Clinical trial NCT04353271
Conditions: Covid 19 Corona Virus Infection
Keywords: covid 19 plaquenil hydroxychloroquine
Sponsor: University of South Alabama
Start date: 2020-04-17; Completion date: 2020-07-08
Enrollment: 3 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To test if the medication Hydroxychloroquine will decrease the amount of virus(as measured by PCR) , 7 days after initiation of therapy compared to control patients receiving placebo.

The study design is a randomized (5 days of medication v. 5 days of placebo) clinical trial initiated immediately after diagnosis in ambulatory health care workers at University of South Alabama Health, or in ambulatory USA patients. At 7 days after enrollment another nasopharyngeal swab will be taken to measure if the virus is still present. At 10 weeks we will measure immunity from Covid-19 using a single blood sample. It is a phase 2/3 clinical trial.

Detailed description:
Hydroxychloroquine (HCQ), which is a less toxic derivative of chloroquine (CQ), has been shown to be effective in inhibiting Covid-19 infection in vitro. The evidence from clinical research trials is sparse and has many flaws. Much of the Chinese experience with Chloroquine comes from a letter to the editor and a news briefing/conference held on February 15, 2020. The letter describes experience with more than 100 patients treated with CQ in multicenter clinical trials but the letter provides no quantitative data to back their claims. At least one non-randomized clinical trial has been performed in Europe. Covid-19 infected patients received 10 days of HCQ daily and underwent daily testing of viral loads from nasopharyngeal swabs. The subjects receiving HCQ were much more likely (P\<0.02) to clear their viral load than subjects who did not receive HCQ. The study had many flaws, which make the conclusions less valuable than rigorously designed randomized clinical trial. This study is designed as a randomized, blinded trial to either confirm or refute the efficacy of HCQ in early treatment of Covid19 infection to ameliorate disease severity, and reduce viral load.

Arms: arm 1: Subjects in this arm will receive the study drug arm 2: Subjects in this arm will take placebo for 6 days
Interventions: intervention 1: Hydroxychloroquine intervention 2: Placebo
Intervention descriptions: intervention 1: Hydroxychloroquine 800 mg initial dose then 6-8 hours later HCQ 600 mg, then 200 mg three times per day for 4 days. intervention 2: Placebo take 4 tabs, then 6-8 hours later take 3 tabs, then take 1 tab three times per day for 4 days.

Protocol documents:
Prot_SAP_000.pdf: 
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A Randomized Phase II Trial of Hydroxychloroquine In Covid-19 Kinetics 
(THICK) 
 
 
Principal Investigator:  
William Richards, M.D.  
Sub Investigators:   
Paul Rider, M.D 
Data and Safety Monitors:  John Vandewaa M.D. 
 
 
 
 
Eduardo Calderon M.D. 
 
Project Manager:  
 
Winona Blount, RN, MSN 
NCT Number: 
 
NCT04353271 
Protocol Number:   
USAH-1001-THICK 
Research Site: 
 
University of South Alabama 
Funding Sponsor: 
 
University of South Alabama College of Medicine  
 
 
Department of Surgery 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIALITYSTATEMENT 
 
This document is confidential and to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and the applicable independent ethics committees or 
institutional review boards. The contents of this document shall not be disclosed to others 
without written authorization from the University of South Alabama, William Richards, MD 
unless it is necessary to obtain informed consent from potential study participants. 


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TABLE OF CONTENTS 
1 
Introduction ........................................................................................................... 3 
2 
Study Design ......................................................................................................... 5 
2.1 
General Design ......................................................................................... 5 
2.1.1 Primary Outcome Variable ............................................................... 5 
2.1.2 Secondary Outcome Variables ........................................................ 5 
3 
Eligibility ................................................................................................................ 5 
3.1 
Inclusion Criteria ...................................................................................... 5 
3.2 
Exclusion Criteria ..................................................................................... 5 
4 
Outcome Measures............................................................................................... 6 
5 
Statistical Plan ...................................................................................................... 7 
5.1 
Sample Size Determination ..................................................................... 7 
5.2 
Statistical Methods ................................................................................... 8 
6 
Study Procedures ................................................................................................. 8 
7 
Subject Recruitment………………………………………… .. ……………………...10 
7.1 
Risks & Benefits ..................................................................................... 12 
8 
Data & Safety Monitoring Plan ........................................................................... 13 
9 
Adverse Events/SAEs ........................................................................................ 15 
10 
Data Management and Collection ..................................................................... 17 
10.1 Confidentiality ........................................................................................ 18 
10.2 Records Storage and Retention ............................................................ 18 
11 
Study Monitoring, Auditing and Inspecting ...................................................... 15 
12 
Budget ................................................................................................................. 19 
13 
Publication Plan .................................................................................................. 19 
14 
References .......................................................................................................... 20 
15 
Attachments ........................................................................................................ 22 
 


