A Randomized, Double-blind, Placebo-Controlled Trial to Evaluate the Efficacy of Ramipril to Prevent ICU Admission, Need for Mechanical Ventilation or Death in Persons With COVID-19
Phase: PHASE2
Conditions: COVID-19
Sponsor: University of California, San Diego

 
 
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RAMIC  
 
CLINICAL RESEARCH PROTOCOL 
UNIVERSITY OF CALIFORNIA SAN DIEGO 
DEPARTMENT OF MEDICINE 
  
CLINICAL PROTOCOL NUMBER:  RAMIC                                                                                                                      
TITLE: A Randomized, Double-blind, Placebo-Controlled Trial to Evaluate the Efficacy of Ramipril to 
Prevent ICU Admission, Mechanical Ventilation or Death in Persons with COVID-19 
ABBREVIATED TITLE:  RAMIC Trial 
AMENDMENT: Amendment 6, December 9, 2020   
ADVARRA NUMBER: Pro00043364              
IND NO: 149827                                                                                                                             
IDENTIFYING WORDS: SARS-CoV-2, hypertension, ACE inhibitor, Angiotensin II receptor blocker, 
mortality 
PRINCIPAL INVESTIGATOR: 
Rohit Loomba, MD, MHSc 
ASSOCIATE INVESTIGATORS: 
Veeral Ajmera, MD, MAS 
Davey Smith, MD, PhD 
Atul Malhotra, MD 
Ravinder Mehta, MD 
Vaishal Tolia, MD, MPH 
Daniel Bouland, MD, FACP 
Jeffrey Yin, Pharm D 
Wesley K. Thompson, Ph.D 
Lisa Richards, NP 

 
 
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RAMIC  
 
Summer Collier, NP 
ESTIMATED DURATION OF STUDY: 1 year 
NUMBER AND TYPE OF PATIENTS: Up to 560 patients with confirmed SARS-CoV-2 diagnosis, ages 
above 18 years, both male and female. 
SUBJECTS OF STUDY:      
 
Number of patients             
Sex                                       
Age Range 
 560                    
 
Male & Female      
             Above 18 years      
 
Volunteers                             
None 
PROJECT USES IONIZING RADIATION: No 
PROJECT USES “DURABLE POWER OF ATTORNEY”: No 
TYPE OF STUDY: Randomized-controlled-trial 
MULTI-INSTITUTIONAL PROJECT: Yes 
 

 
 
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RAMIC  
 
The RAMIC Trial 
  
A Randomized, Double-blind, Placebo-Controlled Trial to Evaluate the Efficacy of Ramipril to Prevent 
ICU Admission, Mechanical Ventilation or Death in Persons with COVID-19 
  
SIGNATURE PAGE 
   
I will conduct the study in accordance with the provisions of this protocol and all applicable protocol-related 
documents. I agree to conduct this study in compliance with applicable United States (US) Food and Drug 
Administration regulations; standards of the International Conference on Harmonization Guideline for 
Good Clinical Practice (E6); Institutional Review Board/Ethics Committee determinations; Good Clinical 
Practice (GCP) guidelines; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements and institutional policies. 
 
I agree to conduct the study according to all stipulations of the protocol, including all statements 
regarding confidentiality, and according to applicable legal regulations and regulatory 
requirements. 
  
Principal Investigator: _______________________________________________ 
           Print/Type 
  
Signed: ___________________________________ Date: _____________ 
 
 
 

 
 
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RAMIC  
 
TABLE OF CONTENTS 
SIGNATURE PAGE 
3 
ABSTRACT 
6 
BACKGROUND 
7 
STUDY OBJECTIVES AND OUTCOMES 
9 
Primary objective: 
9 
Secondary objectives: 
9 
Exploratory objective: 
9 
Primary outcome measure: 
9 
Secondary outcomes: 
9 
STUDY DESIGN 
10 
Randomization 
10 
Recruitment 
10 
Study Visits 
10 
SUBJECT SELECTION 
11 
Inclusion Criteria: 
11 
Exclusion Criteria: 
11 
Subject Enrollment: 
11 
TREATMENT 
13 
STUDY ASSESSMENTS 
14 
Table 1: Schedule of Events 
15 
Premature Discontinuation of Study Drug 
16 
Post-Treatment Phase: 
16 
Long-term follow up visits: 
16 

 
 
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RAMIC  
 
ADVERSE EVENTS AND STUDY MONITORING 
17 
Criteria for discontinuation 
17 
Table 2. Scoring of toxicity for discontinuation 
19 
The risks and discomforts of frequent phlebotomy 
19 
Data and Safety Monitoring 
19 
Adverse Event Reporting 
19 
Patient Privacy 
20 
STATISTICAL METHODS AND CONSIDERATIONS 
191 
APPENDIX A: Screening Diagram 
203 
APPENDIX B: COVID-19 Symptom Assessment 
214 
REFERENCES  
 
 
 
 
 
 
 
 
 
         26 
CREDITS 
 
 
 
 
 
 
 
 
       
 
         28 
 
 
 

