Conditions: Coronavirus Corona Virus Infection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 39
Healthy volunteers: yes

Brief summary:
The proposed hypothesis is that high doses of hydroxychloroquine (HCQ) for at least 2 weeks can be effective antiviral medication both as a treatment in ambulatory patients and prophylaxis/treatment in health care workers because it impairs lysosomal function and reorganizes lipid raft (cholesterol and sphingolipid rich microdomains in the plasma membrane) content in cells, which are both critical determinants of Emerging Viral Disease (EVD) infection. This hypothesis is based on a growing literature linking chloroquine to antiviral activity. It is estimated that enough information exists to launch a clinical trial of hydroxychloroquine for COVID-19.

Detailed description:
Sub-Study 1: COVID-19 patients in self-quarantine. Group 1: Hydroxychloroquine 400 mg bid (two 200 mg tablets taken twice a day; totaling 800 mg per day) for two weeks; Group 2: Placebo 2 pills twice a day for two weeks

Sub-Study 2: Asymptomatic health care worker prophylaxis. Group 1: Hydroxychloroquine 600 mg once a day (three 200 mg tablets taken once a day) for up to 2 months; Group 2: Placebo 3 pills once a day for up to 2 months; cross-over from placebo to HCQ 600 mg once a day is allowed upon confirmatory diagnosis for COVID-19.

PRIMARY OBJECTIVES:

Sub-Study 1 (Patients tested for COVID-19 who meet symptomology and age requirements for eligibility): Rate of hospitalization

Sub-Study 2 (Health Care Workers): Rate of COVID-19 infection (confirmed by accepted testing methods) at 2 months

SECONDARY OBJECTIVES Sub-Study 1: Rate of secondary infection of co-inhabitants, adverse events, and negative for COVID-19 (confirmed by accepted testing methods) at 14 days

Sub-Study 2: Number of shifts missed; rate of adverse events, and hospitalization at 2 months

Arms:
arm 1: Patients tested for COVID-19 who meet symptomology and age requirements for eligibility arm 2: Rate of COVID-19 infection (confirmed by accepted testing methods) at 2 months

Interventions: intervention 1: Group 1 HCQ intervention 2: Group 2 Placebo
Intervention descriptions: intervention 1: Enrolled participants randomized in Group 1 receive the HCQ drug intervention 2: Enrolled participants randomized in Group 2 will receive a placebo drug

Protocol document:
Prot_SAP_000.pdf: 
  
 
 
 
PATCH 2 & 3: (Prevention and Treatment of COVID-19 with 
Hydroxychloroquine)  
A double-blind placebo controlled randomized trial of hydroxychloroquine in 
the prevention and treatment of COVID-19 
 
 
NCT04353037 
 
 
 
 


PATCH 2 & 3 TRIAL  
 
 
 
 
Confidential    5.12.2020 
 
 
  1 
 
 
Co-Principal Investigator 
 
Daniel Griffin, MD PhD 
Chief Division of Infectious Disease 
ProHealth Care Associates 
1 Dakota Drive Suite 205 
New Hyde Park, NY 11042 
516-656-6500 
dg2810@cumc.columbia.edu 
Co-Principal Investigator 
Deneen Vojta, MD 
Chief Medical Officer 
United Health Group Research & Development 
5995 Opus Parkway 
Minnetonka, MN 55343 
952-936-1671 
deneen_vojta@uhg.com 
Co-Principal Investigator 
Ravi Amaravadi, MD (Medicine) 
University of Pennsylvania Perelman School of Medicine 
Department of Medicine, Division of Hematology Oncology 
852 BRB 2/3 421 Curie Blvd  
Philadelphia, PA 19104 
215-796-5159 
ravi.amaravadi@pennmedicine.upenn.edu 
Sub-Investigators/ Professional 
Contributors 
Rachel Jennings, Ph.D. (UnitedHealth Group R&D) 
Michael Lahm (UnitedHealth Group R&D) 
Deborah Sundal (UnitedHealth Group R&D) 
Lida Etemad (UnitedHealth Group R&D) 
Desiree Grogan, RPA-C (ProHealth, NY) 
Clinical Research Coordinators/ 
Lab Manager(s)  
Diane Gerrity (ProHealth, NY) 
Desiree Grogan (ProHealth, NY) 
Medical Monitor 
Daniel Griffin, MD PhD 
Pharmacy  
Avella Pharmacy  
 
Funder 
UnitedHealth Group Research and Development 
Protocol Number 
2020-0003 
Investigational Agent 
Hydroxychloroquine 
IND #: 
Exemption granted 
ClinicalTrials.gov Identifier: 
NCT04353037 
Version: 
05122020 
 


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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
SPONSOR-INVESTIGATOR: 
RAVI AMARAVADI, MD (CO-PI: University of Pennsylvania) 
DANIEL GRIFFIN, MD PhD (CO-PI: ProHealth) 
DENEEN VOJTA, MD (CO-PI: UnitedHealth Group Research and 
Development) 
STUDY TITLE: 
 
PATCH 2 & 3: (Prevention and Treatment of COVID-19 with 
Hydroxychloroquine) A double-blind placebo controlled randomized trial 
of hydroxychloroquine in the prevention and treatment of COVID-19 
 
STUDY ID 
PROTOCOL VERSION 
IRB # 2020-003 
05/12/2020 
I have read the referenced protocol. I agree to conduct the study in accordance to this protocol, in compliance with 
the Declaration of Helsinki, Good Clinical Practices (GCP), and all applicable regulatory requirements and guidelines. 
________________________________________ 
Principal Investigator Name 
 
________________________________________ 
Principal Investigator Name 
_________________________________________ 
Signature 
 
_________________________________________ 
Signature 
 
 
 
________________________________________ 
Institution 
_________________________________________ 
Date 
 
 
 
 
 
 


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Abbreviations: 
 
Ab: antibody 
AE: adverse event 
ALT: alanine aminotransferase 
ANC: absolute neutrophil count 
AST: aspartate aminotransferases 
BID: twice daily 
BP: blood pressure 
BSA: body surface area 
CNS: central nervous system 
CT: computed tomography 
CTCAE: Common Terminology Criteria for 
Adverse Events 
DSMC: Data Safety and Monitoring Committee 
eCRF: electronic case report form 
EKG: electrocardiogram 
FDA: Food and Drug Administration 
FFPE: formalin fixed-paraffin embedded 
HBV: hepatitis B virus 
HCQ: hydroxychloroquine 
HCV: hepatitis C virus 
HUP: Hospital of the University of Pennsylvania 
IHC: immunohistochemistry 
IND: investigational new drug 
INR: international normalization ratio 
IRB: institutional review board 
IV: intravenous 
LLN: lower limit of normal 
LVEF: left ventricular ejection fraction 
PPT1: palmitoyl-protein thioesterase 1 
PR: partial response 
PT: prothrombin time 
PTT: partial thromboplastin time 
SAE: serious adverse event 
SUSAR: Suspected, Unexpected Serious Adverse 
Reaction 
ULN: upper limit of normal 
WBC: white blood cell


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STUDY SUMMARY 
 
Title 
PATCH 2 & 3: (Prevention and Treatment of COVID-19 with 
Hydroxychloroquine) 
A double-blind placebo controlled randomized trial of 
hydroxychloroquine in the prevention and treatment of COVID-19  
Protocol Number 
2020-0003 
Phase 
Phase II 
Methodology 
Double-blind placebo controlled randomized prevention and 
treatment trial   
Study Duration 
1 year 
Study Center(s) 
Virtual trial based out of a clinical research institution – ProHealth 
NY 
Objectives 
PRIMARY OBJECTIVES: 
PATCH 2 (Sub-Study 1, Patients tested for COVID-19 who meet 
symptomology and age requirements for eligibility): Rate of 
hospitalization  
 
PATCH 3 (Sub-Study 2, Health Care Workers): Rate of COVID-19 
infection (confirmed by accepted testing methods) over two months 
(60 days)  
 
SECONDARY OBJECTIVES 
PATCH 2 (Sub-Study 1): Rate of secondary infection of co-
inhabitants, adverse events, and negative for COVID-19 (confirmed 
by accepted testing methods) at 14 days 
  
PATCH 3 (Sub-Study 2): Number of shifts missed, rate of adverse 
events, and hospitalization  
 
Number of Subjects 
PATCH 2 (Sub-Study 1): 500 with interim analysis at time points 
corresponding to 34% and 68% of the desired sample size  
 
*PATCH 3 (Sub-Study 2): 350 with interim analysis at time points 
corresponding 25% and 50% of the desired total sample size 
 
Total: 850 
*Eventual expectation for needing 100% crossover  
Diagnosis and Main 
Inclusion/Exclusion 
Criteria 
PATCH 2 and PATCH 3 Inclusion Criteria 
 
• Willing and able to provide informed electronic consent via 
DocuSign 


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Confidential    5.12.2020                                                                           
 
 
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• Willing to report compliance with HCQ or Placebo (“tablets”) 
in the form of an on-line journal and participate in other forms 
of self-reporting (e.g., symptom tracker and experience log) 
• Willing and able to go to designated areas for testing (COVID-
19/SARS-CoV-2 and/or serologic) and/or administer at home 
testing kits for study data collection purposes. 
• Must be able to swallow and retain oral medication and must 
not have any clinically significant gastrointestinal 
abnormalities that may alter absorption such as malabsorption 
syndrome or major resection of the stomach or bowels 
• Must have adequate baseline organ function  
• Subjects meeting the following criteria by Sub-Study: 
 
PATCH 2 Inclusion (Sub-Study 1): 50-75 years of age; self-
reporting as having a fever within four days prior to time of 
enrollment; and not requiring hospitalization. Enrolled 
individuals will undergo testing for COVID-19 and return 
home for self-quarantine. Patient must be willing and able to 
provide informed consent, agree to testing for COVID-19 at 
time of enrollment to confirm diagnosis, at the end of 
treatment (Day 15, 16 or 17) and two weeks after the end of 
treatment (Day 29, 30 or 31) where Day 1 is defined as the 
first day blinded study drug is taken by the patient. (See 
Appendix- PATCH2 process flows) 
 
PATCH 3 Inclusion (Sub-Study 2): Currently employed as a 
health care worker (Medical Doctor, MD; Doctor of 
Osteopathic Medicine, DO; Nurse Practitioner, NP; 
Physician’s Assistant, PA; and Registered Nurse, RN or other 
members of the medical care team with significant COVID-19 
exposure); asymptomatic and presumed negative for COVID-
19 (no confirmatory testing conducted); scheduled for an 
average of >20 hours per week of clinical care over the next 
two months (or equivalent indicating at least part-time 
employment). Participant will be asked to comply with  their 
employer’s potential or confirmed COVID-19 incident 
protocol and must agree to undergo COVID-19 testing per 
standard of care using an FDA approved method upon the 
presentation of symptoms indicative of an influenza like 
illness; if a confirmatory COVID-19 diagnosis is given, 
participant will be offered to cross-over to HCQ 600 mg qd for 
14 days. At the end of the 60-day medication period, 
participants remaining undiagnosed for COVID-19 will 
undergo virus and serology testing. (See Appendix- PATCH3 
process flows) 
 


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Confidential    5.12.2020                                                                           
 
 
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PATCH 2 & PATCH 3 Combined Exclusion Criteria  
(See Study Exclusions and Content Job Aid)  
• Allergy to hydroxychloroquine, 4 aminoquinolines, or 
quinine 
• Known G6PD deficiency 
• Pregnant or lactating or intention of becoming pregnant 
during the study as self-reported during enrollment 
screening 
• Receiving any trial treatment drug for 2019-nCoV within 
14 days prior to screening evaluation (off label, 
compassionate use or trial related) 
• Known retinal disease including but not limited to macular 
degeneration, retinal vein occlusion, visual field defect, 
diabetic retinopathy 
• History of interstitial lung disease severe emphysema or 
asthma, or chronic pneumonitis Current diagnosis of 
porphyria or psoriasis 
• Serious intercurrent illness that requires active intravenous 
therapy, intense monitoring, or frequent dose adjustments 
for medication including but not limited to infectious 
disease, cancer, autoimmune disease, cardiovascular 
disease 
• Have undergone major abdominal, thoracic, spine or CNS 
surgery in the last two months, or plan to undergo surgery 
during study participation   
• Is receiving cytochrome P450 enzyme-inducing 
anticonvulsant drugs (i.e. phenytoin, carbamazepine, 
Phenobarbital, primidone or oxcarbazepine) within four 
weeks of the start of the study treatment 
• Currently taking digoxin 
• History or evidence of increased cardiovascular risk 
including any of the following: 
o Left ventricular ejection fraction (LVEF) < institutional 
lower limit of normal. Baseline echocardiogram is not 
required 
o Current clinically significant uncontrolled arrhythmias. 
Exception: Subjects with controlled atrial fibrillation 
o History of acute coronary syndromes (including myocardial 
infarction and unstable angina), coronary angioplasty, or 
stenting within 6 months prior to enrollment 
o Current ≥ Class II congestive heart failure as defined by 
New York Heart Association 


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• Deemed unable to participate for medical reasons 
identified by Co-PI and study staff 
Study Product, Dose, 
Route, Regimen 
Hydroxychloroquine, various doses, oral  
Matching placebo, oral 
Duration of 
administration 
PATCH 2 (Sub-Study 1): COVID-19 patients in self-quarantine.  
Arm 1: HCQ 400 mg bid (two 200 mg tablets taken twice a day; 
totaling 800 mg per day) for 14 days 
Arm 2: Placebo 2 pills bid for 14 days 
 
PATCH 3 (Sub-Study 2): Asymptomatic health care worker 
prophylaxis.  
Arm 1: HCQ 600 mg qd (three 200 mg tablets taken once a day) for 
up to 60 days  
Arm 2: Placebo 3 pills qd for up to 60 days; cross-over from placebo 
to HCQ 600 mg qd for 14 days is allowed upon confirmatory 
diagnosis for COVID-19  
Study design  
1:1 randomization in each cohort between the arms  
Duration of trial 
Approximately 1 year  
 
 
1.0 OBJECTIVES 
1.1 Primary Objectives 
PATCH 2 (Sub-Study 1): Rate of hospitalization  
PATCH 3 (Sub-Study 2): Rate of COVID-19 infection (confirmed by accepted testing methods) over 
two months 
 
1.2 Secondary Objectives 
PATCH 2 (Sub-Study 1): Rate of secondary infections for co-inhabitants, rate of adverse events (AEs), 
and rate of COVID-19 negativity (confirmed by accepted testing methods) after 14 days of treatment 
PATCH 3 (Sub-Study 2): Number of shifts missed, rate of hospitalization, and rate of adverse events 
(AEs) 
 
 
 
 


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2.0 
BACKGROUND AND RATIONALE 
2.1 Overview of SARS-CoV-2 and Chloroquine Derivatives 
 
Chloroquine derivatives show preclinical efficacy against coronavirus but very little clinical data is 
available. Emerging viral diseases (EVDs) encompass a growing list of zoonotic viruses that have a major impact 
on global health and economics. These include Ebola, SARS, MERs, Marburg, and the recently identified virus 
that causes COVID-19 disease (Wuhan Coronavirus: SARS-CoV-2) (1). In each of these cases there is currently 
no effective drug treatments or prophylaxis agents that can be quickly applied to large populations at risk for the 
virus. As of March 2020, The SARS-CoV-2 virus has infected more than 180,000 people causing more than 5000 
deaths. This has led to a lockdown of entire megacities in China, international travel bans, and disruptions in 
global supply chains. More alarming is the recent evidence that health care workers are getting infected and dying 
of the virus, wreaking havoc on the chain of care.  In addition, while prior epidemics such as Ebola seemed to be 
contained in Africa, the current COVID-19 global crisis demonstrates how with the extent of globalization and 
international travel, no country is safe from these EVDs.   
 
Coronaviruses are a large family of viruses that commonly infect many animals, including camels, cattle, cats, 
and are often found in bats as their zoonotic reservoir. While it is rare, animal coronaviruses can infect people 
and then spread between people, as had occurred with Middle East respiratory coronavirus (MERS-CoV) and 
severe acute respiratory coronavirus (SARS-CoV), and now the newly emerged coronavirus SARS-CoV-2 (also 
known as COVID-19). The SARS-CoV-2 virus is a betacoronavirus, like MERS-CoV and SARS-CoV.  All three 
of these viruses have their origins in bats. While SARS-CoV and MERS-CoV exhibit significantly higher 
mortality than SARS-CoV-2, the ability to spread between humans is less than SARS-CoV-2. There is emerging 
evidence from Asia that patients can be highly contagious with one patient spreading viral particles to 87% of 15 
sites within the patient’s room. Virus can be shed in urine and feces as well as respiratory secretions increasing 
the likelihood that sick contacts and hospital staff will become infected (2). An epidemiological survey of 72,000 
cases in China found and overall 3.8% infection rate in hospital workers, but a 68% infection rate of hospital 
workers in Wuhan at the epicenter of disease.  This suggests that if low rates of infection are in a community,  the 
likelihood of hospital workers  contracting disease is low, but if there are a large number of cases then the 
likelihood of hospital workers contracting the disease is high (3).   Patients above the age of 50 are more likely to 
die of this disease and the time from diagnosis to death can occur within one month despite access to high-level 
intensive care units (4). A high rate of intra-family transmission and rapid community transmission has been 
documented in Shenzen China (5).  Meanwhile a screen of compounds found that chloroquine prevented and 
eradicated established infection of SARS-CoV-2 virus in vitro. I was contacted by researchers in China who 
indicated that 8/10 coronavirus infected patients treated with chloroquine 500 mg daily cleared their virus. The 
hospital ran out of chloroquine, and they have had to turn to other means of treating the virus. We believe 
hydroxychloroquine is a safer drug than chloroquine and affords the ability to dose escalate to concentrations that 
we know are effective at blocking the lysosome in patients.   
 
Our hypothesis is that high doses of hydroxychloroquine for at least 2 weeks can be effective antiviral medication 
both as a treatment in ambulatory patients and prophylaxis/treatment in health care workers because it impairs 
lysosomal function and reorganizes lipid raft (cholesterol and sphingolipid rich microdomains in the plasma 
membrane) content in cells, which are both critical determinants of EVD infection. This hypothesis is based on a 
growing literature linking chloroquine to antiviral activity.  We believe there is enough information to launch a 
clinical trial of hydroxychloroquine for COVID-19.  
 
2.2 Mechanistic rationale for antiviral properties of chloroquine derivatives  
 


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Confidential    5.12.2020                                                                           
 
 
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2.2a Coronaviruses. Coronaviruses (CoV) infect mammals and birds causing respiratory, gastrointestinal, and 
central nervous system diseases. Coronavirus virions contain an envelope, a helical capsid, and a single-stranded 
RNA genome, the largest among all RNA viruses. The name “coronaviruses” derives from the spike proteins on 
their envelope that give the virions a crown-like shape. CoVs include the following: 1) α-genus:  human 
coronavirus NL63 (HCoV-NL63), porcine transmissible gastroenteritis coronavirus (TGEV), and porcine 
respiratory coronavirus (PRCV) 2) β-genus: SARS-CoV-2/COVID-19, severe acute respiratory syndrome 
coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), mouse hepatitis 
coronavirus (MHV), and bovine coronavirus (BCoV). 3) CoVs of the γ-genus include avian infectious bronchitis 
virus (IBV) and do not infect humans so are valuable laboratory agents (6). Coronaviruses impose health threats 
to humans and animals. SARS-CoV caused the SARS epidemic in 2002 to 2003, with over 8,000 infections and 
a fatality rate of ∼10%. MERS-CoV emerged from the Middle East in 2012 causing 877 infections with a fatality 
rate of ∼36%.  HCoV-NL63 from the α-genus is a widespread pathogen that produces the common cold in healthy 
adults and acute respiratory illness in young children. CoVs are also major animal pathogens.  TGEV and MHV 
cause close to 100% fatality in young pigs and young mice, respectively; BCoV and IBV also cause significant 
healthcare burden for domesticated cattle and chickens, respectively. Therefore, research on coronaviruses has 
strong health and economic implications (6). 
 
