Clinical trial NCT06146374
Conditions: COVID-19
Keywords: Coronavirus Covid-19 Double Blind Healthy Volunteers Multiple Ascending Dose Phase 1 Placebo Controlled Randomized SLV213
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2024-04-09; Completion date: 2024-07-08
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This Phase 1 double blind, placebo-controlled study will evaluate the safety, tolerability, and pharmacokinetics (PK) of multiple ascending doses (MAD) of SLV213 in healthy male and female participants, 18-65 years of age. This study will help to select the most likely suitable dose (e.g., at Maximum Tolerated Dose \[MTD\]) for the treatment of patients with COVID-19 in a pivotal study. This phase 1 double blind, placebo-controlled study will consist of three sequential cohorts of 12 participants each (8 SLV213 and 4 placebo), at doses of 400 mg every 12 hours (Q12h), 600 mg Q12h, and 800 mg Q12h administered orally (PO) for 7 days. After each cohort, a Safety Review Committee (SRC) will evaluate the safety of the regimen before proceeding to dose the next cohort. Randomization will occur into the respective cohorts as above. Upon meeting the Inclusion/Exclusion criteria, subjects will begin treatment with SLV213 or placebo per their assigned cohort. The primary objective is to evaluate the safety and tolerability of multiple ascending doses of SLV213 for 7 days in healthy participants.

Detailed description:
This Phase 1 double blind, placebo-controlled study will evaluate the safety, tolerability, and pharmacokinetics (PK) of multiple ascending doses (MAD) of SLV213 in healthy male and female participants, 18-65 years of age. This study will help to select the most likely suitable dose (e.g., at Maximum Tolerated Dose \[MTD\]) for the treatment of patients with COVID-19 in a pivotal study. This phase 1 double blind, placebo-controlled study will consist of three sequential cohorts of 12 participants each (8 SLV213 and 4 placebo), at doses of 400 mg every 12 hours (Q12h), 600 mg Q12h, and 800 mg Q12h administered orally (PO) for 7 days. After each cohort, a Safety Review Committee (SRC) will evaluate the safety of the regimen before proceeding to dose the next cohort. Randomization will occur into the respective cohorts as above. Upon meeting the Inclusion/Exclusion criteria, subjects will begin treatment with SLV213 or placebo per their assigned cohort. Participants will take their study drug in the fasted state prior to morning and evening meals and will remain as in-patient in the clinical trial unit (CTU) during all treatments and for approximately 48 hours (h) after the last dose for monitoring. After discharge from the CTU, participants will be monitored by CTU staff by telephone to assess for new adverse events and use of concomitant medication since the last visit or contact, approximately weekly for three weeks. Participants will be asked to return to the CTU for further assessment of moderate or severe adverse events (AEs) use of concomitant medications (ConMeds) since the last visit or contact, approximately weekly for three weeks. The primary objective is to evaluate the safety and tolerability of multiple ascending doses of SLV213 for 7 days in healthy participants. The secondary objective is to characterize the multiple dose PK of SLV213 in healthy participants.

Arms: arm 1: 600mg (6x 100mg capsules) of SLV213 (N=8) or placebo (N=4) administered orally every 12 hours for 7 days to healthy male and female participants 18-65 years of age. arm 2: 800mg (8x 100mg capsules) of SLV213 (N=8) or placebo (N=4) administered orally every 12 hours for 7 days to healthy male and female participants 18-65 years of age. arm 3: 400mg (4x 100mg capsules) of SLV213 (N=8) or placebo (N=4) administered orally every 12 hours for 7 days to healthy male and female participants 18-65 years of age.
Interventions: intervention 1: Placebo for SLV213 intervention 2: SLV213
Intervention descriptions: intervention 1: Microcrystalline cellulose in a size 1 orange hard gelatin capsule. intervention 2: SLV213 drug substance (K777) is 4-methylpiperazine-1-carboxylic acid, a vinyl sulfone cysteine protease inhibitor for the treatment of subjects infected with SARS-CoV-2. SLV213 is a white powder substance without excipients or stabilizer that will be packed into gelatin capsules which has been demonstrated to exhibit broad inhibitory properties against host cathepsins (e.g., Cathepsin L).

Protocol documents:
ICF_000.pdf: 
Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 22-0027 
ICF version 4.0 – 08 March 2024 
Page 1 of 32 
 
 
 
Martin Kankam, MD, PhD, MPH, FAPCR 
              Advarra IRB Approved Version 11 Mar 2024 
 
INFORMED CONSENT TO TAKE PART IN A CLINICAL RESEARCH STUDY  
 
 
TITLE:  
A Randomized, Double Blind, Placebo-Controlled, Multiple 
Ascending Dose, Phase 1 Study of SLV213 in Healthy Volunteers 
PROTOCOL NO.:  
DMID 22-0027 
PURPOSE:  
COVID-19 infection 
TYPE OF STUDY:  
Phase 1 – Healthy Participants 
SPONSOR:  
Division of Microbiology and Infectious Diseases (DMID) 
 
National Institute of Allergy and Infectious Diseases (NIAID) 
 
National Institutes of Health (NIH) 
 
5601 Fishers Lane, MSC 9806 
 
Bethesda, Maryland 20892 
STUDY DOCTOR:  
Martin Kankam, MD, PhD, MPH, FAPCR 
RESEARCH SITE 
ADDRESS: 
Altasciences Clinical Kansas, Inc. 
10103 and/or 10203 and/or 10183 Metcalf Avenue 
Overland Park, KS 66212 
TELEPHONE NUMBER  913-696-1601 (24-hour number) 
 
KEY INFORMATION 
The following is a summary of the things you should know about this clinical research study: 
 
• You are invited to take part in a clinical research study of the investigational drug 
SLV213. “Investigational” means that the drug is allowed to be evaluated in healthy 
persons like you in this study by the U.S. Food and Drug Administration (FDA), but not 
approved for use in people by prescription. Your participation is voluntary and your 
consent to participate is sought after you have read and understood information provided 
in this document and have your questions about the study answered before any study tests 
are done. If you consented and then change your mind, you may withdraw from the study 
and notify the study doctor.  
• SLV213 is a compound that is being developed for the treatment of severe infection 
caused by the coronavirus SARS-CoV-2, which was the cause of COVID-19, and variants 
of that virus that still cause active infection. In this study, capsules (pills) of SLV213 
containing the active drug, or placebo (pills containing only inactive ingredients) will be 
administered by mouth with water every 12 hours for 7 days.  
• The purpose of this research study is to collect information about the safety of SLV213, 
that is, if any side-effects occur after taking it, and their type and how severe they are. 
Information will also be collected about the pharmacokinetics (PK) of SLV213 at the 


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 22-0027 
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Martin Kankam, MD, PhD, MPH, FAPCR 
              Advarra IRB Approved Version 11 Mar 2024 
 
doses to be used. (PK means the study of how the body absorbs, changes, and eliminates 
the active drug.) 
• You will be assigned to one of 3 study treatment cohorts (groups), numbered 1 to 3. The 
cohorts will run one after the other in the order they are numbered, that is, Cohort 1 will 
be done before Cohort 2, and Cohort 2 before Cohort 3. The lowest dose, 400 mg every 12 
hours, will be in Cohort 1, the median dose, 600 mg every 12 hours, will be in Cohort 2, 
and the highest dose, 800 mg every 12 hours, will be in Cohort 3. 
• A total of 36 participants will take part in the study, 12 participants in each cohort, and 2/3 
will take the active study drug and 1/3 will take the placebo. You will be assigned only in 
one cohort (group) randomly (like tossing a coin) to receive either the study drug (about 
66% chance) or placebo (about 34% chance).  
• If you decide to participate, you will be in the study for up to 56 days (from Screening 
Visit to Final Visit). There is a Screening Period of up to 27 days to determine if you meet 
the study requirements; a Check-in Visit on the day before dosing with the study drug is to 
start, to confirm you can take part in study and be admitted in the clinical trial unit (CTU) 
on the same day; an Inpatient Treatment and Follow-up Period of 9 days / 8 nights, with 
twice-daily dosing with the study drug or placebo assigned to your cohort every 12 hours 
for 7 days, and 2 days of follow up before discharge to evaluate the effects of the study 
drug; and an Outpatient Follow-up Period with 3 telephone calls by the study staff about 
1, 2 and 3 weeks after receiving the last dose to evaluate delayed effects of the study drug.  
• Screening evaluations will start after signing this form to document your willingness to 
take part in this study. We will collect demographic information about you (age, sex, race 
and ethnicity) and social habits (smoking, alcohol use, drug use, exercise) and complete 
standard medical evaluations (your medical history, history of medications you take, 
physical examination (PE), your vital signs (VS; blood pressure [BP], heart rate [HR], 
respiratory (breathing) rate [RR] and temperature [T]); blood and urine tests; and an 
electrocardiogram (ECG; a paper tracing of the heart signals). BP and HR will be 
measured while resting lying down and after standing. If you meet all screening study 
requirements, you will be asked to return to the clinic on the Check-in day to confirm you 
continue meeting the requirements to participate in the study. If you do, you will be 
admitted as inpatient in the CTU.  
• On study Day 1 through Day 7, you will receive the study drug or placebo dose assigned 
to your cohort (group) every 12 hours, in the morning and evening every day. The study 
drug or placebo pills will be taken by mouth with water. 
o You will fast for various periods of time before receiving each dose depending on the 
study day. You will fast for at least 8 hours before receiving the morning dose on 
Day 1 and at least 8 hours before receiving the evening dose on Day 7. Before all the 
other doses you will fast for at least 2 hours.   
o You will also fast for various periods of time after receiving each dose depending on 
the study day. You will fast at least 4 hours after receiving the morning dose on Day 1 
and at least 4 hours after receiving the evening dose on Day 7. After all the other doses 
you will fast for at least 1 hour.   
o You will be allowed to drink liquids during the periods of fasting except 1 hour before 
and 1 hour after each dose. Study staff will serve you meals after the end of fasting.  


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 22-0027 
ICF version 4.0 – 08 March 2024 
Page 3 of 32 
 
 
 
Martin Kankam, MD, PhD, MPH, FAPCR 
              Advarra IRB Approved Version 11 Mar 2024 
 
• The effects of the study drug on you will be assessed by your reports of symptoms and 
medical evaluations, ECGs, and blood tests.  
• Blood plasma samples will also be collected from a vein in the arm before and after each 
dose, more frequently after the morning dose on Day 1 and the evening dose on Day 7, to 
measure the study drug concentration. The measurement will be used for PK analysis to 
study how your body handles the study drug. Additional blood serum samples will also be 
collected at the same timepoints as the PK samples for future research of the study drug if 
you consent to do so. These serum samples and any unused plasma PK samples will be 
stored for future research if you consent to do so. 
• You will be discharged from the CTU 2 days after the last dose, on Day 9, and you will 
then be contacted by phone about every week, on Days 15, 21 and 28, to check how you 
feel and if you have any symptoms and take any new medications.  
• You may be asked to return to the research site for evaluation of any new symptoms as 
needed after these phone contacts.  
• You will be discharged from the study on Day 28 or later if there is a medical need for 
further follow up.  
• Risks that could be caused by the study drugs are: 
o SLV213 was safe and well-tolerated in a previous study in healthy people who took a 
single dose of the study drug in the range of doses to be used in this study.  
The most common side effects thought to be related to the study drug were: 
 Headache 
 Change in taste 
 Change in the feces 
 One participant had a syncope (a transient [lasting for a short period of time] loss 
of consciousness with a drop in blood pressure when standing up) 30 minutes after 
taking a median dose, but not at later times, and in others who took two times and 
four times higher doses did not have the same symptoms.   
o Potential side effects are: 
 An allergic reaction. Symptoms include: 
 Rash 
 Wheezing and difficulty breathing 
 Dizziness and fainting 
 Swelling around the mouth, throat or eyes 
 A fast pulse 
 Sweating 
 Vomiting, especially in higher doses 
 Decreased food intake 
 Abnormal liver tests, that are transient 
 Increased heart rate with a drop in blood pressure when standing. 


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 22-0027 
ICF version 4.0 – 08 March 2024 
Page 4 of 32 
 
 
 
Martin Kankam, MD, PhD, MPH, FAPCR 
              Advarra IRB Approved Version 11 Mar 2024 
 
o SLV213’s potential to cause mutations and cancer needs further testing, and there are 
no long-term studies to evaluate this risk in animals and humans. However, this risk is 
considered low because the study drug will be administered for a short time in this 
study. 
• Risks that could be caused by the study procedures are: 
o There may be side effects of inserting needles or a catheter (plastic tube) in the vein 
(IV) to collect blood, such as local pain, bruising, bleeding, phlebitis (inflammation or 
infection of the vein) or thrombophlebitis (clotting of blood in the vein) at the site of 
the IV catheter. 
o There may be side effects caused by the blood volume removed for testing, such as 
dizziness standing or feeling tired, or anemia (low blood counts). The amount of blood 
that will be drawn during the study is about 385 mL (13 ounces, about 1.6 cups). This 
is less than the volume when you donate blood, which is 500 mL (about 16.5 ounces, 
2 cups).  
o There could be side effects from the ECG patches, such as a rash or minor irritation of 
the skin with itching. There could also be a need to shave a small area of the skin to 
place the patch. 
• The CTU study staff will monitor your well-being during the study, evaluate you 
medically, and provide appropriate treatment as required. Precautions will be taken to 
minimize complications from blood draws or flushing the IV catheter.  
• The study has no direct benefit for you. Knowledge gained in the study could be of future 
benefit to public health and to individuals with infections, who might benefit if the study 
drug is licensed.  
• There are no alternatives to the research study. You are free to consent to participate in the 
study or not to participate or to withdraw after you consented initially. You will be 
compensated for the study days and procedures you complete. You will not be penalized if 
you withdraw from the study. 
• Your personal health information will be protected. Your study medical record, laboratory 
test results and storage tubes containing your blood (plasma or serum) and urine 
specimens will be coded and will not identify you by name or provide any other personal 
information that can identify you. 
 