 
 
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RAMIC  
 
ABSTRACT  
As of early April, 2020, the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected over 1.1 million people globally and 
caused over 62,000 deaths. Currently, no drug therapies have yet been proven to be effective in treating 
COVID-19 patients, although several are under investigation or in development. Among COVID-19 cases, 
pre-existing comorbidities such as hypertension, diabetes, and cardiovascular disease have been shown to 
be associated with higher risk of developing severe symptoms and higher risk of mortality1. Recent data 
suggest that use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers 
(ARBs) may be associated with lower risk of morbidity and mortality in patients with COVID-192,3,4.  
ACEIs and ARBs are part of the renin-angiotensin-aldosterone system (RAAS) inhibiting agents and 
considered as one of the first-line therapies for the management of a large proportion of patients with 
hypertension. However, continued use of ACEI/ARB has become controversial in the setting of COVID-
19. The reason for this controversy stems from the fact that ACEIs and ARBs use may increase the 
expression of ACE2 receptor5-7, which is the known cellular receptor and a necessary entry point for SARS-
COV-2 infection8. Therefore, continued use of ACEIs and ARBs among patients with COVID-19 infection 
is controversial due to theoretical concerns of potentially increased cellular invasion of SARS-COV-2 or 
enhanced susceptibility towards SARS-COV-2 infection. Conversely, it has been indicated that ACE2 
expression is downregulated following SARS infection, resulting in excessive activation of RAAS and 
exacerbated pneumonia progression mediated by angiotensin9,10. Therefore, administration of ACEI/ARB 
may in turn be beneficial by blocking the angiotensin-induced hyperactivation of RAAS and thereby 
preventing acute lung injury and risk of adult respiratory distress syndrome in patients with COVID-19. 
Ramipril is an ACE inhibitor that is approved by the FDA for the treatment of hypertension, to reduce the 
risk of heart failure and death post-myocardial infarction, and reduction of risk of myocardial infarction, 
stroke, and death from cardiovascular causes. The drug’s suppressing effects on the renin-angiotensin-
aldosterone system (RAAS) system leads to inhibition of tissue and circulating ACE activity.  This leads 
to cessation of angiotensin II-related vasoconstrictive, proinflammatory, and pro-oxidative effects and 
improvement in hypertension, inflammation and oxidative stress. These properties may be useful. 
Ramipril has not been studied in SARS-CoV-2 infected patients. In this study we propose to treat 560 
patients with ramipril or placebo for 14 days. After an initial evaluation for COVID-19 status, medical 
history, and symptom assessment, patients will receive either 2.5 mg/day of ramipril or placebo. Patients’ 
symptoms and study endpoints will be monitored at regular intervals. Additional follow-up will be 
performed at day 28. As an exploratory objective, biomarkers of the RAAS axis will also be monitored. 
The primary endpoints of successful therapy will be improved survival, reductions in ICU admissions, 
and/or reductions in use of mechanical ventilator support. Secondary endpoints will be the proportion of 
patients needing continued hospitalization, time to mortality, time to ICU admission, time to discharge from 
hospital, proportion of patients developing hypotension and needing pressor support, and proportion of 
patients developing septic shock. 

 
 
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RAMIC  
 
BACKGROUND 
The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2)11, is projected to infect millions of people worldwide and lead to 240,000 
deaths in the United States. Currently, no drug therapies have been proven to be effective in treating 
COVID-19 patients, although several are under investigation or in development. Emerging data suggest 
hypertension, along with diabetes and cardiovascular disease, predisposes individuals to increased risk for 
more severe COVID-19 symptoms and higher mortality1. Angiotensin-converting enzyme inhibitors 
(ACEIs) or angiotensin receptor blockers (ARBs) block the renin-angiotensin aldosterone system (RAAS) 
and are commonly prescribed treatments for patients with these conditions. Use of this drug class for 
COVID-19 patients has been a subject of controversy, because they have been reported in animal studies 
to increase expression of ACE2, the known receptor and cellular entry point for SARS-CoV-2, and thus 
may increase susceptibility to the virus5,6. Supporting this observation, higher urinary and circulating ACE2 
levels have been observed in patients with hypertension and diabetes, respectively, who underwent 
treatment with ARBs and ACEIs76.  
Use of ACEIs/ARBs in COVID-19 patients: However, several lines of evidence suggest use of ACEIs 
and ARBS may offer protective effects in COVID-19 patients. A recent study from Shenzhen, China 
reported that serum angiotensin II levels were significantly elevated in COVID-19 patients with pneumonia 
and were linearly correlated with viral load and lung injury2.  This observation, combined with animal 
studies, has led to the hypothesis that SARS-CoV-2 infection may lead to downregulation of ACE2 
expression and subsequent activation of the RAAS system, which in turn may contribute to the severe levels 
of lung injury and respiratory failure widely observed in hospitalized COVID-19 patients2,12. If this working 
model is correct, use of ACEIs and ARBs may offer therapeutic benefit in treatment of the COVID-19 
patient population. This hypothesis is supported by another recent study of 1128 adult COVID-19 patients 
admitted to 9 hospitals in Hubei Province, China3. In this retrospective cohort study of hospitalized COVID-
19 patients with hypertension, the 28-day all-cause mortality rate among patients who had inpatient 
treatment with ACEI/ARB (n=188) compared with ACEI/ARB nonusers (n=940) was 3.7% vs 9.8%, a 
difference that was statistically significant. In this study, inpatient ACEI/ARB treatment associated with a 
lower mortality risk, although the findings may be influenced by confounding factors. Further support 
comes from previous studies showing ACEIs/ARBs may benefit patients with acute lung injury (ALI) or 
acute respiratory distress syndrome (ARDS)13-16.  
Ramipril: First approved for clinical use nearly 3 decades ago, Ramipril is a 2-aza-bicyclo [3.3.0]-octane-
3-carboxylic acid derivative that has potent antihypertensive properties. It undergoes de-esterification in 
the liver to form ramiprilat, its active metabolite and a nonsulfhydryl ACE inhibitor. Ramipril is approved 
by the FDA for the treatment of hypertension, to reduce the risk of heart failure and death post-myocardial 
infarction, and reduction of risk of myocardial infarction, stroke, and death from cardiovascular causes. The 
drug’s mitigating effects on hypertension are largely attributed to its suppression of the RAAS system. 
Ramipril’s inhibition of tissue and circulating ACE activity results in reduced angiotensin II formation.  
The drug is generally well tolerated with the most prevalent adverse effects in patients with hypertension 
being headache, dizziness, and fatigue.  
 

