COVID-19 Clinical Trial
Official title:
Military COVID-19 Hydroxychloroquine Pre-exposure and Post-exposure Prophylaxis Study
There is significant interest throughout the United States in performing a well-designed
study to evaluate whether there is value in using Hydroxychloroquine or Chloroquine as a
pre-exposure prophylaxis or post-exposure prophylaxis regimen for COVID-19 patients and at
risk personnel.
We have designed a prospective double blinded randomized controlled clinical trial to answer
just this question.
The study will consist of 4 arms:
1. A placebo control arm of 450 patients
2. A low dose prophylaxis arm of 450 patients treated with 200mg Hydroxychloroquine daily
3. A high dose prophylaxis arm of 450 patients treated with 400mg Hydroxychloroquine daily
4. A post-exposure arm of 100 patients treated with 400mg Hydroxychloroquine daily for 7
days.
Since December of 2019 COVID-19 is a rapidly spreading virus presently infecting over
1,000,000 individuals worldwide, over 250,000, and over 6,000 deaths in the United States as
of 03/31/2020.1
Presently there are no FDA approved treatments or immunizations against COVID-19; however,
the FDA has granted an EUA for the treatment of hospitalized patients with
hydroxycholorquine.2
Depending on case series the expected case fatality rate for COVID-19 without treatment is
between 0.5-10% with the most likely range between 1-3% which is >10x the expected case
fatality rate of seasonal influenza.
Several studies have reported anecdotal and promising preliminary data on the treatment of
Coronavirus. Based on the limited evidence from these studies, pre-exposure prophylaxis, or
post-exposure prophylaxis may be beneficial.3-21
Due to the nature of the work in the Pentagon multiple critical individuals are unable to
practice effective social distancing measures in order to ensure their mission critical jobs
for continuity of government and national defense.
Any medication, treatment protocol, or epidemiological control measure which appears safe
preliminarily and can be implemented must be tested and put into practice immediately in
order to protect senior leaders and other mission critical personnel.
1. https://www.worldometers.info/coronavirus/country/us/
2. EUA Hydroxychloroquine sulfate Health Care Provider Fact Sheet, version date 3/28/2020 -
attached in study documents.
3. Colson P, et al. Chloroquine and hydroxychloroquine as available weapons to
fightCOVID-19. International Journal of Antimicrobial Agents
https://doi.org/10.1016/j.ijantimicag.2020.105932
4. Zhou D, et al. COVID-19: a recommendation to examine the effect of hydroxychloroquine in
preventing infection and progression, Journal of Antimicrobial Chemotherapy,
https://doi.org/10.1093/jac/dkaa114
5. Multicenter collaboration group of Department of Science and Technology of Guangdong
Province and Health Commission of Guangdong Province for chloroquine in the treatment of
novel coronavirus pneumonia. Expert consensus on chloroquine phosphate for the treatment
of novel coronavirus pneumonia Chinese Journal of Tuberculosis and Respiratory Diseases
43, no. 0. https://www.ncbi.nlm.nih.gov/pubmed/32075365.
6. Yao X, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of
Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2
(SARS-CoV-2). Clin Infect Dis. 2020 Mar 9. https://www.ncbi.nlm.nih.gov/pubmed/32150618.
7. Cortegiana, et al. A systematic review on the efficacy and safety of chloroquine for the
treatment of COVID-19. J Crit Care. 2020 Mar 10.
https://www.sciencedirect.com/science/article/pii/S0883944120303907.
8. Hydroxychloroquine clinical trial (NCT04261517).
https://clinicaltrials.gov/ct2/show/NCT04261517?cond=covid-19&draw=8.
9. WHO. Clinical management of severe acute respiratory infection when novel coronavirus
(nCoV) infection is suspected. Accessed 2020 Mar 12.
https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-
infection-when-novel-coronavirus(ncov)-infection-is-suspected.
10. CDC. Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus
Disease (COVID-19). Accessed 2020 Mar 12.
https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html
.
11. Gross AE, Bryson ML. Oral Ribavirin for the Treatment of Noninfluenza Respiratory Viral
Infections: A Systematic Review. Ann Pharmacother. 2015 Oct;49(10):1125-35.
https://www.ncbi.nlm.nih.gov/pubmed/26228937.
12. Arabi YM, et al. Ribavirin and Interferon Therapy for Critically Ill Patients With
Middle East Respiratory Syndrome: A Multicenter Observational Study. Clin Infect Dis.
2019 Jun 25. https://www.ncbi.nlm.nih.gov/pubmed/31925415.
13. Mo Y, Fisher D. A review of treatment modalities for Middle East Respiratory Syndrome. J
Antimicrob Chemother. 2016 Dec;71(12):33403350.
https://www.ncbi.nlm.nih.gov/pubmed/27585965.