2.2b CoV infection requires functional lysosomes. Receptor recognition by viruses is the first and essential step of viral 
infections of host cells. An envelope-anchored spike protein mediates coronavirus entry into host cells by first binding to a 
receptor on the host cell surface and then fusing viral and host membranes. CoVs recognize a number of different host 
receptors. Once the receptor is bound, there is viral and cell membrane fusion, followed by endocytosis and lysosomal 
processing. CoVs like SARS enter the cell through lipid raft enriched endocytosis (7). The details of the interaction between 
the virus spike protein, virus membrane and the lipid rafts are not worked out. In the lipid raft literature, it is often the case 
that lipid rafts (semisolid phase membrane filled with cholesterol and sphingolipids) are only physiologically functional if 
there is a non-lipid raft membrane region next to it.  After membrane fusion, endosomal pH acidification is a fusion trigger 
for CoVs and other viruses including influenza virus and vesicular stomatitis virus (VSV). For instance the use of lysosomal 
inhibitor blocked the entry of the model coronavirus IBV (8). The authors directly assessed the pH dependence of IBV 
fusion and found that fusion only occurs at acidic pH. For some CoVs that harbor a non-cleaved spike protein on their 
surface, such as MHV-2 and SARS-CoV, it has been shown that they rely on lysosomal proteases for productive entry. In 
fact one study found that bat cells have more efficient lysosomal proteolysis than human cells providing an explanation for 
why bats are preferred zoonotic hosts for CoVs (9).  
 
2.2c Evidence that chloroquine prevents coronavirus infection. It has been reported that chloroquine has strong antiviral 
effects on SARS-CoV infection and spread in vitro (10-12). In to increasing endosomal/lysosomal pH, these studies 
demonstrated that CQ abrogates glycosylation of ACE2, the cellular receptor of SARS-CoV, which may contribute further 
to infection suppression. The IC50 of chloroquine for inhibition of SARS-CoV in vitro is 8.8 micromolar which would 
require higher concentrations than typically delivered in malaria. Importantly, the suppressive effects are observed when 
the cells are treated with chloroquine either before or after exposure to the virus, suggesting both prophylactic and 
therapeutic treatment paradigms could be employed (10, 11). The work by Kayaerts looked at human coronavirus OC43 
which causes neonatal death in mice. Treatment with chloroquine of pregnant mothers provided a 98.6% protection against 
death in newborn mice. This is in the only in vivo demonstration of chloroquine efficacy against a CoV.  DeWilde et al. 
screened a library of 348 FDA-approved drugs for anti- MERS-CoV activity in cell culture and only four compounds 
(chloroquine, chlorpromazine, loperamide, and lopinavir) were found to inhibit the viral replication (50% effective 
concentrations, EC50 3–8 lmol/L) (12). The protective activity of chloroquine against CoVs such as SARS, MERS and 
COVID-19 has not yet been established in animal models.  
 
2.2d Chloroquine is active against COVID-19/ SARS-CoV-2: A recent paper from Wuhan China isolated 
SARS-CoV-2 (the virus that causes COVID-19 disease) and tested 6 modern antiviral drugs and chloroquine and 
found that the best suppressors of viral infection were remdesivir (IC50 0.77 µmol) and chloroquine (IC50 1 
µmol) (13). Only chloroquine given at 10 µM was able to suppress infection either with pretreatment, at the time 


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Confidential    5.12.2020                                                                           
 
 
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of infection, or after infection occurred. This has led to clinical trials and off label use of chloroquine in China 
(Dr. Amaravadi personal communication with scientists in China). There are Chinese guidelines for the use of 
chloroquine 500 mg bid for the treatment of COVID-19 (Ref). In addition, an update provided by Chinese 
physicians suggests initial experience with chloroquine and/or hydroxychloroquine have been positive (ref).  
Hospitals have run out of chloroquine, and doctors are not confident on proper dosing of hydroxychloroquine. 
Careful clinical trials with optimized chloroquine derivatives would be well received in a hot zone.  
 
2.3 Clinical experience with high dose hydroxychloroquine in cancer patients 
 
In contrast to CQ, which can produce blindness at high cumulative doses, our recent body of work has 
demonstrated that high dose HCQ can be administered safely to humans for months. Our work on autophagy as 
a resistance mechanism to cancer therapy had identified CQ derivatives as potential anti-cancer agents (14). Since 
HCQ has had a longer track record of dose escalation and chronic dosing in rheumatoid arthritis and lupus, we 
chose HCQ as our lysosomal autophagy inhibitor to test in combination regimens in cancer patients. We reported 
the first 6 phase I dose escalation clinical trials involving HCQ in combination with FDA approved anti-cancer 
drugs in refractory stage IV cancer patients (15-20). In most patients on these trials we were able to escalate the 
dose of HCQ to 1200 mg per day and dose patients in some cases safely for more than one year. In over 220 
patients treated across multiple studies the rate of grade 3-4 non-hematological toxicities was < 10%. Most of 
these had more to do with the severity of the cancer and would likely not be seen in a healthy population. 
Specifically, no retinal, cardiac, neurological, hepatic or renal toxicity was observed. Hematological toxicities 
could be attributed to the other cancer drug (chemotherapy) that HCQ was paired with, and the most common 
side effects included manageable gastrointestinal symptoms such as bloating, diarrhea, constipation and mild non-
bloody diarrhea. 
 
2.4 Low dose versus high dose HCQ 
 
In HCQ studies in cancer patients we conducted population pharmacokinetic studies and pharmacodynamic 
studies and determined that 800-1200 mg daily was required to effectively and consistently impair the lysosome 
in peripheral blood mononuclear cells. Our PK studies determined that it took roughly 2 weeks to achieve steady 
state in cancer patients. For these reasons there is rationale to propose a high dose (600 mg po bid) prolonged 
schedule treatment (2 weeks). In contrast an in vitro study recently published which included PK-PD modeling 
extrapolated from published PK studies indicated that HCQ was very active against COVID-19 but only 400 mg 
po bid X1 followed by 200 mg po bid for 5-10 days was enough for treatment. A recent non-randomized open 
label French trial Geuret et al Int J Antimicrobial Agents 2020) showed that 600 mg qd of HCQ cleared virus in 
70 % of mildly ill hospitalized patients compared to 12.5% at 6 days of control patients. This generates a major 
question in how to use this agent in different populations that can best be answered in this two-part placebo 
controlled randomized trial.   
 
3.0 PARTICIPANT SELECTION 
The inclusion and exclusion criteria apply to both patient (PATCH 2) and health care worker (PATCH 3) 
populations unless indicated otherwise. 
 
3.1 PATCH 2 and PATCH 3 Inclusion Criteria (See Study Process Flows) 
• Willing and able to provide informed electronic consent via DocuSign 
• Willing to report compliance with HCQ or Placebo (“tablets”) in the form of an on-line journal and 
participate in other forms of self-reporting (e.g., symptom tracker and experience log) 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
11 
 
• Willing and able to go to designated areas for testing (COVID-19/SARS-CoV-2 and/or serologic) and/or 
administer at home testing kits for study data collection purposes. 
• Must be able to swallow and retain oral medication and must not have any clinically significant 
gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major 
resection of the stomach or bowels 
• Must have adequate baseline organ function  
• Subjects meeting the following criteria by Sub-Study: 
 
PATCH 2 Inclusion (Sub-Study 1): 50-75 years of age; self-reporting as having a fever within four 
days prior to time of enrollment; and not requiring hospitalization. Enrolled individuals will undergo 
testing for COVID-19 and sent home for self-quarantine. Patient must be willing and able to provide 
informed consent, agree to testing for COVID-19 at time of enrollment to confirm diagnosis, at the end 
of treatment (Day 15, 16 or 17) and two weeks after the end treatment (Day 29, 30 or 31) where Day 1 is 
defined as the first day blinded study drug is taken by the patient. (See Appendix- PATCH2 process 
flows) 
 
PATCH 3 Inclusion (Sub-Study 2): Currently employed as a health care worker (Medical Doctor, MD; 
Doctor of Osteopathic Medicine, DO; Nurse Practitioner, NP; Physician’s Assistant, PA; and Registered 
Nurse, RN or other members of the medical care team with significant COVID-19 exposure); 
asymptomatic and presumed negative for COVID-19 (no confirmatory testing conducted); scheduled for 
an average of >20 hours per week of clinical care over the next two months (or equivalent indicating at 
least part-time employment).  Participant will be asked to comply with  their employer’s potential or 
confirmed COVID-19 incident protocol and must agree to undergo COVID-19 testing per standard of 
care using an FDA approved method upon the presentation of symptoms indicative of an influenza like 
illness; if a confirmatory COVID-19 diagnosis is given, participant will be offered to cross-over to HCQ 
600 mg qd for 14 days. At the end of the 60-day medication period, participants remaining undiagnosed 
for COVID-19 will undergo virus and serology testing. (See Appendix- PATCH3 process flows) 
 
PATCH 2 & PATCH 3 Combined Exclusion Criteria  
(See Study Exclusions and Content Job Aid)  
• Allergy to hydroxychloroquine, 4 aminoquinolines, or quinine 
• Known G6PD deficiency 
• Pregnant or lactating or intention of becoming pregnant during the study as self-reported during 
enrollment screening 
• Receiving any trial treatment drug for 2019-nCoV within 14 days prior to screening evaluation (off 
label, compassionate use or trial related) 
• Known retinal disease including but not limited to macular degeneration, retinal vein occlusion, 
visual field defect, diabetic retinopathy 
• History of interstitial lung disease severe emphysema or asthma, or chronic pneumonitis Current 
diagnosis of porphyria or psoriasis 
• Serious intercurrent illness that requires active intravenous therapy, intense monitoring, or frequent 
dose adjustments for medication including but not limited to infectious disease, cancer, autoimmune 
disease, cardiovascular disease 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
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• Have undergone major abdominal, thoracic, spine or CNS surgery in the last two months, or plan to 
undergo surgery during study participation   
• Is receiving cytochrome P450 enzyme-inducing anticonvulsant drugs (i.e. phenytoin, 
carbamazepine, Phenobarbital, primidone or oxcarbazepine) within four weeks of the start of the 
study treatment 
• Currently taking digoxin 
• History or evidence of increased cardiovascular risk including any of the following: 
o Left ventricular ejection fraction (LVEF) < institutional lower limit of normal. Baseline 
echocardiogram is not required 
o Current clinically significant uncontrolled arrhythmias. Exception: Subjects with controlled atrial 
fibrillation 
o History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary 
angioplasty, or stenting within 6 months prior to enrollment 
o Current ≥ Class II congestive heart failure as defined by New York Heart Association 
• Deemed unable to participate for medical reasons identified by Co-PI and study staff 
 
4.0 PARTICIPANT REGISTRATION/PROCEDURES  
 
The following information is to be provided at the time of registration to the trial: 
 
Participant Identification Information for PATCH 2 & PATCH 3: 
• Participant initials (first and last) 
• Participant’s chronic medical problems 
• Gender 
• Birth date (mm/yyyy) 
• Race 
• Ethnicity 
• Nine-digit ZIP code 
• State of residence 
• County of residence 
• Cell phone number and alternate numbers  
• Email address  
 
Participant Identification Information for PATCH 2 Only (Sub-study 1): Identify the number of fulltime 
inhabitants at the residence where the participant will stay during the 14-day self-quarantine as well as ages and 
sex of each co-inhabitant and relationship to the study participant.   
 
 
 


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Confidential    5.12.2020                                                                           
 
 
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Participant Procedure for PATCH 2 (Sub-Study 1) (See study process flows) 
1. Interested participants self-refer for study by completing online eligibility checklist on study portal 
(www.patchstudy.com) 
2. Review inclusion and exclusion criteria: participant is 50-75 years of age and self-reported as having a 
fever within the last four days will undergo swab testing for COVID-19 per clinical care guidelines and 
approach, and then sent home for a self-imposed quarantine 
3. Reviews the study and the Informed Consent Form with the subject and obtains informed consent via 
DocuSign 
4. Participant study ID is assigned, and subsequently, randomized into a study arm (HCQ or placebo). 
5. Package containing blinded study drug, study journals (medicine log, symptom tracker and experience 
log) and study documents (details on aims, design, consent forms, and any additional instructions) 
delivered to address provided by participant as place of residence during period of self-quarantine. Day 
1 is defined as the first day the blinded study drug is taken by the participant 
6. Lab provides participant’s COVID-19 test results to designated Co-PI with designee 
7. PI or designee calls participant informing them of result, discussing how to proceed on the trial (if 
positive, continue taking medication; otherwise, stop) and documenting discussion. 
8. Each day, participants will record 1) temperature (to be reported twice daily, either via thermometer or 
self-report); 2) time medication taken; 3) any symptoms and AEs; and 4) if any co-inhabitants develop 
symptoms and/or become positive for COVID-19 (confirmed by accepted testing methods) 
9. Three times a week, participants will be called by clinical research coordinators to assess AEs and 
symptoms with all discussions well-documented. Clinical research coordinators may clinically escalate 
any medical determinations to Co-PI 
10. After Day 14, which marks the end of the treatment period, participants will no longer be expected to 
continue self-reporting information into the study portal. Participant will undergo follow-up testing for 
COVID-19 at two additional time points. The first will be either day 15, 16 or 17, with the second on 
either on day 29, 30 or 31 
11. If during active participation, the participant reports worsening of symptoms related to COVID-19 from 
baseline, this is reported to the PI for further clinical evaluation 
 
Participant Procedure PATCH 3 (Sub-Study 2) (See study process flows) 
1. Interested participants self-refer for study by completing online eligibility checklist on study portal 
(www.patchstudy.com) 
2. Review inclusion and exclusion criteria:  
o Currently employed as a health care worker (Medical Doctor, MD; Doctor of Osteopathic 
Medicine, DO; Nurse Practitioner, NP; Physician’s Assistant, PA; and Registered Nurse, RN or 
other members of the medical care team with significant COVID-19 exposure);  
o Asymptomatic and presumed negative for COVID-19 (no confirmatory testing conducted);  
o Scheduled for an average of >20 hours per week of clinical care over the next two months (or 
equivalent indicating at least part-time employment).   
o Willing to comply with their employer’s potential or confirmed COVID-19 incident protocol  
o Agrees to undergo COVID-19 testing per standard of care using an FDA approved method upon 
the presentation of symptoms indicative of an influenza like illness (if a confirmatory COVID-19 
diagnosis is given, participant will be offered to cross-over to HCQ 600 mg qd for 14 days.) 
3. Reviews the study and the Informed Consent Form with the subject and obtains informed consent via 
DocuSign 
4. Participant study ID is assigned, and subsequently, randomized into a study arm (HCQ or placebo). 


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Confidential    5.12.2020                                                                           
 
 
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5. Package containing blinded study drug supply, study journals (medicine log, symptom tracker and 
experience log) and study documents (details on aims, design, consent forms, and any additional 
instructions) are delivered to the address provided by participant as place of residence during study. 
Delivery of blind study drug supply will occur in two shipments, each containing a 30-day supply. Day 1 
is defined as the first day the blinded study drug is taken by the participant. 
6. Each day active medication is taken (HCQ or placebo), participants will record 1) temperature (to be 
reported twice daily, either via thermometer or self-report); 2) time medication taken; and 3) any 
symptoms and AEs. 
7. Every week, clinical research coordinators will review the study portal to assess for AEs and indication 
of reported symptoms indicative of influenza like illness.  The research coordinator will also review self-
reported fever and/or temperature.  If COVID-19 symptoms are evident, the research coordinator will 
outreach to the HCW (at clinic or by phone). Clinical research coordinators may clinically escalate any 
medical determinations to Co-PI following study portal review. 
8. The HCW also has access to the study coordinators via the study phone number.  If the HCW feels 
symptomatic, then he/she should call the clinical research coordinator team, and document symptoms in 
the study portal. Clinical research coordinators may clinically escalate any medical determinations to Co-
PI. 
9. If during the study symptoms indicative of an influenza like illness present, participant will be asked to 
comply with their employer’s potential or confirmed COVID-19 incident protocol and be tested for 
COVID-19 by an accepted method. Participants negative for COVID-19 continue with the assigned 
blinded study drug regimen. 
10. If confirmed COVID-19 diagnosis, participant will be unblinded. Participants assigned to HCQ can 
continue with medication schedule. Individuals assigned to the placebo arm will be offered the 
opportunity to cross-over to HCQ 600 mg daily for 14 days. Individuals will be expected to continue 
self-reporting temperature, time medication taken and any symptoms/AEs into the study portal while 
taking active HCQ medication. 
11. Participants who remain undiagnosed for COVID-19 by the end of the medication period (Day 60) will 
be asked to undergo COVID-19 and serology testing for IgM/IgG on either Day 61, 62, or 63. 
 
5.0 RANDOMIZATION 
Randomization will be done using computer generated randomization numbers. Randomization will be 
stratified by age. Treatment will start upon receipt of the product by the patient after enrolling in the 
study, notifying the pharmacy and having the product/placebo sent.  
 
Blinding: Both sub-studies will have a double-blind placebo-controlled design.   
 
Unblinding: (See study process flows) 
o For PATCH 2 (Sub-study 1), If patient in PATCH 2 experiences worsening of symptoms, a Co-PI will 
be notified to take appropriate clinical action. Co-PI can choose to unblind for clinical determinations.  
 
o For PATCH 3 (Sub-Study 2), confirmation of a COVID-19 diagnosis would trigger the unblinding 
pathway for a participant (for details see Section 4.0, Participant Registration, PATCH 3 (Sub-Study 2) 
Participant Procedure). 
 
 


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Confidential    5.12.2020                                                                           
 
 
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6.0 TREATMENT PLAN    
PATCH 2 (Sub-Study 1) 500 patients with 2 interim analyses  
• 
Arm 1 (HCQ): Hydroxychloroquine 400 mg bid (two 200 mg tablets taken twice a day; totaling 800 mg per day) 
for 14 days 
• 
Arm 2 (Placebo): Two pills taken twice daily (totaling four pills each day) for 14 days 
 
PATCH 3 (Sub-Study 2) 350 participants with 2 interim analyses 
• 
Arm 1 (HCQ): Hydroxychloroquine 600 mg qd (three 200 mg tablets taken once day) for 60 days 
• 
Arm 2 (Placebo): Three pills once a day for 60 days with optional crossover to HCQ 600 mg qd for 14 days upon 
presentation of symptoms indicative of an influenza like illness and subsequent confirmatory diagnosis for 
COVID-19 
 
7.0 DETAILS OF STUDY TREATMENT 
7.1a Hydroxychloroquine 
Mechanism of Action: The mechanism of action is not fully understood. Previously it was thought that HCQ 
and other chloroquine derivatives are weak bases that deacidify lysosomes through purely chemical basis. 
Recently our group has identified the missing molecular target of HCQ as palmitoyl protein thioesterase 1 
(PPT1). 
Figure 1.  Schematic of PATCH 2 and PATCH 3 Study Designs  
 


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Confidential    5.12.2020                                                                           
 
 
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Storage and formulation: HCQ tablets are manufactured by a number of generic drug companies as well as Novartis. Each 
tablet contains 200 mg hydroxychloroquine sulfate (equivalent to 155 mg base). It is dispensed in a tight, light-resistant 
container as defined in the USP/NF.HCQ should be stored at room temperature up to 30° C (86° F). 
Pharmacokinetics: The PK of HCQ is characterized by a large volume of distribution, binding to red blood 
cells, and long time to peak concentration and steady state. Population PK studies in cancer patients have 
demonstrated dose proportional change in exposure. 
Administration: Hydroxychloroquine is an oral medication available in 200 mg tablets. HCQ will be supplied 
by the study team via Avella Pharmacy. Tablets of HCQ are available in 200 mg strength. In PATCH 2 (Sub-
Study 1), HCQ will be administered in divided doses (every 12 hours) with each dose consisting of two 200 mg 
tablets (or 400 mg bid), totaling 800 mg daily. The two daily doses of HCQ should be taken 12 hours apart, 
for example, 9 am and 9 pm. In PATCH 3 (Sub-Study 2), HCQ will be administered as three 200 mg tablets 
taken once a day (600 mg qd) at the same time. Hydroxychloroquine sulfate tablets should be taken with a meal 
or a glass of milk. Participants will be required to keep a study journal and document the time HCQ doses are 
taken; journal completion will be reviewed by study staff. The HCQ schedule may be adjusted if necessary, to 
minimize gastrointestinal side effects. 
For complete information please refer to the package inserts at http://dailymed.nlm.nih.gov/dailymed/ 
 
7.1b Placebo 
 
There will be no active medication in the placebo tablets, which will be supplied by the study team via Avella 
Pharmacy and mailed to the participant’s provided address. In PATCH 2 (Sub-Study 1), placebo will be 
administered in two divided doses (every 12 hours) with each dose consisting of two tablets, totaling four 
tablets daily. The two daily doses of placebo should be taken 12 hours apart, for example, 9 am and 9 pm. In 
PATCH 3 (Sub-Study 2), placebo will be administered as three tablets taken once a day at the same time. 
Tablets should be taken with a meal or a glass of milk. Participants will be required to keep a study journal and 
document the time placebo doses are taken. The dosing schedule may be adjusted if necessary, to minimize, 
gastrointestinal side effects. Journal completion will be reviewed by study staff.  
 