 
 
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RAMIC  
 
Hypothesis 
We hypothesize that Ramipril 2.5 mg po once daily will perform better than placebo in reducing the 
composite of all-cause mortality, need for ICU admission or invasive mechanical ventilator support among 
hospitalized patients with COVID-19. 
 
Specific Aims 
We plan to conduct a randomized, double-blinded, placebo-controlled clinical trial to examine the efficacy 
of ramipril at 2.5 mg orally daily versus placebo given over 14 days to improve COVID-19 patient outcomes 
including mortality, ICU admission rates, and rates of invasive mechanical ventilator use.  
In this study, we propose to randomize up to 510 patients with SARS-CoV-2 infection, as confirmed by 
PCR or clinical presentation consistent with COVID-19 infection (fever or cough or shortness of breath) 
with positive IgM serology, to either ramipril or placebo for 14 days. We plan to enroll a total of 560 
patients, expecting some drop outs prior to randomization. After an initial medical history and screening 
labs and procedures, patients will be randomized to receive either ramipril 2.5  mg or placebo orally for 14 
days. Patients’ symptoms and study endpoints will be monitored at regular intervals. After 14 days, in 
patient participants will undergo end-of-treatment visit with collection of lab results from medical records, 
if done as part of routine medical care. An additional follow-up visit will be performed at day 28. For 
outpatient participants, the Day 14 and Day 28 visits will be virtual. 
As an exploratory objective, biomarkers of the RAAS axis, will also be monitored in a subset of patients. 
The primary endpoints of successful therapy will be improved survival, reductions in ICU admissions, 
and/or reductions in use of invasive mechanical ventilator support. Secondary endpoints will be the 
proportion of patients needing continued hospitalization, time to mortality, time to ICU admission, time to 
discharge from hospital, proportion of patients developing hypotension and needing pressor support, acute 
kidney injury and proportion of patients developing septic shock. 
 
 
 

 
 
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RAMIC  
 
STUDY OBJECTIVES AND OUTCOMES  
Primary objective: 
To examine the efficacy of ramipril 2.5 mg orally daily over 14 days versus placebo in patients with 
COVID-19 infection in improving survival and reduction in need for admission to intensive care unit or 
invasive mechanical ventilation. 
  
Secondary objectives: 
Proportion of patients needing continued hospitalization at day 14 
Time to discharge from the hospital 
(For discharged to outpatient sub-group only) Need for hospitalization 
Proportion of patients developing hypotension and needing pressor support 
Proportion of patients developing septic shock defined as sepsis with hypotension requiring vasopressors 
to maintain MAP ≥ 65 and serum lactate > 2 mmol/L after fluid resuscitation (Sepsis-3 JAMA 2016) 
Acute kidney injury defined by KDIGO guidelines, increase in serum creatinine by ≥ 0.3 mg/dL within 24 
hours or increase in serum creatinine ≥ 1.5 times baseline. 
Composite of mortality or need for ICU admission or invasive mechanical ventilator use within a 28-day 
window 
 
Exploratory objective: 
To examine the efficacy of ramipril in improving biomarkers of the renin-angiotension-aldosterone axis 
To examine racial differences in response to treatment with ramipril in patients with COVID-19 infection 
Primary outcome measure: 
Composite outcome includes mortality (yes/no) or need for ICU admission or invasive mechanical 
ventilation (yes/no) at 14-day from the start of treatment (or at any point within the 14-day window). 
Secondary outcomes: 
1. Proportion of patients needing continued hospitalization at day 14 
2. Time to discharge from the hospital 
3. (For outpatient sub-group only) Need for hospitalization 
4. Proportion of patients developing hypotension and needing pressor support 
5. Proportion of patients developing septic shock 
6. Proportion of patients developing acute kidney injury  
7. Composite of mortality or need for ICU admission or invasive mechanical ventilator use within a 
28-day window 

