Effect of Antimalarial Drugs to Rabies Vaccine for Post-exposure Prophylaxis.

Study Overview
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Brief Summary
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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
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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.

Official Title
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Effect of Antimalarial Drugs on the Immune Response to Rabies Vaccine for Post-exposure Prophylaxis. A Randomized, Open Label, Trial in Healthy US Adults Age 18-60 Years

Conditions
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Rabies

Intervention / Treatment
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* Drug: Chloroquine
* Drug: Atovaquone and Proguanil
* Drug: Doxycycline
* Biological: Rabies Vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide signed and dated informed consent form. Willing to comply with all study procedures and be available for the duration of the study. Male or female, aged ≥ 18 to ≤ 60 years on day of inclusion. In good general health based on medical history and physical exam Exclusion Criteria: 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. 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. Previous history of receiving the rabies vaccine. Previous history of receiving rabies immune globulin. 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 exclusion criteria. Use of any immunosuppressive drug at the time of the study or 30 days previously. Topical steroids will not be considered an immunosuppressive drug and their use will not be considered an exclusion criteria. Any immunosuppressive disorder, such as HIV infection, common variable immunodeficiency, active cancers or chemotherapy. History of renal insufficiency or requiring dialysis. Have any condition that would, in the opinion of the site investigator, place the subject at an unacceptable risk of injury or render the subject unable to meet the requirements of the protocol. Identified as an employee of the Investigator or study center, with direct involvement in the proposed study or other studies under the direction of that Investigator or study center, as well as family members (i.e., immediate, husband, wife and their children, adopted or natural) of the employee or the Investigator. Previous adverse reaction to any of the antimalarial drugs used in this study. Temporary Exclusion Criteria: Moderate or severe acute illness/infection (according to investigator judgment) or febrile illness (temperature ≥ 38.0°C [≥ 100.4°F]) on day 0.. A prospective subject should not be included in the study until the condition has resolved or the febrile event has subsided. If the delay for the febrile illness exceeds the window between screening and vaccination, or if deemed necessary by the investigator, a prospective subject may be re-screened once the fever has resolved. Recent or scheduled receipt of any vaccine 4 weeks prior to day 0.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chloroquine<br>Chloroquine Phosphate tablet for oral administration 500 mg chloroquine phosphate (equivalent to 300 mg base) | Drug: Chloroquine<br>* FDA approve dosing schedule<br>* Other names: Chloroquine Phosphate;Biological: Rabies Vaccine<br>* FDA approve dosing schedule<br>* Other names: RabAvert;|
| Experimental: Atovaquone and Proguanil (Malarone)<br>Malarone tablet for oral administration 250 mg atovaquone and 100 mg proguanil hydrochloride. RabAvert rabies vaccine, at least 2.5 IU of rabies antigen. | Drug: Atovaquone and Proguanil<br>* FDA approve dosing schedule<br>* Other names: Malarone;Biological: Rabies Vaccine<br>* FDA approve dosing schedule<br>* Other names: RabAvert;|
| Experimental: Doxycycline<br>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. | Drug: Doxycycline<br>* FDA approve dosing schedule<br>* Other names: Doxycycline Hyclate;Biological: Rabies Vaccine<br>* FDA approve dosing schedule<br>* Other names: RabAvert;|
| Active Comparator: Rabies<br>RabAvert rabies vaccine, at least 2.5 IU of rabies antigen. | Biological: Rabies Vaccine<br>* FDA approve dosing schedule<br>* Other names: RabAvert;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 6 weeks for Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Groups and at 4 weeks for Rabies Group | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 21 days for Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Groups and 7 days for Rabies Arm | 
| 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. | 28 days for Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Groups and 14 days for Rabies Arm | 
| 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. | Up to 8 weeks for Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Groups and up to 6 weeks for Rabies Arm |