7.2 Concomitant Medication, Drug-Drug interactions and Procedures 
Participants will be instructed not to take any medications, including over the counter products, without first 
consulting with the study team. The study phone number and additional contact information will be provided 
with the welcome packet, allowing for the study team to be contacted if the participant is seen by a health care 
provider or medications are changed. 
Drug Interactions  
Insulin or antidiabetic drugs: As HCQ may enhance the effects of a hypoglycemic treatment, a decrease 
in doses of insulin or antidiabetic drugs may be required.  
Drugs that prolong QT interval and other arrhythmogenic drugs: HCQ can prolong the QT interval and should 
not be administered with other drugs that have the potential to induce cardiac arrhythmias. Also, there may be 
an increased risk of inducing ventricular arrhythmias if HCQ is used concomitantly with other arrhythmogenic 
drugs.  
Antiepileptics: The activity of antiepileptic drugs might be impaired if co-administered with HCQ.  


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Confidential    5.12.2020                                                                           
 
 
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Cyclosporin: An increased plasma cyclosporin level was reported when cyclosporin and HCQ were 
co-administered.  
Because HCQ has known effects on P450 enzymes, participants requiring anti-convulsants may be treated with 
any of the non-enzyme inducing anti-convulsants which include: felbamate, valproic acid, gabapentin, 
lamotrigine, tiagibine, topiramate, or levetiracetam. Due to the fact that both zonisamide and HCQ accumulate 
in red blood cells, zonisamide should be avoided if possible. Other concomitant medications may be permitted. 
The following medications and treatments are not allowed during the study. The sponsor must be notified if the 
participant receives any of these during the study: 
1. PATCH 2 and 3 (Sub-Studies 1 and 2): Any investigational or off-label antiviral therapy  
2. Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic or hormonal therapy for cancer 
treatment, except as noted in the exclusion criteria. Concurrent use of hormones for noncancer-related 
conditions (e.g. insulin for diabetes, hormone replacement therapy) is acceptable. 
3. Immunosuppressive medications, including, corticosteroids at doses exceeding 10mg/day of prednisone or 
equivalent, methotrexate, azathioprine, and TNF-alpha blockers. Use of immunosuppressive medication for the 
management of study treatment-related AEs or in subjects with contrast allergies is acceptable. In addition, use 
of topical, inhaled and intranasal corticosteroids is permitted 
4. Live attenuated vaccines during the study through 180 days after the last dose of both drugs 
 
7.3 Duration of Protocol Treatment and Follow-up.  
PATCH 2 (Sub-Study 1) duration of treatment is 14 days (two weeks) with follow-up with COVID-19 testing 
on Day 15, 16 or 17, and Day 29, 30 or 31 where Day 1 marks the first day blinded study drug is taken by the 
participant. 
  
PATCH 3 (Sub-Study 2) duration of treatment is up to 60 days with an option to cross-over for participants 
taking placebo upon presentation of symptoms indicative of an influenza like illness and testing positive for 
COVID-19 (or a COVID-19 diagnosis is made by a health care provider). Participants remaining undiagnosed 
for COVID-19 by Day 60 will undergo testing for SARS-CoV-2 and IgM/IgG antibodies on either Day 61, 62, 
or 63. The maximum study medication duration and follow-up testing is 63 days.  
 
7.4 Crossover from Control to HCQ arm.   
  
PATCH 2 (Sub-Study 1): There is no cross-over. 
 
PATCH 3 (Sub-Study 2): Participants that develop symptoms indicative of an influenza like illness and 
diagnosed with COVID-19 will be unblinded. If they were assigned to the placebo arm and deemed appropriate, 
they will be offered the option crossover to HCQ 600 mg qd for 14 days.  
 
 


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Confidential    5.12.2020                                                                           
 
 
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8.0 TOXICITY CRITERIA, MONITORING, DOSE DELAYS AND MODIFICATIONS 
8.1 Toxicity Criteria 
This study will utilize the DAIDS table for grading adult adverse events (AEs). A copy of the DAIDS grading 
system is available at: https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf. All appropriate 
treatment areas should have access to a copy of the DAIDs grading table. 
8.2 Dose Delays 
Major Events are Grade 3 and 4 hematologic and non-hematologic toxicities that are not treatment related. 
Treatment should be delayed for major events if HCQ may further complicate the non-treatment related event.  
If a major event requires a delay of treatment, treatment must be delayed until toxicity is resolved (≤ Grade 2 or 
≤ Baseline). For treatment-related toxicities and major events, if toxicity is not resolved in ≤ 7 days, participant 
will be taken off treatment unless there is an exception granted by the medical monitor.  
8.3 Ocular toxicity 
The only toxicity that requires discontinuation of HCQ is retinopathy. Published literature indicates HCQ 
retinopathy is idiosyncratic and is uncommon in patients receiving HCQ for less than a few years. Our ongoing 
study of dabrafenib, trametinib, and HCQ (BAMM; NCTNCT02257424) found no clinically meaningful ocular 
toxicity in 10 patients studied extensively with serial ocular exams (21). Therefore, we have not included 
mandatory ocular exams in this protocol. However, if there is a visual field deficit, retinal vein occlusion, serous 
retinopathy, bullseye retinopathy, or retinal detachment, HCQ should be permanently discontinued. 
 
8.4 Participant Safety Monitoring and Data Collection 
Adverse events will be captured via self-report by participants within the study portal. Participants are 
instructed to contact the study team at the phone number provided in the Welcome Packet to report all adverse 
events. The study team will reach out to the participant to gather additional information surrounding the adverse 
event in order to complete DAIDS grading if necessary. Additional information pertaining to the adverse event 
will be captured within the study portal by the study team and reviewed by the PI’s for causality to study drug. 
Adverse events meeting seriousness criteria will be reported to the IRB as noted below.  
 
PATCH 2 (Sub-Study 1):  
Clinical Symptom Monitoring: Participants will be contacted three times per week to assess AEs and COVID-
19 symptoms and collect/review self-reported AE’s. Worsening COVID symptoms and/or new or worsening 
AE’s will be reviewed by the PI’s for causality to study drug. 
Temperature Measurements: Home quarantined participants will be asked to report twice daily either presence of 
fever or temperature and record the measurements.  
COVID-19/SARS-CoV-2 Testing: On Days 15-17 and 29-31, participants will undergo follow-up testing for 
COVID-19.  
Pill Count and Journal: Participants will be contacted three times per week and following the end of treatment to 
compare data entry on the portal and collect any missed entries over the phone.  
Monitoring Co-Inhabitants: Participants will be contacted three times per week to identify if any co-inhabitants 
have developed symptoms and/or tested positive for COVID-19. Participants will also be asked to provide a 
description of co-inhabitants’ symptomology, and time of positive testing for COVID-19 via self-reporting. 
 
PATCH 3 (Sub-Study 2):  
Adverse events will be captured solely based on participant self-reporting via the study portal and/or by calling 
the study team at the number provided in the Welcome Packet. The study team will review the portal for self-
reported AE’s not previously reported to the study team.  New AEs not previously reviewed which cannot be 


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Confidential    5.12.2020                                                                           
 
 
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graded based upon self-reported data within the portal will require follow-up from the study team to gather 
additional information from the participant. New or worsening AE’s will be reviewed by the PI”s for causality 
to study drug.  
COVID-19/SARS-CoV-2 testing: Upon the presentation of symptoms indicative of an influenza like illness, 
participants will be asked to undergo testing for SARS-CoV-2 virus. Participants undiagnosed for COVID-19 at 
Day 60 will also be tested for SARS-CoV-2 and IgM/IgG antibodies (via serology testing) on either Day 61, 62, 
or 63.  
Clinical Symptom monitoring: The study team will assess AEs, symptoms, and record temperature (either 
reported temperature or self-report of fever) for any participants taking active medication (placebo or HCQ).  
Worsening COVID symptoms and/or new or worsening AE’s will be reviewed by the PI’s for causality to study 
drug. The rate of conversion to receiving a positive COVID-19 test result in each arm at the 2-month mark will 
be used to assess the primary endpoint.   
Pill count and Journal: Participants will be contacted to compare data entry on the portal and collect any missed 
entries over the phone.  
 
Participants will be instructed to call 911 upon immediate presentation of the following symptoms as identified 
by the CDC as requiring emergency action: bluish lips or face; new confusion/dizziness or inability to arouse; 
persistent pain or pressure in the chest (not caused by coughing); and difficulty breathing (including severe 
shortness of breath and single word speech). 
 
Participant confidentiality is strictly held in trust by all personnel granted access to the trial data. Therefore, the 
study data, and all other information generated will be held in strict confidence. No information concerning the 
study, or the data will be released to unauthorized parties.  
 
The study investigators and study team, the research sponsor and its designees, personnel from ProHealth with 
authorized access to study data, government agencies, reviewing Institutional Review Board (IRB), regulatory 
agencies and/or company supplying study product may inspect all documents and records required to be 
maintained by the sponsor, including but not limited to, clinical, pharmacy and lab records for participants 
enrolled in the study. All applicable parties will permit access to such records.  
 
The participant’s study contact information will be securely stored within the online study portal for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as long as 
dictated by the reviewing IRB and institutional policies.  
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be 
transmitted to and stored at UHG R&D in a de-identified manner. This will not include participant’s contact or 
identifying information, unless otherwise specified in the informed consent form. Rather, individual participants 
and their research data will be identified by a unique study identification number. The study data entry and study 
management systems will be secured, and password protected. At the end of the study, study data will be de-
identified and may be made public. 
 
UHG R&D follows the standards of HITRUST for data management and data governance. Our data always 
remains encrypted in transit and at rest. Our data has managed access with expiration dates, and we follow 
minimum use guidelines with regard to dataset usage. UHG R&D uses Google Cloud Platform (GCP) for the 
storage of all encrypted data.  UHG R&D has a dedicated Data Integration team for data management and data 
governance objectives and this team serves as the "Gate Keeper" of identifiable data. UHG R&D utilizes a "Clean 
Room" for data acquisition and isolation of identifiable data. The Clean Room is an environment that requires 
elevated access permission by a separate set of credentials. Access is limited to a small scope of approved "white 


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Confidential    5.12.2020                                                                           
 
 
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listed" locations and to specific individuals filling a specific list of objectives associated with the Data Services 
department at UHG R&D. 
 
8.5 Hydroxychloroquine Dose Reduction 
Any Adverse Event Grade 3 or higher requires HCQ to be withheld. Treatment may be resumed once toxicity is 
≤ Grade 2 according to the below Dose Reduction Schema (Table 1). If toxicity does not resolve or improve to 
≤ Grade 2 within 7 days, participant will be withdrawn from active treatment unless granted an exception by the 
Medical Monitor. Medical Monitor should be notified of all toxicities requiring dose withholding or dose 
adjustments via email or phone.  
  
Any AE = Grade 2 and attributed as possibly, probably or definitely related to HCQ will result in a dose 
reduction of HCQ as described in Table 1.  
 
If AE remains = Grade 2 following the first dose reduction and attributed as possibly, probably or definitely 
related to HCQ following the second dose reduction, then the participant should discontinue treatment.  
No more than 2 dose reductions are allowed. It is recommended that dose reductions occur at a minimum of 48 
hours apart.   
 
Table 1: Dose Reduction Schema 
Sub-Study 
Dose mg/day 
First dose reduction  
Second Dose reduction  
1 (PATCH 2) 
400 mg (two tablets) 
twice daily 
400mg (two tablets) once 
daily  
200 mg (one tablet) once 
daily  
2 (PATCH 3) 
600 (three tablets) mg 
daily   
400 mg (two tablets) once 
daily  
200 mg (one tablet) once 
daily  
 
Reported non-serious toxicities attributable to HCQ include nausea, anorexia, vomiting, constipation, diarrhea 
and rash.  For any of these AEs occurring at Grade < 2, HCQ may be continued and the AE managed with 
supportive care. For Any AE with a Grade ≥ 3, HCQ will be held until the toxicity improves to ≤ Grade 2, after 
which HCQ may be restarted at a reduced dose as described in Table 1.   
Example:  Management of diarrhea in randomized subjects   
Grade 1: (an increase in stool up to 3 per day) results in no change to HCQ 
Grade 2: (an increase in stool up to 4-6 per day) results in a Dose Reduction according to Table 1  
Grade 3+: (an increase in stool up to 7 or more per day) results in Withholding of HCQ until AE at 
Grade level 2 or less, followed by a reduction in dose per Table 1.   
9.0 ADVERSE EVENTS AND REPORTING 
The timely reporting of adverse events (including toxic deaths) is required by the Food and Drug 
Administration. The reporting of toxicities is part of the data reporting for this study. The investigator is 
responsible for ensuring that all adverse events (AEs) and serious adverse events (SAEs) as self-reported during 
the study are collected and reported to the FDA, appropriate IRB(s), in accordance with CFR 312.32 (IND 
Safety Reports). 


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Confidential    5.12.2020                                                                           
 
 
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9.1 Adverse Events Definition 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity during 
the study that does not necessarily have a causal relationship with this treatment. Intercurrent illnesses or injuries 
should be regarded as adverse events. Abnormal results of diagnostic procedures are considered to be adverse 
events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests or considered by the investigator to be of clinical 
significance 
9.2 Adverse Events Reporting Period 
The study period during which adverse events must be reported is defined as the period from the initiation of 
the first study treatment to the last administration of study treatment. 
9.3 Adverse Events Post Study 
All unresolved adverse events at the conclusion of the dosing period should be followed by the investigator 
until the event is resolved, the participant is lost to follow-up, or the adverse event is otherwise explained. At 
the last scheduled contact, the study staff should instruct each participant to report any subsequent event(s) that 
the participant, or the participant’s personal physician, believes might reasonably be related to participation in 
this study. 
9.4 Adverse Events Assessment and Recording 
At each contact with the participant, the investigator or study staff will assess for information on adverse events 
and review all self-reported AE’s via the study portal. Information surrounding adverse events should be 
recorded in the study portal. Related signs, symptoms, and abnormal diagnostic procedures results should be 
recorded in the study portal and grouped under one diagnosis as applicable. 
Adverse events can be spontaneously reported or elicited during open-ended questioning. Adverse events will 
be measured and graded in accordance with the document entitled Division of AIDS (DAIDs) Table for Grading 
the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 issued by the US 
Department of Health and Human Services. The clinical course of each event should be followed until 
resolution, stabilization, or until it has been determined that the study treatment or participation is not the cause. 
Serious adverse events that are still ongoing at the end of the study period must be followed up to determine the 
final outcome. Any serious adverse event that occurs after the study period and considered to be at least 
possibly related to the study treatment or study participation should be recorded and reported immediately. 
9.4.1 Relationship to Study Drug 
The causal relationship can be one of the following: 
• Related: There is a possible, probable or definite causal relationship between study drug 
administration and the AE 
• Not related: There is evidence suggesting a causal relationship to something other than the study 
drug.  
 
9.5 Abnormal Laboratory Values 


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Confidential    5.12.2020                                                                           
 
 
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This trial does not require any safety laboratory assessments. However, in the event a participant has a standard 
of care labs completed which are self-reported and meet the DAIDS criteria for Grade 2 or greater, and cannot 
be attributed to another cause, study drug should be held and or reduced in accordance with section 8 above. 
 
9.6 Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated transaminases). However, 
if a constellation of signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, it is ok to report the information that is currently available. If a diagnosis is 
subsequently established, it should be reported as follow-up information. 
9.7 Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such conditions should be 
reported as medical and surgical history. A preexisting medical condition should be re-assessed throughout the 
trial and reported as an AE or SAE only if the frequency, severity, or character of the condition worsens during 
the study. When reporting such events, it is important to convey the concept that the preexisting condition has 
changed by including applicable descriptors (e.g., “more frequent headaches”). 
10.0 SERIOUS ADVERSE EVENTS 
A serious adverse event is any AE that is: 
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• a suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study drug 
• an important medical event 
• All Serious Adverse Events (SAEs) that occur following the participant’s written consent to participate in 
the study must be reported, whether related or not related to study drug. If applicable, SAEs must be 
collected that relate to any later protocol-specified procedure. 
• Following the participant’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, are collected, including those thought to be associated with protocol-specified 
procedures. The investigator should report any SAE occurring after these aforementioned time periods, 
which is believed to be related to study drug or protocol-specified procedure. 
• An SAE report should be completed for any event where doubt exists regarding its seriousness; 
• If the investigator believes that an SAE is not related to study drug but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study procedure), the 
relationship should be specified in the narrative section of the SAE Report Form. 
All SAEs should be followed to resolution or stabilization. Serious adverse events that are ongoing at the end of 
the study period must be followed to determine the outcome. Any serious adverse event that occurs after the 
study period and is at least possibly related to the study treatment or study participation should be recorded and 
reported immediately to the Medical Monitor and the IRB per the IRB reporting guidelines.   


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Confidential    5.12.2020                                                                           
 
 
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All adverse events that do not meet any of the criteria for serious should be regarded as non-serious adverse 
events. 
10.1 Important Medical Event 
Important medical events are those that may not be immediately life threatening but are clearly of major clinical 
significance. They may jeopardize the participant and may require intervention to prevent one of the other 
serious outcomes noted above. For example, drug overdose or abuse, a seizure that did not result in in-patient 
hospitalization, or intensive treatment of bronchospasm in an emergency department would typically be 
considered serious. 
10.2 Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and 
reported as a serious adverse event unless specifically instructed otherwise in this protocol. Any condition 
responsible for surgery should be documented as an adverse event if the condition meets the criteria for an 
adverse event. 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse event in 
the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a preexisting 
condition. Surgery should not be reported as an outcome of an adverse event if the purpose of the surgery 
was elective or diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it is a 
worsening or increase in frequency of hospital admissions as judged by the clinical investigator. 
Expected adverse events are those adverse events that are listed or characterized in the Package Insert or current 
Investigator Brochure. 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or current Investigator Brochure 
(I.B.) or not identified. This includes adverse events for which the specificity or severity is not consistent with 
the description in the P.I. or I.B. For example, under this definition, hepatic necrosis would be unexpected if the 
P.I. or I.B. only referred to elevated hepatic enzymes or hepatitis. 
10.3 Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 12.1), regardless of 
attribution, will be reported to the appropriate parties. When recording a death, the event or condition that 
caused or contributed to the fatal outcome should be reported as the single medical concept. If the cause of 
death is unknown and cannot be ascertained at the time of reporting, report “Unexplained Death”. 
10.4 Pregnancy 
If a female subject becomes pregnant while receiving investigational therapy or within 120 days after the last 
dose of study drug, the investigator must immediately notify the Sponsor in accordance with SAE reporting 
guidelines. Follow-up to obtain the outcome of the pregnancy should also occur. Abortion, whether accidental, 
therapeutic, or spontaneous, should always be classified as serious, and expeditiously reported as an SAE. 
Similarly, details of the birth, and the presence or absence of any congenital anomaly/birth defect or maternal 
and/or newborn complications in a child born to a female subject exposed to the study drug should be reported 
as an SAE. Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported. In order for Sponsor or designee to 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
24 
 
collect any pregnancy surveillance information from the female partner must sign an informed consent form for 
disclosure of this information. Any pregnancy that occurs in a female partner of a male study participant should 
be reported. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. In order for 
Sponsor or designee to collect any pregnancy surveillance information from the female partner, the female 
partner must sign an informed consent form for disclosure of this information. 
 