INTRODUCTION 
You are being asked to be a volunteer in a clinical research study. You cannot be in this study if 
you are in another research study or have been in another study within the past month. Before you 
agree to be a part of this study, it is very important that you read and understand the study plan 
and in what ways you will need to cooperate. This consent form may have words in it that you do 
not understand. You may ask the study doctor or the study staff to explain any words or 
information that you do not understand. If you sign and date this form, it means you want to be in 
this study. 
 
This form describes the reason for the study, and the way the study will be done. It also describes 
the benefits, risks, discomforts, and warnings about the study. This form will also explain how 


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 22-0027 
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Page 5 of 32 
 
 
 
Martin Kankam, MD, PhD, MPH, FAPCR 
              Advarra IRB Approved Version 11 Mar 2024 
 
your medical information will be used, and who may see it. It describes your rights as a volunteer 
in the study. 
 
The study staff will ask you many questions. Your answers must be completely truthful. Your 
health history and any changes in the way you feel during the study are very important. You must 
tell the study staff about any changes in your health or the way you feel. If you are not truthful, 
you may harm yourself by being in this study. By signing this consent form, you understand that 
you must provide truthful answers for your safety.  
 
Altasciences Clinical Kansas, Inc., the research site, is being paid by the Division of 
Microbiology and Infectious Diseases (DMID) of the National Institute of Allergy and Infectious 
Diseases (NIAID), part of the National Institutes of Health (NIH). DMID is also referred to as the 
“study sponsor” in this document. 
 
BACKGROUND AND PURPOSE  
The study doctor, DMID, and the study drug company, Selva Therapeutics, Inc, are conducting 
this research study of SLV213, an investigational drug that is being developed as a potential 
treatment of infections caused by coronaviruses related to the viruses that caused COVID-19. This 
research study is the first one where the effects of SLV213 taken every 12 hours for 7 days will be 
studied to determine the safety, tolerability, and PK of the study drug.  
 
SLV213 capsules contain K777, a synthetic antibiotic that can block enzymes called Cathepsin L 
that are present in human cells and are used by the coronavirus to facilitate its entry into the cells 
that results in the infection. (Enzymes are specialized proteins that perform multiple functions in 
cells). SLV213 is considered investigational in this study because it is not a licensed/approved 
drug and will be used in total daily doses that are higher and the duration of study treatment is 
longer than the doses and duration of study treatment previously used in people. 
 
SLV213 is evaluated in healthy persons before it is tested in people with infections in order to 
understand the safety profile and the PK of the study drug. It is expected that the study drug will 
be effective in infections for which the number of existing effective oral treatments are limited 
and, if given early after infection it could decrease the need for hospitalization or the development 
of severe disease.  
 
INFORMATION ABOUT THE STUDY 
This study will be done at one research site (described as clinical trial unit [CTU] in this 
document) in the U.S. Study participants will be adults between 18 to 65 years of age who are in 
good health, do not take certain medications, and, for women, who are not pregnant or 
breastfeeding. There will be a total of approximately 36 male and female participants in this 
study, assigned in 3 cohorts (groups) of 12 participants each. In each group, 8 participants will 
take active study drug (SLV213), and 4 participants will take placebo (inactive ingredients) 
randomly (like tossing a coin), with the chances being 66% to receive active study drug and 34% 
to receive placebo. The study drug doses will be taken in the form of capsules by mouth with 
water every 12 hours, morning, and evening, for 7 days. If you are eligible to take part in the 
study, you will take the same dose and the same number of capsules each time, according to the 
group you will be placed in after you consent to take part in the study and meet the study 


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 22-0027 
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Page 6 of 32 
 
 
 
Martin Kankam, MD, PhD, MPH, FAPCR 
              Advarra IRB Approved Version 11 Mar 2024 
 
requirements. Each dose of SLV213 (the active study drug) for each group are: 400 mg (Group 
1), 600 mg (Group 2) and 800 mg (Group 3).  
 
The study drug doses, the number of capsules taken in each cohort, and the duration of study 
treatment are shown in the following table: 
 
Cohort Number 
Study Drug 
Study Drug 
Dose 
Daily Study Treatments / 
Frequency 
Duration 
1 
SLV213 
or placebo 
400 mg 
SLV213 
Or placebo 
4x100 mg capsules study drug or  
4 capsules placebo 
By mouth every 12 hours 
7 days 
2 
SLV213 
or placebo 
600 mg 
SLV213 
Or placebo 
6x100 mg capsules study drug or  
6 capsules placebo 
By mouth every 12 hours 
7 days 
3 
SLV213 
or placebo 
800 mg 
SLV213 
Or placebo 
8x100 mg capsules study drug or  
8 capsules placebo 
By mouth every 12 hours 
7 days 
 
Additional participants may also be admitted to the CTU before dosing and may serve as back-up 
study participants. You may be selected to participate in this research study as either a regular 
study participant or as a back-up study participant. If you were selected as a back-up but did not 
receive a study treatment, you could be placed in a future group if you are still interested in taking 
part in the study. If you are placed in a future cohort, you may have to repeat screening 
assessments. 
 
The study will take up to 56 days to complete and is made up of the following periods: a 
Screening Period up to 27 days (Day -28 to Day -2), with a single visit during which you will 
have screening evaluations and tests; a Check-in Visit (Day -1), during which you will have 
screening tests repeated to confirm your eligibility. If you still qualify, you will be admitted into 
the CTU, where you will stay overnight, and enrolled into the study; an Inpatient Study Treatment 
and Follow-up Period lasting 9 days/8 nights, with eligibility reviewed before the study treatment 
is administered on Day 1, twice daily doses, 12 hours apart, of the study drug or placebo from 
Day 1 to Day 7 and a follow-up of 2 days after the last dose (Days 8 and 9), with discharge from 
the CTU on Day 9; and an Outpatient Follow-up Period of up to 21 days after the last study 
treatment, that is conducted through the phone with study staff on Day 15 (±2 days), Day 21 
(±2 days) and Day 28 (±2 days) and, if needed, visits to the CTU for medical evaluation after the 
phone calls. 
 
 
 


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Martin Kankam, MD, PhD, MPH, FAPCR 
              Advarra IRB Approved Version 11 Mar 2024 
 
The schedule for screening, check-in / enrollment, study treatment, and outpatient follow-up 
periods is shown in the table below: 
 
Screening Period  
Inpatient Study  
Treatment and Follow-up 
Outpatient Follow Up 
Screening  
Check-in/ 
Enrollment 
Dosing 
Follow-up 
Day -28 to Day -2 
Day -1 
Day 1 to Day 7 
Days 8 and 9 
Day 9 (discharge) 
Days 15, 21, and 28 
(±2 days each) - 
Day 28 (final visit) 
 
Screening Visit: This visit can be completed in a single visit, anytime from 28 to 2 days before 
receiving study drug or placebo. During this visit, you will be informed about the study, have 
your questions answered and, if you decide to participate in the study, as shown by signing and 
dating this consent form, you can immediately start having screening assessments. These will 
include medical evaluations (medical and medication history, vital signs [BP, HR, RR, and T] and 
physical examination [PE]), and ECG. BP and HR will be measured while resting lying down and 
after standing. If you pass these assessments, you will have standard clinical laboratory blood 
tests (blood counts, chemistries, coagulation tests) and urine tests, a pregnancy test if you are 
female, a test to confirm if you are post-menopausal if you’re female, tests for HIV and Hepatitis 
B and C, and urine tests for detecting illegal drugs, alcohol, and cotinine (nicotine products). We 
will contact you in a few days to let you know if you passed the screen tests or not or if we want 
you to return to the CTU to repeat any lab tests. If you passed the screen tests you will be given an 
appointment for the second visit. You should come in the CTU for the second visit prepared to be 
admitted on the same day if you continue meeting the requirements to participate in the study.  
 
Check-in Visit (Day -1): This visit is the day before receiving study drug or placebo. During this 
visit your medical information will be reviewed, VS will be taken with BP and HR measured 
while resting lying down and after standing, a PE will be done, and standard clinical lab blood 
and urine lab tests, a pregnancy test if you are female, and urine tests for detecting illegal drugs, 
alcohol, and cotinine (nicotine products) will be done. You will stay in the CTU waiting for the 
results of the tests. If the test results are acceptable, you will be admitted into the CTU, where you 
will stay overnight, and enrolled into the study.  
 
Inpatient Study Treatment and Follow-up Period: Eligibility for starting dosing will be confirmed 
in the morning on Day 1, followed by baseline VS measurements and BP and HR measured while 
resting lying down and at 1 and 3 minutes after standing, and ECG. An intravenous catheter will 
be inserted in one of your forearm veins for withdrawing blood before and after receiving the 
study treatment. During the Dosing Period (Days 1 to 7), you will receive the study drug or 
placebo by mouth with water twice daily, 12 hours apart (in the morning and evening). You will 
fast, meaning you will not have any solid food, for various periods of time before and after dosing 
depending on the study day but you will be able to drink liquids except 1 hour before and 1 hour 
after each dose. You will have medical observations, collection of blood (plasma) for PK analysis 
(measurement of the study drug concentration in plasma to evaluate how your body handles the 
study drug) and, if you consented, additional blood (serum) for future research. You will stay in 
the CTU during the Inpatient Follow-up Period of 2 days after the last dose of the study drug or 


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 22-0027 
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Page 8 of 32 
 
 
 
Martin Kankam, MD, PhD, MPH, FAPCR 
              Advarra IRB Approved Version 11 Mar 2024 
 
placebo (Days 8 and 9), to complete medical observations and will be discharged from the CTU 
on Day 9. 
 
Outpatient Follow-up Period: After you are discharged, study staff will contact you by phone 
three times about a week apart to ask how you are doing and if you had experienced any illness or 
seen a doctor or had any new symptoms since the last time and taken any medications. You will 
complete the study on Day 28 if the study doctor determines that your medical assessment is 
stable and there is no need for further follow up. If there is a medical concern, you may be asked 
to return to the CTU to follow up on any abnormal lab tests or other findings as necessary until 
they are no longer present, or they are not clinically significant in the judgement of the study 
doctor.   
 
Details of medical assessments and study procedures on each study visit from screening to the end 
of the study are described below. (See WHAT WILL HAPPEN DURING THE STUDY?).  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
MEDICAL MONITORING 
The study staff will monitor you for side effects during your stay in the CTU and provide medical 
care as needed if you have any medical problems. Guidelines have been created to evaluate the 
safety of the study drug. If you have any side effects, we will evaluate your symptoms and treat 
you as indicated according to standard medical practices. 
 
WHAT WILL HAPPEN DURING THE STUDY? 
 
SCREENING PERIOD (Day -28 to Day -1) 
 
SCREENING VISIT (Day -28 to Day -2): 
During this visit, you will be informed about the study, have your questions answered and, if you 
decide you want to participate in the study, show your intent by signing and dating this consent 
form.  
 
After signing this consent and before you begin the study, your demographic information (age, 
gender, race, ethnicity) will be recorded and you will have the following screening tests done to 
determine if you are in good health and qualify to continue participation in the study: 
 
• Complete medical history and medication review. 
• Review of contraception (birth control) methods you are practicing. 
• Vital signs (VS; blood pressure [BP], heart rate [HR], breathing rate [RR} and oral 
temperature [T]) measured lying down. BP and HR will also be measured at 1 and 3 
minutes after standing. 
• Height and weight measured, and Body Mass Index (BMI) calculated. 
• Complete Physical Examination. 