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Introduction:  
 
A recent review of Hydroxychloroquine (HCQ) use for Cvovid-19 infections concludes: “There 
is sufficient pre-clinical rationale and evidence regarding the effectiveness of chloroquine for 
treatment of COVID-19 as well as evidence of safety from long-time use in clinical practice for 
other indications to justify clinical research on the topic.” [1] 
 
Background:  
 
HCQ, which is a less toxic derivative of chloroquine (CQ), has been shown to be effective in 
inhibiting Covid-19 infection in vitro.  CQ and HCQ increase the pH of acidic intracellular 
organelles such as endosomes/lysosomes essential for membrane fusion, which inhibits Covid-19 
entry into the cell. [2]  [3]  
 
HCQ is FDA approved for treatment of Rheumatoid arthritis and lupus erythematosus. 
Oral absorption of HCQ in humans is very efficient. Furthermore, a safe dosage 6 to 6.5 
mg/kg/day of HCQ has been shown to generate serum levels of 1.4-1.5 micromolar in humans.  
Therefore, a safe oral dosage of HCQ will reach concentrations in tissues (liver spleen kidney 
and lung) that should inhibit Covid-19 infection. [3]  Indeed, a French study demonstrated mean 
HCQ serum concentration of 0.46 micrograms/ml + 0.2 in human subjects receiving HCQ 
standard doses for treatment of Covid-19. [4] 
 
Much of the Chinese experience with Chloroquine comes from a letter to the editor and a news 
briefing/conference held on February 15, 2020. The letter describes experience with more than 
100 patients treated with CQ in multicenter clinical trials. The authors claim “Chloroquine 
phosphate is superior to the control treatment in inhibiting the exacerbation of pneumonia, 
improving lung imaging findings, promoting a virus negative conversion and shortening the 
disease course”. The letter provides no quantitative data to back their claims. [2] Another 
Chinese study demonstrated both HCQ and CQ have in vitro antiviral activity and anti-
inflammatory effects but the HCQ is preferred because of its much better safety profile. They 
tested dosing schedule similar to that proposed herein and projected it would achieve effective 
treatment effects while preserving a good safety profile. These authors emphasize the need for a 
loading dose of HCQ to achieve faster clinical effect. [5] 
 
At least one non-randomized clinical trial has been performed in France. [4]  Covid-19 infected 
patients received 10 days of 600 mg of HCQ daily (divided doses of 200mg) with viral loads 
from nasopharyngeal swabs tested daily.  Patients who deteriorated received Azithromycin AZ at 
a dose of 500 mg on day 1 and 250 mg/day for 4 successive days.  Untreated patients from 
another hospital and inpatients who refused to be enrolled in the experimental protocol were used 
as negative controls.   
 
 


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Day 3 post inclusion % of negative PCR 
Day 6 post inclusion % of negative PCR 
Controls N=16 
1/16 =    6.3% 
2/16 = 12.5%  
HCQ N=14 
5/14 =    35.7% ^ 
8/14 = 57.1%  * 
 
The subjects receiving HCQ were much more likely (P<0.02) to clear their viral load than 
subjects who did not receive HCQ. This limited study had many flaws and should be 
corroborated with randomized, blinded trials to either confirm or refute the efficacy of HCQ is 
early treatment of Covid19 infection to ameliorate disease severity, and reduce viral load.  
 
Anticipated dates of study: March 27, 2020 – December 1, 2020 
 
Hypothesis:  
 
Oral Hydroxychloroquine taken in PCR positive patients/or health care workers with high 
suspicion of disease presence will increase the number of PCR negative patients, 7 days 
after initiation of therapy compared to control patients receiving placebo.  
 