11.0 IRB NOTIFICATION  
The UHG IRB requires expedited reporting of those events related to study participation that are unforeseen and 
indicate that participants or others are at increased risk of harm. The IRB will not acknowledge safety reports or 
bulk adverse event submissions that do not meet the criteria outlined below. The IRB requires researchers to 
submit reports of the following problems within 10 working days from the time the investigator becomes aware 
of the event: 
• Any adverse event (regardless of whether the event is serious or non-serious, on-site or off-site) that 
occurs any time during or after the research study, which in the opinion of the principal investigator is: 
Unexpected (An event is “unexpected” when its specificity and severity are not accurately reflected in the 
protocol-related documents, such as the IRB-approved research protocol, any applicable investigator brochure, 
and the current IRB-approved informed consent document and other relevant sources of information, such as 
product labeling and package inserts.) 
AND 
Related to the research procedures (An event is “related to the research procedures” if in the opinion of the 
principal investigator or sponsor, the event was more likely than not to be caused by the research procedures.) 
Deaths occurring for participants on-study and within 30 days of study drug administration that are considered 
unforeseen and indicates participants or others are at increased risk of harm (i.e. unexpected and 
probably/definitely related), must be reported to the IRB within 24 hours of notification. 
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical 
Investigator’s study file. 
For clinical drug trials, the following events are also reportable to the IRB: 
• Any adverse experience that, even without detailed analysis, represents a serious unexpected adverse 
event that is rare in the absence of drug exposure (such as agranulocytosis, hepatic necrosis, Stevens-
Johnson syndrome). 
• Any adverse event that would cause the sponsor to modify the investigators brochure, protocol or 
informed consent form, or would prompt other action by the IRB to assure protection of human 
participants. 
• Information that indicates a change to the risks or potential benefits of the research, in terms of severity 
or frequency. For example: 
-- An interim analysis indicates that participants have a lower rate of response to treatment than initially 
expected. 
-- Safety monitoring indicates that a particular side effect is more severe, or more frequent than initially 
expected. 


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Confidential    5.12.2020                                                                           
 
 
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-- A paper is published from another study that shows that an arm of your research study is of no 
therapeutic value. 
• Change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic used in a 
research protocol. 
• Breach of confidentiality 
• Change to the protocol taken without prior IRB review to eliminate apparent immediate hazard to a 
research participant. 
• Incarceration of a participant when the research was not previously approved under Subpart C and the 
investigator believes it is in the best interest of the participant to remain on the study. 
• Complaint of a participant when the complaint indicates unexpected risks, or the complaint cannot be 
resolved by the research team. 
• Protocol violation (meaning an accidental or unintentional deviation from the IRB approved protocol) 
that in the opinion of the investigator placed one or more participants at increased risk or affects the 
rights or welfare of participants. 
The IRB will accept other reports when the investigator is unsure whether the event should be reported, and the 
IRB will review such reports to determine whether the event meets the threshold for an unanticipated event 
presenting risk to the participant.  Reports requiring IRB consideration or consultation are to be emailed to 
Tracy Ziolek, Vice President, Human Research Affairs at UnitedHealth Group at tracy_ziolek@uhg.com. 
 
11.1 Reporting Process to IRB. 
Principal Investigators are encouraged to submit reports of unanticipated problems posing risks to participants 
or others via a written report of the event (including a description of the event with information regarding its 
fulfillment of the above criteria, follow-up/resolution and need for revision to consent form and/or other study 
documentation) within 7 working days to the UnitedHealth Group Office of Human Research Affairs (OHRA).  
Participating sites should follow local, institutional guidelines on Event Reporting. For reportable deaths, the 
initial submission to the IRB may be made by contacting Tracy Ziolek at tracy_ziolek@uhg.com. 
This study is IND exempt and reporting to the FDA is voluntary using a MedWatch 3500 or via the FDA’s 
website for voluntary reporting. 
12.0 PARTICIPANT WITHDRAWAL 
Each participant has the right to withdraw from the study at any time without prejudice. The investigators may 
discontinue any participant’s participation for any reason, including adverse event or failure to comply with the 
protocol. Should a participant withdraw from the study, the reason(s) must be recorded within the study portal.  
Reasons for withdrawal include the following: 
• Progression of Disease: Remove participant from study at the time progressive disease is documented. 
• Extraordinary Medical Circumstance: If at any time the treating physician feels constraints of this protocol 
are detrimental to the participant’s health the participant should be withdrawn. 
• Participant’s refusal to continue treatment: In this event, document the reason(s) for treatment refusal. 
• Failure to comply with protocol (as judged by the investigator such as compliance below 80%, failure to 
maintain appointments, etc.). 
• Delay in treatment > 7 days due to toxicity or ongoing toxicity ≥ Grade 2 following two (2) dose 
reductions.   


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Confidential    5.12.2020                                                                           
 
 
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13.0 MEDICAL MONITORING 
It is the responsibility of the investigators to oversee the safety of the study at their site. This safety monitoring 
will include careful assessment and appropriate reporting of adverse events, as noted above, as well as the 
construction and implementation of a site data and safety monitoring plan. Medical monitoring by an independent 
clinician, will include a regular assessment of the number and type of serious adverse events on a periodic basis.   
13.1 Study Monitoring Plan 
This study will be monitored by the investigators and sub-investigators, as appropriate. Such monitoring will 
include at least weekly meetings of the study team to review accrual, toxicity, SAEs. Dose escalations and study 
finding. In addition, the PI will ensure that data are completed in a timely manner and their designee will review 
the data for accuracy, completeness and integrity.  
13.2 Auditing and Inspecting 
The investigator will permit the Office of Human Research Affairs, UnitedHealth Group to review records, data 
and facilities at mutually agreeable times. This study will be audited on an as needed basis with a complete review 
occurring at completion of enrollment. If enrollment numbers are not met, audit will occur in alignment with 
being notified of closure of the trial. 
14.0 SCHEDULE OF EVENTS  
See appropriate Process Flows for PATCH 2 (Sub-Study 1) and PATCH 3 (Sub-Study 2)  
 
15.0 MEASUREMENT OF EFFECT 
15.1 Definitions 
Evaluable for toxicity:  All participants will be evaluable for toxicity from the time of their first treatment with 
HCQ or placebo through final assessment. 
Evaluable for primary outcome: Participants who received at least one continuous week of HCQ will be evaluable 
for the primary outcome.   
15.2 Response Criteria 
PATCH 2 (Sub-Study 1): Measurement of SARS-CoV-2 positivity confirmed by an accepted testing method. 
Rate of hospitalization will be defined by a hospitalization occurring within 30 days of the date of participant 
enrollment. 
PATCH 3 (Sub-Study 2): Rate of COVID-19 infection will be defined by measurement of SARS-CoV-2 
identified by accepted testing methods.  
 
16.0 STATISTICAL CONSIDERATIONS 
16.1 Sample size calculation  
Because we are uncertain about the outcome values for both control (placebo) and treatment (HCQ) arms of the 
study, we will use group-sequential methods, allowing us to stop early for both efficacy and futility.  We conduct 
two interim analyses and a final analysis, after approximately 1/3, 2/3, and 100% of participants have completed. 


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Confidential    5.12.2020                                                                           
 
 
27 
 
We will use the Hwang-Shih-DeCani alpha spending rules.  Boundaries for efficacy and futility decisions are 
shown below.  Futility boundaries are non-binding. 
 
z-value ──── Boundaries ──── 
Information 
Stage 
Efficacy 
Futility 
Proportion 
1 
2.7819 
-0.8235 
0.3400 
2 
2.2653 
0.4262 
0.6800 
3 
1.6813 
1.6813 
1.0000 
 
p-value ──── Boundaries ──── 
Information 
Stage 
Efficacy 
Futility 
Proportion 
1 
0.00270 
0.79490 
0.3400 
2 
0.01175 
0.33497 
0.6800 
3 
0.04636 
0.04636 
1.0000 
 
 
PATCH 2 (Sub-Study 1), Home quarantined patients with COVID-19: We will assume the null 
hypothesis that in the placebo arm 70% will recover without requiring hospitalization. For the low dose HCQ 
cohort 95% of home quarantined patients recover without requiring hospitalization. We will continue to 
enroll and randomize patients at the time of testing 1:1 HCQ to control until we reach at least 100 patients 
with at least 50 in the low dose HCQ arm and at least 50 in the placebo arm who have tested positive 
COVID19. The one-sided z- test (alpha=.05) will have an at least 90% power to detect a significant difference 
between the groups of greater than 25% between the population rates. We estimate we will need to enroll 500 
patients at the time of testing to reach the 100 patients who test positive for COVID19. 
 
The hypothesis will be tested with only patients who tested positive for COVID19 using a one-sided test, 
with a z-score corresponds to the log of the odds-ratio for recovery between the two groups. We will obtain 
the estimate of the odds ratio, and 95% CI, from logistic regression. As a secondary analysis, we will stratify 
the analysis, and obtain separate estimates of the odds-ratio by group. However, we are not powered to test 
the interaction for significance, and we do not expect significance within group.   
 
 
Interim analysis: We will perform two interim analyses at 34% and 68% completion, testing for early efficacy 
or futility, using z-score boundaries that follow Hwang-Shih-DeCani alpha spending rules.  Following those 
rules, we have 90% power using 100% of the sample, if scenario is true.  
 
PATCH 3 (Sub-Study 2), Prophylaxis in Health Care Workers: The transmission of SARS-COV-2 from 
patient to hospital worker depends on many factors including specifics of standard care to prevent 
transmission, but especially on the number of patients seen at a given hospital or outpatient practice. Across 
China the reported hospital worker infection rate is 3.8%, but in Wuhan it is reported as 58% at the height of 
the epidemic. We will use a 10% transmission rate as the null hypothesis (low dose group). In order for HCQ 
to be considered effective our alternative hypothesis will be a 1% transmission rate. With a 1:1 randomization 
for the HCQ to control arms we would require a total of 350 health care workers across all participating 
ProHealth NY and AHN sites.  With the placebo group of 175 participants and the high dose HCQ arm of 
175 participants, a one-sided z-test (alpha=0.05) comparing the rates in the two groups would have an at least 
80% power to detect a significant difference when the difference in the population rates is at least 9%.  
 
The hypothesis will be tested using a one-sided test, with a z-score corresponds to the log of the odds-ratio 
for the rate of transmission between the two groups. We will obtain the estimate of the odds ratio, and 95% 
CI, from logistic regression.   
 


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Confidential    5.12.2020                                                                           
 
 
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Interim analysis: We will perform two interim analyses at 25% and 50% completion, testing for early efficacy 
or futility, using z-score boundaries that follow Hwang-Shih-DeCani alpha spending rules.  Following those 
rules, we have 80% power using 100% of the sample, if our 10% versus 1% scenario is true.  
 
Z-Value Boundaries ────────────────────────────────────────────────────────── 
 
──── Boundaries ──── 
Information 
Stage 
Efficacy 
Futility 
Proportion 
1 
2.9473 
-1.2318 
0.2500 
2 
2.5825 
-0.2676 
0.5000 
3 
1.6664 
1.6664 
1.0000 
 
P-Value Boundaries ────────────────────────────────────────────────────────── 
                  ──── Boundaries ──── 
Information 
Stage 
Efficacy 
Futility 
Proportion 
1 
0.00160 
0.89099 
0.2500 
2 
0.00491 
0.60550 
0.5000 
3 
0.04782 
0.04782 
1.0000 
 
16.2 Analysis of Secondary Endpoints. 
Secondary outcomes will be analyzed as summary statistics, with group means, odds-ratios, and 95% CIs. 
We may conduct exploratory analyses using regression methods appropriate for each type of measure.  Tests 
for significance of estimated parameters will not be reported as we will not be controlling for multiple testing. 
 
PATCH 2 (Sub-Study 1): Rate of secondary infection of housemates is a binomial count by household. We 
will summarize the proportion or rate by group, with 95% CI. With sufficient data, we will explore subgroups, 
patient, and secondary patient characteristics using logistic regression. Rate of hospitalization is a binary 
measure. We will summarize rates by group and estimate the odds-ratio for treatment. Adverse event rates 
will be summarized as a count by participant, and mean count by group, and we will estimate a rate-ratio for 
treatment.  We will summarize rates by group and estimate the odds-ratio for treatment. 
 
PATCH 3 (Sub-Study 2): Rate of hospitalization is a binary measure. We will summarize rates by group 
and estimate the odds-ratio for treatment. Adverse event rates will be summarized as a count by participant, 
and mean count by group, and we will estimate a rate-ratio for treatment. We will summarize the count of 
shifts missed by group and estimate the rate ratio for treatment.   
 
REFERENCES 
1. 
Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. 
Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 
2020. Epub 2020/02/08. doi: 10.1001/jama.2020.1585. PubMed PMID: 32031570. 
2. 
Ong SWX, Tan YK, Chia PY, Lee TH, Ng OT, Wong MSY, Marimuthu K. Air, Surface Environmental, and Personal 
Protective Equipment Contamination by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) From a Symptomatic 
Patient. JAMA. 2020. Epub 2020/03/05. doi: 10.1001/jama.2020.3227. PubMed PMID: 32129805. 
3. 
Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak 
in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020. Epub 
2020/02/25. doi: 10.1001/jama.2020.2648. PubMed PMID: 32091533. 
4. 
Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 
150 patients from Wuhan, China. Intensive Care Med. 2020. Epub 2020/03/04. doi: 10.1007/s00134-020-05991-x. PubMed PMID: 
32125452. 
5. 
Liu J, Liao X, Qian S, Yuan J, Wang F, Liu Y, Wang Z, Wang FS, Liu L, Zhang Z. Community Transmission of Severe 
Acute Respiratory Syndrome Coronavirus 2, Shenzhen, China, 2020. Emerg Infect Dis. 2020;26(6). Epub 2020/03/04. doi: 
10.3201/eid2606.200239. PubMed PMID: 32125269. 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
29 
 
6. 
Li F. Receptor recognition mechanisms of coronaviruses: a decade of structural studies. J Virol. 2015;89(4):1954-64. Epub 
2014/11/28. doi: 10.1128/JVI.02615-14. PubMed PMID: 25428871; PMCID: PMC4338876. 
7. 
Wang H, Yang P, Liu K, Guo F, Zhang Y, Zhang G, Jiang C. SARS coronavirus entry into host cells through a novel 
clathrin- and caveolae-independent endocytic pathway. Cell Res. 2008;18(2):290-301. Epub 2008/01/30. doi: 10.1038/cr.2008.15. 
PubMed PMID: 18227861. 
8. 
Chu VC, McElroy LJ, Chu V, Bauman BE, Whittaker GR. The avian coronavirus infectious bronchitis virus undergoes direct 
low-pH-dependent fusion activation during entry into host cells. J Virol. 2006;80(7):3180-8. Epub 2006/03/16. doi: 
10.1128/JVI.80.7.3180-3188.2006. PubMed PMID: 16537586; PMCID: PMC1440383. 
9. 
Zheng Y, Shang J, Yang Y, Liu C, Wan Y, Geng Q, Wang M, Baric R, Li F. Lysosomal Proteases Are a Determinant of 
Coronavirus Tropism. J Virol. 2018;92(24). Epub 2018/09/28. doi: 10.1128/JVI.01504-18. PubMed PMID: 30258004; PMCID: 
PMC6258935. 
10. 
Keyaerts E, Li S, Vijgen L, Rysman E, Verbeeck J, Van Ranst M, Maes P. Antiviral activity of chloroquine against human 
coronavirus OC43 infection in newborn mice. Antimicrob Agents Chemother. 2009;53(8):3416-21. Epub 2009/06/10. doi: 
10.1128/AAC.01509-08. PubMed PMID: 19506054; PMCID: PMC2715625. 
11. 
Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, Seidah NG, Nichol ST. Chloroquine is a potent 
inhibitor of SARS coronavirus infection and spread. Virol J. 2005;2:69. Epub 2005/08/24. doi: 10.1186/1743-422X-2-69. PubMed 
PMID: 16115318; PMCID: PMC1232869. 
12. 
de Wilde AH, Jochmans D, Posthuma CC, Zevenhoven-Dobbe JC, van Nieuwkoop S, Bestebroer TM, van den Hoogen BG, 
Neyts J, Snijder EJ. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East 
respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother. 2014;58(8):4875-84. Epub 2014/05/21. 
doi: 10.1128/AAC.03011-14. PubMed PMID: 24841269; PMCID: PMC4136071. 
13. 
Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G. Remdesivir and chloroquine effectively 
inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020. Epub 2020/02/06. doi: 10.1038/s41422-020-
0282-0. PubMed PMID: 32020029. 
14. 
Amaravadi RK, Lippincott-Schwartz J, Yin XM, Weiss WA, Takebe N, Timmer W, DiPaola RS, Lotze MT, White E. 
Principles and current strategies for targeting autophagy for cancer treatment. Clin Cancer Res. 2011;17(4):654-66. Epub 2011/02/18. 
doi: 10.1158/1078-0432.CCR-10-2634. PubMed PMID: 21325294; PMCID: PMC3075808. 
15. 
Rangwala R, Chang YC, Hu J, Algazy K, Evans T, Fecher L, Schuchter L, Torigian DA, Panosian J, Troxel A, Tan KS, 
Heitjan DF, Demichele A, Vaughn D, Redlinger M, Alavi A, Kaiser J, Pontiggia L, Davis LE, O'Dwyer PJ, Amaravadi RK. 
Combined MTOR and autophagy inhibition: Phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid 
tumors and melanoma. Autophagy. 2014;10(8). PubMed PMID: 24991838. 
16. 
Rangwala R, Leone R, Chang YC, Fecher L, Schuchter L, Kramer A, Tan KS, Heitjan DF, Rodgers G, Gallagher M, Piao S, 
Troxel A, Evans T, Demichele A, Nathanson KL, O'Dwyer PJ, Kaiser J, Pontiggia L, Davis LE, Amaravadi RK. Phase I trial of 
hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma. Autophagy. 2014;10(8). 
PubMed PMID: 24991839. 
17. 
Vogl DT, Stadtmauer EA, Tan KS, Heitjan DF, Davis LE, Pontiggia L, Rangwala R, Piao S, Chang YC, Scott EC, Paul TM, 
Nichols CW, Porter DL, Kaplan J, Mallon G, Bradner JE, Amaravadi RK. Combined autophagy and proteasome inhibition: A phase 1 
trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma. Autophagy. 2014;10(8). PubMed PMID: 
24991834. 
18. 
Rosenfeld MR, Ye X, Supko JG, Desideri S, Grossman SA, Brem S, Mikkelson T, Wang D, Chang YC, Hu J, McAfee Q, 
Fisher J, Troxel A, Piao S, Heitjan DF, Tan KS, Pontiggia L, O'Dwyer PJ, Davis LE, Amaravadi RK. A phase I/II trial of 
hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly 
diagnosed glioblastoma multiforme. Autophagy. 2014;10(8). PubMed PMID: 24991840. 
19. 
Mahalingam D, Mita M, Sarantopoulos J, Wood L, Amaravadi R, Davis LE, Mita A, Curiel TJ, Espitia CM, Nawrocki ST, 
Giles FJ, Carew JS. Combined autophagy and HDAC inhibition: A phase I safety, tolerability, pharmacokinetic, and 
pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid 
tumors. Autophagy. 2014;10(8). PubMed PMID: 24991835. 
20. 
Barnard RA, Wittenburg LA, Amaravadi RK, Gustafson DL, Thorburn A, Thamm DH. Phase I clinical trial and 
pharmacodynamic evaluation of combination hydroxychloroquine and doxorubicin treatment in pet dogs treated for spontaneously 
occurring lymphoma. Autophagy. 2014;10(8). PubMed PMID: 24991836. 
21. 
Nti AA, Serrano LW, Sandhu HS, Uyhazi KE, Edelstein ID, Zhou EJ, Bowman S, Song D, Gangadhar TC, Schuchter LM, 
Mitnick S, Huang A, Nichols CW, Amaravadi RK, Kim BJ, Aleman TS. FREQUENT SUBCLINICAL MACULAR CHANGES IN 
COMBINED BRAF/MEK INHIBITION WITH HIGH-DOSE HYDROXYCHLOROQUINE AS TREATMENT FOR ADVANCED 
METASTATIC BRAF MUTANT MELANOMA: Preliminary Results From a Phase I/II Clinical Treatment Trial. Retina. 2018. doi: 
10.1097/IAE.0000000000002027. PubMed PMID: 29324592; PMCID: PMC6039280. 
 