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• A 12-lead ECG (standard recording) - This will require attachment of electrodes from the 
ECG machine to your chest, arms, and legs. Male participants may have to have their 
chest hair shaved for the ECG. Female participants may not be allowed to wear a bra 
during ECG-related procedures. 
• Blood and urine collected for clinical laboratory tests (blood counts, chemistries, 
coagulation tests and urinalysis). (You will be asked to not eat or drink anything other 
than water for at least 4 hours before blood collection.) 
• Urine tests for alcohol, drug screen for illegal drugs, and cotinine test (for detecting 
nicotine products). (The tests for alcohol and illegal drugs must be negative to qualify.) 
• A serum pregnancy test if female. (The test must be negative to qualify.) 
• Blood collected for measurement of follicle-stimulating hormone if post-menopausal 
female. 
• A blood test for HIV, the virus that causes AIDS, and blood tests for Hepatitis B and 
Hepatitis C Viruses. (Test results must be negative to qualify.) 
o Note that it may take weeks or months after being infected with HIV for the test to be 
positive. If you have a positive HIV or Hepatitis B and C test, you cannot be in the 
study. If these tests are positive, you will be notified by study staff at the CTU and 
given information on how to follow up for further medical care. As required by law, 
positive test results for HIV and Hepatitis must be reported by the CTU to the State 
Department of Health. If you have any questions about what information is required to 
be reported, please ask the study staff. If the CTU becomes aware during your 
participation in this study that there is any change in the HIV or Hepatitis test results, 
you will be withdrawn from the study. Your test results are private (confidential); 
however, this cannot be guaranteed. For example, it is possible for a court of law to get 
health or study records without your permission. The study doctor may be required to 
report these results to the local health authorities.  
 
You will be told of the results of medical tests and whether you can continue participating in the 
study. 
 
• If you do not meet the study requirements, you will be discharged from the study.  
o You will be told why you were not selected for the study. 
o If there is a medical condition or abnormal laboratory test that needs further medical 
attention, you will be counselled to follow up with your primary doctor or contact 
community physicians or clinics where you can go for testing and follow up.  
o You may sign a release form to allow the CTU to release medical tests to you or send 
them to your own doctor or clinic. 
• If your medical tests confirm your eligibility to participate in the research study, the study 
staff will ask you to return to the CTU on Day -1 to complete the inpatient screening tests 
to confirm your eligibility to participate in the study. 
o You will be told to come prepared to stay for the inpatient study treatment if you pass 
the tests.  


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              Advarra IRB Approved Version 11 Mar 2024 
 
o You will be counselled to avoid pregnancy, use appropriate contraception (both male 
and female), and avoid prohibited medications, tobacco and other nicotine products, 
alcohol, and marijuana and illegal drugs. 
o You should avoid strenuous physical activity. 
 
CHECK-IN VISIT (Day -1) (1 day before the study treatment period) 
On this day, you will have medical evaluations and blood and urine clinical lab tests, a urine 
pregnancy test (if you are a female), urine tests for alcohol, illicit drugs and cotinine, and a test for 
COVID-19 (collected through a nasal swab) to confirm that you continue meeting the 
requirements for admission and receiving the study drugs. All urine tests for alcohol, illicit drugs, 
and cotinine (for nicotine products) and the COVID-19 test should be negative to qualify. The 
study doctor will review the results of your tests to see if you still qualify. 
 
• If you do not meet the study requirements, you will be discharged on this day. You will be 
told why you were not selected for the study. If there is a medical condition or abnormal 
laboratory test that needs further medical attention, you will be counselled to follow up 
with your primary doctor or contact community physicians or clinics where you can go for 
testing and follow up. You may sign a release form to allow the CTU to release medical 
tests to you or send them to your own doctor or clinic. 
• If you meet the study requirements, you will be admitted to the CTU.  
 
After you are admitted, you will complete an orientation of the inpatient facility, and asked to 
read the House Rules that describe what you are expected to follow while you stay in this facility 
and participate in the study.  
 
• You will be told what study treatment cohort (group) you were assigned to and review the 
procedures that will be performed during the Inpatient Study Treatment period. You will 
not be told if you are going to receive active study drug or placebo. 
• You will be counseled to avoid excessive exercise. 
• You will be encouraged to drink plenty of fluids to keep well hydrated. 
• You will receive dinner and snacks in the Research Site. 
• You will eat dinner, but you will not be allowed to eat anything for about 8 hours before 
your first dose the following morning. During that time, you will be allowed to drink 
water or other liquids offered by the CTU up until 1 hour before dosing the next morning. 
 
INPATIENT STUDY TREATMENT AND FOLLOW-UP PERIOD (Days 1 to 9) 
You will receive the study drug orally (by mouth) every 12 hours daily in the morning and 
evening on Days 1 to 7 and stay followed as inpatient until Day 9. Food and liquids will be 
restricted for various periods of time before and after each dose during Days 1 to 7 as described 
below. The following procedures will be done during this period: 
 
 
 


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              Advarra IRB Approved Version 11 Mar 2024 
 
DAY 1 (In-patient Study Treatment): 
 
Before the Morning Dose: 
• You will not eat any food at least 8 hours before taking the first dose of the study drug 
(dosing) on the morning of Day 1. That means that you will not eat breakfast before 
dosing. You will be allowed to drink water or other liquids offered by the CTU staff 
during that time up until 1 hour before taking the morning dose.  
• If you have new symptoms since admission, your medical history will be updated, and you 
may have a physical exam to evaluate them. Any medications you took will be reviewed. 
The results of the above will be reviewed to see if you still qualify to receive the study 
drug.  
• You will have an IV catheter placed in a vein in your forearm to draw blood. 
• You will have your vital signs (VS) checked about 30 min before dosing starts while lying 
down. BP and HR will also be measured at 1 and 3 minutes after standing. 
• You will have a blood PK sample (blood sample to measure the concentration of the study 
drug, 6 mL) and a research sample if you consented (3.5 mL) drawn about 30 minutes 
before dosing starts. 
• You will be randomized (like throwing a dice) to receive active study drug (SLV213) or 
placebo (an inactive compound) before the morning dose on Day 1. You will not be told if 
you are going to receive active study drug or placebo. You will receive the same dose of 
the active study drug or placebo on all study treatment days.   
Morning Dose: 
• You will receive the study drug or placebo by mouth with at least 240 mL (8 fluid ounces, 
about 1 cup) of water (See the table on page 5 about the number of pills you will take 
depending on the group you are assigned to). 
 
After the Morning Dose: 
• You should report any side effects that you may experience after each dose and any 
other time until the end of the study. You will also be observed for side-effects. 
• You will have a physical exam done as needed for evaluation of new symptoms after 
dosing starts until the end of the study. 
• You will have Vital Signs measured about 2 hours after the morning dose lying down. 
BP and HR will also be measured at 1 and 3 minutes after standing. 
• Any medication that you take will be recorded to the end of the study. 
• You will not eat solid food at least 4 hours after you take the morning dose, but you will 
be able to drink water or other liquids offered by the CTU staff starting 1 hour after the 
dose.  
• You will have blood samples drawn for plasma PK (6 mL each) and future research if you 
consented (3.5 mL each) at 30 min, and 1, 2, 4, 6, 8 and 12 hours after the morning dose 
(Day 1 only).  
• You will have the blood drawing IV line checked periodically by the study staff to make 
sure it works and flushed or removed and replaced if needed. Let the study staff know if 
you experience any discomfort or other symptoms at the site of the IV line. 


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              Advarra IRB Approved Version 11 Mar 2024 
 
• You will start drinking fluids 1 hour after you took the study treatment,  
• You may be served a meal 4 hours after the first dose. Let the study staff know if you have 
any nausea and you cannot eat. 
• You will be counseled to avoid excessive exercise until the study end. 
 
Before the Evening Dose: 
• You will not eat any food at least 2 hours before taking the evening dose. You will be 
allowed to drink water or other liquids offered by the CTU study staff up until 1 hour 
before taking the evening dose. The study staff will serve food.  
• If you have new symptoms, you will have a physical exam and any medications you took 
will be reviewed. 
• Your vital signs measured within 30 min before the evening dose lying down. BP and 
HR will also be measured at 1 and 3 minutes after standing. 
• You will have the IV line for drawing blood checked to make sure it works and flushed or 
removed and replaced if needed. 
• You will have blood collected for plasma PK (6 mL) and future research if you consented 
(3.5 mL) about 30 minutes before the evening dose (This is the same sample as the one 
collected 12 hours after the morning dose).  
 
Evening Dose: 
• You will receive the study drug or placebo by mouth with at least 240 mL (8 fluid ounces, 
about 1 cup) of water (See the table on Page 5). 
 
After the Evening Dose:  
• You should report any side effects that you may experience after each dose and at 
any other time until the end of the study. You will also be observed for side-effects. 
• You may have a physical exam done as needed for evaluation of new symptoms.  
• Any medication that you take will be recorded. 
• You will not eat solid food at least 1 hour after you take the second dose, but you will be 
able to drink water or other liquids offered to you by the CTU study staff starting 1 hour 
after the dose.  
• You will have your vital signs measured lying down. BP and HR will also be measured at 
1 and 3 minutes after standing.  
• You will have the blood drawing IV line checked periodically by the study staff to make 
sure it works and flushed or removed and replaced if needed. Let the study staff know if 
you experience any discomfort or other symptoms at the site of the IV catheter. 
• You may be served a meal 1 hour after the evening dose. Let the study staff know if you 
have any nausea and you cannot eat.  
• Since you will receive the study drug or placebo doses at about the same time every 
day on Days 2-7, the CTU study staff will arrange to have your meals served at times 
that allow you to have your food and water or other liquids, while at the same time 
keeping in place the restriction for food and fluid intake before and after each dose 
on each future dosing day.  


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              Advarra IRB Approved Version 11 Mar 2024 
 
DAY 2 to DAY 6 (In-patient Study Treatment): 
 
You will continue taking 2 doses of study drug or placebo twice a day, one in the morning and 
one in the evening, about 12 hours apart. 
 
You will not eat any food for about 2 hours before and 1 hour after each dose on each one of 
Days 2 to 6. Let the study staff know if you have any nausea and you cannot eat. 
 
You will be able to drink water or other liquids offered by the CTU staff at all times except 1 hour 
before and 1 hour after each dose. 
 
Before Dosing: 
• You should report any side effects that you may experience. 
• Any medication that you take will be recorded to the end of the study. 
• Your blood draw IV line will be checked periodically to make sure it works and flushed or 
removed and replaced if needed. 
• Your vital signs will be measured within 30 min before dosing lying down. BP and HR 
will also be measured at 1 and 3 minutes after standing. 
• You will have blood samples collected for clinical lab tests (blood counts, chemistries, and 
coagulation tests) on Days 2, 4 and 6 (before the morning dose). You will be required to 
fast at least 4 hours prior to blood collection.  
• You will have urine collected on Day 4 (before the morning dose). 
• You will have an ECG on Day 4 (before the morning dose). 
• You will have blood drawn for plasma PK (6 mL) and for future research if consented 
(3.5 mL) within 30 minutes before the morning dose (this is the same as the blood sample 
drawn 12 hours after the previous evening dose) and 30 minutes before the evening dose 
every day of Days 2 to 6. 
 
Dosing:  
• You will take the study drug or placebo with at least 240 mL (8 fluid ounces, about 1 cup) 
of water. 
 
After Dosing: 
• You should report any side effects that you may experience after each dose and any 
other time on each day.  
• You will be observed for side-effects after taking each dose. 
• You may have a physical exam for evaluation of your symptoms. 
• Any medication that you take will be recorded. 
• You will have Vital Signs measured about 2 hours after each dose lying down. BP and HR 
will also be measured at 1 and 3 minutes after standing. 
• You will have blood drawn for plasma PK (6 mL) and for future research if consented 
(3.5 mL) 12 hours after each dose on Days 2 to 6. 
 


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ICF version 4.0 – 08 March 2024 
Page 14 of 32 
 
 
 
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              Advarra IRB Approved Version 11 Mar 2024 
 
DAY 7 (In-patient Study Treatment): 
 
Before the Morning Dose: 
• You will not eat any food at least 2 hours or drink any water or other fluids at least 1 hour 
before the morning dose. Let the study staff know if you have any nausea and you cannot 
eat.   
• You should report any side effects that you may experience. 
• Any medication that you take will be recorded. 
• Your blood draw IV line will be examined checked periodically to make sure it works and 
flushed or removed and replaced if needed. 
• Your vital signs will be measured within 30 min before dosing lying down. BP and HR 
will also be measured at 1 and 3 minutes after standing. 
• You will have blood drawn for plasma PK (6 mL) and for future research if consented 
(3.5 mL) within 30 minutes before the morning dose (this is the same as the blood sample 
drawn 12 hours after the evening dose on Day 6). 
 
Morning Dose: 
• You will take the study drug or placebo with at least 240 mL (8 fluid ounces, about 1 cup) 
of water. 
 
After the Morning Dose: 
• You should report any side effects that you may experience.  
• You will have a physical exam done as needed for evaluation of new symptoms. 
• You will have Vital Signs measured about 2 hours after the morning dose lying down. BP 
and HR will also be measured at 1 and 3 minutes after standing.  
• Any medication that you take will be recorded. 
• You will not eat solid food at least 1 hour after the morning dose, but you will be able to 
drink water or other fluids offered by the CTU study staff starting 1 hour after the dose. 
Let the study staff know if you have any nausea and you cannot eat. 
• You will have blood samples drawn for plasma PK (6 mL) and future research if you 
consented (3.5 mL) at 12 hours after the morning dose.  
• You will have the blood drawing IV line checked periodically to make sure it works and 
flushed or removed and replaced if needed. Let the study staff know if you experience any 
discomfort or other symptoms at the site of the IV line. 
• You will be counseled to avoid excessive exercise until the study end. 
 