Study design: 
 
ARM 
Intervention 
A: Experimental/Hydroxychloroquine 
Hydroxychloroquine 200mg tablets 
800mg orally once, then 600mg orally 6 -
8hours after first dose, then 200mg 3 times 
per day for 4 consecutive days 
 
B: Control Placebo  
Placebo 4 placebo tablets once, followed in 6 
to 8 hours by 3 tablets, then 3 tablets 3 times 
per day for 4 consecutive days 
 
 
Inclusion Criteria 
 
• Symptoms occurring within  3 days prior to patient presenting to USA Facility for PCR 
nasopharyngeal swab 
• Nasopharyngeal swab positive for Covid-19 infection and/or exposure and/or symptoms 
congruent with fever and cough 
• Male or Female age 19 to 89 years 
• Able to take oral medications 
• Patients not requiring hospitalization 


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• Provision of informed consent 
 
Exclusion Criteria: 
 
• Known history of EKG QTc prolongation abnormality   
• Contraindication or allergy to hydroxychloroquine  
• Retinal eye disease 
• Known glucose-6 phosphate dehydrogenase (G-6-PD) deficiency 
• Known chronic kidney disease, stage 4 or 5 or receiving dialysis 
• Weight < 40 kg 
• Current use of: hydroxychloroquine or cardiac medicines of: flecainide, Tambocor; 
amiodarone, Cordarone, Pacerone; digoxin or Digox, Digitek, Lanoxin; procainamide or 
Procan, Procanbid, propafenone, Rythmal) 
• Known hepatic disease (cirrhosis, hepatitis) 
• Active treatment for cancer (chemotherapy, radiation, surgery within 3 months 
• On immunosuppressive drugs steroids, antirejection medications. 
• Recipient of solid organ transplant 
• Pregnancy/breastfeeding 
• Past medical history Porphyria (may exacerbate disease) 
• PMH Psoariasis (can worsen disease) 
• No access to internet or email 
• Current suicidal thoughts according to Columbia scale 
• In the screening process before signing consent, subjects will be asked if they are 
suicidal.  If this response is yes, patients will be excluded from trial and directed to the 
National Suicide Prevention Lifeline: 1-800-273-8255. 
 
Primary Outcome Measures: 
1. NP swab viral load COVID19 Disease % of negative PCR NP swabs [ Time Frame: 7 
days] 
 
2. Ordinal Scale of COVID19 Disease Severity [ Time Frame: 6 days] 
 
Participants will self-report disease severity status as one of the following 5 options; no 
COVID19 illness (score of 1), COVID19 symptoms present according to USA Health screening 
tool (score of 2), COVID19 symptoms present according to USA Health screening tool  with 
hospitalization (score of 3), or COVID19 symptoms present according to USA Health screening 
tool with subject hospitalization and ICU care (score of 4), or COVID19 with death (score of 5). 
Increased scale score indicates greater disease severity. 
 
Outcome is reported as the percent of participants who fall into each category per arm. 
 
Secondary Outcome Measures: 
 
1. Incidence of Hospitalization [ Time Frame: 14 days] 


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Outcome reported as the number of participants in each arm who require hospitalization 
for COVID19-related disease. 
 
2. Incidence of Death [ Time Frame: 90 days] 
 
Outcome reported as the number of participants in each arm who expire due to COVID-
19-related disease. 
 
3. Incidence of Confirmed SARS-CoV-2 Detection [ Time Frame: 14 days] 
 
Outcome reported as the number of participants in each arm who have confirmed SARS-
CoV-2 infection. 
 
4. Incidence of Symptoms Compatible with COVID19 (possible disease) [ Time Frame: 90 
days] 
 
Outcome reported as the number of participants in each arm who self-report symptoms 
compatible with COVID19 infection. 
 
5. Incidence of All-Cause Study Medicine Discontinuation or Withdrawal [ Time Frame: 14 
days] 
 
Outcome reported as the number of participants in each arm who discontinue or withdraw 
medication use for any reason. 
 
6. Immunity to Covid-19 [Time frame: 6 + 2 weeks] 
 
Blood tests to determine level of immunity in each subject 
 
Power analysis: 
 
 Full enrollment in the study will occur when 58 subjects are enrolled into the study. 
 