14. Darunavir/cobicistat clinical trial (NCT04252274).
https://clinicaltrials.gov/ct2/show/NCT04252274.
15. Wang M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel
coronavirus (2019-nCoV) in vitro. Cell Research. 2020 30;269-71.
https://www.nature.com/articles/s41422-020-0282-0.
16. Gamino-Arroyo AE, et al. Efficacy and Safety of Nitazoxanide in Addition to Standard of
Care for the Treatment of Severe Acute Respiratory Illness. Clin Infect Dis. 2019 Dec
69;11:1903-11. https://academic.oup.com/cid/article/69/11/1903/5308603.
17. Yao TT, et al. A Systematic Review of Lopinavir Therapy for SARS Coronavirus and MERS
Coronavirus-A Possible Reference for Coronavirus Disease-19 Treatment Option. J Med
Virol. 2020 Feb 27. https://www.ncbi.nlm.nih.gov/pubmed/32104907.
18. Young BE, et al. Epidemiologic Features and Clinical Course of Patients Infected With
SARS-CoV-2 in Singapore. JAMA. 2020 Mar 3.
https://jamanetwork.com/journals/jama/fullarticle/2762688
19. Li Y, et al. Extraordinary GU-rich single-strand RNA identified from SARS coronavirus
contributes an excessive innate immune response. Microbes Infect. 2013 Feb;15(2):88-95.
https://www.ncbi.nlm.nih.gov/pubmed/23123977
20. Xiaoling X, et al. Effective treatment of Severe COVID-19 Patients with Tocilizumab.
[Pre-print - not peer reviewed]. http://chinaxiv.org/abs/202003.00026.
21. NephJC (nephrology online journal club) detailed review with links to society
statements. Accessed 2020 Mar 16. http://www.nephjc.com/news/covidace2.
The primary aim of this study is to determine whether pre-exposure prophylaxis decreases the
incidence of COVID-19 infections amongst personnel, and the secondary aim is to determine
whether post-exposure prophylaxis decreases the severity of illness and speeds the return to
work of personnel.
The Pentagon Medical Facilities consist of 2 separate medical clinics and 2 separate dental
clinics that collaborate on daily activities. Operational personnel with special medical
requirements such as aviators and Personnel Reliability Program (PRP) personnel are typically
seen in the Pentagon Flight Medicine Clinic while other personnel are seen in the DiLorenzo
Tricare Health Clinic Pentagon.
Based on the EUAs for hydroxychloroquine & chloroquine, which are in critical national
shortage, and inpatient treatment protocols, hydroxychloroquine and chloroquine show
potential for treatment of patients hospitalized for COVID-19. We suspect that treatment of
early or asymptomatic exposed patients with chloroquine may decrease infection rates or limit
infection severity if pre-treated or treated early
Describe all the data variables, information to be collected, the source of the data, and how
the data will be operationally measured.
Study Procedures:
Inclusion criteria:
All mission critical personnel enrolled to the DiLorenzo Tricare Health Clinic or Pentagon
Flight Medicine Clinic unable to telework or appropriately socially distance with access to
the Pentagon during the declared public health crisis.
Exclusion criteria:
Known recovered COVID-19 patient, G6PD deficient individuals, individuals with significant QT
abnormalities, non-compliant patients, and patients who refuse randomization or consent.
Recruitment by Arms:
1. 2, 3. Individuals will be approached by protocol staff and any other staff added to the
protocol after initial submission during their screening for clinical visits or access
screening to critical spaces. They will be asked 2 questions:
a. Are you aware of an ongoing study within the Pentagon attempting to determine the
efficacy of a medication to prevent or treat COVID-19 infections?
i. If the individual answers yes:
a. Have you already elected or are you interested in participating?
i. If yes they are or are interested in participating they will be referred for
enrollment as appropriate.
ii. If not they will be thanked for their time.
ii. If the individual answers no:
a. Would you like to learn more or are you interested in enrolling?
i. Yes: Referred for enrollment.
ii. No: They will be thanked for their time.
4. PIs and AIs who are seeing patients for possible COVID-19 exposure or who have tested
positive as part of their routine clinical duties will offer enrollment to arm 4 these
individuals. At their first visit.
Consent:
Informed and appropriately witnessed consent* as required will be obtained by the PI or any
other AI added in subsequent modifications to the protocol. Due to telemedicine and social
distancing with the ongoing crisis this will be by distance mechanisms including digital
versus wet signature as clinically indicated based on the situation to minimize patient and
provider risks.
Patients will be assigned sequential patient identifier numbers during their consent process
for tracking purposes.
Initial procedures for safety monitoring including CBC, CMP, UA, G6PD testing (if prior
records unavailable), and EKG (if prior records unavailable) will be obtained after consent.
