RabiesPhase 4MALRABNCT02564471
Effect of Antimalarial Drugs to Rabies Vaccine for Post-exposure Prophylaxis.
A Phase 4 study testing Chloroquine, Atovaquone and Proguanil and Doxycycline in people with Rabies, run by State University of New York - Upstate Medical University at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 60 yearsHealthy volunteers can take part
- Conditions the study is for
- Rabies
- What is being tested?
- Chloroquine, Atovaquone and Proguanil and Doxycycline
- Type of treatment
- Vaccines, Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 103 participants
- Where
- 1 siteUnited States
- Study dates
- 11 Nov 2016to Feb 2019
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
State University of New York, Upstate Medical University (SUNY-UMU)
Syracuse, New York, 13210
About this study
Official title: 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
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.
Read the 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.
- Conditions
- Rabies
- Being tested
- Chloroquine, Atovaquone and Proguanil, Doxycycline, Rabies Vaccine
- Medical subject headings
- Rabies
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ChloroquineDrug
Also called Chloroquine Phosphate
FDA approve dosing schedule
Atovaquone and ProguanilDrug
Also called Malarone
FDA approve dosing schedule
DoxycyclineDrug
Also called Doxycycline Hyclate
FDA approve dosing schedule
Rabies VaccineBiological
Also called RabAvert
FDA approve dosing schedule
| Study group | Role | What they receive |
|---|---|---|
| Chloroquine | Experimental | Chloroquine Phosphate tablet for oral administration 500 mg chloroquine phosphate (equivalent to 300 mg base) Receives: Drug: Chloroquine; Biological: Rabies Vaccine |
| Atovaquone and Proguanil (Malarone) | Experimental | Malarone tablet for oral administration 250 mg atovaquone and 100 mg proguanil hydrochloride.
RabAvert rabies vaccine, at least 2.5 IU of rabies antigen. Receives: Drug: Atovaquone and Proguanil; Biological: Rabies Vaccine |
| Doxycycline | Experimental | 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. Receives: Drug: Doxycycline; Biological: Rabies Vaccine |
| Rabies | Active comparator | RabAvert rabies vaccine, at least 2.5 IU of rabies antigen. Receives: Biological: Rabies Vaccine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 6 weeks for Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Groups and at 4 weeks for Rabies Group
Secondary outcomes (3)
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.
Measured: 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.
Measured: 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.
Measured: Up to 8 weeks for Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Groups and up to 6 weeks for Rabies Arm
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Sep 2015 (estimated)
- Study start11 Nov 2016
- Primary completionAug 2018
- Study completionFeb 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for RabiesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 103 participants (actual)
Sponsor and investigators
- Lead sponsor
- State University of New York - Upstate Medical University
- Sponsor type
- University, hospital or other
- Collaborators
- Walter Reed Army Institute of Research (WRAIR), Kansas State University
- Responsible party
- Principal investigator, Timothy Endy, MD MPH, State University of New York - Upstate Medical University
- Investigators
- Timothy Endy, MD, Principal investigator, State University of New York - Upstate Medical University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02564471
- Sponsor's protocol ID
- 790117
- Acronym
- MALRAB
- Status last verified
- Apr 2021
- First submitted
- 29 Sep 2015
- Last updated
- 13 May 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
Endy TP, Keiser PB, Cibula D, Abbott M, Ware L, Thomas SJ, Polhemus ME. Effect of Antimalarial Drugs on the Immune Response to Intramuscular Rabies Vaccination Using a Postexposure Prophylaxis Regimen. J Infect Dis. 2020 Mar 2;221(6):927-933. doi: 10.1093/infdis/jiz558.
PubMed 31743394
Study at a glance
From the registry record, last updated by the sponsor on 13 May 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT02564471
- Acronym / sponsor ID
- MALRAB / 790117
- Conditions
- Rabies
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 103 participants (actual)
- Lead sponsor
- State University of New York - Upstate Medical UniversityUniversity, hospital or other
- Collaborators
- Walter Reed Army Institute of Research (WRAIR), Kansas State University
- Study start
- 11 Nov 2016 (actual)
- Primary completion
- Aug 2018 (actual)
- Study completion
- Feb 2019 (actual)
- First posted
- 30 Sep 2015 (estimated)
- Results
- Posted 13 Apr 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Chloroquine | Experimental | Drug: Chloroquine, Biological: Rabies VaccineChloroquine Phosphate tablet for oral administration 500 mg chloroquine phosphate (equivalent to 300 mg base) |
| Atovaquone and Proguanil (Malarone) | Experimental | Drug: Atovaquone and Proguanil, Biological: Rabies VaccineMalarone tablet for oral administration 250 mg atovaquone and 100 mg proguanil hydrochloride. RabAvert rabies vaccine, at least 2.5 IU of rabies antigen. |
| Doxycycline | Experimental | Drug: Doxycycline, Biological: Rabies VaccineDoxycycline 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. |
| Rabies | Active comparator | Biological: Rabies VaccineRabAvert rabies vaccine, at least 2.5 IU of rabies antigen. |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (13 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ChloroquineAlso: Chloroquine PhosphateFDA approve dosing schedule | Drug | Chloroquine |
| Atovaquone and ProguanilAlso: MalaroneFDA approve dosing schedule | Drug | Atovaquone and Proguanil (Malarone) |
| DoxycyclineAlso: Doxycycline HyclateFDA approve dosing schedule | Drug | Doxycycline |
| Rabies VaccineAlso: RabAvertFDA approve dosing schedule | Biological | Atovaquone and Proguanil (Malarone), Chloroquine, Doxycycline, Rabies |
Primary outcome
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
Time frame: 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).
3 secondary outcomes
GMT Over Protective Titer Prior to Third Dose of PCECV
Time frame: 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
Time frame: 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
Time frame: Up to 8 weeks for Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Groups and up to 6 weeks for Rabies Arm
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 May 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 31743394Endy TP, Keiser PB, Cibula D, Abbott M, Ware L, Thomas SJ, Polhemus ME. Effect of Antimalarial Drugs on the Immune Response to Intramuscular Rabies Vaccination Using a Postexposure Prophylaxis Regimen. J Infect Dis. 2020 Mar 2;221(6):927-933. doi: 10.1093/infdis/jiz558.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Timothy Endy, MD principal investigator
State University of New York - Upstate Medical University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Chloroquine, Atovaquone and Proguanil and Doxycycline in people with Rabies, run by State University of New York - Upstate Medical University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 May 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 13 Apr 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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 (time frame: 6 weeks for Chloroquine, Atovaquone and Proguanil (Malarone) and Doxycycline Groups and at 4 weeks for Rabies Group). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02564471, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 May 2021.