 
 


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Confidential    5.12.2020                                                                           
 
 
30 
 
Appendix 1:  PATCH 2 Process Flows 
 
Person feels COVID-
19 symptoms and 
seeks testing & 
treatment at a study 
site
COVID-19 test 
performed, 
inclusion/ exclusion 
considered, & study 
offered at clinical 
site
Eligible patient 
registers at 
www.patchstudy.com 
and speaks with the 
study lead to 
consent 
to the study
The patient receives 
the study package at 
home which includes 
the study ID,  
medication (56 x 
200mg pills) & study 
materials
The patient confirms 
receipt at 
www.patchstudy.org 
and begins the 
study.  
Day 1
AM/ PM 
Medication + 
Temp + Tracking 
+ Study call  
Day 2
AM/ PM 
Medication + 
Temp + Tracking 
Day3
AM/ PM 
Medication + 
Temp + Tracking
  + Study call  
Day 4
AM/ PM 
Medication + 
Temp + Tracking 
Day 5
AM/ PM 
Medication + 
Temp + Tracking 
+ Study call  
Day 6
AM/ PM 
Medication + 
Temp + Tracking  
Day 7
AM/ PM 
Medication + 
Temp + Tracking 
Day 8
AM/ PM 
Medication + 
Temp + Tracking 
+ Study call  
Day 9
AM/ PM 
Medication + 
Temp + Tracking 
Day 10
AM/ PM 
Medication + 
Temp + Tracking 
Day 11
AM/ PM 
Medication + 
Temp + Tracking
   + Study call 
Day 12
AM/ PM 
Medication + 
Temp + Tracking 
+ Study call  
Day 13
AM/ PM 
Medication + 
Temp + Tracking  
Day 14
AM/ PM Medication 
+ Temp + Tracking 
+ Study Call
$50 Amazon Gift 
Card for tracking 
completion
Week Three
(Day 15-17)
 COVID-19 Testing & 
$50 Amazon Gift 
Card for testing 
completion
Week Five
(Day 29-31)
 COVID-19 Testing &
$50 Amazon Gift 
Card for testing 
completion
Study End
Awareness/ 
Enrollment
Test
Call
Self
Key
PATCH2 STUDY: Patients   (500 Participants)          
Randomized trial of hydroxychloroquine in the treatment of COVID-19
High-Level Patient Journey Map
Study Start
 
 
 


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Confidential    5.12.2020                                                                           
 
 
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 PATCH2 STUDY: Patients   (500 Participants)
Awareness &  Identification    Randomized trial of hydroxychloroquine in the prevention and treatment of COVID-19                                                       
Patient Pre-study
Awareness & Identification
Start
Patient experiences  COVID-19 
Symptoms at home
Patient seeks 
COVID testing 
and/or care at 
a care setting 
(drive-up or 
practice) 
that is 
participating 
in the study
Seeks Testing/ 
Care at Study 
Site? 
Study Flyers Posted 
in Clinical Settings
Yes
End
No
Administer 
COVID 
Collection 
Test
(Positive/ 
negative value 
only- No CT 
value)
Describe Study for 
COVID-19 Positive 
Patients, Share Flyer & 
URL & Inform of 
possible Study 
Outreach
(Confirm Phone 
Number)
Ship 
sample to 
lab 
following 
practice 
guidelines 
Quarantine? 
Study Brochure & URL
Practice Talking Points
EMR: 
Flag Patient in 
EMR  (based 
on fever 
symptom) for 
Study 
Enrollment 
Outreach
(Practice to 
determine 
process)
 History of fever 
in the past 4 
days (e.g. above 
100.4)?
Not study eligible
Provide Standard Care
No
Yes
Study Team uses Study Site to Monitor for 
patients who began study enrollment 
(See Inbound Enrollment Process)
Study Team uses EMR flagged patients 
as enrollment queue.  Refresh daily to 
most recent diagnosed. 
(See Outbound Enrollment Process)
EMR
No
Patient is a potential for
 study outreach
Put in study queue
Patient logs into study site 
and begins enrollment.
Required outreach 
by Study Team 
For Consent
Between 50 
and 75 years of 
age. 
Practice 
determines 
COVID-19 test is 
necessary? 
No
Yes
Yes
Yes
 
 
 
PATCH2 STUDY: Patients   (500 Participants)
Enrollment Channels   Randomized trial of hydroxychloroquine in the treatment of COVID-19          
Primary Enrollment 
Channel
Secondary Enrollment Channel 
(as needed)
Patient receives Study 
Brochure when seeking 
COVID-19 Testing and 
decides to enroll in the study. 
• 
Study Team uses Study Site to Monitor for patients who 
began study enrollment.  
• 
These patients  require an outreach by the study team
• 
Study Team uses EMR to Monitor for patients who are study qualified and may be 
interested in the study  
• 
These patients may receive an outreach for the study pending on inbound interest 
volume and length of EMR queue
EMR
Identified 
study 
qualified 
flagged in 
EMR
Study team 
build study 
queue from 
EMR.  Work 
most recently 
seen patients 
first
Phone
Patient 
Outreach & 
Study 
Description
(phone)
Interest? 
Study site 
access during 
enrollment call? 
 If Phone only, 
Then study lead 
enters patient 
information in 
online study tool 
on their behalf
No
Yes
End
No
Patient goes to Study URL 
(www.patchstudy.com) to 
express interest in the 
patient study. 
 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
32 
 
PATCH2 STUDY: Patients   (500 Participants)
Enrollment    Randomized trial of hydroxychloroquine in the treatment of COVID-19          
Patient Enrollment  
(Study Portal + phone)
Patient Study 
Call Script
Consent 
Talking Points
Inclusion/ Exclusion Criteria 
Questions
Create User Profile/ Log-in
PATCH
Valid 
Shipping
Address?
 Live Consent 
with Study 
Personal
(Phone)
(DocuSign)
PATCH
Phone
COVID-19 Testing Results 
Check
Results 
Known? 
COVID 
Positive? 
Yes
Not Yet
Known
Patient calls 855-223-6987 to 
complete medication review and  
live consent
Start
Home Page: 
Select “Patient” on the PATCH home page to enroll in the study
Yes
End
No
Patient Study Consent Preview  
(Content)
Automatic 
Exclusions? 
Study Experience Review 
No
Additional Contact 
permission for reminders 
(ie Texting, email)
PATCH
Yes
Study Voice Mail: Study Lead call 
back to complete enrollment
Yes
Consent
Go to 
Medication 
Fulfillment
End
Yes
End
No
Unable to 
obtain
PATCH
Job Aid:  Exclusion Criteria 
& Drug Interaction Guide  
Offline 
medical 
determinatio
n with PI?
Connect 
with Study 
Lead?
Medication 
review for 
exclusions 
No
Yes
Study Lead  consults with 
clinical PI- Daniel Griffin, MD 
PhD or Deneen Vojta, MD 
for medical determination. 
Marks decision in the study 
tool (Date and time 
stamped). 
Call Back
Yes
PATCH
PATCH
Study Lead 
determines 
exclusions?
End
Yes
No
Validate Address for Welcome 
Kit & Provide Shipping 
Instructions
PATCH
 
 
PATCH2 STUDY: Patients   (500 Participants)
Randomization & Study ID Process
UHG R&D
HCW Study ID 
Creation
Placebo or 
Active?
Consented Study 
Participant
ID Generation 
Process
HCW or 
Patient?
Patient Study ID 
Creation
Patient
Placebo or 
Active?
Placebo
Active
Placebo
Active
Study Participant 
is fully matched 
with a study ID 
PATCH
PATCH
New Enrollee is placed in Contact Queue 
for shipments vendor (CSM)
Study  ID + Name/ Address are required 
for shipment purposes
Reference Enrollment 
Documents For 
Consenting Processes
HCW
New Enrollee Moves to Fulfillment Step
PATCH
 
 
PATCH2 STUDY: Patients   (500 Participants)
Medication & study kit determinations
PATCH2 STUDY:  PATIENT 
POPULATION
500 Participants
PARTICIPANT PACKAGE 1: Blinded Label
PATIENT + PLACEBO   
(A total of 250 shipments)
• 
Pill Bottle containing 200mg placebo pills (56 count)
• 
Instructions:  (Take 400mg (2 pills) in the AM daily and 400mg (2 pills) in 
the PM- 12 hours apart- for 14 days.  no refill)
• 
Patient Thermometer (as available)
• 
Study ID Card
• 
Study Journal/ Instructions/ FAQ/ Side effect & Contact information
PARTICIPANT PACKAGE 1: Blinded Label
PATIENT + ACTIVE MEDICATION 
(A total of 250 shipments)
• 
Pill Bottle containing 200mg pills (56 count)
• 
Instructions:  (Take 400mg (2 pills) in the AM daily and 400mg (2 pills) in 
the PM- 12 hours apart- for 14 days.  no refill)
• 
Patient Thermometer (as available)
• 
Study ID Card
• 
Study Journal/ Instructions/ FAQ/ Side effect & Contact information
56 
count
Active
blinded
200 mg
56 
count
Placebo
blinded
200 mg
 
 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
33 
 
 
PATCH2 STUDY: Patients   (500 Participants)
Participation    Randomized trial of hydroxychloroquine in the treatment of COVID-19                                                     
Patient Experience (with no adverse events or worsening symptoms)
“Package One” Includes: 
Study ID, Medication (placebo or active), Study 
Purpose Reminder, Study Instructions, Consent 
summary,  Contact Information, Journal/ Experience 
Log and Pens (Thermometers as available)
Patient 
Confirmed 
Package Receipt 
in Study Portal? 
Patient Receive “Welcome Kit” 
by courier delivery at designated 
address (CSM Vendor)
See previous 
enrollment 
steps
PATCH
Study Lead calls 
patient to 
confirm receipt 
of welcome kit
No
Study 
participation 
phase start
Yes
AM & PM:  Participants will 
record in study portal: 
1) temperature (to be taken twice 
daily) 
2) times medication taken 
(400mg (2 pills) to be taken twice 
daily)
3) any symptoms and adverse 
events 
4) If any co-inhabitants (people in 
household) develop symptoms 
and/or become positive for 
COVID-19 (confirmed by accepted 
testing methods).
Medication Directions: 
Take 400mg (2 pills) in the AM 
daily and 400mg (2 pills) in the 
PM- 12 hours apart- for 14 days. 
Week One Participant Activities 
Day One: 
AM: Medication
AM: Temperature
AM: Study Log
PM: Medication
PM: Temperature
PM: Study Log
Study Call:  Clinical 
Symptom Monitoring
Testing results if avail.
(Approx. 45 min)
Day Two: 
AM: Medication
AM: Temperature
AM: Study Log
PM: Medication
PM: Temperature
PM: Study Log
(Approx. 30 min)
Day Three:  
AM: Medication
AM: Temperature
AM: Study Log
PM: Medication
PM: Temperature
PM: Study Log
Study Call:  Clinical 
Symptom Monitoring
Testing results if avail.
(Approx. 45 min)
Day Four: 
AM: Medication
AM: Temperature
AM: Study Log
PM: Medication
PM: Temperature
PM: Study Log
(Approx. 30 min)
Day Five:  
AM: Medication
AM: Temperature
AM: Study Log
PM: Medication
PM: Temperature
PM: Study Log
Study Call:  Clinical 
Symptom Monitoring
Testing results if avail.
(Approx. 45 min)
Day Six:  
AM: Medication
AM: Temperature
AM: Study Log
PM: Medication
PM: Temperature
PM: Study Log
(Approx. 30 min)
Day Seven:  
AM: Medication
AM: Temperature
AM: Study Log
PM: Medication
PM: Temperature
PM: Study Log
(Approx. 30 min)
Week Two Participant Activities
Day Eight (8): 
AM: Medication
AM: Temperature
AM: Study Log
PM: Medication
PM: Temperature
PM: Study Log
Study Call:  Clinical 
Symptom Monitoring
(Approx. 45 min)
Day Nine (9):  
AM: Medication
AM: Temperature
AM: Study Log
PM: Medication
PM: Temperature
PM: Study Log
(Approx. 30 min)
Day Ten (10):  
AM: Medication
AM: Temperature
AM: Study Log
PM: Medication
PM: Temperature
PM: Study Log
(Approx. 30 min)
Day Eleven (11): 
AM: Medication
AM: Temperature
AM: Study Log
PM: Medication
PM: Temperature
PM: Study Log
Study Call:  Clinical 
Symptom Monitoring
(Approx. 45 min)
Day Twelve (12):  
AM: Medication
AM: Temperature
AM: Study Log
PM: Medication
PM: Temperature
PM: Study Log
(Approx. 30 min)
Day Thirteen (13):  
AM: Medication
AM: Temperature
AM: Study Log
PM: Medication
PM: Temperature
PM: Study Log
(Approx. 30 min)
Day Fourteen (14):  
AM: Medication
AM: Temperature
AM: Study Log
PM: Medication
PM: Temperature
PM: Study Log
Study Call: Symptom 
Monitoring & Next 
Steps- Meds Complete
$50 Amazon Gift Card 
for tracking completion
PATCH
All activities are 
logged in the study 
portal
See data protocol and 
data dictionary as 
sources of truth
Week Three Participant Activities  (Days 15 -21)
Days 15, 16 or 17 
COVID 19 Testing - Patient visit a designated clinic for follow-up 
Track testing complete in Study Portal and the day of the test 
(Test must be between day 15 and day 28 to be study valid)
Week Five Participant Activities (Days (29-31)
Days 29, 30 or 31 
COVID 19 Testing - Patient visit a designated clinic for follow-up 
Track testing complete in Study Portal and the day of the test  
(Test must be between days 29 and 43 to be study valid)
STUDY 
COMPLETION
Week Four  No Study Activity  (Days 22-28)
Generate $50  Amazon Gift 
Card for Week 5 Testing
Generate $50  Amazon Gift 
Card for Week 3 Testing
Test 
COVID-19 
negative?
EMR
EMR
EMR
Disenrollment
Test 
COVID-19 
negative?
Test 
COVID-19 
negative?
EMR
EMR
PATCH
PATCH
 
 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
34 
 
PATCH2 STUDY: Patients   (500 Participants)
Symptoms/ Adverse Events    Randomized trial of hydroxychloroquine in the treatment of COVID-19                                                          
Patient Experience – with Symptoms and/or Adverse Events
Clinical 
Research 
Coordinator
“Study lead”
• 
Three times a week for two weeks (six calls total), participants will be 
called by clinical research coordinators to assess for adverse events and 
symptoms.  All discussions are well-documented.
• 
 The clinical research coordinators will review the study portal to assess 
for Adverse Events (AE). 
Patient
IF adverse events or worsening symptoms: 
• 
IF severe (see protocol and job aid for 
content) call 911.  
• 
IF otherwise, then call the study lead and 
track symptoms in the study portal (as able). 
Adverse events 
and/or 
worsening 
symptoms from 
baseline?
Remain in 
self-
quarantine 
Patient calls Study Lead to  
report worsening symptoms 
from baseline (unexpected or 
severe related to COVID-19)
Study Lead tracks detailed call 
notes in tracker. Informs of 
follow-up call within 24 hours. 
Phone
PATCH
Study Lead  consults 
with clinical PI- 
Daniel Griffin, MD 
PhD or Deneen 
Vojta, MD for 
medical 
determination. Mark 
recommendations  
in the study tool 
(Date and time 
stamped). 
PATCH
Study Lead to call Patient to 
inform of PI of medical 
determination.  Uses talking 
points entered into the PATCH 
study tool
PATCH
Phone
PATCH
PATCH
Medication 
adverse 
event?  
Severe?
(see protocol 
criteria) 
Yes
Call 911/ 
Go to ER
No
Severe?
(see protocol 
criteria) 
No
Yes
Determine 
purpose of call 
No
Yes
Patient logs 
symptoms in 
study log
PATCH
Study Lead  consults with clinical PI- Daniel 
Griffin, MD PhD or Deneen Vojta, MD for 
medical determination. Marks decision in 
the study tool (Date and time stamped). 
Study Lead to call Patient to 
inform of recommendation.  
Communicate next steps. 
PATCH
Offline 
medical 
determination 
with PI
No
Phone
end
PATCH
 
 
 
 
 
 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
35 
 
Appendix 2: PATCH 3 Process Flow  
 
Health Care 
Worker
 Health Care Worker 
“HCW”(MD, DO, NP, 
PA or RN)  is exposed 
to COVID-19 patients 
and qualifies for the 
study
HCW registers at 
www.patchstudy.com 
and speaks with the 
research coordinator 
to consent to the 
study
The HCW  receives 
the study package at 
home which includes 
the study ID,  
medication (90 x 
200mg pills) & study 
materials
The HCW confirms 
receipt at 
www.patchstudy.com 
and begins the study.  
Study End
Enrollment
 PATCH3 STUDY: HEALTH CARE WORKERS   (350 Participants)          
Randomized trial of hydroxychloroquine in the prevention of COVID-19
Health Care Worker (HCW) Journey Map
Study Start
Daily Tracking: 
• Medication,
• AM/ PM 
Temp, 
• Symptoms/ 
Adverse 
Events 
1
2
3
4
5
6
7
Week 1
8
9
10
11
12
13
14
Week 2
15
16
17
18
19
20
21
Week 3
22
23
24
25
26
27
28
Week 4
29
30
31
32
33
34
35
Week 5
36
37
38
39
40
41
42
Week 6
43
44
45
46
47
48
49
Week 7
50
51
52
53
54
55
56
Week 8
Clinical 
Research 
Coordinator
Test
Call
Self
Key
If HCW experiences 
influenza like 
symptoms, then she/
he immediately self-
quarantines and seeks 
testing  
IF COVID-19 
symptoms are evident 
through the study 
portal, THEN the 
research coordinator 
will outreach to the 
HCW
If HCW is 
symptomatic, then 
she/he calls the 
Clinical Research 
Coordinator for 
medication crossover 
consideration and 
tracks symptoms in 
the study portal.
Weekly, the 
clinical research 
coordinators will 
review the study 
portal for tracking, 
med adherence, AE, 
symptoms and 
temperature 
Medication Refill? 
57
58
59
60
61
62
63
Week 9
[COVID-19 Test Administered 
between days 61 and 63]
Week 10
COVID-19 Test Results Reported and Entered into the Study Tool
LGC COVID Test?
 