Information used: From the Gautret study [4] the following estimates are available: 
Proportion of negative PCRs on day 6 in HCQ treated patients = 0.571 
Proportion of negative PCRs on day 6 in patients from control group = 0.125 
That is the difference of 0.446 was observed in two group proportions. 
 
Power analysis: Using 5% type I error rate and 80% or 85% power to estimate the difference of 
0.40, 0.45, 0.50 (i.e. 40%, 45%, 50%) in the proportion of negative PCRs in two groups 
(treatment and control) the following sample sizes are needed from each group.  
 
 


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Difference to estimate 
Power = 0.80 
Power = 0.85 
0.40 
19 
22 
0.45 
15 
17 
0.50 
12 
14 
 
We will use a difference to estimate of 0.4 and a power calculation of 0.80, which indicates 19 
patients in each arm needed to achieve a 5% type I error rate.   
 
A significant limitation of the study is our current turnaround on the PCR nasopharyngeal swab 
test which is 96 hours awaiting test results.  It is important to start the healthcare workers with 
significant exposure and with symptoms started on medication; before they deteriorate, therefore 
we will enroll some patients without actual confirmation of a positive PCR test. We anticipate 
that testing using an in house USA clinical pathology test will be available within 2-4 weeks and 
provide 6-hour turn around. Until that, time we estimate 25% of health care workers who have an 
exposure and symptoms will have a negative PCR. Therefore, we will increase the number of 
subjects in each arm of the study in order to account for ineligibility or who dropout from the 
studies. We estimate 25% of subjects enrolled in the study will not return for day 6 
nasopharyngeal swab.  Patients may be feeling so well that they decline to return or they are 
hospitalized at a non-USA hospital and unable to obtain a swab on day 6. The number needed in 
each group will be increased by 50% to ensure that we have 19 patients in each group (N=29 
each group) to ensure that the study is adequately powered.   
 
Fisher’s test will be used to compare proportions from two groups. 
 
Study Procedures 
 
Schedule of Events 
 
 
Pre- Treatment 
Period 
 
 
Day 6 
 
Day 7 
 
Day 30 
 
 
End of Study 
6 Weeks 
Consent 
X 
 
 
 
 
PCR NP Swab St 
X 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
Medical History  
X 
 
 
 
 
Severity Of 
Symptom Survey 
X 
X 
 
X 
 
Repeat PCR NP 
Swab 
 
 
X 
 
 
Lab Draw for 
immunology studies  
 
 
 
 
X 
 
 
 


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Consent Process  
 
1. Informed Consent will be thoroughly explained over the phone. Consent will then be 
emailed to subject.  If the subject is an employee, subject will return consent via their 
employee email. If the subject is a non-employee, the subject will sign his or her 
informed consent in person before any trial related processes are to begin.  To reduce 
transmission of Covid-19 we will also be utilizing other options- see options 2 and 3. 
 
2. To avoid transmission of Covid-19, it is preferable by the PI and best practice that a 
physical paper consent be eliminated. As an alternative to paper, the subject will sign his 
or her informed consent via Redcap, which will deliver an unsigned informed consent to 
the subject through email and signed consent back to Research Clinical Coordinator 
through email.  Subject will be verified via photo ID upon arrival at testing site on Day 1 
before any trial related processes begin or medication is dispensed. 
 
3. In the event we are not able to utilize Redcap or email- the subject will give verbal 
consent to two Research Clinical Coordinators over the phone to avoid a physical paper 
consent, thereby avoiding transmission of Covid-19.  The signatures of both Research 
Clinical Coordinators who receive verbal consent from subject will suffice/replace 
subject’s physical signature.  Reason patient is unable to sign should be documented as 
prevention of transmission of Covid-19. Subject will be verified via photo ID upon 
arrival at testing site on Day 1 +/- 1day before any trial related processes begin or 
medication is dispensed.  
 