 
 
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RAMIC  
 
STUDY DESIGN 
This is a randomized, double-blinded, placebo-controlled clinical trial to examine the efficacy of ramipril 
at 2.5 mg orally daily versus placebo given over 14 days to improve outcomes in patients with documented 
COVID-19 infection. 560 subjects will be randomized, monitored at regular intervals for the 14 days, and 
will be invited to continue participating in the study for an additional 1 year for monitoring. Study 
participants and investigators will be blinded to study assignment.  
Randomization  
Randomization will occur in a 2:1 ratio to treatment and placebo study arms respectively using permuted 
block randomization by UCSD investigational drug services. 
Recruitment  
Recruitment will occur through referral from patients presenting to the emergency department, urgent care, 
other ambulatory clinics or currently hospitalized. In addition, system lists generated to track patients 
undergoing testing for COVID-19 infection will be used for recruitment in accordance with the partial 
HIPAA waiver. Study sites will communicate study availability to their emergency departments, urgent 
care, other ambulatory clinics and hospital wards. Given the scope of the pandemic and lack of effective 
therapies we anticipate rapid study accrual.  
Study Visits  
All subjects: Study visits will occur virtually and in accordance with IRB guidelines to reduce the risk of 
SARS-CoV-2 transmission and preserve personal protective equipment. Informed consent will be obtained 
by study personnel by videoconference or telephone. A HIPAA waiver will be completed by study subjects 
so that study personnel can extract relevant data from the medical record. Subjects may be asked to provide 
copies of their COVID-19 test results, medical history, imaging results and concomitant medications. 
Subsequent study visits will occur by videoconference or telephone.  
Inpatients only: Regular laboratory assessment will be extracted from the medical record on inpatients.  
Discharged to outpatient only: A mobile phlebotomy unit maybe used for blood draws for outpatient 
subjects (Sites will seek approval from UCSD prior to use of third party vendor for mobile phlebotomy 
services). Patients discharged from the hospital at any point after randomization will receive sufficient 
drug/placebo to complete the study and will continue to be monitored by videoconference or telephone and 
will follow up for end of treatment (EOT)/Day 14.  

 
 
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RAMIC  
 
SUBJECT SELECTION 
Inclusion Criteria: 
● Age ≥ 18 years 
● Willing and able to provide written informed consent prior to performing study procedures OR 
legally authorized representative has been fully informed and has given voluntary written informed 
consent in compliance with local regulations. 
● Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection confirmed by 
polymerase chain reaction (PCR) test ≤ 7 days before randomization 
OR 
Clinical presentation consistent with COVID-19 infection (fever or cough or shortness of breath) 
with positive IgM serology 
Exclusion Criteria: 
● Participation in any other clinical trial of an experimental treatment for COVID-19 (compassionate 
use of hydroxycholoroquine, choloroquine, azithromycin or emergency use authorization of 
remdesivir outside of a clinical trial is allowed) 
● Requiring mechanical ventilation at screening 
● Requiring ICU care at admission/screening visit 
● NSAID use within 12 hours of randomization or requiring continued NSAID use during this trial. 
Use of ASAs is permitted. 
● Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 X upper limit of normal 
(ULN) 
● Estimated GFR < 40 mL/min 
● History of serum creatinine ≥ 2 mg/dl in the previous 28 days 
● Systolic BP < 100 mm hg or diastolic BP < 65 mm hg 
● Hypersensitivity to ACEI 
● History of angioedema 
● Outpatient use of ACE inhibitor or Angiotensin II receptor blocker in the last 7 days 
● History of renal artery stenosis 
● Serum potassium ≥ 5.1 mEq/L  
● Pregnancy or breastfeeding 
● Use of aliskiren, amifostine, lithium, sacubitril, within 7 days  
 
Subject Enrollment: 
Prior to initiating the study, each site must have the protocol and informed consent form approved as 
appropriate by the appropriate institutional review board or ethics committee. Potential subjects may be 
referred to the research team in one of two ways 1) Patients with positive PCR testing for SARS-COV2 or 
with positive IgM serologic testing for SARS-COV2 and clinical presentation consistent with infection 

 
 
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RAMIC  
 
(fever or cough or shortness of breath) who present to the emergency department, urgent care, other 
ambulatory clinics or are hospitalized may be referred to participate. Patients with a clinical suspicion of 
COVID-19 infection may also be referred to participate. Candidates referred to the study will undergo 
informed consent using one of the following: 1) Subjects will be consented in-person, or by 
videoconference or telephonically, which must occur in the presence of a co-signing witness. A paper copy 
of the consent form can be provided by a designated health care provider caring for the patient. 2) 
Alternately, electronic methods may be used for consenting subjects. An electronic copy of the signed 
consent will be provided to the subject. After obtaining informed consent, a structured interview will be 
performed to review the past medical history and medication history. Requisite screening labs and 
procedures will be reviewed.  Patients meeting all eligibility criteria and having no exclusion criteria will 
be enrolled in the study.  The screening process is outlined in Appendix A (Screening Diagram). 
 