 
 
 PATCH3 STUDY: HEALTH CARE WORKERS   (350 Participants)
Study Awareness       Randomized trial of hydroxychloroquine in the prevention of COVID-19                                                       
HCW Study Awareness
Start: 
Heath Care Worker (MD, DO, NP, PA or 
RN or other members of the medical care 
team with significant COVID-19  
exposure) learns of study is considering 
participation
HCW  is scheduled 
to work no less 
than 20 hours/wk  
in the next two 
months
Out of study scope
Health Care Worker, 
“HCW”  is exposed to 
COVID-19 patients
Exposure?  
Work Hours 
+20/ wk?
HCW has not yet 
been diagnosed 
with COVID-19 
(PCR Negative)
Test 
Negative or 
no test? 
HCW his 
asymptomatic to 
COVID-19 (no 
cough, no fever, no 
sore throat)
Symptoms?
No
Yes
No
Yes
COVID- 19 
positive
Yes
Known COVID-19 
symptoms
Has personal interest 
in participating in this 
Human Subject 
research study?
No one is required to 
participate
No
Interest?
No
Study Flyers Posted in Clinical Settings
Study Information shared by Research Coordinator 
Team in Meetings at Clinical Site (Group Settings)
 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
36 
 
 PATCH3 STUDY: HEALTH CARE WORKERS   (350 Participants)
Enrollment       Randomized trial of hydroxychloroquine in the prevention of COVID-19                                                       
HCW Study Enrollment
Coordinator call 
HCW to inform of 
decision
Exclusion 
Criteria 
Questions
Create User 
Profile/ Log-in
Verbally validate 
HCW has not yet 
been diagnosed 
with COVID-19 PCR 
www.patchstudy.com home/
landing page: 
Select “Health Care Worker” on 
the PATCH home page to enroll 
in the study
Automatic 
exclusion? 
Study 
Experience 
Review 
HCW  is scheduled to 
work no less than 20 
hours/wk  in the next 
two months
Health Care Worker 
“HCW”  is exposed 
to COVID-19 
patients
HCW is asymptomatic to 
COVID-19 (no cough, no fever, 
no sore throat)
End
Yes
Validate Address for 
Welcome Kit & 
Provide Shipping 
Instructions
Valid 
Shipping
Address?
 Live Consent 
with Research 
Coordinator
(Phone) 
Phone
HCW calls study 
phone line to 
complete 
medication review 
and  live consent
HCW  Study 
Consent Preview 
(Content) and 
DocuSign
Yes
Study Voice 
Mail: 
Coordinator 
call back to 
complete 
enrollment
Yes
Consent
Go to 
Medication 
Fulfillment Page
No
Unable
 to 
obtain
Offline 
medical 
determinatio
n with PI?
Connect with 
Coordinator?
Live 
Medication 
review for 
exclusions 
No
Yes
Research Coordinator  
consults with clinical PI- 
Daniel Griffin, MD PhD or 
Deneen Vojta, MD for 
medical determination. 
Marks decision in the study 
tool (Date and time 
stamped). 
Coordinator 
determines 
exclusions?
End
Yes
No
Additional Contact 
permission for 
reminders 
(ie Texting, email)
Eligible? 
End
No
Yes
Start
Tested?
COVID 
Positive? 
End
Yes- Offer to enroll 
in Patient Study 
if home quarantined
Yes
No
Yes
No
Yes
HCW Study 
Call Script
Job Aid:  Exclusion Criteria 
& Drug Interaction Guide  
Consent 
Talking Points
 
 
  
 PATCH3 STUDY: HEALTH CARE WORKERS   (350 Participants)
Randomization & Study ID Process (Offline- not consumer facing)
UHG R&D
HCW Study ID 
Creation
Placebo or 
Active?
Consented Study 
Participant
ID Generation 
Process
HCW or 
Patient?
Patient Study ID 
Creation
Patient
Placebo or 
Active?
Placebo
Active
Placebo
Active
Study Participant 
is fully matched 
with a study ID 
New Enrollee is placed in Contact Queue 
for shipments vendor (CSM)
Study  ID + Name/ Address are required 
for shipment purposes
Reference Enrollment 
Documents For 
Consenting Processes
HCW
New Enrollee Moves to Fulfillment Step
 
 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
37 
 
 PATCH3 STUDY: HEALTH CARE WORKERS   (350 Participants)
Medication & study kit determinations       Randomized trial of hydroxychloroquine in the prevention of COVID-19                                                       
 PATCH3 STUDY: HEALTH CARE WORKERS
  350 Participants
PARTICIPANT PACKAGE 1: Blinded Label
HCW + ACTIVE MEDICATION  
• 
Pill bottle containing 200mg pills (90 count)
• 
Instructions: Take 600mg (3 pills) in the AM daily for 
a total of 30 days. One refill will be shipped to you.
• 
Study Journal (Instructions/ FAQ/ Side effect & 
Contact information)
• 
Medication Guide
• 
Thermometer
• 
Pen
 PARTICIPANT PACKAGE 2: Blinded Label
HCW + ACTIVE MEDICATION   
• 
Pill Bottle containing 200mg pills (90 count)
• 
Instructions: Take 600mg (3 pills) in the AM daily 
for 30 days. No refill.
• 
Medication guide
Symptom 
onset and/
or adverse 
events? 
PARTICIPANT PACKAGE 1: Blinded Label
HCW + PLACEBO
• 
Pill bottle containing 200mg placebo pills (90 count)
• 
Instructions: Take 600mg (3 pills) in the AM daily for 
a total of 30 days. One refill will be shipped to you.
• 
Study Journal (Instructions/ FAQ/ Side effect & 
Contact information)
• 
Medication Guide
• 
Thermometer
• 
Pen
 PARTICIPANT PACKAGE 2: Blinded Label
HCW + PLACEBO MEDICATION  
• 
Pill bottle containing 200mg placebo pills (90 
count)
• 
Instructions: Take 600mg (3 pills) in the AM daily 
for 30 days. No refill.
• 
Medication guide
Yes (+ Swab Testing) 
Cross Over:
If test is positive then un-blind
(If rapid progression of symptoms 
then go to ER and un-blind)
Symptom 
onset? 
No
Study 
Shipments 
Complete
90 count
Active
blinded
200 mg
90 count
Placebo
blinded
200 mg
90 count
Active
blinded
200 mg
No
 PARTICIPANT PACKAGE 2: Un-blinded Label
HCW + ACTIVE MEDICATION   
• 
Pill Bottle containing 200mg pills (42 count)
• 
Instructions:  Take 600mg (3 pills) in the AM daily 
for 14 days.  No refill
• 
Medication guide
42 count
Active
unblind
200 mg
90 count
Placebo
blinded
200 mg
Yes + 
Swab Testing
Mark test positive 
in study tool
(If rapid progression of 
symptoms then go to ER)
 
 
 PATCH3 STUDY: HEALTH CARE WORKERS   (350 Participants)
Participation       Randomized trial of hydroxychloroquine in the prevention of COVID-19                                                       
Welcome Kit
Medication 
re-fill
Testing Kit
“Package One” Includes: 
Study ID, Medication  200mg pills/ 90 count- 
(placebo or active), Journal/Experience Log (study 
purpose reminder, study instructions, consent 
summary,  contact information), Medication Guide, 
Pen and Thermometer
HCW Confirmed 
Package Receipt 
in Study Portal? 
HCW Receive “Welcome Kit” by 
courier delivery at designated 
address (CSM Vendor)
Coordinator calls 
HCW to confirm 
receipt of welcome 
kit
No
GO TO STUDY 
START
Yes
“Package Two” Includes: 
Pill Bottle containing 200mg pills (90 count)
Instructions:  Take 600mg (3 pills) in the AM daily for 
60 days. No refill
See 
enrollment 
for trigger
Coordinator calls to gather 
study data and confirm 
participation. 
End
Coordinator 
confirms active 
participation on 
Day 21 by 
validating portal 
tracking
Active 
Participant? 
No
Yes, trigger shipment
Active 
Participant? 
Yes
No
LGC Single Test + 
PATCH3 study 
instructions 
Shipment 
triggered by LGC
At the end of week seven or 
start of week eight (between 
days 48-50), the research 
coordinator communicates 
with the HCW to inform of  
testing kit shipment during a 
study check-in call.  
Coordinator- DO:  Trigger LGC 
test kit shipment in study 
tool.  
Phone
PATCH
HCW Confirmed 
Package Receipt 
in Study Portal? 
Coordinator calls 
HCW to confirm 
receipt/ answers 
questions
No
Yes
STUDY 
COMPLETION
Coordinator: 
COVID-19 Testing 
Results Captured 
in Study Tool & 
shared with 
HCW? 
LGC Lab Receives 
PCR testing 
results from 
study participant 
and runs tests.  
 LGC sends PCR 
testing results 
via FTP to UHG  
R&D by 6am ET 
HCW 
Immediately ship  
Nose Swab test 
via UPS 
HCW conducts PCR 
& POC home tests 
on days 61-63.  
If questions, use 
LGC help tools or 
support line.
HCW loads POC 
(IGG/IGM) results 
into the study 
tool
 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
38 
 
 PATCH3 STUDY: HEALTH CARE WORKERS   (350 Participants)
Participation       Randomized trial of hydroxychloroquine in the prevention of COVID-19                                                       
 PATCH3 STUDY: HEALTH CARE WORKERS
  350 Participants
WEEK ONE HCW ACTIVITIES
STUDY 
COMPLETION
WEEK TWO HCW ACTIVITIES
DAILY
8
9
10
11
12
13
14
WEEK THREE HCW ACTIVITIES
DAILY
15
16
17
18
19
20
21
WEEK FOUR HCW ACTIVITIES
DAILY
22
23
24
25
26
27
28
WEEK FIVE HCW ACTIVITIES
DAILY
29
30
31
32
33
34
35
WEEK SIX HCW ACTIVITIES
DAILY
36
37
38
39
40
41
42
WEEK SEVEN HCW ACTIVITIES
DAILY
43
44
45
46
47
48
49
WEEK EIGHT HCW ACTIVITIES
DAILY
50
51
52
53
54
55
56
WEEK NINE HCW ACTIVITIES
DAILY
57
58
59
60
61
62
63
COVID-19 
Testing Results 
Captured in 
Study Tool and 
communicated 
to participant? 
HCW completes COVID-19 
Testing on Days 61-63. 
See fulfillment process
Yes
No- Validate
Completion 
with HCW
LGC
PATCH
Research Coordinator may call participants to: 
• 
Gather study data
• 
Check for adverse events
• 
Check symptoms
• 
Remind to seek testing at end of study
WEEK TEN  HCW ACTIVITIES
The HCW will record daily in the study site the following:
1) Temperature (to be taken twice daily- AM & PM) 
2) Medication- Times medication taken- 600mg/ 3 pills, once a day
3) Study Log (including symptoms and adverse events)  
Medication Directions:  Take 600mg (3 pills) in the AM daily for a total of 60 days. 
PATCH
All study 
activities 
are logged
STUDY START
DAILY
1
2
3
4
5
6
7
TESTING
64
65
66
67
68
69
70
Test Results Reported & Entered 
into Study Tool
PATCH
TESTING
 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
39 
 
 PATCH3 STUDY: HEALTH CARE WORKERS   (350 Participants)
Symptoms and/or Adverse Events       Randomized trial of hydroxychloroquine in the prevention of COVID-19                                                       
Health Care Worker (HCW) Experience – with Symptoms and/or Adverse Events
Phone
HCW calls Research Coordinator to  
report COVID-19 test taken. 
Coordinator tracks detailed call notes 
in study tracker.
Clinical 
Research 
Coordinator
• 
Every week, the Research Coordinators will review the study portal to 
assess for Adverse Events (AE) and indication of reported symptoms 
indicative of influenza like illness.  The research coordinator will also 
review for temperature.  
• 
IF COVID-19 symptoms are evident, THEN the research coordinator will 
outreach to the HCW (at clinic or by phone).
Health Care 
Worker
• 
If symptomatic or experiencing adverse events, 
then call Research Coordinator and track symptoms 
in the study portal.
• 
If symptoms are an influenza like, then  
immediately self-quarantine seek testing.  
COVID-19 
Symptomatic?
Seek testing 
for COVID-19  
Confirmed 
COVID-19  
infection 
positive? 
self-quarantine 
following 
clinical 
guidelines 
Research 
Coordinator 
enters positive 
COVID-19 
testing results 
in study tracker
PATCH
Severe? 
(see protocol 
guidelines)  
HCW logs 
reaction 
symptoms in 
study log
Testing 
Results 
Known?
Adverse event 
to 
medication?  
No
HCW follows 
current clinical 
guidelines for 
COVID-19
Severe?
(see protocol 
guidelines)
Yes
Yes
PATCH
Call 911
Yes
Research Coordinator  consults with 
clinical PI- Daniel Griffin, MD PhD or 
Deneen Vojta, MD for medical 
determination. Marks decision in the study 
tool (Date and time stamped). 
Research Coordinator to 
call HCW to inform of 
recommendation.  
Communicate next steps. 
Phone
PATCH
continue 
study 
No
HCW logs 
reaction 
symptoms in 
study log
No
Yes
No
No- check  back
Yes
HCW moves to 
“un-blinded” 
status
Offline 
medical 
determination 
with PI
Determine 
purpose of call 
PATCH
PATCH
PATCH
Go to Cross-
over Page
 
 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
40 
 
 PATCH3 STUDY: HEALTH CARE WORKERS   (350 Participants)
Cross-over Flow       Randomized trial of hydroxychloroquine in the prevention of COVID-19                                                       
Cross-over Flow To Study End
Research 
Coordinator enters 
positive COVID-19 
testing results in 
study tracker
PATCH
HCW continues daily tracking in Study 
Tool through study completion
Report all adverse events and 
symptoms
Starts 
active HCQ 
medication  
Tracks in 
study tool 
for the next 
14 days. 
End
Coordinator to call HCW to inform of “placebo” 
status.  Informs HCW that a shipment of the 
active drug can be triggered. 
Asks HCW to accept cross-over
Ask HCW to confirm receipt of active medication 
in study portal
Phone
Coordinator to call HCW to inform of 
“active drug” status. Communicate 
continue medications.  
Phone
PATCH
Accept 
cross-over?
Coordinator Triggers 
Active Medication 
Shipment in study tool. 
Will include crossover 
to active drug.  600mg 
(3 pills) for 14 days. 
Package containing 
200mg pills (42 count) 
PATCH
HCW moves to 
“un-blinded” 
status
Placebo? 
PATCH
Coordinator  to 
outreach to 
team for  
placebo vs active 
drug 
information.  
Let’s Get Checked Testing Kit 
(home testing) shipped.  Conduct test 
between study days 61 and 63. 
Coordinator 
Triggers 
shipment of 
Let’s Get 
Checked Testing 
Kit (one kit + 
study directions) 
 Conduct Let’s Get 
Checked Testing Kit 
(home testing) the 
day after active 
medication is 
complete  (days 15-
17 from start of 
active HCQ). 
Receive 
Active HCQ? 
Day 9-10:
Active in 
study? 
Study Complete 
No
Yes
Yes
No
No
Yes
Yes
LGC Kit 
reciept? 
No
Complete 
active HCQ 
and 
tracking? 
Yes
PATCH
PATCH
Yes
No
Submitted 
Results? 
Results 
Received?
Study 
Complete 
 
 
 
 
 
 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
41 
 
Appendix 3: PATCH 2 Job Aid 
PATCH2   STUDY LEAD JOB AID 
 
A 
PATCH2 AUTOMATIC STUDY EXCLUSIONS 
Consumer Language for Enrollment Exclusions 
• 
These exclusions are automatic during the online enrollment experience in the enrollment portal  
• 
If indicated exclusion response is selected, it is an automatic exclusion from the study 
Automatic 
Portal 
Exclusion 
Are you between the ages of 50-75? [yes/ no] 
 
If NO 
Have you had a fever within the last four days?  [yes/ no] 
 
If NO 
Do you require hospitalization? [yes/ no] 
 
If YES 
Are you able to self-quarantine at home for 14 days? [yes/ no] 
 
If NO 
Have you been tested for COVID-19? [yes/ no] 
 
If NO 
 
B 
AUTOMATIC CLINICAL EXCLUSIONS 
Consumer Language for Enrollment Exclusions 
• 
These exclusions are automatic during the online enrollment experience in the enrollment portal  
• 
If “yes” to any, it is an automatic exclusion from the study. 
Automatic 
Portal 
Exclusion 
Protocol Language:  Allergy to hydroxychloroquine, 4 
aminoquinolines, or quinine  
Do you have an allergy to hydroxychloroquine 
(HCQ), aminoquinolines, or quinine?    [yes/ no] 
 
X 
Protocol Language:  Patients with G6PD deficiency 
Do you have a G6PD deficiency?  [yes/ no] 
 
X 
Protocol Language:  Pregnant or lactating or positive pregnancy 
test during pre-medication examination 
Are you pregnant? [yes/ no] 
 
X 
Are you breast feeding? [yes/ no] 
 
X 
Protocol Language:  Receiving any trial treatment drug for 2019-
ncov within 14 days prior to screening evaluation (off label, 
compassionate use or trial related) 
Have you been in any other drug trial for COVID-19? 
[yes/ no] 
 
X 
Protocol Language:  Patients with serious intercurrent illness 
that requires active infusional therapy, intense monitoring, or 
frequent dose adjustments for medication including but not 
limited to infectious disease, cancer, autoimmune disease, 
cardiovascular disease. 
Are you on any IV or other serious medications, 
such as chemotherapy? [yes/ no] 
 
 
X 
Protocol Language:  Patients who have undergone major 
abdominal, thoracic, spine or CNS surgery in the last 2 months, or 
plan to undergo surgery during study participation.   
Have you had any surgery in the last two months? 
[yes/ no] 
X 
Protocol Language:  Patients currently taking digoxin   
Do you take the medication, digoxin or lanoxin?  
[yes/ no] 
 
X 
(From Medication Section) 
Have you ever had a seizures?  [yes/ no] 
 
X 
(From Medication Section) 
Have you ever had a transplant? [yes/ no] 
X 
 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
42 
 
Protocol Language:  History or evidence of increased 
cardiovascular risk including any of the following: 
• 
Left ventricular ejection fraction (LVEF) < institutional lower 
limit of normal. Baseline echocardiogram is not required; 
• 
Current clinically significant uncontrolled arrhythmias. 
Exception: Subjects with controlled atrial fibrillation; 
• 
History of acute coronary syndromes (including myocardial 
infarction and unstable angina), coronary angioplasty, or 
stenting within 6 months prior to enrollment; 
• 
Current ≥ Class II congestive heart failure as defined by New 
York Heart Association. 
Do you have any heart disease such as congestive 
heart failure, history of heart attack, angina, 
arrhythmias or atrial fibrillation (also called AFib)?  
[yes/ no] 
 
X 
 
C 
STUDY LEAD DECIDED EXCLUSIONS 
Consumer Language for Enrollment Exclusions 
• 
These exclusions will be asked prior to the consent call through the study enrollment portal.  “Yes” response do not trigger an 
automatic exclusion.  
• 
“Yes” responses require a live conversation between the prospective participant and the study lead during live consent.  
• 
If a medical consult is needed, then the study lead will conduct a medical consult with study PIs.  Track all medical consult 
language in the study portal.   
• 
Call the prospective study participant back with the final decision (yes or no) on enrollment.  If he/she is eligible, then finish 
study consenting, and trigger tablet + journal shipment  
 
DISEASE EXCLUSIONS 
Protocol Language 
Study Portal Language 
Eye Disease:  Known retinal disease 
including but not limited to macular 
degeneration, retinal vein occlusion, 
visual field defect, diabetic retinopathy 
Do you have eye disease?  [yes/ no] 
(if yes)  Please describe. [open text] 
INCLUDED IF:  
MEDICAL CONSULTATION IF: 
EXCLUSION IF: 
Wears eye glasses 
 
Any eye disease 
 
Protocol Language 
Study Portal Language 
Lung Disease:  History of interstitial 
lung disease, severe emphysema or 
asthma, or chronic pneumonitis 
unrelated COVID-19.  
Do you have lung disease, such as asthma or emphysema? [yes/ no] 
(if yes)  Please describe. [open text] 
INCLUSION IF: 
MEDICAL CONSULTATION IF: 
EXCLUSION IF: 
If moderate or controlled 
 
If in question, then medical 
consult 
If severe, then exclude  
 
 
Protocol Language 
Study Portal Language 
Porphyria and Psoriasis: Due to risk of 
disease exacerbation patients with 
porphyria or psoriasis are ineligible 
unless the disease is well-controlled, 
and they are under the care of a 
specialist for the disorder who agrees 
to monitor the patient for 
exacerbations.  
Do you have porphyria?  [yes/ no] 
Do you have psoriasis? [yes/ no] 
INCLUSION IF: 
MEDICAL CONSULTATION IF: 
EXCLUSION IF: 
If moderate or controlled 
 
If in question, then medical 
consult 
If severe, then exclude  
 
 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
43 
 
MEDICATION EXCLUSIONS 
Study Portal 
Language 
Please list all medications that you are currently taking    [text fields- one per medication] 
• 
The following medications are not allowed during the study.   
• 
The sponsor must be notified if the participant receives any of these during the study. 
• 
Participants must be instructed not to take any medications, including over the counter products, without first consulting 
with the investigator.  
• 
IF a study participant sees another provider, they are instructed to bring their study journal to this provider visit.  
• 
IN ADDITION, the participant should contact the study lead any time they seek medical treatment.    
 
Drug Classes 
Protocol Language 
Anticonvulsant  
• 
(Exclude) Patients receiving cytochrome P450 enzyme-inducing anticonvulsant drugs (i.e. phenytoin, 
carbamazepine, Phenobarbital, primidone or oxcarbazepine) within 4 weeks of the start of the study 
treatment   
 
• 
Acceptable drug alternatives include:  Because HCQ has known effects on P450 enzymes, patients 
requiring anti-convulsants may be treated with any of the non-enzyme inducing anti-convulsants 
which include: felbamate, valproic acid, gabapentin, lamotrigine, tiagibine, topiramate, or 
levetiracetam. Due to the fact that both zonisamide and HCQ accumulate in red blood cells, 
zonisamide should be avoided if possible. All other concomitant medications are permitted. 
 