Randomization:  
 
Double Blind Randomization will be allocated 1:1 between placebo and Hydroxychloroquine 
arms. Dr. Madhuri Mulekar, Chair of Mathematics and Statistics at the University of South 
Alabama, will create randomization schedule. Chronological patient IDs will be provided to the 
MCI outpatient pharmacy. Brittney Carden, PharmD will be responsible for opening the 
randomization assignment and dispensing the appropriate drug (hydroxychloroquine or placebo).  
All parties are to remain blinded except Brittney Carden, PharmD 
 
Treatment Schedule:  
 
Subjects will be randomized to Arm A or B 
 
ARM A: Experimental Arm 
 
• Enrolled subjects randomized to experimental arm (Arm A), will receive the study drug 
hydroxychloroquine. 
 
• Subjects will take investigational drug hydroxychloroquine 200mg tablets, 4 tabs orally, 
once.  Six to eight hours after the first dose, 3 tablets (each 200mg) will be taken.  After 
the first day, subjects will take 1 tab (200mg) three times daily for 4 consecutive days (4 


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days in a row). 
 
 
• On day 6 subjects will receive a phone call from the Clinical Research Coordinator and 
be presented with health survey.  
 
• On day 7 subjects will have a scheduled follow-up at a USA Health Facility for repeat of 
nasopharyngeal swab. 
  
• At 30 days +/- 3 days subject will receive phone call from Clinical Research Coordinator 
and be presented with a health survey (See Appendix A). 
 
• There will be a 6-week +/- 2 weeks blood-draw to test for Covid-19 antibodies.  Subjects 
will arrive to Mastin Clinic for blood draw via Clinical Research Coordinator.  Subjects 
will also be presented with health screen survey identical to health screen survey on day 6 
(See Appendix A). 
 
ARM B: Control Arm 
 
• On day 1 +/- 1 day Subjects will take placebo-hydroxychloroquine 200 mg tablets, 4 tabs 
orally, once.  Six to eight hours after the first dose, 3 tablets will be taken.  After the first 
day, subjects will take 1 tab (200mg) three times daily for 4 consecutive days (4 days in a 
row). 
 
• On day 6 subjects will receive a phone call from the Clinical Research Coordinator and 
be presented with a health survey (See Appendix A).  Increased scale score represents 
greater symptom severity.  
 
• On day 7 subjects will have a scheduled follow-up at USA Health screening tent for 
repeat of nasopharyngeal swab.  
 
• At 30 days +/- 3 days subject will receive phone call from Clinical Research Coordinator 
and be presented with a health survey (See Appendix A). 
 
• There will be a 10-week +/- 2 weeks blood draw to test for Covid-19 antibodies.  
Subjects will arrive to Mastin Clinic for blood draw to be done by the Clinical Research 
Coordinator.  Subjects will also be presented with health screen survey identical to health 
screen survey on day 6 (See Appendix A). 
 
Recruitment and Compensation/Reimbursement 
 
All subjects that meet enrollment criteria are eligible to enroll in the study as long as patient 
meets inclusion/exclusion criteria. Confirmation of diagnosis will be based on laboratory testing, 
PCR nasopharyngeal swab.  In regards to all subjects, a confirmatory positive PCR 
nasopharyngeal swab results are not needed to start treatment.  Our lab testing process of NP 


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swabs is taking 24 to 96 hours to return a positive result. In the case of a patient with high 
clinical suspicion based on exposure or symptoms per USA approved screening questionnaire 
(See Appendix B), the patient will also be enrolled prior to confirmatory testing.  Please see 
inclusion section for other requirements of enrollment.  
 
Subject will receive compensation for time and travel: 
 
• There will be one $25.00 gift card for return to USA Health Facility and completion of 
second nasopharyngeal swab on day 7. 
• There will be one $25.00 gift card for return to Mastin Clinic at 6 weeks visit post lab 
draw to compensate for their time and effort driving to USA.   
• If subject completes all aspects of the trial, the subject is eligible for the (2) gift cards 
stated above, respectively, in the total amount of $50.00. 
 
Drug Information:  
 
Hydroxychloroquine 
 
Other names:  
PLAQUENIL ® 
Classification: 
Aminoquinoline; antimalarial agent  
Molecular Weight: 433.95 
CAS Number:  
118-42-3 
 
Mode of Action:  Hydroxychloroquine has been shown to be effective against Covid-19 
infection in vitro.   Increases the pH of acidic intracellular organelles such as 
endosomes/lysosomes essential for membrane fusion, which inhibits Covid-19 entry into 
the cell. {Gao, 2020} {Liu, 2020}; impairs complement-dependent antigen-antibody 
reactions 
 
Description:  Hydroxychloroquine is a 4-aminoquinoline typically used in the treatment 
of malaria, rheumatoid arthritis, and lupus erythematosus. 
 