Before the Evening Dose: 
• You will not eat any food at least 8 hours or drink any fluids at least 1 hour before the 
evening dose.  
• You should report any side effects that you may experience. 
• Any medication that you take will be recorded. 


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              Advarra IRB Approved Version 11 Mar 2024 
 
• Your blood draw IV line will be checked periodically to make sure it works and flushed or 
removed and replaced if needed.  
• Your vital signs will be measured within 30 min before dosing lying down. BP and HR 
will also be measured at 1 and 3 minutes after standing. 
• You will have blood drawn for plasma PK (6 mL) and for future research if you consented 
(3.5 mL) within 30 minutes before the evening dose (this is the same sample as blood 
drawn 12 hours after the morning dose). 
 
Evening Dose: 
• You will take the study drug or placebo with at least 240 mL (8 fluid ounces, about 1 cup) 
of water. 
 
After the Evening Dose:  
• You should report any side effects that you may experience. You will also be observed 
for side-effects. 
• You may have a physical exam done as needed for evaluation of new symptoms after 
dosing starts until the end of the study. 
• Any medication that you take will be recorded to the end of the study. 
• You will not eat solid food at least 4 hours after you take the evening dose, but you will be 
able to drink water or fluids offered by the CTU staff starting 1 hour after the dose. Let the 
study staff know if you have any nausea and you cannot eat.  
• You will have your vital signs measured about 2 hours after the evening dose lying down. 
BP and HR will also be measured at 1 and 3 minutes after standing.  
• You will have blood samples drawn for plasma PK (6 mL each) and future research if you 
consented (3.5 mL each) at 30 min, and 1, 2, and 4 hours after the evening dose. 
• You will have the blood drawing IV line checked periodically to make sure it works and 
flushed or removed and replaced if needed. Let the study staff know if you experience any 
discomfort or other symptoms at the site of the IV catheter. 
• The study staff will let you know if they will flush the blood draw line to keep it open so 
that it can be used on the following day or removed and replaced. 
• You may start drinking water or other liquids offered by the staff 1 hour after the evening 
dose. 
• You will be served a meal 4 hours after the evening dose. Let the study staff know if you 
have any nausea and you cannot eat.  
 
Since you will have to fast for at least 4 hours after the evening dose, the CTU study staff 
will arrange to have your evening meal late in the evening. 
 
DAY 8 (Inpatient Follow-up): 
• 
You should report any side effects that you may experience. 
• 
You will have vital signs measured lying down. BP and HR will also be measured at 1 and 
3 minutes after standing. 


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Page 16 of 32 
 
 
 
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              Advarra IRB Approved Version 11 Mar 2024 
 
• 
You will have blood and urine samples collected for clinical laboratory tests. You will be 
required to fast at least 4 hours prior to blood collection. 
• 
You will have an ECG. 
• 
You will have blood sample drawn 4 times on Day 8 for plasma PK (6 mL each) and for 
future research (3.5 mL each) at 6, 8, 12 and 24 hours after the evening dose on Day 7. 
• 
You may have a physical examination for evaluation of your symptoms. 
• 
Any medication that you take will be recorded. 
• You will be served all three meals today at regular hours and drink water and fluids 
offered by the staff.   
 
Day 9 (Inpatient Follow-Up / Discharge): 
• 
You will be asked about any new symptoms you developed since the day before 
• 
You will be asked about any medications you took. 
• You will have vital signs measured lying down. BP and HR will also be measured at 1 and 
3 minutes after standing. 
• 
You will have a complete physical examination. 
• 
You will have blood drawn 2 times on Day 9 for plasma PK (6 mL each) and for future 
research (3.5 mL each) at 36 and 48 hours after the evening dose on Day 7. 
• 
You will then have the IV blood draw catheter removed and the blood draw site inspected.  
• 
You should report any discomfort you have at the blood draw site. 
• 
If you are female, you will be counseled to continue contraception and avoid pregnancy 
for 30 days after the last dose of study drug. 
• 
If you are male, you will be counseled you and your female partner to use appropriate 
contraception and you should also avoid sperm donation for 30 days after the last dose of 
study drug. 
• 
You should avoid excessive exercise. 
• 
You will be provided contact information and instructions to report to the Research Site 
(CTU) any side effects or new symptoms you experience and any medication that you 
take that after your discharge. 
• 
You will review with the CTU study staff your contact information and be told you will 
be expecting telephone calls to ask you about how you are doing and medications you are 
taking.  
• 
You will be discharged in the evening of Day 9. 
 
OUTPATIENT FOLLOW UP 
(DAYS 15 (±2 days), 21 (±2 days) and 28 (±2 days) - Day 28 is Final Visit): 
• You should report to or visit the CTU if you have any side effects or an illness after 
your discharge from the CTU on Day 9. 
• CTU study staff will contact you by phone about every week for three weeks after your 
discharge from the clinic to ask how you are doing, if you had any side-effects or visited 
your physician or the ER since the last visit or call, and if you used any medications after 
your discharge. 


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Page 17 of 32 
 
 
 
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              Advarra IRB Approved Version 11 Mar 2024 
 
• You may be asked to return to the CTU for a clinical exam and any tests, as needed, to 
evaluate any new symptoms or follow up any previous symptoms or abnormal labs.  
• You will be counseled to avoid any prohibited medications until the end of the study. 
• You will be counseled to avoid pregnancy and continue contraception for 30 days after the 
last dose.  
• If you are male, you will be counseled to avoid donating sperm for 30 days after last dose.  
• You should avoid excessive exercise. until after the last call from the clinic on Day 28.  
• 
The study staff will let you know on Day 28 if you have completed the study or need to 
return to the clinic for follow up of any on-going side effects. 
 
UNSCHEDULED VISITS (Out-patient follow up) 
You may be asked to report to the research site for an unscheduled visit if the study staff feel it is 
necessary for your safety. This may occur if you experienced any side effects that require further 
evaluation after any of the scheduled out-patients visits on Days 15, 21 and 28, and at any time 
after your discharge from the inpatient stay on Day 9 if you have any ongoing side effects. During 
those visits, you will be asked about the medical history of the event and have VS measured 
(lying down and BP and HR at 1 and 3 minutes after standing) and a focused physical 
examination as needed, and clinical laboratory tests, ECG, and other tests as indicated. You will 
be told if further follow up is needed.  
 
EARLY TERMINATION: 
If you choose to withdraw from the study or are terminated by the study doctor before you 
complete the study, you will not receive any more doses of study drug or placebo. However, you 
will be asked to consent to remain in the study to complete safety and PK blood collections 
following the last study dose you received.  
 
If you do not consent to remain in the study, the following activities could be completed 
depending on your clinical status:   
 
• You will be asked to provide information on the side-effects you may experience. 
• You will be asked to document medications you take. 
• You may have the Vital Signs measured lying down. BP and HR will also be measured at 
1 and 3 minutes after standing. 
• You will have a physical examination. 
• You will have a 12-lead ECG if needed. 
• You will have blood drawn and/or urine collected for clinical laboratory tests if needed. 
• You may have blood drawn for plasma PK (6 mL) and for future research (3.5 mL each) if 
needed. 
• The study staff will give you information and tell you if you need to return for follow up 
for another visit. 
 
The study staff may also request to have procedures performed that are not listed above to ensure 
your safety throughout the study. 


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 22-0027 
ICF version 4.0 – 08 March 2024 
Page 18 of 32 
 
 
 
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              Advarra IRB Approved Version 11 Mar 2024 
 
ADDITIONAL DRUG AND ALCOHOL SCREENS 
Random urine drug and alcohol screens may be repeated at any time during the study if the study 
staff suspects alcohol or drug use. If you test positive for drug or alcohol use at any time after the 
first dose of study drug, you may be discontinued from the study. 
 
CONTROLLED SEARCH 
Designated study staff reserves the right to do a controlled search by having you put on a gown in 
order to have your clothes and person checked for disallowed items that may have been brought 
into the research site. This search involves removing all undergarments as well as putting on a 
gown so that there is no place the disallowed items could be kept. 
 
At each admission into the research site, a search of your clothing, like pockets, and bags will 
occur. You will not be required to remove your clothing or undergarments, but study staff may 
ask you to turn your pockets inside out or check areas of clothing that could conceal restricted 
items. Study staff will also perform a bag check and confiscate any items not permitted to be 
brought into the research site. These belongings will be returned to you at discharge from the 
research site. 
 
BLOOD SAMPLES 
Blood samples will be drawn by single needle-sticks or through an IV catheter, as determined by 
the study staff. An IV catheter is a small plastic tube inserted into your arm vein by a needle. The 
needle is removed, but the tube temporarily remains in your vein. This tube allows the removal of 
blood without having to stick you each time. It will be removed every 3-4 days or sooner if not 
required for frequent blood collection or not working well or if you have local pain or vein 
irritation.  
 
Blood will be collected for the following tests during the study: 
 
1. For clinical laboratory tests (blood counts, chemistries, and coagulation tests) to evaluate 
the effects of the study drug on your body organs. If you complete the study, the total 
volume of blood collected for this purpose will be about 100 mL, (about 3.3 ounces, a bit 
less than 7 tablespoons). Additional blood samples may be drawn during the study, if the 
study staff considers it necessary for monitoring your health. Blood samples left after all 
routine clinical laboratory testing is done will be discarded by the clinical safety 
laboratory.   
 
2. For plasma PK tests to measure the concentration of SLV213, the investigational drug, 
and study how your body handles the study drug after each dose (how fast it enters your 
circulation after taking it by mouth, how high is the peak concentration and how long it 
last, and how long the drug stays in your body). The total volume of blood collected for 
this purpose will be about 180 mL (6 ounces, about ¾ of a cup). Plasma samples left over 
after testing, will be stored for future research at the sponsor’s (NIAID) storage area if you 
consent (give your permission to do so).   
 
3. For serum for future research with SLV213, to see if it has an effect on other body 
systems that are not evaluated during this study, such as the immune system, which is the 
system that protects against infections. The total volume of blood collected for this 


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Page 19 of 32 
 
 
 
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              Advarra IRB Approved Version 11 Mar 2024 
 
purpose is about 105 mL (about 3.5 oz, a bit less than half a cup.). These samples will also 
be collected and stored if you give permission to do so.   
 
If all of these samples above are collected, the total volume of blood drawn from you will 
be about will be about 384.7 mL (a bit less than 13 oz or around 1.6 cups). For 
comparison, a standard blood donation at a blood collection center, once in a 56-day 
period, is about 500 mL (a bit under 17 ounces or a bit over 2 cups).   
 
 For more information about collected samples for future research see section see below on page 
(See section on Blood Specimens for Future Research Testing below).  
 
YOUR ROLE IN THIS STUDY 
Taking part in a research study can be an inconvenience to your daily life. Please consider the 
study time commitments and responsibilities as a research participant when you are deciding to 
participate. Your responsibilities as a participant include the following: 
 
• You cannot participate in this study if you have participated in a prior study within the 
past 30 days. 
• We ask you to provide accurate responses to questions about your past medical and 
surgical history (illnesses and surgeries you had including abnormal lab tests, X-rays, and 
other procedures), medications you are taking, medications you are allergic to and your 
family history. Failure to respond accurately may result in side-effects that may be 
harmful after you receive the study drug(s). 
• You must read, and agree to follow, the House Rules at the Research Site if you want to 
take part in this study. House Rules discuss proper behavior at the Research Site and are 
important to ensure your safety and make sure the study results are accurate. Failure to 
follow these rules may result in reduced compensation or involuntary discharge from this 
study. 
• You must report any side effects and medical problems to the study staff. 
• You must give true and complete answers to any questions. 
• You must be able to comply with the study procedures and visit schedule. 
• You must follow all instructions from the study staff. 
• You must inform the study staff if you decide to discontinue your participation in the 
study. If you decide to discontinue your participation in the study, you may be asked to 
consent to stay in the study and complete any remaining procedures for the most recent 
study treatment period. If you do not consent to complete any remaining procedures, you 
will be asked to complete the early termination visit procedures as described in this 
consent form. 
• You must agree to use an effective method of contraception, as defined later in this 
consent form, throughout the study and for 30 days after the last dose. If you are male, you 
must agree not to donate sperm for 30 days after dosing and, if you are sexually active, 
you and partner to use safe contraception. 
• You must not do any strenuous activity for 2 days before the dosing starts and at any time 
during the study until discharge on Day 9. 


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Page 20 of 32 
 
 
 
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              Advarra IRB Approved Version 11 Mar 2024 
 
• Refrain from consumption of red wine, Seville oranges, grapefruit, or grapefruit juice, 
[pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices] from 7 days before the 
start of the study until discharge on Day 9.  
• Refrain from alcohol use 7 days before starting dosing and for the duration of the trial.  
• You must not use marijuana or other illegal drugs during the study. 
• You will be recommended to avoid using nicotine products from a week before starting 
dosing. Smoking is prohibited during the in-patient period of the study following Check-in 
(Day -1) to discharge from the CTU (Day 9) 
• You must not participate in another research study at any time during this study or 
continue participating in another study and have blood draws. This includes studies of a 
drug, biologic (such as vaccine or proteins), device, or blood product. 
 