Antiviral 
• 
(Exclude) Any investigational or off-label antiviral therapy   
• 
(Include)  Patients with HIV may participate   
• 
(Include)  Patients with herpes may participate 
Cancer Treatments 
• 
(Exclude) Anyone receiving active cancer treatments.   
• 
(Exclude) Any concurrent chemotherapy, radiotherapy (except radiotherapy as designated in this 
study or radiotherapy indicated for CNS metastasis) 
• 
(Exclude) Immunotherapy,  
• 
(Exclude) Biologic or hormonal therapy for cancer treatment, except as noted in the exclusion criteria.  
• 
(Include)  A Cancer survivor receiving no treatments may participate 
• 
(Include)  Concurrent use of hormones for non-cancer-related conditions (e.g. insulin for diabetes, 
hormone replacement therapy). 
Immunosuppressive   • 
(Exclude) Immunosuppressive medications, including, corticosteroids at doses exceeding 10mg/day of 
prednisone or equivalent, methotrexate, azathioprine, and TNF-alpha blockers.  
• 
(Include) Use of immunosuppressive medication for the management of study treatment related AEs 
or in subjects with contrast allergies is acceptable.  
• 
(Include) In addition, use of topical, inhaled and intranasal corticosteroids is permitted. 
 
Live attenuated 
vaccines 
• 
(Exclude) If using live attenuated vaccines during the study through 180 days after the last dose of 
both drugs.  Examples include: MMR, Zostavax, Polio, Varicella 
• 
(Include) If using non-living vaccines.  Examples include: Flu vaccine, Pneumonia vaccine 
Insulin or 
antidiabetic drugs 
• 
Reduce dosage consideration.  As HCQ may enhance the effects of a hypoglycemic treatment, a 
decrease in doses of insulin or antidiabetic drugs may be required. 
Arrhythmogenic  
• 
Drugs that prolong QT intervals.  
• 
HCQ can prolong the QT interval and should not be administered with other drugs that have the 
potential to induce cardiac arrhythmias.  
• 
Also, there may be an increased risk of inducing ventricular arrhythmias if HCQ is used concomitantly 
with other arrhythmogenic drugs 
 
Antiepileptics 
• 
Side effect.  The activity of antiepileptic drugs might be impaired if co-administered with HCQ. 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
44 
 
Cyclosporin 
• 
Side effect. An increased plasma cyclosporin level was reported when cyclosporin and HCQ were co-
administered  
 
See medication look up tool  
for inclusion or exclusion guidance related to specific medications 
 
D 
EMERGENCY INDICATIONS  
 
EMERGENCY 
SYMPTOMS    (911) 
Protocol Language 
 
 
Participants will be instructed to call 911 upon immediate presentation of the following symptoms as 
identified by the CDC as requiring emergency action:  
• 
Bluish lips or face 
• 
New confusion/dizziness or inability to arouse 
• 
Persistent pain or pressure in the chest (not caused by coughing) 
• 
Difficulty breathing (including severe shortness of breath and single word speech) 
 
 
 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
45 
 
E 
SIDE EFFECT GUIDE  
 
Directions 
• 
Ask the study doctor if you have questions about the signs or symptoms of any side effects. 
• 
Please tell the study doctor or study staff right away if you have any side effects. 
• 
Please tell them if you have any other problems with your health or the way you feel during the study, whether or not you think these 
problems are related to the study drugs. 
 
Serious  
Protocol Language 
Side effects 
occurring at a 
frequency which 
cannot be 
estimated from 
available data 
• 
Convulsions 
• 
Heart problems (e.g. breathlessness with exercise or even at rest, swelling of the legs, ankles and feet, 
irregular heartbeats that feel rapid or pounding, chest pain, sudden fainting) 
• 
Hypoglycemia (low blood sugar) (e.g. sweating, shakiness, weakness, dizziness, fast heartbeat, nausea, 
irritability, blurred vision, confusion, loss of consciousness) 
• 
Increased sensitivity to sunlight. Skin rash due to sunlight can be reduced by appropriate use of 
sunscreen creams 
• 
Liver problems with symptoms such as: unusual tiredness, nausea, vomiting, abdominal pain, or 
jaundice (yellow discoloration of the eyes or skin) 
• 
Long-lasting involuntary muscle contraction; impairment of voluntary movements, tremor 
• 
Lowered blood cell counts (e.g. fatigue, weakness, increase susceptibility to infections or bleeding) 
• 
Muscle weakness 
• 
Psychosis (e.g. hallucinations, loss of contact with reality) 
• 
Severe breathing problem (bronchospasm, angioedema) 
• 
Severe skin problem 
• 
Suicidal thoughts 
Rare 
Protocol Language 
These occurring in 
0.1 to 1% of 
participants 
receiving this drug 
• 
Dizziness 
• 
Hair loss or bleaching of hair 
• 
Loss of skin pigment or increase in skin pigment (bluish-black color) 
• 
Nerve and muscle disorders (e.g. tingling, numbness, burning pain, weakness, cramps, and spasms 
• 
Ringing in the ears, decreased hearing 
Common 
Protocol Language 
These occur in 1 to 
10% of participants 
receiving this drug 
• 
Diarrhea 
• 
Vomiting 
• 
Loss or lack of appetite (anorexia) 
• 
Headache 
• 
Nervousness, emotional changes 
• 
Rash, itchy rash 
• 
Visual problem: blurred vision, difficulty focusing, seeing halos around lights, especially at night, seeing 
light flashes and streaks, night blindness, visual field loss, change in eye color (eye pigmentation), 
difficulty focusing eye, difficulty reading (skipped words).   
• 
Notes on Vision:  HCQ may rarely cause problems with your vision.  A review of over 1000 patients taking HCQ 
found that this side effect occurred in only 1 patient and only after they had taken the drug for 7 years.  Vision 
problems include visual disturbances such as flickering or flashing lights, dimming of your vision (things appear 
darker) and decreased vision that could progress to blindness. 
Very Common 
Protocol Language 
These occur in 10% 
or more of 
participants 
receiving this drug 
• 
Nausea 
• 
Stomach pain 
• 
Stomach cramps 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
46 
 
F.  PATCH2 PATIENTS WELCOME BOX 
 
Content  
Description 
 
THE MEDICATION BOTTLE  
Blinded - 56 tabs 
Protocol number: UHG R&D 2020-0003 
Medication ID: [bottle serial number]  
Contents: 56 tablets 
Directions: Take two tablets by mouth every morning and every evening for 
14 days 
Store at [insert storage instructions from the manufacturer]  
Caution: New Drug - Limited by Federal (or United States) law to 
investigational use 
 
THE HYDOXYCHLOROQUINE MEDICATION GUIDE 
• 
The HCQ Medication Guide opens with: “You have received your 
medication tablets in this box. These tablets may be a placebo or they 
may be the active hydroxychloroquine (HCQ) medication. Below is a list 
of possible side effects from taking active HCQ.”  
• 
This guide will be shipped in the welcome kit that comes via courier in 
the overnight package from CSM. 
 
 
THE STUDY JOURNAL 
• 
15 page Study Journal 
• 
Includes a variety of study information, contact information, FAQ, 
reminders and study tracking examples 
• 
Will be shipped in the welcome kit that comes via courier in the 
overnight package from CSM 
 
A THERMOMETER 
• 
A thermometer will be sent to all patient participants. 
• 
It will be all white 
 
 
PEN 
• 
This ink pen will be shipped in the welcome kit that comes via courier in 
the overnight package from CSM 
 
 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
47 
 
E 
FREQUENTLY ASKED QUESTIONS (FAQ)  
 
Type of 
Question 
Question 
Response 
Study Info 
What will be expected of me 
if I decide to participate in 
this study?  
A package will be sent to you with either HCQ active or placebo pills. We 
ask that you take your medication according to the package direction, 
check your temperature twice daily, record and report any adverse 
events, and upload this information daily through the study portal at 
patchstudy.com for the full duration of this study. You’ll also be asked to 
get your swab samples taken at the end of the study. 
Study Info 
How can I enroll and 
participate in this study? 
If you are interested in learning more and want to enroll in this research 
study, go to our study portal at patchstudy.com. You will then be asked 
to create a user profile and answer a few eligibility questions. If eligible, 
you will sign a consent form via the study portal and provide a valid 
shipping address to receive your pills and study materials. Once 
completed, call us at 1-855-223-6987 to confirm your enrollment and 
consent to our study. 
Study Info 
What happens to my data, 
who sees it, and how is it 
used?  
To ensure your privacy, a study ID will be used in place of your name 
whenever researchers outside of the clinic access your information. Your 
information may be shared with individuals and organizations that 
conduct or watch over this research. Sharing your health data will be in 
accordance with the consent form and applicable data privacy laws. The 
data collected will be used in analysis to determine the efficacy of HCQ 
as an antiviral medication for COVID-19. 
PATCH2  
What is the PATCH2 Study?  
PATCH, also known as Prevention and Treatment of COVID-19 with 
Hydroxychloroquine (HCQ), is a research study that is being conducted 
by ProHEALTH NY, University of Pennsylvania, and UnitedHealth Group 
Research & Development to determine if HCQ can be an effective 
antiviral medication for treating COVID-19.  
PATCH2 
How long will I be required 
to participate? 
We expect that your taking part in this research will last for 5 weeks 
including follow-up visits.  
 
What happens if I sign-up 
and change my mind later? 
You can stop taking part in this research at any time. If you choose to 
drop out, there will be no penalty and you won’t lose any benefits. You’ll 
still get all the same medical care and benefits that you’re entitled to. If 
you decide to leave this research, contact the research team at 1-855-
223-6987.  
Medication 
Info 
What is hydroxychloroquine 
standardly used for? 
Hydroxychloroquine is a quinoline medicine used to treat or prevent 
malaria. Hydroxychloroquine is also an antirheumatic medicine and is 
used to treat symptoms of rheumatoid arthritis and systemic lupus 
erythematosus. 
Medication 
Info 
What happens if I miss a 
dose? 
Take the missed dose as soon as you remember. Skip the missed dose if 
it is almost time for your next scheduled dose. Do not take extra 
medicine to make up the missed dose. 
Medication 
Info 
What is 
Hydroxychloroquine? 
Hydroxychloroquine, also known as HCQ, is an antiviral medication that 
has been used for many years for the treatment of other illnesses such 
as malaria, lupus, and rheumatoid arthritis. Chloroquine derivatives have 
shown preclinical efficacy against COVID-19, but little clinical data is 
available. 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
48 
 
Adverse 
Event 
 
What happens if I overdose? 
Seek emergency medical attention or call the Poison Help line at 1-800-
222-1222. An overdose of hydroxychloroquine can be fatal, especially in 
children. 
 
Hydroxychloroquine overdose must be treated quickly. You may be told 
to induce vomiting right away (at home, before transport to an 
emergency room). Ask the poison control center how to induce vomiting 
in the case of an overdose. 
 
Overdose symptoms may include drowsiness, vision changes, slow heart 
rate, chest pain, severe dizziness, seizure (convulsions), or shallow 
breathing. 
Adverse 
Event 
What should I do if I 
experience side effects? 
If severe, such as bluish lips or face; new confusion/dizziness or inability 
to arouse; persistent pain or pressure in the chest (not caused by 
coughing); and difficulty breathing (including severe shortness of breath 
and single word speech), call 911 immediately. 
 
If not severe, track side effects at patchstudy.com and discuss symptoms 
during your next study call. 
Adverse 
Event 
What is an adverse event? 
An adverse event (AE) is any symptom, sign, illness or experience that 
develops or worsens during the course of the study. An adverse event 
does not need to be directly related to the study treatments. 
 
The following examples are considered adverse events: 
• If you experience an illness during the study 
• If you have a diagnostic procedure and the results are abnormal 
• If you seek an additional treatment during the study based on a 
diagnostic test 
Adverse 
Event 
What if my partner or I 
becomes pregnant? 
Under FDA guidelines, that is considered an adverse event. Please call 
the study team at 1-855-223-6987 between 8am and 5pm. 
Adverse 
Event 
What should I do if I 
experience and adverse 
event? 
If you are experiencing a health emergency, call 911 
Please do share any adverse event with your study team. 
• Please track all adverse events in the study portal at patchstudy.com  
• You can also call the study team to discuss your adverse event at 1-
855-223-6987 between 8am and 5pm. 
Adverse 
Event 
What will happen if I report 
an adverse event during the 
study? 
We care about your health and safety.  
• A study lead will follow up with you to gather more information and 
determine if any changes need to be made to the medicine you are 
taking. 
• Additionally, the information will be analyzed as part of the study 
results." 
Adverse 
Event 
What should I do if I have an 
adverse event, but it is the 
end of the study? 
During your last call with the study team, please make a plan for follow-
up. Our study team will continue to follow up with you until your 
adverse event is resolved. We also encourage you to share events with 
your personal physician. 
HCQ vs CQ 
What is the difference 
between the recently 
published study in Brazil and 
There are several key but crucial differences between the recently 
published study in Brazil and the PATCH studies: 
1. The Brazil study involved chloroquine, not hydroxychloroquine. 
Chloroquine is chemically similar to hydroxychloroquine but the 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
49 
 
the PATCH studies being 
conducted at ProHEALTH? 
two have very different safety records at high doses with 
hydroxychloroquine being the safer of the two.  
 
2. Participants in the Brazil study were taking two additional 
antibiotics (Ceftriaxone and Azithromycin) which are known to 
exacerbate this problem. 
 
3. Not only is the medication itself different, but so is the dose. The 
daily dose in the Brazil study was very high. 
 
4. The PATCH study populations are different from the Brazil study 
which involved individuals hospitalized for COVID-19, which is 
not the case here. 
 
 
 
 
 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
50 
 
 
Appendix 4: PATCH 3 Job Aid 
PATCH3  STUDY LEAD JOB AID 
 
A 
PATCH3 AUTOMATIC STUDY EXCLUSIONS 
Consumer Language for Enrollment Exclusions 
• 
These exclusions are automatic during the online enrollment experience in the enrollment portal  
• 
If indicated exclusion response is selected, it is an automatic exclusion from the study 
Automatic 
Portal 
Exclusion 
Are you a health care worker scheduled to working an average of 20 hours a week for the next 2 months?  
 
If NO 
Are you currently asymptomatic and presume not to have COVID? 
 
If NO 
Have you had a fever within the last four days?  [yes/ no] 
 
If NO 
Do you require hospitalization? [yes/ no] 
 
If YES 
Are you able to self-quarantine at home for 14 days? [yes/ no] 
 
If NO 
Have you been tested for COVID-19? [yes/ no] 
 
If NO 
 
B 
AUTOMATIC CLINICAL EXCLUSIONS 
Consumer Language for Enrollment Exclusions 
• 
These exclusions are automatic during the online enrollment experience in the enrollment portal  
• 
If “yes” to any, it is an automatic exclusion from the study. 
Automatic 
Portal 
Exclusion 
Protocol Language:  Allergy to hydroxychloroquine, 4 
aminoquinolines, or quinine  
Do you have an allergy to hydroxychloroquine (HCQ), 
aminoquinolines, or quinine?    [yes/ no] 
X 
Protocol Language:  Patients with G6PD deficiency 
Do you have a G6PD deficiency?  [yes/ no] 
 
X 
Protocol Language:  Pregnant or lactating or positive 
pregnancy test during pre-medication examination 
Are you pregnant? [yes/ no] 
 
X 
Are you breast feeding? [yes/ no] 
 
X 
Protocol Language:  Receiving any trial treatment drug for 
2019-ncov within 14 days prior to screening evaluation (off 
label, compassionate use or trial related) 
Have you been in any other drug trial for COVID-19? 
[yes/ no] 
 
X 
Protocol Language:  Patients with serious intercurrent illness 
that requires active infusional therapy, intense monitoring, or 
frequent dose adjustments for medication including but not 
limited to infectious disease, cancer, autoimmune disease, 
cardiovascular disease. 
Are you on any IV or other serious medications, such 
as chemotherapy? [yes/ no] 
 
 
X 
Protocol Language:  Patients who have undergone major 
abdominal, thoracic, spine or CNS surgery in the last 2 months, 
or plan to undergo surgery during study participation.   
Have you had any surgery in the last two months? 
[yes/ no] 
X 
Protocol Language:  Patients currently taking digoxin   
Do you take the medication, digoxin or lanoxin?  [yes/ 
no] 
 
X 
(From Medication Section) 
Have you ever had a seizures?  [yes/ no] 
 
X 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
51 
 
(From Medication Section) 
Have you ever had a transplant? [yes/ no] 
X 
Protocol Language:  History or evidence of increased 
cardiovascular risk including any of the following: 
• 
Left ventricular ejection fraction (LVEF) < institutional 
lower limit of normal. Baseline echocardiogram is not 
required; 
• 
Current clinically significant uncontrolled arrhythmias. 
Exception: Subjects with controlled atrial fibrillation; 
• 
History of acute coronary syndromes (including 
myocardial infarction and unstable angina), coronary 
angioplasty, or stenting within 6 months prior to 
enrollment; 
• 
Current ≥ Class II congestive heart failure as defined by 
New York Heart Association. 
Do you have any heart disease such as congestive 
heart failure, history of heart attack, angina, 
arrhythmias or atrial fibrillation (also called AFib)?  
[yes/ no] 
 
X 
 
C 
STUDY LEAD DECIDED EXCLUSIONS 
Consumer Language for Enrollment Exclusions 
• 
These exclusions will be asked prior to the consent call through the study enrollment portal.  “Yes” response do not trigger an 
automatic exclusion.  
• 
“Yes” responses require a live conversation between the prospective participant and the study lead during live consent.  
• 
If a medical consult is needed, then the study lead will conduct a medical consult with study PIs.  Track all medical consult 
language in the study portal.   
• 
Call the prospective study participant back with the final decision (yes or no) on enrollment.  If he/she is eligible, then finish 
study consenting, and trigger tablet + journal shipment  
 
DISEASE EXCLUSIONS 
Protocol Language 
Study Portal Language 
Eye Disease:  Known retinal disease 
including but not limited to macular 
degeneration, retinal vein occlusion, 
visual field defect, diabetic retinopathy 
Do you have eye disease?  [yes/ no] 
(if yes)  Please describe. [open text] 
INCLUDED IF:  
MEDICAL CONSULTATION IF: 
EXCLUSION IF: 
Wears eye glasses 
 
Any eye disease 
 
Protocol Language 
Study Portal Language 
Lung Disease:  History of interstitial 
lung disease, severe emphysema or 
asthma, or chronic pneumonitis unrelated 
COVID-19.  
Do you have lung disease, such as asthma or emphysema? [yes/ no] 
(if yes)  Please describe. [open text] 
INCLUSION IF: 
MEDICAL CONSULTATION IF: 
EXCLUSION IF: 
If moderate or 
controlled 
If in question, then medical 
consult 
If severe, then exclude  
 
 
Protocol Language 
Study Portal Language 
Porphyria and Psoriasis: Due to risk 
of disease exacerbation patients with 
porphyria or psoriasis are ineligible unless 
the disease is well-controlled, and they 
Do you have porphyria?  [yes/ no] 
Do you have psoriasis? [yes/ no] 
INCLUSION IF: 
MEDICAL CONSULTATION IF: 
EXCLUSION IF: 


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Confidential    5.12.2020                                                                           
 
 
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are under the care of a specialist for the 
disorder who agrees to monitor the 
patient for exacerbations.  
If moderate or 
controlled 
If in question, then medical 
consult 
If severe, then exclude  
 
MEDICATION EXCLUSIONS 
Study Portal 
Language 
Please list all medications that you are currently taking    [text fields- one per medication] 
• 
The following medications are not allowed during the study.   
• 
The sponsor must be notified if the participant receives any of these during the study. 
• 
Participants must be instructed not to take any medications, including over the counter products, without first consulting 
with the investigator.  
• 
IF a study participant sees another provider, they are instructed to bring their study journal to this provider visit.  
• 
IN ADDITION, the participant should contact the study lead any time they seek medical treatment.    
 
Drug Classes 
Protocol Language 
Anticonvulsant  
• 
(Exclude) Patients receiving cytochrome P450 enzyme-inducing anticonvulsant drugs (i.e. phenytoin, 
carbamazepine, Phenobarbital, primidone or oxcarbazepine) within 4 weeks of the start of the study 
treatment   
 
• 
Acceptable drug alternatives include:  Because HCQ has known effects on P450 enzymes, patients 
requiring anti-convulsants may be treated with any of the non-enzyme inducing anti-convulsants 
which include: felbamate, valproic acid, gabapentin, lamotrigine, tiagibine, topiramate, or 
levetiracetam. Due to the fact that both zonisamide and HCQ accumulate in red blood cells, 
zonisamide should be avoided if possible. All other concomitant medications are permitted. 
 