 

 
 
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RAMIC  
 
TREATMENT 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria are eligible for enrollment. 
The subject will be considered to be randomized when the first dose of investigational product is ingested. 
Participants will be randomized one of two treatment arms and receive either ramipril 2.5 mg/day (1 
capsule) or placebo (1 capsule) orally for a total of 14 days. Study drug is supplied by Pfizer Inc. to the site 
pharmacist who will then distribute the appropriate drug/placebo to the inpatient pharmacy for distribution 
to the patient. Alternately, the site investigator may receive and dispense study drug to the subjects. The 
study site pharmacist/site investigator is required to maintain records of all study drug/placebo 
administration. Study drug/placebo should preferentially be administered after 8 hours of fasting.  
At each visit, particular attention will be paid to symptoms associated with the possible side effects of 
ramipril and patients will complete a standardized symptom scale.  
All patients will be advised to abstain from concomitant NSAID while on study drug/placebo. Use of ASAs 
are permitted during the trial. 
Inpatients: For patients admitted to the hospital, a 14-day supply of study drug/placebo will be provided 
to the inpatient pharmacy from the site pharmacist for daily administration by the health care team. 
Participants were advised to consume the drug in the morning after eight hours of fasting. 
Discharged to outpatient: For outpatient subjects, study drug/placebo will be provided to complete a 14-
day treatment course. Participants were advised to consume the drug in the morning after eight hours of 
fasting. 
STUDY ASSESSMENTS 
Study subjects will attend a virtual information session during which the primary consent document, and 
the UCSD HIPAA forms are reviewed, discussed and signed. The following study procedures will be 
completed at this visit for all study subjects: 
1. Review concomitant medication use 
2. Review past medical history 
3. Review and record blood tests. Complete blood count (CBC) and Comprehensive 
Metabolic Panel (CMP) are required and should be obtained through the study if not 
obtained for routine clinical care.  
4. Review and record clinical chest x-ray and computed tomography results, if available. 
5. Review vital signs: heart rate, blood pressure, oxygen saturation and the use of 
supplemental oxygen, body temperature, and respiratory rate, if available. 
6. Symptom assessment: Structured tool (Appendix B) 
7. Outcome assessment 
 
 
 

 
 
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RAMIC  
 
Table 1: Schedule of Events 
Assessment 
  
Treatment Period 
End of 
Study 
Early 
Terminatio
n 
 Visit Date 
Screening 
RAND 
D3 
D7 
D14 
D28 
  
 Visit Window 
  
  
  
  
 
± 7  
  
 Visit 
V1  
V2  
V3  
V4  
V5  
V6  
ET 
Informed Consent 
X 
  
  
  
  
  
  
Review of Positive 
SARS-CoV-2 Molecular 
Test 
X 
  
  
  
  
  
  
Screening Labs and 
Procedures1 
X 
  
  
  
  
  
  
Medical History 
X 
 
  
  
  
  
  
Concomitant Medication 
History 
X 
X2 
X 
X 
X 
X 
X   
Collect Vital Signs 
  
X 
 
 
 
 
 
Imaging Data Extraction 
 
X 
 
 
 
 
 
Biomarker Assessment 
and Biobank3 
X6 
  
X 
 
  
X 
inpatient 
only  
X 
inpatient 
only  
X 
inpatient only  
includes 
serologic 
testing 
  
Symptom Assessment 
(Telephone or Video) 
  
X  
X  
X  
X  
X  
X  

 
 
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RAMIC  
 
Laboratory Assessment4 
  
X5 
 
X 
inpatient 
only 
X 
inpatient 
only 
X 
inpatient 
only  
X 
inpatient only 
X 
inpatient only 
Dispensing of Study 
Drug 
  
X 
  
  
  
  
  