PROHIBITED MEDICATIONS, VACCINATIONS, and BLOOD DONATIONS  
Additional restrictions to ensure the health and safety of study participants are listed below: 
 
• Please report all prescription medications, including contraceptive hormones (pills, 
patches, or injections and intrauterine devices containing hormones), and non-prescription 
medications, herbs, vitamins, or nutritional supplements you are taking at the time of 
Screening and on check-in (Day -1). Their use without the knowledge of the site physician 
may cause an interaction with the study drug and increase your risk of having a severe 
side-effect.  
• You must not take any prescription medications within 14 days before check-in on Day -1 
(a day before the start of study drug treatments) or during the study. Certain drugs should 
be avoided for a longer period before taking the study drug.  
• If you are female, you must not use contraceptives containing hormones (pills, patched, 
injections, or intrauterine devices containing hormone) during the study. (See below 
Information about Birth Control). 
• If you are male, you must not use condoms containing spermicides during the study. (See 
below Information about Birth Control). 
• You must not take any over the counter (OTC), non-prescription medications, herbs, 
vitamins, or nutritional supplements including St. John’s wort from at least about 14 days 
before dosing) and for the duration of the study. 
• Report any symptoms that you may experience. The study doctor may allow the use of 
acetaminophen up to 1,000 mg a day for 1-3 days as needed for any common pains and 
aches (headache, muscle pains), or medication for other common disturbances if approved 
by the study doctor(s).   
• You must not donate any blood or blood products (red cells, white cells, platelets, plasma) 
during the course of this study. Tell the study doctor if you donated any blood or blood 
products within 3 months before dosing. If you did, we could delay your screening. 
• You must not receive any blood or blood products during this study unless it is medically 
necessary. 
 
 
 


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              Advarra IRB Approved Version 11 Mar 2024 
 
RISKS OF THE INVESTIGATIONAL DRUGS 
 
Observed Risks with SLV213: 
There were no identified risks associated with SLV213 in a completed study in 40 healthy 
participants who were given single doses by mouth ranging from 50 mg to 800 mg. The most 
common complaints that were mild and transient and seen at all doses were: 
• Headache 
• Change in taste 
• Change in the feces (stool) 
 
There was no evidence of injury to the liver or the heart at any dose. The most severe event was 
orthostatic hypotension with syncope (passing out while standing up because of a drop in blood 
pressure) in one participant 30 min after a dose of 200 mg. The participant recovered without 
consequences and the event did not happen at later timepoints in the same participant or in others 
who took higher doses of 400 mg and 800 mg. Overall, the drug was well tolerated, there were no 
serious adverse events or reactions.  
 
Potential Risks with SLV213: 
SLV213 has the potential to cause: 
• An allergic reaction, like all chemicals. Symptoms include: 
o Rash 
o Wheezing and difficulty breathing 
o Dizziness and fainting 
o Swelling around the mouth, throat or eyes 
o A fast pulse 
o Sweating 
• Vomiting, especially at high doses 
• Decreased food intake 
• Abnormal liver tests, that are transient  
• Increased heart rate with a drop in blood pressure when standing and may result in 
syncope (transient loss of consciousness).  
 
Further testing is needed to understand the potential for SLV213 to alter the function of the liver, 
kidneys, brain and heart. Long-term studies in animals and humans are not available.  
 
Potential Drug Interactions: 
There are no clinical data on drug interactions with the SLV213. However, based on the 
knowledge about the metabolism of the study drug, medications strongly metabolized by 
CYP3A4 and CYP2D6 or are strong inducers or strong inhibitors of these two enzymes should be 
avoided from 14 days before the first dose to the end of the study to prevent any adverse effects 
after administration of SLV13. There is a very long list of substances that are in this category, and 
except for grapefruit juice and St. John’s wort, the remaining are drugs available by prescription, 
which are prohibited for use in this clinical trial. You are reminded to report what prescription 


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              Advarra IRB Approved Version 11 Mar 2024 
 
or non-prescription medications and supplements you take, and we will let you know if the 
drug is permitted or prohibited.  
 
Use During Pregnancy and Lactation: 
The effects of the study drugs on the pregnant mother and the fetus have not been studied 
Therefore, you should not participate in the study if you are pregnant or plan to become pregnant 
during the study or if you are currently breastfeeding. 
 
Overdose: 
There is no specific antidote in case of overdose. The same measures as recommended for other 
drugs (treatment cessation, adequate hydration, and kidney dialysis) will be provided as medically 
necessary. 
 
Drug Abuse and Dependency: 
No clinical experience available. 
 
BLOOD SAMPLE RISKS 
There may be side effects of drawing blood from a vein with a needle and/or IV catheter 
placement. Local pain, bruising, bleeding, redness, swelling, or induration (palpable hard area) 
might occur at the site of the needle stick where blood is drawn. Infection at the blood draw site is 
possible but unlikely as aseptic technique will be used. There is a possibility of dizziness or 
fainting while your blood is being drawn. Precautions will be taken to minimize the above side 
effects. There is a small risk your blood counts will decrease slightly during the course of the 
study, but not expected to cause anemia (low blood counts that cause symptoms and need 
treatment). Any symptoms that may occur are usually reversible with good nutrition and drinking 
fluids. 
 
ECG RISKS 
ECG patches may cause a skin reaction such as redness or itching. You may also experience 
localized skin discomforts and/or hair loss associated with the placement of ECG patches. 
 
UNKNOWN RISKS 
You may have side effects or discomforts that are not listed in this form. Some side effects may 
not be known yet. New ones could happen to you. Tell the study staff right away if you have any 
problems. 
INFORMATION ABOUT BIRTH CONTROL  
 
Females: 
The effects of study drug(s) on the unborn child are not known at this time. Therefore, it is 
important that women who are pregnant, may become pregnant or who are breastfeeding NOT 
participate in this study. If you are a woman who can get pregnant, you must use an acceptable 
form of birth control that is very effective in preventing pregnancy for at least one month before 
screening. You must also agree to continue using acceptable contraception until dosing and for at 
least 30 days after dosing, and to avoid becoming pregnant during this study. 
 
The following are acceptable forms of birth control for this study: 
 


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Martin Kankam, MD, PhD, MPH, FAPCR 
              Advarra IRB Approved Version 11 Mar 2024 
 
• Intrauterine devices (IUD) without hormones. 
• Surgery to prevent pregnancy in females (such as bilateral tubal ligation, salpingectomy 
[removal of the tubes], oophorectomy [removal of the ovaries], or hysterectomy [removal 
of the uterus], or Essure® placement with a history of documented radiological 
confirmation test at least 90 days after the procedure). 
• If in a monogamous relationship and the male partner uses a barrier method without 
spermicide) 
• Being in a monogamous relationship with a partner who has had vasectomy for 180 days 
or more before your planned study treatment with study drug. 
 
True abstinence (meaning 100% of the time without sexual intercourse with vaginal penetration).  
 
Tell the study staff if you use any other forms of birth control. 
 
If at any time during this study you think you may be pregnant, you are requested to contact the 
CTU study doctor, Martin Kankam, MD, at 913-696-1601 (24 hours). 
 
Males: 
The effect of study drug(s) on the unborn child is unknown at this time. The effect of the study 
drug on the male reproductive system is unknown. Therefore, you must agree to use an acceptable 
form of birth control from dosing with study drug through at least 30 days after the last dose. 
Acceptable birth control means not having sex (abstinence) or having a vasectomy. If you are 
sexually active, you should agree to use a condom without spermicide throughout this study and 
for at least 30 days after dosing. Tell the study staff if you use any other form of birth control. 
 
You should also not donate sperm for 30 days after the last dose. 
 
It is also recommended that you make certain that your female partner is also using an acceptable 
form of birth control if you have not had a vasectomy and are using a condom. If you think that 
your partner may be pregnant at any time during this study to 30 days after dosing, you are 
requested to contact the CTU study doctor, Martin Kankam, MD, at 913-696-1601 (24 hours).  
 
REPORTING PREGNANCY 
If you are a female capable of becoming pregnant, you should report to the study staff if you miss 
your period and suspect you are pregnant or if you become pregnant during the 30 days after 
dosing. With your permission, you will continue to be followed for safety during this study. You 
are requested to provide pregnancy outcome to the study staff upon delivery or pregnancy 
termination. 
 
If you are a male capable of causing pregnancy and your female partner becomes pregnant during 
the 30 days after dosing, we ask you to inform study staff of the pregnancy and provide 
pregnancy outcome upon delivery or pregnancy termination. 
 
INFORMATION ON USE OF ALCOHOL, MARIJUANA OR ILLEGAL DRUGS 
You are not allowed to use alcohol, marijuana, or illegal drugs (such as cocaine, etc.) because 
they may cause you serious harm and are strictly forbidden while you are in this study. You will 


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              Advarra IRB Approved Version 11 Mar 2024 
 
be tested for drugs and alcohol at Screening and on Check-in (Day -1). If you are found to be in 
possession of or using marijuana or other illegal drugs at the CTU, then Altasciences Clinical 
Kansas, Inc. is obligated to report the use of marijuana or other illegal drugs to the appropriate 
legal authorities. 
 
INFORMATION ON ACTIVITIES TO AVOID 
You should avoid excessive exercise from 48 hours before dosing until the discharge from the 
research site on Day 9.  
 
NEW INFORMATION ABOUT STUDY DRUG(S) 
The study doctor or study staff will discuss with you any important new information, findings, or 
changes to the way the research will be performed that may affect your decision to remain in this 
study. If this happens, you will be asked to decide if you want to keep taking part in this study. 
You may be given an additional informed consent and will be asked to agree in writing that you 
were told about these new findings. 
 
BENEFITS TO THE STUDY PARTICIPANT 
The goal of this research study is to provide scientific information. You will not receive any 
medical benefits. This study may help doctors and scientists learn things about the study drug that 
will help others. 
 
ALTERNATE THERAPY 
This is a clinical research study. It is not treatment or therapy. The other choice is to not 
participate in this study. 
 
PAYMENT FOR PARTICIPATION 
If, after screening, you are enrolled in the study and complete all the study visits, you will receive 
a total of up to $5,250.00 at the completion of your participation in the study to help cover the 
costs of your participation and compensate you for your time. If after enrollment your 
participation is ended early, or if you withdraw for any reason, the amount you will be paid will 
be prorated and the payment made when your participation in the study ends. This means that you 
will receive payment only for the portion of the study that you completed and only after your 
participation in the study has been completed. Payment will be prorated as follows: 
 
Visit 1 
Screening 
$200.00 
Visit 2 
Day -1 Admit 
$375.00 
Visits 3-9 
Days 1 to Day 7 In-house study treatments 
$3,375.00 
Visit 10 
Day 8 In-house follow-up 
Visit 11 
Day 9 Discharge 
Visit 12 
Day 15 Follow-Up telephone call  
$85.00 
Visit 13 
Day 21 Follow-Up telephone call  
$85.00 
Visit 14 
Day 28 Follow-Up telephone call/ End of Study 
$85.00 
Completion Amount 
$1,045.00 
Total 
$5,250.00 
 
Visit 1 will be compensated in the amount of $200.00 at the completion of the visit.  


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Martin Kankam, MD, PhD, MPH, FAPCR 
              Advarra IRB Approved Version 11 Mar 2024 
 
Visits 2 through 11 (9 overnight stays) will be compensated in the amount of $3,750.00 ($375.00 
per overnight stay) at discharge on Visit 11. 
 
Visit 12, 13, and 14 will be compensated in the amount of $85.00 for each visit completed by 
telephone. Compensation will be issued in the form of a check, pre-loaded MasterCard, or cash. 
The form of compensation will be determined by the study staff. 
 
For any outpatient visit that occurs on a weekend, the associated compensation will be paid on the 
next business day. 
 
Unscheduled visits may be compensated up to $50.00 as determined by the study staff. 
 
All visits must be completed within the scheduled timeframe in order to receive the end of study 
completion amount of $1,045.00 on Visit 14. Failure to complete all visits within the allowable 
timeframe will make you ineligible to receive the completion amount. 
 
Money may be deducted from your study compensation if you do not follow the in-house rules or 
other reasonable instructions given by the study staff. For example, if illegal substances are 
brought into the CTU or you are found to be using an illegal substance while in house, up to half 
of your previously earned amount may be deducted and you may be withdrawn from the study as 
determined by the study staff. 
 
If you withdraw or are withdrawn from the study early, you will only be compensated for the 
visits that you complete. 
 
The remainder of your earned in-house stipend will be compensated to you on the originally 
scheduled study day/date of discharge from the in-house portion of the study. 
 
You may be required to report the compensation received for this study to the Internal Revenue 
Service (IRS) as taxable income. According to the IRS guidelines, you will be responsible for 
paying taxes on any compensation that you receive from your study participation. Altasciences 
Clinical Kansas, Inc. will send you a 1099-form for this purpose. Altasciences Clinical Kansas, 
Inc. will also report to the IRS any compensation that you receive that total $600.00 or more for 
the calendar year. You must tell Altasciences Clinical Kansas, Inc. of your new mailing address if 
you move after your participation in a study. This is to make sure you receive your 1099 for your 
year-end tax reporting. 
 