Assignment to groups 1, 2, or 3:
Patients will be randomized to groups 1-3 by a random number generators' results
(https://www.google.com/search?sxsrf=ALeKk03SHGo_yHevMbw4jIPVd85kc7e8Sg%3A1586372945822&sourc
e=hp&ei=USGOXqqgL6mGytMPo-268Ag&q=random+number+1-3&oq=random+nu&gs_lcp=CgZwc3ktYWIQAxgEMgUIA
BCDATICCAAyAggAMgIIADICCAAyAggAMgIIADICCAAyAggAMgIIADoECCMQJzoFCAAQkQJKJAgXEiAwZzE3NGcxNjlnMT
czZzc4ZzEwNmc5N2c5OGc4N2c4NUoXCBgSEzBnMWcxZzJnMWcxZzFnMWcxZzFQvQJYhxRg4zdoAXAAeACAAaEBiAH3B5I
BAzcuM5gBAKABAaoBB2d3cy13aXo&sclient=psy-ab) pre-recorded in a sealed plain envelope.
Medication retrieval:
The patient will then present to the DTHC pharmacy with their envelope and copy of their
enrollment consent to retrieve their medications. The pharmacist will open their envelope and
hand them medication 1, 2, or 3 as appropriate, and record their study number and group
number on a running spreadsheet maintained without PII in the pharmacy.
Patients will provide their study number to the pharmacy for any refills during the duration
of the study.
If an individual is on pre-exposure prophylaxis and develops COVID-19 they will continue on
treatment through the post-exposure prophylaxis window of 7 days on the dose they were
assigned at randomization.
Records collection:
Patient records will be queried in five ways: 1. At study enrollment 2. During consent
patient's will be asked to inform study personnel if they become sick or exposed to COVID-19;
patients will present with concerns 3. Monthly records reviews will be conducted to determine
if patients have become positive or are displaying signs of COVID-19 4. When the study
personnel are informed by public health officials of a positive COVID-19 patient assigned to
the Pentagon 5. When the declared public health emergency is over or the study ends (at its 1
year anniversary if the public health emergency has not ended).
Results will be retrieved from AHTLA, CHCS, request to treating civilian providers for care
outside the MHS, Essentris, and MHS imaging systems such as Impax.
Records collection will include as appropriate:
1. Date of exposure - to determine optimal timing of post-exposure prophylaxis during data
analysis.
2. Date of positive test - to determine optimal timing of post-exposure prophylaxis on data
analysis.
3. Medical comorbidities as they are known or become known including HTN, DM, Male Gender,
Age, Pulmonary Disease, Health Care Worker / First Responder, and/or known cardiac
disease. - to control and test for cofounding conditions as well as risk stratify
4. CXR results, Chest CT results, Intracranial Imaging results, cardiac testing, CBCs,
CMPs, COVID-19 test results, Infectious Disease notes, Pulmonary notes,
Cardiology/Cardiac surgery notes, and Neurology notes. - to control and test for
cofounding conditions as well as risk stratify. To determine whether an individual is
safe to enroll and receive study medications. To determine if an individual under
therapy has become infected and guage severity of the infection. All imaging being
performed is for standard of care and not study purposes.
5. Date of symptom onset - to determine optimal timing of post-exposure prophylaxis during
data analysis. To determine time to event.
6. Date of resolution - to assess effects of medication treatment on duration and severity
of disease.
7. All medications that the patient is on or has been on within the proceeding 1 month - to
assess for possible complications or medication interactions.
8. Hospitiization records, particulary records with regards to ICU admission, ICU
discharge, need for supplemental oxygen, length of stay, ICU length of stay, and/or need
for mechanical ventilation - to properly assess severity, disease duration, and course
for secondary outcome analysis.
9. Date of treatment start - to assess for optimal timing of initiation of secondary
prophylaxis or time to onset of symptoms after prophylaxis.
10. Date of treatment termination - to assess for relapses or worsening timing after
cessation of treatment.
- Witness:
"In order to conduct human research in this Commonwealth of Virginia, informed consent must
be obtained if the person who is to be the human subject is as follows:(i) capable of making
an informed decision, then it shall be subscribed to in writing by the person and witnessed;
or (ii) incapable of making an informed decision at the time consent is required, then it
shall be subscribed to in writing by the person and witnessed. Therefore the "impartial
witness" section in the consent form will be used for all subjects consented in the
Commonwealth of Virginia.
Responsibilities of the impartial witness include the following:
- Read the informed consent and all written materials given to the subject
- Confirm the subject was presented sufficient information to assure that the subject was
truly informed
- Sign and date the informed consent form after the informed consent and any other written
information provided to the subject is read and explained.
A signature from the impartial witness will serve as documentation of this process within the
subject's study file. The subject will also need to sign and date or mark the informed
consent showing appropriate consent for participation."
;
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