Review of Treatment 
Adherence 
  
  
X 
X 
X  
X  
X 
AE/SAE Assessment 
 
X 
X 
X 
X 
X 
X 
Study Endpoint 
Determination 
  
  
X 
X 
X 
X 
X 
Boxes shaded red are required study procedures. Others are as available. All procedures apply to both inpatients and outpatients, unless otherwise 
indicated. 
1As outlined in study figure: Complete blood count with differential, comprehensive metabolic panel, oxygen saturation and confirmation of 
pregnancy status. These tests should be obtained through the study if not obtained for routine clinical care. 
2Only required if greater than 24 from screening visit 
4Laboratory assessment: Complete blood count with differential, comprehensive metabolic panel.  
Premature Discontinuation of Study Drug 
Patients meeting a primary endpoint for the study defined as invasive mechanical ventilation or transfer to 
the intensive care unit or death will stop study drug/placebo. In addition, patients who discontinue due to 
toxicity rules defined below may stop the study drug/placebo. Additional data on secondary endpoints will 
continue to be collected and the SOE will be completed when possible.  
Post-Treatment Phase: 
At the end of the 14-day treatment phase, patients will be followed for another 14 days until day 28 and 
receive a phone visit to assess any changes in the clinical status related to primary and secondary outcomes. 
It is not possible to predict the outcome of this study, but if ramipril appears to have a significant effect on 
COVID-19 outcomes, we will likely develop a follow-up protocol to assess its impact on long-term 
virologic cure, immune function, lung function and long-term survival and re-infection due to COVID. 
ADVERSE EVENTS AND STUDY MONITORING 
Safety will be assessed on a continuous basis in the study. Adverse events are any unfavorable or unintended 
sign, symptoms or diagnosis that occurs in a study participant during the conduct of the study independent 
of attribution. All adverse events will be recorded on case report forms within 72 hours if it meets any of 
the following criteria: ≥ Grade 3 toxicity (per Table 2) or those that lead to cessation of study drug/placebo 
regardless of toxicity. 

 
 
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RAMIC  
 
Risks and hazards of Ramipril: 
First approved for clinical use nearly 30 years ago, ramipril has been evaluated for safety in over 4,000 
patients with hypertension17-21. In placebo-controlled trials, the most frequent clinical side effects reported 
included headache (5.4%), dizziness (2.2%), and fatigue (2.0%). Only fatigue has been observed to be more 
common in ramipril groups, compared to the placebo group. Side effects have generally been observed to 
be mild and transient and were not dose-dependent. Discontinuation of ramipril due to side effects occurred 
in 3% of US patients in clinical trials. The common reasons cited for discontinuation were: cough (1.0%), 
dizziness (0.5%), and impotence (0.4%). In the Heart Outcomes Prevention Evaluation study (HOPE 
study)22-23, 4,645 patients taking ramipril 10 mg daily were followed over a 5-year period. Patients in this 
study were either normotensive or under treatment with other antihypertensive agents. In this study, the 
only notable side effect that led to excess discontinuation of ramipril was cough. Ramipril is a well-studied 
and reasonably safe drug. However, we will monitor study subjects carefully for any adverse reactions 
either via physical exams for inpatients or through remotely conducted visits by phone or video for 
outpatients.  
Criteria for discontinuation 
Any patient meeting ≥ Grade 3 toxicity (per Table 2) or meeting the primary endpoint will have the study 
drug/placebo discontinued. There is no recommended dose modification. Outpatients will also be screened 
for symptoms and those with symptoms consistent with any of the below adverse events will be assessed 
by the site PI to determine the need for cessation of study drug/placebo.   
Table 2. Scoring of toxicity for discontinuation 
Adverse 
events 
1 
2 
3 
4 
5 
Allergic 
reaction 
Transient 
flushing or 
rash, 
 
Intervention 
not indicated 
Intervention or 
infusion 
interruption 
indicated; 
 
Responds 
promptly to 
symptomatic 
treatment 
(e.g., 
antihistamines
, NSAIDS, 
narcotics); 
 
Prophylactic 
medications 
indicated for 
<=24 hrs 
Prolonged (e.g., 
not rapidly 
responsive to 
symptomatic 
medication 
and/or brief 
interruption of 
infusion); 
 
Recurrence of 
symptoms 
following initial 
improvement; 
 
Hospitalization 
indicated for 
clinical sequelae 
(e.g., renal 
impairment, 
Life 
threatening 
consequences; 
 
Urgent 
intervention 
indicated 
Death 

 
 
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RAMIC  
 
pulmonary 
infiltrates) 
Anaphylaxis 
 
 
Symptomatic 
bronchospasm, 
with or without 
urticaria; 
 
Parenteral 
intervention 
indicated; 
 
Allergy-related 
edema/angioede
ma; 
 
Hypotension 
Life-
threatening 
consequences; 
 
Urgent 
intervention 
indicated 
Death 
Hypotension 
 
 
SBP < 90 mm 
hg or DBP < 50 
mm hg 
Requiring 
vasopressor 
support 
Death 
ALT 
(U/L) 
Baseline-1.5x 
baseline 
>200 and > 
1.5x baseline 
>400 and > 2x 
baseline 
401-800 and > 
3x baseline 
>800 
AST 
(U/L) 
Baseline-1.5x 
baseline 
>200 and > 
1.5x baseline 
>400 and > 2x 
baseline 
401-800 and > 
3x baseline 
>800 
Total 
Bilirubin 
(mg/dL) 
0.1 to 1 
1.1 to 2 and 
direct bilirubin 
>0.5 
2 to 5 and direct 
bilirubin > 1 
5.1 to 10 
>10 
Potassium 
(mg/dL) 
5.1-5.3 
> 5.3-5.5 
> 5.5- 6.0 
Investigator can 
assess for 
possible 
hemolysis 
> 6.0 
Death 
Creatinine 
(mg/dL) 
Creatinine 
level increase 
of >0.3 
mg/dL; 
Creatinine 
1- 1.5 x above 
baseline 
Creatinine 
1.5 - 2x above 
baseline 
Creatinine >2x 
baseline or 
>2.0 mg/dL; 
Hospitalization 
indicated 
Life-
threatening 
consequences; 
 