COMPENSATION FOR INJURY 
 
• In the event you experience an adverse reaction (side-effect), illness or injury during this 
study, you should immediately seek treatment. It is important that you tell the CTU study 
doctor, Martin Kankam, MD, if you have experienced one of these events. You must 
contact the study staff at (913) 696-1601 as soon as you are able. You may obtain medical 
care in the same way as you would ordinarily receive any other medical treatment. 
Immediate necessary care, emergency treatment, and professional services will be 
available to research participants just as they are to the community generally. No long-


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              Advarra IRB Approved Version 11 Mar 2024 
 
term medical care or financial compensation for research-related injuries will be provided 
by the NIH or the Federal Government. 
• Medical care will be given to you at no cost if you are injured because of being in this 
study. 
• While you are in this study, you may be injured because of your personal conduct or 
during activities, which are not part of this study. There are no plans to pay you for these 
types of injuries. 
 
PREP ACT DECLARATION 
A Declaration under the Public Readiness and Emergency Preparedness Act (PREP Act) was 
issued by the Secretary of the United States Department of Health and Human Services on March 
10, 2020. This Declaration limits the legal rights of a participant in clinical studies utilizing 
COVID-19 countermeasures, such as the study SLV213, used in this study. Because this study is 
covered by the PREP Act Declaration, covered persons, such as the manufacturers, study sponsor, 
researchers, healthcare providers and others have liability immunity (that is, they cannot be sued 
by you or your family under the laws of the United States). 
 
If you believe that you may have been harmed as a result of this study, certain claims for serious 
injury or death caused by the countermeasure may be eligible for compensation through the 
Countermeasures Injury Compensation Program (CICP). This is a program set up by the Health 
Resources and Services Administration (HRSA) of the United States Government. Information 
about this program can be found at https://www.hrsa.gov/cicp/about/index.html or by calling  
1-855-266-2427. If you are eligible for this program, you must file a claim within one year of the 
administration or use of the covered countermeasure. A factsheet on CICP and how to file a 
Request for Benefits Package to the CICP Summary, will be provided to you. 
 
COSTS TO YOU  
There is no cost to you to participate in this study. You do not have to pay for any study-related 
medicines, procedures, or study treatment at the Research Site during this study. 
 
SOURCE OF FUNDING 
This research study is being funded by NIAID/NIH, which has a contract with a company named 
DVC to do studies like this one. Altasciences Clinical Kansas, Inc. is a partner of Altasciences, 
Inc. a subcontractor of DVC, to conduct this research study under the direction of 
Martin Kankam, MD. 
  
VOLUNTARY PARTICIPATION IN THIS STUDY  
Your participation in this study is voluntary. You will be starting this study of your own free will 
and without any kind of pressure. You may quit this study any time you wish. If you withdraw 
from this study, you will not be penalized. You will not lose any benefits to which you were 
otherwise entitled. 
 
If you have health problems, you will get medical attention. You may be withdrawn from this 
study by the study staff and/or the sponsor of this study, without your consent, if it is in your best 
medical interest. It is possible that the study staff and/or sponsor may think you can stay in this 
study. You must decide what you want to do. 


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Martin Kankam, MD, PhD, MPH, FAPCR 
              Advarra IRB Approved Version 11 Mar 2024 
 
The study staff may stop your participation in this study at any time without your consent for any 
of the following reasons: 
 
• If you don’t follow the study staff’s instructions; 
• If something serious happens to you which may require treatment; 
• If the study staff decides it is in the best interest of your health, and welfare to discontinue 
further participation; and 
• If you do not later consent to any future changes that may be made in the study plan.  
 
The sponsor may stop this study for other reasons not known now. 
 
The FDA or the Institutional Review Board (IRB, see below) may also terminate this study if 
there are safety concerns. 
 
IF YOU WITHDRAW FROM THE STUDY 
If you do not complete this study for any reason, you will be asked to undergo a physical exam, 
vital signs measurement, 12-lead ECG, blood and urine laboratory tests, and tests for the 
measurement of study drug concentration in your blood if early termination occurs within 
24 hours of dosing. This is needed to identify any changes that may have occurred after you 
began to take the study drug and to protect your safety, health, and welfare. 
 
If you received any amount of the study drug but withdraw from the trial within 24 hours after 
dosing, you will be encouraged to continue follow-up (with your consent) for safety assessments. 
We may also ask you to provide PK blood and urine sample(s) to complete scheduled collection if 
you had received study drug on the day you withdrew from the study. 
 
BLOOD SPECIMENS FOR FUTURE RESEARCH TESTING 
We would like to ask your permission to store any residual (left-over) blood (plasma) collected 
for testing the study product concentration (plasma PK). With your consent, we will store leftover 
blood for additional research that is not part of this study, also known as secondary research. 
The samples will be stored in a NIAID/DMID repository and may be shared with the company or 
other researchers for purposes to develop diagnostics or further research for treatment of COVID-
19, such as to evaluate the metabolism and other effects of SLV213. No genetic testing will be 
done with the blood. You may choose not to store leftover blood, or change your mind later and 
withdraw your consent, which means all your samples at the end of the study will be destroyed. 
You may continue in the main study even if you do not agree or withdraw consent for storing 
leftover samples. There is no benefit to you, however, society may benefit from additional 
research. The risks of leftover samples used for other research is a possible loss of privacy. Your 
samples will be coded or linked to your data (for example, results from this study); however, no 
information that identifies you will be released to the company or researchers. Please initial and 
date your choice below in the box to the left of the YES or NO answers. 
 
 
 
 


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Page 28 of 32 
 
 
 
Martin Kankam, MD, PhD, MPH, FAPCR 
              Advarra IRB Approved Version 11 Mar 2024 
 
 
YES 
You may store my unused blood samples in coded tubes for an 
indefinite period of time. The link to my personal identifying 
information will not be sent to other researchers or the company 
that receives the samples. 
(Initials)                (Date) 
 
 
NO 
You may not store my unused blood samples for secondary 
research. Destroy all unused samples at the end of the study.  
(Initials)                (Date) 
 
 
With your consent, we would also like to collect and store extra blood (serum) for additional 
research that is not part of this study, also known as secondary research. The extra blood will be 
drawn when study blood is drawn, for a total volume of 90 mL (6 tablespoons). The samples will 
be stored in a NIAID/DMID repository and may be shared with the company or other researchers 
for purposes to develop diagnostics or further research for treatment of COVID-19, for example 
to evaluate the metabolism and other effects of SLV213. No genetic testing will be done with the 
blood. You may choose not to provide the extra blood or change your mind later and withdrawn 
from the collection of extra blood samples. You may continue in the main study even if you do 
not agree now or withdraw consent later for extra samples. There is no benefit to you, however, 
society may benefit from additional research. The risks of extra samples are similar to risks for 
drawing blood for this study. Your samples will be coded or linked to your data (for example, 
results from this study); however, no information that identifies you will be released to the 
company or researchers. Please initial and date your decision below in the box to the left of the 
YES or NO answers.     
 
 
YES.  
You may collect, store for unlimited period of time, and use 
additional serum samples for secondary (other) research.  
(Initials)                (Date) 
 
 
NO.  
Do not collect, store, and use additional serum samples for 
secondary (other) research.  
(Initials)                (Date) 
 
 
CERTIFICATE OF CONFIDENTIALITY 
To help us protect your privacy, we have a Certificate of Confidentiality from NIH. The study 
staff can use this certificate to legally refuse to give information that may identify you in any 
federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for 
example, if there is a court subpoena. The study staff will use the certificate to resist any demands 
for information that would identify you, except for reporting of communicable diseases, such as 
Hepatitis Virus and HIV infections, to state and local health departments, or for reporting 
possession or use of marijuana or other illegal drugs while at the CTU to the appropriate legal 
authorities. 
  


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 22-0027 
ICF version 4.0 – 08 March 2024 
Page 29 of 32 
 
 
 
Martin Kankam, MD, PhD, MPH, FAPCR 
              Advarra IRB Approved Version 11 Mar 2024 
 
A Certificate of Confidentiality does not prevent disclosure of your information to the NIH, FDA, 
or federal funding agency. Information from this study will be given to DMID and Selva 
Therapeutics, Inc, the pharmaceutical organization developing SLV213 and other drugs for the 
treatment of infectious diseases. Any persons or companies, which are contracted by the sponsor 
for conducting this study, measuring study drug level in blood samples, monitoring the execution 
of this study, and analyzing the data, will have access to the research information during and after 
this study. The information will also be given to the FDA. It may be given to governmental 
agencies in other countries where the study drug may be considered for approval. 
 
Medical records which identify you and the consent form signed by you will be looked at and/or 
copied for research or regulatory purposes by: 
 
• The sponsor 
• An agent for the sponsor 
• An agent for the study doctor 
• The FDA 
• Department of Health and Human Services (DHHS) agencies 
• The Institutional Review Board, Advarra IRB. 
 
Absolute confidentiality cannot be guaranteed because of the need to give information to these 
parties. The results of this research study may be presented at meetings or in publications. Your 
identity will not be disclosed in those presentations. 
 
• Altasciences Clinical Kansas, Inc. will handle the medical information obtained in this 
study with the strictest confidence. It will be protected as required by laws and/or 
regulations. It will not be made publicly available. 
• If the results of this study are published, you will not be identified by name. 
• Your identity will not be disclosed to anyone else, unless required by law. 
 
By signing this consent, you authorize Altasciences Clinical Kansas, Inc. to verify your study 
participation history with other businesses that conduct clinical research studies. 
  
A Certificate of Confidentiality does not prevent you or a member of your family from voluntarily 
releasing information about yourself or your involvement in this research. If you give your 
consent to release information to a medical care provider, an insurer, or other person to receive 
research information, then the researchers will not withhold that information. 
 
 
 


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ICF version 4.0 – 08 March 2024 
Page 30 of 32 
 
 
 
Martin Kankam, MD, PhD, MPH, FAPCR 
              Advarra IRB Approved Version 11 Mar 2024 
 
PRIMARY CARE PHYSICIAN NOTIFICATION  
We would like your permission to contact the doctor you see regularly to let them know that you 
are taking part in this study. It is important for all your doctors to know that you may be taking an 
experimental drug. Your doctor will want to know and think about all the drugs you are taking 
before giving you any new ones. While you are in the study, the study doctor will ask about your 
symptoms. If you have symptoms after the study ends, your other doctor may want to contact the 
study personnel. 
 
If you agree, your primary care physician (regular doctor) will be informed of your participation 
in the study. Indicate your choice below by initialing only one (1) section below. 
 
 
_____________________ 
(Initials                     Date) 
I do not have a primary care physician.  
 
_____________________ 
(Initials                     Date) 
I do not want my primary care physician notified.  
 
_____________________ 
(Initials                     Date) 
I would like my primary care physician notified and below is 
my physician’s contact information.  
Physician’s Name: 
_________________________________________  
Address: 
_________________________________________________  
               
_________________________________________________   
Phone No.: 
_______________________________________________  
  
 
 
 


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Page 31 of 32 
 
 
 
Martin Kankam, MD, PhD, MPH, FAPCR 
              Advarra IRB Approved Version 11 Mar 2024 
 
PERSONS TO CONTACT FOR QUESTIONS, CONCERNS, OR COMPLAINTS 
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns, or complaints about the study, please contact the study doctor at the 
telephone number listed on the first page of this consent document. If you seek emergency care, 
or hospitalization is required, alert the treating physician that you are participating in this research 
study.  
 
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research participants. If you have any questions about your rights as a research 
participant, and/or concerns or complaints regarding this research study, contact: 
 
• By mail: 
 
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Dr., Suite 600 
Columbia, MD 21044 
• or call toll free: 
877-992-4724 
• or by email: 
 
adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: Pro00073286. 
 
 
 


Division of Microbiology and Infectious Diseases (DMID) / Protocol Number 22-0027 
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Page 32 of 32 
 
 
 
Martin Kankam, MD, PhD, MPH, FAPCR 
              Advarra IRB Approved Version 11 Mar 2024 
 
CONSENT 
I have read all information in this document, and all my questions have been answered to my 
satisfaction. I voluntarily consent to participate in this study. I will be given a signed and dated 
copy of this consent form and have been told the description of the study drug, and the name, 
address, and phone number of the study physician. My signature gives my consent to participate. 
By signing and dating this form, I have not given up any of my legal rights as a research 
participant. 
 