How Supplied:  Hydroxychloroquine should be ordered per standard of care methods. 
The investigators will supply hydroxychloroquine for this study. 
 
Preparation:  Crystalline solid, tablet, as sulphate; each tablet contains 200 mg 
hydroxychloroquine sulfate; equivalent to 155 mg base 
 
Storage:  Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C 
(59°F to 86°F). Protect from light 
 
Stability:  Stable for 2 years at specifications above 
 
Route of Administration:  Oral 
 


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Method of Administration: Subjects will take Hydroxychloroquine 200mg tablets- 4 
tabs orally once, then 3 tabs orally 6 -8hours after first dose, then 1 tab three times per 
day for 4 consecutive days. Take with food or milk.  
 
Patient Care Implications:  Refer to the protocol for information on evaluation and 
management of potential adverse effects 
 
Sodium Chloride (placebo) 
 
Other names:  n/a 
Classification:  Electrolyte supplement, oral; sodium salt 
Molecular Weight:  n/a 
CAS Number:  n/a  
 
Mode of Action:  n/a; placebo 
 
Description:  Placebo drug 
 
How Supplied:  Placebo should be ordered per standard of care methods. The 
investigators will supply the placebo for this study. 
 
Preparation:  Tablet, oral: sodium chloride: 1.0 gram 
Storage:  Store at room temperature 
 
Stability:   n/a 
 
Route of Administration:  Oral tablet 
 
Method of Administration:  Subjects randomized to control arm will take 4 placebo 
tablets once, followed in 6 to 8 hours by 3 tablets, then 1 tablet three times per day for 4 
consecutive days.  
 
Patient Care Implications:  Refer to the protocol for information on evaluation and 
management of potential adverse effects. 
 
Risks:   
 
This clinical trial has greater than minimal risk. 
Potential Adverse Drug Reactions (ADRs) 
 
GI upset (take with food), dizziness, headache, anxiety, lack of appetite, weight loss, diarrhea, 
skin discoloration, hair loss, nausea/vomiting, abdominal pain, retinopathy (concentration 
dependent; more common with prolonged durations [> 1-5yrs] of therapy), rash/pruritus, 
myopathy, cardiomyopathy, bone marrow suppression (agranulocytosis, anemia, aplastic anemia, 
leukopenia, thrombocytopenia), hypoglycemia, suicidal ideation. 
 


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Benefits 
 
HCQ may reduce the viral load at day 7 which will reduce the subject’s symptoms and severity 
of disease. Reduction of the viral load also reduces the chance that subjects will spread the 
disease to friends, family or the general population. Early treatment thus would interrupt the 
transmission of disease in the community and end the epidemic. 
  
Data Safety Monitoring Plan  
 
Type of Research Data or Events to be Monitored: 
 
We will capture study accruals, protocol deviations, protocol violations, unanticipated problems, 
and adverse events. On day 6 after initiation of the study we will call the patient to confirm next 
day drive thru Nasopharyngeal (NP) swab testing for viral load and, we will also complete the 
phone questionnaire documenting self-reported clinical status. We will ascertain for adverse 
events on day 6 and report serious adverse events including hospitalization with exacerbation of 
disease. On day 30, we will complete a phone questionnaire documenting self-reported clinical 
status. We will call the subject at 8 weeks post initiation of study to confirm clinic appointment 
and to document adverse events. At the 6-week time, we will draw blood for the antibody 
testing, ascertain occurrence of adverse events and answer a question about your health. We do 
not anticipate any adverse events occurring after the 10-week time.  
 
Methods and Frequency of Analysis: 
 
We will formally assess patient safety on day 6, day 30 and week 10. The department of surgery 
has published phone numbers for patient access and care. They can reach the on call physician 
and reach the PI or his designee 24/7/365 by phone. The on call physician will call the PI to 
report serious adverse events.  
 