Dialysis 
indicated 
Death 
Table 2. Scoring of toxicity for dose modification. Scoring of toxicity from the CTC Version 4.0, with 
modifications is proposed given the short duration of therapy and consideration of signs and symptoms 

 
 
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RAMIC  
 
related to COVID-19 infection. Due to the nature of the trial and to minimize exposure to SARS-CoV2 
monitoring laboratory assessments while on study drug/placebo will only occur in hospitalized patients. 
Grade 3, 4, 5 reactions warrant drug/placebo discontinuation 
The risks and discomforts of frequent phlebotomy  
Blood samples will be obtained to document changes in levels of biochemical markers of the RAAS system 
and to monitor the metabolic effects and toxicities of ramipril. Blood collection by venipuncture is 
associated with mild discomfort, and the possibility of localized bruising, phlebitis, or extravasation. The 
risk of infection or fainting is extremely small.  
Data and Safety Monitoring 
The UC San Diego Clinical and Translational Research Institute will appoint an independent data safety 
monitoring board (DSMB) composed of two independent physicians and one statistician. The DSMB will 
undertake a review of the interim data from the study to ensure the safety of study participants and to 
recommend changes to the study including early termination or modification of the study if it appears futile. 
The DSMB will review a summary of data by randomized treatment arm for the primary outcome, toxicity 
and adverse events. A planned interim analysis will occur after approximately 50% of the planned 
enrollment from the trial has been completed, approximately 280 patients.  
The principal investigator and research coordinator of this protocol will monitor data and safety regularly 
at weekly meetings. These meetings are separate from regular clinical rounds and consist of review of all 
study patients including flow sheets of major safety and efficacy measurements.  All measurements and 
tests are well established in clinical medicine.  Yearly reports are made to the UCSD IRB regarding safety 
and efficacy. 
Adverse Event Reporting 
All serious adverse events will be reported to the local IRB and sponsor within 7 days.  Unexpected and 
related fatal or life-threatening events will be reported within 48 hours and reports will be sent to the FDA, 
MEDWATCH 
program 
(telephone 
1-800-FDA-1088; 
or 
via 
the 
Internet 
at 
www.fda.gov/medwatch/index.html.) 
Patient Privacy 
All data and study forms will be in secured locations (locked room or cabinet) and access is limited to study 
personnel.  Subject names are not used; instead a name code is assigned upon enrollment.  Release of data 
to persons or organizations outside study personnel will require written consent of the subject. 
All consents will be stored in well-marked binders in locked file cabinets located in private offices at UCSD 
Medical center. Databases with identifying information will be secure as they will be password protected 
and encrypted.  Staff will be trained in HIPPA guidelines and confidentiality issues. 
  
 
 

 
 
Page 19 of 25 
RAMIC  
 
STATISTICAL METHODS AND CONSIDERATIONS 
The primary outcome of this study will be represented by a composite of outcomes which will include 
mortality, ICU admission, and/or need for ventilator use within a 14-day period. Statistical analyses will 
compare outcomes between treatment versus placebo-arms. It is not possible to predict what the 
spontaneous or therapeutic response rate will be. Thus, we predict that the spontaneous improvement rate 
would be zero to less than 1%. In the primary analysis, we assume that the 14 day mortality/ICU 
admission/Ventilator use of placebo and ramipril-treatment group to be 22% and 12%, and the proportion 
of the sample from placebo to ramipril-treatment group to be 1:2. Therefore, using Whittemore’s formula 
(Whittemore, 1981), we estimate a sample size of 510 patients--340 in the ramipril arm and 170 in the 
placebo arm—will be required to detect effects with a power 80% (or higher) with a Type I error rate of 
alpha = 0.05. This formula is used for logistic regression which has an overall event proportion of P and an 
odd ratio of r at one standard deviation above the mean of the predictor. 
Statistical analysis plan: 
The primary outcome will first be analyzed using a 2x2 contingency table (treatment by outcome) and 
testing will use Fisher’s exact test. Primary analyses will be Intent to Treat (ITT). 
We expect to enroll up to 560 patients in this study and randomize at least 510 of them to either treatment 
or placebo arm for a full 2 weeks with a follow-up evaluation. Therapeutic intervention trials have had 
variable dropout rates. Previous short-term studies of ramipril had less than 10 % dropouts. Therefore, we 
expect less than a 10% dropout rate. Dropouts would be considered non-responders based upon intention 
to treat analysis. A modified intention to treat analysis will be done in which we will exclude the patients 
who dropped out before getting the week 2 exit evaluation. 
 