Antiviral 
• 
(Exclude) Any investigational or off-label antiviral therapy   
• 
(Include)  Patients with HIV may participate   
• 
(Include)  Patients with herpes may participate 
Cancer Treatments 
• 
(Exclude) Anyone receiving active cancer treatments.   
• 
(Exclude) Any concurrent chemotherapy, radiotherapy (except radiotherapy as designated in this 
study or radiotherapy indicated for CNS metastasis) 
• 
(Exclude) Immunotherapy,  
• 
(Exclude) Biologic or hormonal therapy for cancer treatment, except as noted in the exclusion criteria.  
• 
(Include)  A Cancer survivor receiving no treatments may participate 
• 
(Include)  Concurrent use of hormones for non-cancer-related conditions (e.g. insulin for diabetes, 
hormone replacement therapy). 
Immunosuppressive   • 
(Exclude) Immunosuppressive medications, including, corticosteroids at doses exceeding 10mg/day of 
prednisone or equivalent, methotrexate, azathioprine, and TNF-alpha blockers.  
• 
(Include) Use of immunosuppressive medication for the management of study treatment related AEs 
or in subjects with contrast allergies is acceptable.  
• 
(Include) In addition, use of topical, inhaled and intranasal corticosteroids is permitted. 
 
Live attenuated 
vaccines 
• 
(Exclude) If using live attenuated vaccines during the study through 180 days after the last dose of 
both drugs.  Examples include: MMR, Zostavax, Polio, Varicella 
• 
(Include) If using non-living vaccines.  Examples include: Flu vaccine, Pneumonia vaccine 
Insulin or 
antidiabetic drugs 
• 
Reduce dosage consideration.  As HCQ may enhance the effects of a hypoglycemic treatment, a 
decrease in doses of insulin or antidiabetic drugs may be required. 
Arrhythmogenic  
• 
Drugs that prolong QT intervals.  
• 
HCQ can prolong the QT interval and should not be administered with other drugs that have the 
potential to induce cardiac arrhythmias.  
• 
Also, there may be an increased risk of inducing ventricular arrhythmias if HCQ is used concomitantly 
with other arrhythmogenic drugs 


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Confidential    5.12.2020                                                                           
 
 
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Antiepileptics 
• 
Side effect.  The activity of antiepileptic drugs might be impaired if co-administered with HCQ. 
Cyclosporin 
• 
Side effect. An increased plasma cyclosporin level was reported when cyclosporin and HCQ were co-
administered  
 
See medication look up tool  
for inclusion or exclusion guidance related to specific medications 
 
D 
EMERGENCY INDICATIONS  
 
EMERGENCY 
SYMPTOMS    (911) 
Protocol Language 
 
 
Participants will be instructed to call 911 upon immediate presentation of the following symptoms as 
identified by the CDC as requiring emergency action:  
• 
Bluish lips or face 
• 
New confusion/dizziness or inability to arouse 
• 
Persistent pain or pressure in the chest (not caused by coughing) 
• 
Difficulty breathing (including severe shortness of breath and single word speech) 
 
 
 


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Confidential    5.12.2020                                                                           
 
 
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E 
SIDE EFFECT GUIDE  
 
Directions 
• 
Ask the study doctor if you have questions about the signs or symptoms of any side effects. 
• 
Please tell the study doctor or study staff right away if you have any side effects. 
• 
Please tell them if you have any other problems with your health or the way you feel during the study, whether or not you 
think these problems are related to the study drugs. 
 
Serious  
Protocol Language 
Side effects occurring 
at a frequency which 
cannot be estimated 
from available data 
• 
Convulsions 
• 
Heart problems (e.g. breathlessness with exercise or even at rest, swelling of the legs, ankles and 
feet, irregular heartbeats that feel rapid or pounding, chest pain, sudden fainting) 
• 
Hypoglycemia (low blood sugar) (e.g. sweating, shakiness, weakness, dizziness, fast heartbeat, 
nausea, irritability, blurred vision, confusion, loss of consciousness) 
• 
Increased sensitivity to sunlight. Skin rash due to sunlight can be reduced by appropriate use of 
sunscreen creams 
• 
Liver problems with symptoms such as: unusual tiredness, nausea, vomiting, abdominal pain, or 
jaundice (yellow discoloration of the eyes or skin) 
• 
Long-lasting involuntary muscle contraction; impairment of voluntary movements, tremor 
• 
Lowered blood cell counts (e.g. fatigue, weakness, increase susceptibility to infections or bleeding) 
• 
Muscle weakness 
• 
Psychosis (e.g. hallucinations, loss of contact with reality) 
• 
Severe breathing problem (bronchospasm, angioedema) 
• 
Severe skin problem 
• 
Suicidal thoughts 
Rare 
Protocol Language 
These occurring in 0.1 
to 1% of participants 
receiving this drug 
• 
Dizziness 
• 
Hair loss or bleaching of hair 
• 
Loss of skin pigment or increase in skin pigment (bluish-black color) 
• 
Nerve and muscle disorders (e.g. tingling, numbness, burning pain, weakness, cramps, and spasms 
• 
Ringing in the ears, decreased hearing 
Common 
Protocol Language 
These occur in 1 to 10% 
of participants 
receiving this drug 
• 
Diarrhea 
• 
Vomiting 
• 
Loss or lack of appetite (anorexia) 
• 
Headache 
• 
Nervousness, emotional changes 
• 
Rash, itchy rash 
• 
Visual problem: blurred vision, difficulty focusing, seeing halos around lights, especially at night, 
seeing light flashes and streaks, night blindness, visual field loss, change in eye color (eye 
pigmentation), difficulty focusing eye, difficulty reading (skipped words).   
• 
Notes on Vision:  HCQ may rarely cause problems with your vision.  A review of over 1000 patients 
taking HCQ found that this side effect occurred in only 1 patient and only after they had taken the 
drug for 7 years.  Vision problems include visual disturbances such as flickering or flashing lights, 
dimming of your vision (things appear darker) and decreased vision that could progress to blindness. 
Very Common 
Protocol Language 
These occur in 10% or 
more of participants 
receiving this drug 
• 
Nausea 
• 
Stomach pain 
• 
Stomach cramps 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
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F.  PATCH3 HEALTH CARE WORKER WELCOME KIT 
Shipment 1:  
Content  
Description 
 
THE MEDICATION BOTTLE  
Blinded - 90 tabs 
Medication ID: [bottle serial number]  
Contents: 90 tablets 
Instructions: Take 3 tablets in the AM daily for a total of 30 days. One refill 
will be shipped to you. 
Store at [insert storage instructions from the manufacturer]  
Caution: New Drug - Limited by Federal (or United States) law to 
investigational use 
 
THE HYDOXYCHLOROQUINE MEDICATION GUIDE 
• 
The HCQ Medication Guide opens with: “You have received your 
medication tablets in this box. These tablets may be a placebo or they 
may be the active hydroxychloroquine (HCQ) medication. Below is a list 
of possible side effects from taking active HCQ.”  
 
 
THE STUDY JOURNAL 
• 
15 page Study Journal 
• 
Includes a variety of study information, contact information, FAQ, 
reminders and study tracking examples 
 
 
A THERMOMETER 
• 
A thermometer will be sent to all health care worker participants to 
track their temperature 
• 
It will be all white 
 
 
PEN 
• 
An ink pen will be sent to all health care workers to use with the study 
journal 
 


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Confidential    5.12.2020                                                                           
 
 
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REMINDER CARD 
• 
The reminder card is to help remind health care workers to get their 
weekly oxygen level checked at work and track the number of hours 
they missed due to their own COVID-19 symptoms 
 
Shipment 2: 
Content  
Description 
 
THE MEDICATION BOTTLE  
Blinded - 90 tabs 
Medication ID: [bottle serial number]  
Contents: 90 tablets 
Instructions: Take 3 tablets in the AM daily for a total of 30 days. One refill 
will be shipped to you. 
Store at [insert storage instructions from the manufacturer]  
Caution: New Drug - Limited by Federal (or United States) law to 
investigational use 
 
 
THE HYDOXYCHLOROQUINE MEDICATION GUIDE 
• 
The HCQ Medication Guide opens with: “You have received your 
medication tablets in this box. These tablets may be a placebo or they 
may be the active hydroxychloroquine (HCQ) medication. Below is a list 
of possible side effects from taking active HCQ.”  
 
 
 
 
 
 
 


PATCH 2 & 3 TRIAL 
 
Confidential    5.12.2020                                                                           
 
 
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PATCH3 HEALTH CARE WORKER CROSSOVER KIT 
Content  
Description 
 
CROSSOVER MEDICATION  
Unblinded Active HCQ - 42 tabs 
Medication ID: [bottle serial number]  
Contents: 42 tablets 
Directions: Take 3 pills in the AM daily for 14 days.  No refill. 
Store at [insert storage instructions from the manufacturer]  
Caution: New Drug - Limited by Federal (or United States) law to 
investigational use 
 
 
CROSSOVER GUIDE 
This guide is to support the health care worker with instructions when 
crossing over from placebo to HCQ should they qualify. 
 
 
E 
FREQUENTLY ASKED QUESTIONS (FAQ)  
 
Type of 
Question 
Question 
Response 
Study Info 
What is the PATCH Study? 
 
PATCH, also known as Prevention and Treatment of COVID-19 with 
Hydroxychloroquine (HCQ), is a research study that is being conducted 
by ProHEALTH NY, University of Pennsylvania, and UnitedHealth Group 
Research & Development to determine if HCQ can be an effective 
antiviral medication for preventing and treating COVID-19. 
Study Info 
What will be expected of me 
if I decide to participate in 
this study? 
 
A package will be sent to you with either HCQ active or placebo pills. We 
ask that you take your medication according to the package direction, 
check your temperature twice daily or report symptoms of fever, record 
and report any adverse events, and upload this information daily 
through the study portal at patchstudy.com for the full duration of this 
study. You’ll also be asked to get your swab samples taken at the end of 
the study. 
Study Info 
Can anyone join? 
 
The PATCH2 Study is focused on recruiting patients who are:  
• between the ages of 50-75 years of age 
• experiencing COVID-19 symptoms such as cough, fever, and/or 
sore throat 
• being sent home for a 14-day self-quarantine after being 
tested for COVID-19 


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Confidential    5.12.2020                                                                           
 
 
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The PATCH3 Study is focused on recruiting health care workers (MD, DO, 
PA, NP, RN or other members of the medical care team with significant 
COVID-19 exposure) who are: 
• not diagnosed with COVID-19 or PCR negative 
• exposed to patients with COVID-19 
• asymptomatic (no cough, fever or sore throat) 
• scheduled to work 20+ hours per week for the next two 
months 
Study Info 
How can I enroll and 
participate in this study? 
 
If you are interested in learning more and want to enroll in this research 
study, go to our study portal at patchstudy.com. You will then be asked 
to create a user profile and answer a few eligibility questions. If eligible, 
you will sign a consent form via the study portal and provide a valid 
shipping address to receive your tablets and study materials. Once 
completed, call us at 1-855-223-6987 between 8am to 5pm to confirm 
your enrollment and consent to our study. 
Study Info 
What happens to my data, 
who sees it, and how is it 
used? 
 
To ensure your privacy, a study ID will be used in place of your name 
whenever researchers outside of the clinic access your information. Your 
information may be shared with individuals and organizations that 
conduct or watch over this research. Sharing your health data will be in 
accordance with the consent form and applicable data privacy laws. The 
data collected will be used in analysis to determine the efficacy of HCQ 
as an antiviral medication for COVID-19. 
Study Info 
Will being in this research 
benefit me? 
 
There is no anticipated benefit for you directly. There may be future 
benefits for society based on the outcomes of the research for those 
who are at risk of infection. 
Study Info 
Are there risks to being in 
this research study? 
 
The risks of this research are mainly related to taking 
Hydroxychloroquine (HCQ). The side effects of HCQ are well known and 
include: 
• 
Potential drug interactions with other medications. The study 
team will review the list of medications that should not be taken 
with HCQ before confirming that you are eligible to participate. 
If you take any of the drugs that may interact with HCQ you will 
not be eligible to participate. Because of this risk of drug 
interactions, it is important for you to inform the study team of 
all drugs, vitamins, and supplements you are currently taking or 
if you receive any new prescriptions during the course of the 
study. 
Study Info 
Who can I contact if I have 
more questions? 
For additional questions or you want to learn more, please reach out to 
our Study Team at 1-855-223-6987 between 8am to 5pm.  
PATCH3  
What is the PATCH3 Study? 
 
PATCH, also known as Prevention and Treatment of COVID-19 with 
Hydroxychloroquine (HCQ), is a research study that is being conducted 
by ProHEALTH NY, University of Pennsylvania, and UnitedHealth Group 
Research & Development to determine if HCQ can be an effective 
antiviral medication for preventing COVID-19. 
PATCH3 
How long will I be required 
to participate? 
We expect that your taking part in this research will last for 9 weeks, 
including additional follow-up visits. 


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Confidential    5.12.2020                                                                           
 
 
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PATCH3 
What will be expected of me 
if I decide to participate in 
this study? 
 
A package will be sent to you with either HCQ active or placebo pills. We 
ask that you take your medication according to the package direction, 
check your temperature twice daily or report symptoms of fever, 
measure your oxygen level weekly while at work, track the number of 
work hours missed due to COVID-19 symptoms, and record and report 
any adverse events, and upload this information daily through the study 
portal at patchstudy.com for the full duration of this study. You’ll also be 
asked to get your swab samples taken at the end of the study. 
PATCH3 
What happens if I sign-up 
and change my mind later? 
 
You can stop taking part in this research at any time. If you choose to 
drop out, there will be no penalty and you won’t lose any benefits. You’ll 
still receive the same work benefits that you’re entitled to. If you decide 
to leave this research, contact the research team at 1-855- 223-6987 
between 8am to 5pm. 
PATCH3 
What happens to my data, 
who sees it, and how is it 
used? 
 
To ensure your privacy, a study ID will be used in place of your name 
whenever researchers outside of the clinic access your information. Your 
information may be shared with individuals and organizations that 
conduct or watch over this research. Sharing your health data will be in 
accordance with the consent form and applicable data privacy laws. The 
data collected will be used in analysis to determine the efficacy of HCQ 
as an antiviral medication for COVID-19. 
Medication 
Info 
What is 
Hydroxychloroquine? 
 
Hydroxychloroquine, also known as HCQ, is an antiviral medication that 
has been used for many years for the treatment of other illnesses such 
as malaria, lupus, and rheumatoid arthritis. Chloroquine derivatives have 
shown preclinical efficacy against COVID-19, but little clinical data is 
available. 
Medication 
Info 
How do I take the HCQ 
active or placebo 
medication? 
 
You must be able to swallow and retain oral medication and must not 
have any clinically significant gastrointestinal abnormalities that may 
alter absorption such as malabsorption syndrome or major resection of 
the stomach or bowels, gastric bypass, and lap banding. 
Medication 
Info 
What happens if I miss a 
dose? 
 
Take the missed dose as soon as you remember. Skip the missed dose if 
it is almost time for your next scheduled dose. Do not take extra 
medicine to make up the missed dose. 
Medication 
Info 
What if I am taking other 
medication(s) for a different 
condition or using over-the-
counter product(s)? 
Please let the Study Team know what other medications you are 
currently taking before starting the study. We also ask that you do not to 
take any medications, including over-the-counter products, without first 
consulting with the Study Team. 
Medication 
Info 
What should I avoid while 
taking hydroxychloroquine? 
 
Avoid taking an antacid or Kaopectate (kaolin-pectin) within 4 hours 
before or after you take hydroxychloroquine. Some antacids can make it 
harder for your body to absorb hydroxychloroquine. 
Medication 
Info 
What medications are not 
allowed during the study? 
 
Please make the Study Team aware at 1-855-223-6987 during your call 
between 8am to 5pm if you are taking any investigational or off-label 
antiviral therapy such as: 
 
1. Active cancer treatments (e.g. chemotherapy, radiotherapy, 
immunotherapy, biologic or hormonal therapy). 
2. Immunosuppressive medications, including, corticosteroids at 
doses exceeding 10mg/day of prednisone or equivalent, 
methotrexate, azathioprine, and TNF-alpha blockers. 
3. Live attenuated vaccines 


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Confidential    5.12.2020                                                                           
 
 
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Medication 
Info 
How do you determine who 
gets the HCQ active or 
placebo drug? 
You will be randomized by using computer generated randomization 
numbers. 
Adverse 
Event 
 
What are some common 
side effects of 
hydroxychloroquine? 
Mild and transient headache, dizziness, and gastrointestinal complaints 
(diarrhea, loss of appetite, nausea, abdominal cramps and, on rare 
occasions, vomiting). 
Adverse 
Event 
What are some rare side 
effects of 
hydroxychloroquine? 
Cardiomyopathy (chronic disease of the heart muscle) has been rarely 
reported with high daily dosages of hydroxychloroquine. 
 
Adverse 
Event 
What should I do if I 
experience side effects? 
 
If severe, such as bluish lips or face; new confusion/dizziness or inability 
to arouse; persistent pain or pressure in the chest (not caused by 
coughing); and difficulty breathing (including severe shortness of breath 
and single word speech), call 911 immediately. 
 
If not severe, track side effects at patchstudy.com and discuss 
symptoms during your next study call. 
Adverse 
Event 
What happens if I overdose? 
Seek emergency medical attention or call the Poison Help line at 1-800-
222-1222. An overdose of hydroxychloroquine can be fatal, especially in 
children.  
 
Hydroxychloroquine overdose must be treated quickly. You may be told 
to induce vomiting right away (at home, before transport to an 
emergency room). Ask the poison control center how to induce vomiting 
in the case of an overdose. 
 
Overdose symptoms may include drowsiness, vision changes, slow heart 
rate, chest pain, severe dizziness, seizure (convulsions), or shallow 
breathing. 
Adverse 
Event 
What is an adverse event? 
 
An adverse event (AE) is any symptom, sign, illness or experience that 
develops or worsens during the course of the study. An adverse event 
does not need to be directly related to the study treatments.  
The following examples are considered adverse events: 
• If you experience an illness during the study 
• If you have a diagnostic procedure and the results are 
abnormal 
• If you seek an additional treatment during the study based on 
a diagnostic test 
Adverse 
Event 
What if my partner or I 
become pregnant? 
Under FDA guidelines, that is considered an adverse event. Please call 
the study team at 1-855-223-6987 between 8am and 5pm. 
Adverse 
Event 
What should I do if I 
experience an adverse 
event? 
If you are experiencing a health emergency, call 911. 
Please do share any adverse event with your study team. 
• Please track all adverse events in the study portal at 
patchstudy.com  
• You can also call the study team to discuss your adverse event 
at 1-855-223-6987 between 8am and 5pm. 
Adverse 
Event 
What will happen if I report 
an adverse event during the 
study? 
We care about your health and safety.  
• A study lead will follow up with you to gather more 
information and determine if any changes need to be made to 
the medicine you are taking. 


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Confidential    5.12.2020                                                                           
 
 
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• Additionally, the information will be analyzed as part of the 
study results. 
 
Adverse 
Event 
What should I do if I have an 
adverse event, but it is the 
end of the study? 
During your last call with the study team, please make a plan for follow-
up. Our study team will continue to follow up with you until your 
adverse event is resolved. We also encourage you to share events with 
your personal physician. 
HCQ vs CQ 
What is the difference 
between the recently 
published study in Brazil and 
the PATCH studies being 
conducted at ProHEALTH? 
There are several key but crucial differences between the recently 
published study in Brazil and the PATCH studies: 
5. The Brazil study involved chloroquine, not hydroxychloroquine. 
Chloroquine is chemically similar to hydroxychloroquine but the 
two have very different safety records at high doses with 
hydroxychloroquine being the safer of the two.  
 
6. Participants in the Brazil study were taking two additional 
antibiotics (Ceftriaxone and Azithromycin) which are known to 
exacerbate this problem. 
 
7. Not only is the medication itself different, but so is the dose. The 
daily dose in the Brazil study was very high. 
 
8. The PATCH study populations are different from the Brazil study 
which involved individuals hospitalized for COVID-19, which is 
not the case here.