We will perform an interim analysis after 30 patients are enrolled to evaluate the efficacy, data 
acquisition and adherence to protocol.  A summary of this information will be provided to the 
physicians (ID experts JV, EC, and Clinician PR) who will monitor the safety of the subjects, as 
well as, the DSMB.  
 
Person(s) Responsible for Data Monitoring: 
 
The research nurse working closely with the physicians (ID experts JV, EC, and Clinician PR) 
shall be responsible for reporting adverse events, protocol violations to the PI who would 
investigate and report serious adverse events to the IRB and FDA. We will use standard 
reporting to the FDA for adverse events.  
 
Specify the name and role of the person responsible for submitting reports of unanticipated 
problems, adverse events, protocol deviations and protocol violations to the IRB and indicated 
entities (e.g. NIH, FDA, sponsor).  When the investigator is the sponsor of the IND/IDE, include 
the plan for reporting adverse events to the FDA and, when applicable, to investigators at other 
sites. 


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Reporting Unanticipated Problems, Adverse Events, Protocol Deviations and 
Protocol Violations: 
 
Unanticipated problems, adverse events, protocol deviations and protocol violations will be 
reported on an ongoing basis per protocol. A summary of events will be formally reported after 
interim analysis and within 30 days after the end of the study.  
 
Procedures and Time Frames for Communicating Outcomes: 
 
An interim analysis after 30 patients are enrolled to evaluate the efficacy data and adherence to 
protocol will be performed.  Review and completion of the report will take no more than 2 
weeks. The interim analysis is anticipated to occur at the halfway time point of the study. Final 
analysis will be obtained within 1 month of the last subject visit for blood draw.  
 
Emergency Actions: 
 
Unless there is an emergency, all parties are blinded with the exception of the pharmacist  
 
Unblinding 
 
The PI will be unblinded to the arm of the study if there is a serious adverse event deemed 
possibly related to study medications ie sudden death, or life-threatening allergic reaction. The 
unblinded pharmacist will be contacted to provide the PI with the randomization envelope for the 
subject. 
 
Stopping Rules 
 
In the event a subject is enrolled in trial based on exposure and/ or symptoms and the PCR 
nasopharyngeal swab results negative,  the patient will be contacted to determine if there are any 
adverse events related to the study medication.  
 
The study will be evaluated for safety and efficacy when 30 subjects have been randomized. 
Study will stop accruing if there is evidence of Serious Adverse Events (death, or serious life-
threatening complications) thought to be caused by Hydroxychloroquine; for example, cardiac 
event with prolonged QTc interval. Enrollment will not be interrupted if the subject is taking 
placebo when SAE occurs. The study will also be stopped after interim analysis shows a 
statistically significant (P<0.01) reduction in % negative PCR tests at 6 days post inclusion. The 
safety monitors (i.e. the physicians (ID experts JV, EC, and Clinician PR) will be unblinded and 
they will determine if there is need to stop the study completely if SAE is related to the study.  
 
Precautions for Maintaining Data Integrity: 
 
On a weekly basis the PI will review with study staff adherence to the IRB-approved protocol 
and review validity and integrity of the data collected.  


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Study Monitoring, Auditing and Inspection: 
 
The Office of Research Compliance will perform will conduct a monitoring visit after enrollment 
of the fifth subject. Continuing monitoring visits will occur every four weeks during active 
recruitment. A monitoring report will be provided to the PI, Director of Clinical Trials and the 
USA IRB.  
 
Adverse Events/Serious Adverse Events 
 
Definition of an Adverse Event (AE)  
 
Any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. Therefore, an AE can be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product (attribution of unrelated, unlikely, possible, probable, or definite). 
(International Conference on Harmonization [ICH], E2A, E6). Any worsening (i.e., any 
clinically significant adverse change in frequency and/or intensity) of a preexisting condition that 
is temporally associated with the use of the investigational product, is also an adverse event. 
 
Definition of a Serious Adverse Event (SAE)  
 
A serious adverse event is any adverse event occurring at any dose or during any use of 
investigational product that: 
 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is another important medical event  
 
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause under study that occurs to any subject from first day of study drug administration through 
90 days following cessation of treatment, or the initiation of new anti-cancer therapy, whichever 
is earlier, whether or not related to the investigational product, must be reported within 24 hours 
to the Coordinating Center at the University of South Alabama and Principal Investigator. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to either product that is brought to the attention of the investigator at any 
time outside of the time period specified in the previous paragraph also must be reported 
immediately to the Coordinating Center at the University of South Alabama and Principal 
Investigator. 
 