Primary and secondary outcomes will be assessed comparing placebo and treatment arms using 
parametric or non-parametric tests as indicated. 
The major primary outcome to be evaluated is a composite of mortality or need for ICU admission or 
invasive mechanical ventilator use within a 14-day window. 
The major secondary outcomes to be evaluated are: 
1. Proportion of patients needing continued hospitalization at day 14 
2. Time to discharge 
3. (For discharged to outpatient sub-group only) Need for hospitalization 
4. Proportion of patients developing hypotension and needing pressor support 
5. Proportion of patients developing septic shock 
6. Proportion of patients developing acute kidney injury 
7. Composite of mortality or need for ICU admission or invasive mechanical ventilator use within a 
28-day window 
 
 

 
 
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RAMIC  
 
APPENDIX A: Screening Diagram 
 

 
 
Page 21 of 25 
RAMIC  
 
APPENDIX B: COVID-19 Symptom Assessment 
 
COVID-19 Symptom Assessment  
Pt ID_____________  
Purpose:  To evaluate the symptoms of COVID-19 infection    
 
1. Has the patient had a fever? 
Never 
Yes 
(0) 
( 1) 
 
 
 
 
 
2. What was the highest measured temperature in the last 24 hours? 
____________ Farenheit 
 
3. Is the patient short of breath or trouble breathing?  
No 
Yes 
(0) 
(1) 
 
 
4. Does the patient have a cough? 
No 
Yes 
(0) 
( 1) 
 
5. Does the patient have loss of sense of smell or change in taste? 
No 
Yes 
(0) 
(1) 
 
6. Does the patient have light-headedness? 
No 
Yes 
(0) 
(1)  
 
7. Does the patient have body aches? 
No 
Yes 
(0) 
(1) 
 
8. Does the patient have chest pain? 
No 
Yes 
(0) 
(1) 
 
 
 
Alert 
site 
investigator to 
follow up 
Proceed to question 3 
 

 
 
Page 22 of 25 
RAMIC  
 
9. Does the patient have drenching sweats? 
No 
Yes 
(0) 
(1) 
 
10. Does the patient have diarrhea? 
No 
Yes 
(0) 
(1) 
 
 
Completed by ________________________  
 
Signature        _________________________ 
 
Date                  ________________________ 
 
 
 

 
 
Page 23 of 25 
RAMIC  
 
REFERENCES 
1 
Wu, Z. & McGoogan, J. M. Characteristics of and Important Lessons From the Coronavirus 
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2 
Liu, Y. et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral 
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3 
Zhang, P. et al. Association of inpatient use of angiotensin converting enzyme inhibitors and 
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4 
Liu, Y et al. Anti-hypertensive Angiotensin II receptor blockers associated to mitigation of disease 
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5 
Ferrario, C. M. et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor 
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6 
Klimas, J. et al. Perinatally administered losartan augments renal ACE2 expression but not cardiac 
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7 
Soro-Paavonen, A. et al. Circulating ACE2 activity is increased in patients with type 1 diabetes 
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375-383, 
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Shang, J. et al. Structural basis of receptor recognition by SARS-CoV-2. Nature, 
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Kuba, K. et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-
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10 
Vaduganathan, M. et al. Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-
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The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and 
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12 
Bavishi, C., Maddox, T. M. & Messerli, F. H. Coronavirus Disease 2019 (COVID-19) Infection 
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13 
Caldeira, D., Alarcao, J., Vaz-Carneiro, A. & Costa, J. Risk of pneumonia associated with use of 
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14 
Imai, Y. et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 
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15 
Kim, J. et al. Effect of Renin-Angiotensin System Blockage in Patients with Acute Respiratory 
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Wirtz, H. et al. Ace inhibitor for lung protection during mechanical ventilation for acute lung 
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Ball, S. G. et al. EFFECT OF RAMIPRIL ON MORTALITY AND MORBIDITY OF 
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Garg, R. & Yusuf, S. OVERVIEW OF RANDOMIZED TRIALS OF ANGIOTENSIN-
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Gerstein, H. C. et al. Effects of ramipril on cardiovascular and microvascular outcomes in people 
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Yusuf, S. et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular 
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Yusuf, S. et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N. Engl. 
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Page 25 of 25 
RAMIC  
 
CREDITS 
PRINCIPAL INVESTIGATOR  
Rohit Loomba, MD, MHSc 
CO-INVESTIGATORS 
Veeral Ajmera, MD, MAS  
Ravinder Mehta, MD  
Vaishal Tolia, MD, MPH  
Daniel Bouland, MD, FACP 
Davey Smith, MD, PhD  
Atul Malhotra, MD 
Jeffrey Yin, Pharm D  
Lisa Richards, NP 
Summer Collier, NP  
Wesley K. Thompson, Ph.D 
COLLABORATORS 
Paul Insel, MD 
Krisna Sriram, PhD 
STUDY COORDINATORS 
Shaniqua Bates 
Kevin Matias  
PROJECT MANAGER 
Kristin Woods 
 
CONTRACT and BUDGETS 
 
Han Nguyen, MPH 
REGULATORY COORDINATOR 
Archana Bhatt 
DATABASE MANANGER  
Ricki Bettencourt  
STUDY STATISTICIANS  
Wes Thompson, PhD  
Xin Tu, PhD 
Tuo Lin