 
Print Participant Name 
 
Date 
Participant's Signature 
 
 
Person Obtaining Informed Consent Printed Name 
 
 
Person Obtaining Informed Consent Signature  
 
Date 
Study Doctor's Signature* 
 
Date 
*The study doctor's signature evidences only that the study doctor has reviewed the consent form 
and the signatures of the participant and person obtaining consent, for compliance. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_002.pdf: 
CLINICAL RESEARCH IN INFECTIOUS DISEASES 
 
 
STATISTICAL ANALYSIS PLAN 
for 
DMID Protocol: 22-0027 
Study Title: 
A Randomized, Double Blind, Placebo-Controlled, 
Multiple Ascending Dose, Phase 1 Study of SLV213 in 
Healthy Volunteers 
 
NCT06146374 
 
Version 1.0 
 
DATE: 18-NOV-2024 
 
RESTRICTED 
 
 


Statistical Analysis Plan - DMID Protocol: 22-0027 
Version 1.0 
18NOV2024 
- 2 - 
RESTRICTED 
STUDY TITLE 
Protocol Number Code: 
DMID Protocol: 22-0027 
Development Phase: 
Phase 1 
Products: 
SLV213 100 mg (capsules containing K777 hydrochloride, the drug substance) 
Matched Placebo (capsules containing Microcrystalline celluloid) 
Form/Route: 
Oral 
Indication Studied: 
COVID-19 
Sponsor: 
Division of Microbiology and Infectious Diseases 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
Clinical Trial Initiation Date: 
March 12, 2024 
Clinical Trial Completion Date: 
July 08, 2024 
Date of the Analysis Plan: 
November 18, 2024 
Version Number: 
1.0 
This study was performed in compliance with Good Clinical Practice. 
Information contained in this publication is the property of Division of Microbiology and Infectious Diseases and is confidential. This 
information may not be disclosed to third parties without written authorization from Division of Microbiology and Infectious Diseases. This 
report may not be reproduced, stored in a retrieval system or transmitted in any form or by any means - electronic, mechanical, recording or 
otherwise - without the prior authorization from Division of Microbiology and Infectious Diseases. This document must be returned to Division of 
Microbiology and Infectious Diseases upon request. 
 


Statistical Analysis Plan - DMID Protocol: 22-0027 
Version 1.0 
18NOV2024 
- 3 - 
RESTRICTED 
TABLE OF CONTENTS 
STUDY TITLE ................................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
PREFACE ...................................................................................................................11 
2. 
INTRODUCTION ......................................................................................................12 
2.1. 
Purpose of the Analyses ..............................................................................................12 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................13 
3.1. 
Study Definitions and Derived Variables ...................................................................15 
4. 
INVESTIGATIONAL PLAN .....................................................................................16 
4.1. 
Overall Study Design and Plan ...................................................................................16 
4.2. 
Discussion of Study Design, Including the Choice of Control Groups ......................16 
4.3. 
Selection of Study Population ....................................................................................16 
4.3.1. 
Inclusion Criteria ........................................................................................................17 
4.3.2. 
Exclusion Criteria .......................................................................................................18 
4.4. 
Treatments ..................................................................................................................19 
4.4.1. 
Treatments Administered ............................................................................................19 
4.4.2. 
Identity of Investigational Product(s) .........................................................................20 
4.4.3. 
Method of Assigning Participants to Treatment Groups (Randomization) ................20 
4.4.4. 
Selection of Doses in the Study ..................................................................................20 
4.4.5. 
Selection and Timing of Dose for Each Participant ...................................................21 
4.4.6. 
Blinding ......................................................................................................................21 
4.4.7. 
Prior and Concomitant Therapy ..................................................................................21 
4.4.8. 
Treatment Compliance ................................................................................................22 
4.5. 
Safety and Pharmacokinetic Variables .......................................................................22 
4.5.1. 
Safety Variables ..........................................................................................................22 
4.5.2. 
PK Variables ...............................................................................................................23 
5. 
SAMPLE SIZE CONSIDERATIONS .......................................................................24 
6. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................25 
6.1. 
General Principles .......................................................................................................25 
6.2. 
Timing of Analyses .....................................................................................................25 


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6.3. 
Analysis Populations ..................................................................................................26 
6.3.1. 
Full Analysis Population.............................................................................................26 
6.3.2. 
Modified Intention-to-Treat (mITT) Population ........................................................26 
6.3.3. 
Safety Population ........................................................................................................26 
6.3.4. 
Pharmacokinetics (PK) Population .............................................................................26 
6.4. 
Covariates and Subgroups ..........................................................................................26 
6.5. 
Handling of Missing Data, Outliers, and BQL Data ..................................................26 
6.5.1. 
Missing Data ...............................................................................................................26 
6.5.2. 
Outliers .......................................................................................................................26 
6.5.3. 
BQL Data ....................................................................................................................27 
6.6. 
Interim Analyses and Data Monitoring ......................................................................27 
6.7. 
Multicenter Studies .....................................................................................................27 
6.8. 
Multiple Comparisons/Multiplicity ............................................................................27 
7. 
STUDY SUBJECTS ...................................................................................................28 
7.1. 
Disposition of Participants ..........................................................................................28 
7.2. 
Protocol Deviations ....................................................................................................28 
8. 
EFFICACY EVALUATION ......................................................................................29 
9. 
SAFETY EVALUATION ..........................................................................................30 
9.1. 
Demographic and Other Baseline Characteristics ......................................................30 
9.1.1. 
Prior and Concurrent Medical Conditions ..................................................................30 
9.1.2. 
Prior and Concomitant Medications ...........................................................................31 
9.2. 
Measurements of Treatment Compliance ...................................................................31 
9.3. 
Adverse Events ...........................................................................................................31 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events ....................31 
9.5. 
Pregnancies .................................................................................................................31 
9.6. 
Clinical Laboratory Evaluations .................................................................................32 
9.7. 
Vital Signs and Physical Evaluations .........................................................................32 
9.8. 
Concomitant Medications ...........................................................................................33 
9.9. 
Other Safety Measures ................................................................................................33 
9.9.1. 
12-Lead Standard Electrocardiogram .........................................................................33 
9.9.2. 
Tolerability .................................................................................................................34 
10. 
PHARMACOKINETICS ...........................................................................................35 


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10.1. 
Noncompartmental Analysis ......................................................................................36 
10.1.1. 
Single-Dose Plasma PK Parameters ...........................................................................37 
10.1.2. 
Multiple-Dose Plasma PK Parameters ........................................................................38 
11. 
IMMUNOGENICITY ................................................................................................41 
12. 
OTHER ANALYSES .................................................................................................42 
13. 
REPORTING CONVENTIONS ................................................................................43 
14. 
TECHNICAL DETAILS ............................................................................................44 
15. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES ...............................................................................................................45 
16. 
REFERENCES ...........................................................................................................46 
17. 
LISTING OF TABLES, FIGURES, AND LISTINGS ..............................................47 
APPENDICES ...............................................................................................................................48 
APPENDIX 1. TABLE MOCK-UPS..........................................................................................49 
APPENDIX 2. FIGURE MOCK-UPS ........................................................................................98 
APPENDIX 3. LISTINGS MOCK-UPS ...................................................................................105 
 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
ALP 
Alkaline Phosphatase 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the plasma concentration-time curve 
AUC(0-t) 
AUC from time zero to the last time with a concentration greater than or equal to the validated 
limit of quantitation of the assay 
AUC(0-∞) 
AUC from time zero to infinity 
AUC(0-12) 
AUC from 0h (time zero [pre-dose]) to 12h after dosing 
AUC(0-48),ss 
AUC from 0h (time zero [pre-dose]) to 48h after dosing at steady state 
AUC(0-last) 
AUC from time zero to the last concentration above the LLOQ 
AUC(0-tau) 
AUC from time zero to the end of the dosing interval 
AUC(0-tau),ss 
AUC from time zero to the end of the dosing interval at steady state 
BID 
Bis In Die (twice a day) 
BMI 
Body Mass Index 
BP 
Blood Pressure 
bpm 
Breaths Per Minute 
BQL 
Below Quantifiable Limit 
BUN 
Blood Urea Nitrogen 
C 
Celsius 
Cavg 
Average concentration during the dosing interval 
CHEM 
Chemistry 
CI 
Confidence Interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CLT 
Total clearance 
Cmax 
Observed maximum concentration 


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Cmax,ss 
Observed maximum concentration at steady state 
Cmin 
Observed minimum concentration at the end of the dosing interval 
Cmin,ss 
Observed minimum concentration at the end of the dosing interval at steady state 
CO2 
Carbon Dioxide 
COAG 
Coagulation 
COVID 
Corona Virus Disease (SARS-CoV-2) 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CTU 
Clinical Trial Unit 
CV% 
Coefficient of Variation  
DBP 
Diastolic Blood Pressure 
DLT 
Dose Limiting Toxicity 
DMID 
Division of Microbiology and Infectious Diseases 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
GM 
Geometric Mean 
h 
Hour 
HBsAg 
Hepatitis B Virus Surface Antigen 
HCG 
β-Human Chorionic Gonadotropin (pregnancy hormone) 
HCV 
Hepatitis C Virus 
HEM 
Hematology 
HIV 
Human Immunodeficiency Virus 
HLGT 
Higher Level Group Term 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 


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IND 
Investigational New Drug 
IQR 
Interquartile Range 
Ke 
Terminal phase elimination rate constant (λz) 
kg 
Kilograms 
L 
Liters 
lbs 
Pounds 
LFT 
Liver Function Test 
LLOQ 
Lower Limit of Quantitation 
m 
Meters 
M/F 
Male to Female (ratio) 
MAAE 
Medically Attended Adverse Event 
MAD 
Multiple Ascending Dose 
mg 
Milligrams 
MedDRA 
Medical Dictionary for Regulatory Activities  
mg 
Milligram 
MH 
Medical History 
mITT 
Modified Intention to Treat 
mL 
Milliliter 
MTD 
Maximum Tolerate Dose 
MO 
Medical Officer 
MOP 
Manual of Procedures 
N 
Number (typically refers to participants) 
NCA 
Noncompartmental Analysis 
ng 
Nanogram 
NIH 
National Institutes of Health 
OTC 
Over-the-Counter 
PD 
Pharmacodynamics 
PE 
Physical Examination 
PI 
Principal Investigator 
PK 
Pharmacokinetics 


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PO 
Per Os (by mouth, orally) 
PT 
Preferred Term 
PT INR 
Prothrombin Time International Normalized Rate 
Q1 
First Quartile (25th Percentile) 
Q12h 
Every 12 hours (twice daily) 
Q3 
Third Quartile (75th Percentile) 
QD 
Quaque Die (once a day) 
QNS 
Quantity Not Sufficient 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RBC 
Red Blood Cell 
Rsq 
Coefficient of determination (R-Squared or R2) 
RAUC 
Accumulation ratio of AUC 
SAE 
Serious Adverse Event 
SAD 
Single Ascending Dose 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SDCC 
Statistical and Data Coordinating Center 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
SS 
Steady state 
SOC  
System Organ Class 
SOP 
Standard Operating Procedures 
t1/2 
Terminal half-life 
TEAE 
Treatment-Emergent Adverse Event 
Tmax 
Time of maximum concentration 
Tmax,ss 
Time of maximum concentration at steady state 
Tmin 
Time of minimum concentration 
UA 
Urinalysis 


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UDS 
Urine Drug Screening 
ULN 
Upper Limit of Normal 
UP 
Unanticipated Problem 
Vd 
Volume of distribution 
Vd,ss 
Volume of distribution at steady state 
VS 
Vital Signs 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 


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1. 
PREFACE 
The Statistical Analysis Plan (SAP) for “A Randomized, Double Blind, Placebo-Controlled, Multiple 
Ascending Dose, Phase 1 Study of SLV213 in Healthy Volunteers” (DMID Protocol 22-0027) describes and 
expands upon the statistical information presented in the protocol. 
This document describes all planned analyses and provides reasons and justifications for these analyses. It 
also includes sample tables, listings, and figures planned for the final analyses. Regarding the final analyses 
and Clinical Study Report (CSR), this SAP follows the International Conference on Harmonisation (ICH) of 
Technical Requirements for Registration of Pharmaceuticals for Human Use Guidelines, as indicated in Topic 
E3 (Structure and Content of Clinical Study Reports) [1], and more generally is consistent with Topic E8 
(General Considerations for Clinical Trials) [2] and Topic E9 (Statistical Principles for Clinical Trials) [3]. 
The structure and content of the SAP provides sufficient detail to meet the requirements identified by the 
Food and Drug Administration (FDA) and ICH, while all work planned and reported for this SAP will follow 
internationally accepted guidelines published by the American Statistical Association [4] and the Royal 
Statistical Society [5] for statistical practice. 
This document contains four sections: (1) a review of the study design, (2) general statistical considerations, 
(3) comprehensive statistical analysis methods for pharmacokinetics (PK), tolerability, and safety outcomes, 
and (4) a list of proposed tables and figures. Within the table, figure, and listing mock-ups (Appendix 1, 
Appendix 2, and Appendix 3), references to CSR sections are included. Any deviation from this SAP will be 
described and justified in protocol amendments and/or in the CSR, as appropriate. The reader of this SAP is 
encouraged to also review the study protocol for details on conduct of the study and the operational aspects of 
clinical assessments. 
 