SAE reports and any other relevant safety information are to be forwarded to the Coordinating 
Center at the University of South Alabama at kledbetter@health.southalabama.edu. All subjects 


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with serious adverse events must be followed up for outcome. 
 
A copy of all 15 Day Reports and Annual Progress Reports will be submitted as required to the 
FDA.  
 
Evaluating Adverse Events 
 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event which 
changes CTCAE grade over the course of a given episode will have each change of grade 
recorded on the adverse event case report forms/worksheets. All adverse events regardless of 
CTCAE grade must also be evaluated for seriousness. All AE/SAE will be reported, regardless 
of the grade.  
 
Data Management and Collection 
 
Study data will be collected and managed using REDCap (Research Electronic Data 
Capture).  REDCap is a secure, web application designed to support data capture for research 
studies, providing user-friendly web-based case report forms, real-time data entry validation (e.g. 
for data types and range checks), audit trails and a de-identified data export mechanism to 
common statistical packages (SPSS, SAS, Stata, R/S-Plus).  REDCap also provides a powerful 
tool for building and managing online surveys. The research team can create and design surveys 
in a web browser and engage potential respondents using a variety of notification methods. 
REDCap data collection projects rely on a thorough study-specific data dictionary defined in an 
iterative self-documenting process by all members of the research team with planning assistance 
from the system owner. The iterative development and testing process results in a well-planned 
data collection strategy for individual studies. REDCap provides a secure, web-based application 
that is flexible enough to be used for a variety of types of research, provide an intuitive interface 
for users to enter data and have real time validation rules at the time of entry. The system was 
developed at Vanderbilt University but is now part of an international and multi-institutional 
consortium which includes the UAB Center for Clinical and Translational Science, of which the 
investigators of this proposal are members. REDCap has been disseminated for use locally at 
other institutions and currently supports 2521 academic/non-profit consortium partners in 116 
countries on six continents and over 600,000 research end-users (www.project-redcap.org).   
 
REDCap system is hosted University of South Alabama secure data center. Only IRB approved 
research team members will have access to the REDCap data platform. Each team member will 
be granted access to the REDCap data system through a secure and unique login. The database 
and the associated components are also part of a redundant backup strategy. Network 
transmissions (data entry, survey submission, web browsing, etc.) in REDCap are protected. The 
award winning and widely followed implementation is in accordance to NIST 800-53 guidelines 
and has been vetted by all key approving parties at University of South Alabama. REDCap is 
also the only instance to have received an authorization to operate (ATO) from NIH/NHLBI. 
 
Data collection for this study will be done through REDCap.  All forms must be completed and 
submitted in a timely fashion electronically.  Forms will be reviewed by the study committee for 


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completeness and by the DSMB for adverse event reporting.   
 
Record Retention 
 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
Government agency regulations and directives require that all study documentation pertaining to 
the conduct of a clinical trial must be retained by the study investigator.  In the case of a study 
with a drug seeking regulatory approval and marketing, these documents shall be retained for at 
least two years after the last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept on file until 
seven years after the completion and final study report of this investigational study. 
 
Study Budget:  
 
This trial will be funded by the University of South Alabama, College of Medicine Department 
of Surgery research account.  
 
Publication Plan:  
 
Publication will be considered once the data analysis is complete.  
 
 


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APPENDIX A 
SELF REPORTED SEVERITY OF SYMPTOMS SURVEY 
Increased scale score indicates greater symptom severity.  To be reported at Day 0, Day 6, 30 
days, and 6 weeks   
Score of 1 
No COVID-19 illness 
 
Score of 2 
COIVD-19 symptoms present according USA Health screening tool  
 
Score of 3 
COVID-19 symptoms present according to USA Health screening tool  
with hospitalization 
 
Score of 4 
COVID-19 symptoms present according to USA Health screening tool 
with hospitalization and ICU care  
 
Score of 5 
COVID-19 with death 
 
 
 
 


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APPENDIX B 


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