frame: 6 weeks for Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Groups and at 4 weeks for Rabies Group
Population: Group 1: 1 subject was excluded from analysis due to presence of rabies antibody titer at baseline, 1 was excluded due to use of steroids during the study; Group 2: 1 subject completed primary endpoint but did not complete the study; Group 3: 1 subject was excluded from analysis due to presence of rabies antibody titer at baseline
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Chloroquine | Geometric Mean Titer (GMT) 14 Days Post Fourth Dose Post Exposure Prophylaxis (PEP) With Purified Chick Embryo Cell Vaccine (PCECV) in Each Malaria Prophylaxis Group Compared to Control to Determine if a Fifth Dose of PEP Would Add Value | 3.45 IU/ml | Geometric Coefficient of Variation 1.62 |
| Atovaquone and Proguanil (Malarone) | Geometric Mean Titer (GMT) 14 Days Post Fourth Dose Post Exposure Prophylaxis (PEP) With Purified Chick Embryo Cell Vaccine (PCECV) in Each Malaria Prophylaxis Group Compared to Control to Determine if a Fifth Dose of PEP Would Add Value | 7.95 IU/ml | Geometric Coefficient of Variation 0.81 |
| Doxycycline | Geometric Mean Titer (GMT) 14 Days Post Fourth Dose Post Exposure Prophylaxis (PEP) With Purified Chick Embryo Cell Vaccine (PCECV) in Each Malaria Prophylaxis Group Compared to Control to Determine if a Fifth Dose of PEP Would Add Value | 8.51 IU/ml | Geometric Coefficient of Variation 0.94 |
| Rabies | Geometric Mean Titer (GMT) 14 Days Post Fourth Dose Post Exposure Prophylaxis (PEP) With Purified Chick Embryo Cell Vaccine (PCECV) in Each Malaria Prophylaxis Group Compared to Control to Determine if a Fifth Dose of PEP Would Add Value | 10.26 IU/ml | Geometric Coefficient of Variation 0.66 |
Secondary
GMT Over Protective Titer 28 Days Post Fourth Dose of PCECV
Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Groups received antimalarial up to day 14 and rabies vaccinations on day 14, 17, 21 (dose 3), and 28 (dose 4). Rabies Group received the rabies vaccination on days 0, 3,7 (dose 3) and 14 (dose 4). For Chloroquine, Malarone and Doxycycline Groups, samples were taken on days 0, 21, 28 and 56. For Rabies Group, samples were taken on days 0, 7, 14 and 42. Rabies virus-specific serum antibody neutralization assay was used to measure rabies virus antibodies, using the rapid fluorescent foci inhibition test (RFFIT). A titer of \>0.5 IU/ml against rabies virus as protective.
Time frame: Up to 8 weeks for Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Groups and up to 6 weeks for Rabies Arm
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Chloroquine | GMT Over Protective Titer 28 Days Post Fourth Dose of PCECV | 2.3 IU/ml | Geometric Coefficient of Variation 1.53 |
| Atovaquone and Proguanil (Malarone) | GMT Over Protective Titer 28 Days Post Fourth Dose of PCECV | 4.96 IU/ml | Geometric Coefficient of Variation 0.78 |
| Doxycycline | GMT Over Protective Titer 28 Days Post Fourth Dose of PCECV | 5.18 IU/ml | Geometric Coefficient of Variation 1.14 |
| Rabies | GMT Over Protective Titer 28 Days Post Fourth Dose of PCECV | 6.87 IU/ml | Geometric Coefficient of Variation 1.04 |
Secondary
GMT Over Protective Titer Prior Fourth Dose of PCECV
Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Groups received antimalarial up to day 14 and rabies vaccinations on day 14, 17, 21 (dose 3), and 28 (dose 4). Rabies Group received the rabies vaccination on days 0, 3, 7 (dose 3) and 14 (dose 4). For Chloroquine, Malarone and Doxycycline Groups, samples were taken on days 0, 21, 28 and 56. For Rabies Group, samples were taken on days 0, 7, 14 and 42. Rabies virus-specific serum antibody neutralization assay was used to measure rabies virus antibodies, using the rapid fluorescent foci inhibition test (RFFIT). A titer of \>0.5 IU/ml against rabies virus as protective.
Time frame: 28 days for Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Groups and 14 days for Rabies Arm
Population: Group 1: 1 subject received all doses but did not complete the study; Group 2: 2 subjects received all doses but did not complete the study.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Chloroquine | GMT Over Protective Titer Prior Fourth Dose of PCECV | 4.15 IU/ml | Geometric Coefficient of Variation 289 |
| Atovaquone and Proguanil (Malarone) | GMT Over Protective Titer Prior Fourth Dose of PCECV | 6.45 IU/ml | Geometric Coefficient of Variation 1.39 |
| Doxycycline | GMT Over Protective Titer Prior Fourth Dose of PCECV | 7.04 IU/ml | Geometric Coefficient of Variation 2.71 |
| Rabies | GMT Over Protective Titer Prior Fourth Dose of PCECV | 6.98 IU/ml | Geometric Coefficient of Variation 1.12 |
Secondary
GMT Over Protective Titer Prior to Third Dose of PCECV
Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Groups received antimalarial up to day 14 and rabies vaccinations on day 14, 17, 21 (dose 3), and 28 (dose 4). Rabies Group received the rabies vaccination on days 0, 3, 7 (dose 3) and 14 (dose 4). For Chloroquine, Malarone and Doxycycline Groups, samples were taken on days 0, 21, 28 and 56. For Rabies Group, samples were taken on days 0, 7, 14 and 42. Rabies virus-specific serum antibody neutralization assay was used to measure rabies virus antibodies, using the rapid fluorescent foci inhibition test (RFFIT). A titer of \>0.5 IU/ml against rabies virus as protective.
Time frame: 21 days for Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Groups and 7 days for Rabies Arm
Population: Group 1: 1 subject completed all doses of vaccine but did not complete the study; Group 2: 2 subjects completed all doses of vaccine but did not complete the study.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Chloroquine | GMT Over Protective Titer Prior to Third Dose of PCECV | 0.14 IU/ml | Geometric Coefficient of Variation 0.62 |
| Atovaquone and Proguanil (Malarone) | GMT Over Protective Titer Prior to Third Dose of PCECV | 0.11 IU/ml | Geometric Coefficient of Variation 0.4 |
| Doxycycline | GMT Over Protective Titer Prior to Third Dose of PCECV | 0.16 IU/ml | Geometric Coefficient of Variation 0.72 |
| Rabies | GMT Over Protective Titer Prior to Third Dose of PCECV | 0.17 IU/ml | Geometric Coefficient of Variation 1.15 |