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2. 
INTRODUCTION 
2.1. 
Purpose of the Analyses 
These analyses will assess the safety, tolerability, and PK of multiple ascending doses (MAD) of SLV213 in 
healthy male and female participants, 18-65 years of age. These analyses will help to select the most likely 
suitable dose (e.g., at Maximum Tolerated Dose [MTD]) for treatment of patients with COVID-19 in a pivotal 
study. This double blind, placebo-controlled study was designed to enroll three sequential cohorts of 
12 participants each (8 SLV213 and 4 placebo) at doses of 400 mg every 12 hours (Q12h), 600 mg Q12h, and 
800 mg Q12h administered per os (PO) (by mouth, orally) for 7 days. 
This study was terminated after Cohort 1 and will not proceed with sequential cohorts. 
 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
OBJECTIVE 
ENDPOINTS (OUTCOME MEASURES) 
Primary 
Primary 
To evaluate the safety and 
tolerability of multiple ascending 
doses SLV213 for 7 days in 
healthy participants. 
Safety: Type, incidence, severity, and relatedness to study drug of all treatment-
emergent systemic, laboratory and electrocardiographic (ECG) adverse events 
(AEs) and serious adverse events (SAEs) in each treatment cohort from the first 
dose (Day 1) through the last visit (Day 28 ± 2 days). 
Tolerability: Summarized by dose cohort and include: 
• 
Number (and percentage) of participants who: 
1) Terminate early or are withdrawn due to treatment-emergent AEs 
assessed as related to intake of study medication. 
2) Have at least 1 treatment-emergent adverse event (TEAE), total and 
per dose level. 
3) Meet Grade 3 abnormal criteria for safety laboratory tests at least once 
post-dose. 
4) Meet Grade 3 abnormal criteria for vital sign measurements at least 
once post-dose. 
5) Meet Grade 3 criteria for safety electrocardiogram (ECG) parameters 
at least once post-dose. 
• 
Proportion of oral medication doses completed. 
Secondary 
Secondary 
To characterize the multiple dose 
pharmacokinetics (PK) of SLV213 
in healthy participants. 
The following single-dose plasma PK parameters will be computed (if 
estimable) from the plasma total concentration-time data over the 12-hour 
period following the morning dose on Day 1 for each cohort: 
• 
Cmax: Observed maximum concentration 
• 
Tmax: Time of maximum concentration 
• 
Cmin: Observed minimum concentration at the end of the dosing interval 
• 
AUC(0-t): Area under the plasma concentration - time curve (AUC) to the 
last time with a concentration greater than or equal to the validated limit of 
quantitation of the assay 
• 
AUC(0-∞): Area under the plasma concentration-time curve to infinity 
• 
AUC(0-12): Area under the plasma concentration - time curve from 0h (pre-
dose) to 12 h after dosing 
• 
AUC(0-last): Area under the plasma concentration - time curve from time 
zero to the last concentration above the lower limit of quantitation (LLOQ)  
• 
AUC(0-tau): Area under the plasma concentration - time curve to the end of 
the dosing interval 
• 
t1/2: Terminal half-life 
• 
CLT: Total clearance 
• 
Ke: terminal phase elimination rate constant 
• 
Vd: Volume of distribution 
• 
Dose-normalized exposure parameters (AUC(0-tau)/Dose and Cmax/Dose) 


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OBJECTIVE 
ENDPOINTS (OUTCOME MEASURES) 
The following multiple-dose plasma PK parameters will be computed (if 
estimable) from the drug total concentration-time data over the  
48-hour dosing interval following the evening dose on Day 7 for each cohort. 
• 
Cmax,ss: observed maximum concentration at steady state (ss) 
• 
Cmin,ss: observed minimum concentration at the end of the dosing interval 
at steady state 
• 
Cavg: calculated average concentration during the dosing interval 
• 
Tmax,ss: Time of maximum concentration (Cmax) at steady state  
• 
Tmin: Time to minimum concentration (Cmin) 
• 
AUC(0-48),ss: area under the plasma concentration - time curve from 0h (pre-
dose) to 48 h after dosing at steady state 
• 
AUC(0-tau),ss: Area under the plasma concentration - time curve to the end 
of the dosing interval at steady state  
• 
t1/2: Terminal half-life  
• 
CLT: Total clearance 
• 
Vd,ss: Volume of distribution at steady state  
• 
Linearity Index: AUC(0-tau),ss (Day 7) / AUC(0-∞) (Day 1) 
• 
RAUC: Accumulation ratio for AUC estimated as AUC(0-tau) (Day 7) / 
AUC(0-tau) (Day 1) 
• 
RCmax: Accumulation ratio for Cmax estimated as Cmax (Day 7) / Cmax 
(Day 1). 
• 
Dose-normalized exposure parameters (AUC(0-tau)/Dose and Cmax/Dose) 
 
Calculate trough plasma concentrations of total SLV213 at 12h after each 
morning and evening dose from Day 1 through Day 7. 
 
 
 


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3.1. 
Study Definitions and Derived Variables 
Adverse Events 
All AEs collected in this study will be considered unsolicited. Treatment-emergent AEs (TEAEs) are defined 
as AEs that occur or worsen after beginning study drug administration. 
Treatment Groups 
Results for safety and PK analyses will be presented by study product and dosage. Participants who received 
placebo will be pooled together and presented as a single treatment group. The treatment groups will be 
presented in the order of 400 mg SLV213 and Placebo. Results from placebo participants will not appear in 
the PK analyses. 600 mg SLV213 and 800 mg SLV213 treatment groups will not be enrolled. 
Baseline 
Any systemic medical condition and last vital sign (VS), electrocardiogram (ECG), and clinical safety 
laboratory test value that are recorded prior to dosing on Day 1 (Check-in/Enrollment and/or Day 1 Pre-
Dose 1) will be considered a baseline finding for the purpose of data analysis. If multiple measurements are 
available, the last measurement prior to dosing will be used as baseline. 
 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
This Phase 1 double blind, placebo-controlled study will consist of three sequential inpatient cohorts of 
12 healthy participants each (8 SLV213 and 4 placebo), at doses of 400 mg Q12h, 600 mg Q12h, and 800 mg 
Q12h for 7 days administered PO. After each cohort has been dosed, a Safety Review Committee (SRC) will 
evaluate the safety of the regimen to Day 15 before proceeding to dose the next cohort. The study will be 
carried out in the United States at a single clinical trial unit site (CTU). Participants who have consented to 
participate in the study, as evidenced by signing the informed consent form (ICF), will undergo study 
procedures to determine their eligibility to receive study drug. An overall schematic of the study design is 
shown in Figure 1. 
After the 400 mg SLV213 treatment group met multiple halting rules, it was recommended by the SMC to not 
proceed with the next sequential dose. The 600 mg SLV213 and 800 mg SLV213 treatment groups will not be 
enrolled. 
Upon meeting Inclusion/Exclusion criteria, participants will begin dosing with SLV213 or placebo per their 
allotted cohort. Participants will take their study drug orally Q12h in the fasted state, prior to morning and 
evening meals. AEs will be noted and graded per the protocol Toxicity Grading Tables (Table 6, Table 7, 
Table 8, and Table 9). Visit assessments are shown in the schedule of events (Table 2). 
Participants will be assigned to receive their treatment according to the randomization carried out by the 
clinical site. For each dosing cohort, randomized participants will be assigned a unique number. Participants 
will be replaced if lost to follow up prior to Day 1 of treatment. The replacement participant would receive the 
same treatment that the participant being replaced would have received. A unique number will be the only 
participant identifier used on all sample collections and return of results. The site’s unblinded pharmacist or 
qualified designee will provide each participant’s study drug to blinded clinical staff at the participating site. 
All doses will be administered to the participant at the site by delegated staff under the observation of licensed 
clinical staff authorized to administered study drug (PI, or sub-investigator or licensed clinicians listed in 
Form 1572). The investigational drug blind is maintained by the dispensing pharmacist through a 
randomization schedule. 
Full details about timing of analyses are found in Section 6.2. 
4.2. 
Discussion of Study Design, Including the Choice of Control Groups 
Given that the present study constitutes a follow-up to a completed single ascending dose (SAD) Phase 1 
safety trial, a placebo control will also be utilized for the current multiple ascending dose (MAD) study. In 
light of this, healthy volunteers aged 18 to 65 years old will be selected in a randomized fashion to constitute 
a representative sample of the broader population affected by COVID-19. Due to the MAD nature of this trial, 
the study will allow for an assessment of safety and PK following multiple doses of SLV213 through 28 days 
post the first dose. 
4.3. 
Selection of Study Population 
This study will enroll healthy volunteers 18 to 65 years old. Participants will be enrolled in an equitable way 
with best practices to balance sex and age applied to the study population. Recruitment of not more than 5/3 
or less than 3/5 Male-to-Female (M/F) ratio for each experimental group and not more than 3/1 or less than 
1/3 M/F ratio for each placebo group may be obtained. Should a participant replacement be necessary within a 


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cohort, the replacement participant will receive the same treatment, and attempts will be made to be of the 
same gender as the withdrawn participant. Participant Inclusion and Exclusion Criteria must be confirmed by 
a study clinician licensed to make medical diagnoses. No exemptions are granted on Participant 
Inclusion/Exclusion Criteria in DMID-sponsored studies. 
4.3.1. 
Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Provision of signed and dated informed consent form. 
2. Able to understand and willing to be available for all study visits and comply with all study procedures including 
Lifestyle Considerations (see Protocol v4.0 Section 5.4) throughout the study. 
3. Male and Female individuals, age 18-65 inclusive at time of enrollment. 
4. Good general health by medical history (MH), physical examination (PE), and vital signs (VS), clinical laboratory 
tests and ECG within normal reference range.1 
• Note 1: Lab exceptions include: lab test values that are within Grade 1 range per the Toxicity Table 
(Table 8) are acceptable if not considered to be clinically significant by the investigator (PI, sub-
investigator, or authorized clinician), with the exception of liver function tests (LFT) (transaminases 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), 
total and direct bilirubin, serum creatinine, estimated glomerular filtration rate (eGFR) per the 
CKD-EPI formula, and urine protein, which must be within the laboratory normal reference range. 
• Note 2: Screening laboratory values that fall outside the laboratory normal reference ranges and 
the ranges are not listed within the Toxicity Table (Table 8) (e.g., decrease activated partial 
thromboplastin time [aPTT]) that are deemed Not Clinically Significant by the PI will be acceptable. 
5. Ability to take oral medication and be willing to adhere to the dosing regimen. 
6. Women of childbearing potential1 must have practiced or use true abstinence2 or use at least one acceptable 
primary form of contraception3 for specified periods4 before, during and after dosing. 
• Note 1: Not of childbearing potential – post-menopausal females (defined as having a history of 
amenorrhea for at least one year) or a documented status as being surgically sterile (hysterectomy, 
bilateral oophorectomy, salpingectomy, tubal ligation, or Essure® placement with a history of 
documented radiological confirmation test at least 90 days after the procedure). 
• Note 2: True abstinence is 100% of the time without sexual intercourse (the male’s penis enters the 
female’s vagina). Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation 
methods] and withdrawal are not acceptable methods of contraception). 
• Note 3: Acceptable forms of primary contraception include a monogamous relationship with a 
vasectomized partner who has been vasectomized for 180 days or more before the participant 
receiving the study product, tubal ligation, non-hormonal intrauterine device, and if in a 
monogamous relationship with a male partner who uses a barrier method without spermicide. 
• Note 4: Specified periods include at least 30 days prior to screening, during the period between 
screening and completion of dosing, and until at least 30 days following receipt of the last dose of 
study product. 
7. Women of childbearing potential must have a negative serum β-human chorionic gonadotropin (HCG) pregnancy 
test at screening and a negative urine HCG pregnancy test at check-in (Day-1) within 24 hours before receiving 
the initial study product. 


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8. Male participants receiving the study product must use acceptable contraception and refrain from donating sperm 
from the day of first dose until 30 days after the last dose or be vasectomized.1 
• Note 1: Acceptable contraception includes abstinence from intercourse with a female of 
childbearing potential or use of a male condom without spermicide when engaging in any activity 
that allows for the passage of ejaculate to a female during the intervention period and for at least 
30 days after ending study dosing, or surgical sterilization for 180 days or more. 
9. Willing to avoid excessive physical exercise starting within 48 h prior to dosing and until discharge from the CTU 
on Day 9. 
10. No history of acute febrile or infectious illness for at least 7 days prior to the administration of study drug. 
4.3.2. 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Pregnant or lactating. 
2. History of any chronic disease that may increase risk to subject or interfere with endpoint assessment.1: 
• Note 1: With the exception of stable chronic medical conditions that do not require prescribed oral 
or injectable medications (e.g., Type 2 diabetes managed by diet only). 
3. History of bradycardia, orthostatic hypotension or orthostatic tachycardia, Long COVID or history of 
dysautonomia.1 
• Note 1: Exception is sinus bradycardia (HR <60 bpm) in healthy participants (e.g., conditioned 
athletes) could be enrolled per investigator’s clinical judgement. 
4. Known history of a clinically significant food or drug allergy/hypersensitivity including known allergy/ 
hypersensitivity to ingredients of the study drug or placebo. 
5. Current seasonal allergies with ongoing symptoms for more than a week prior to dosing requiring 
glucocorticoids and/or frequent use of antihistamines for treatment. 
6. History of any clinically significant disease or disorder, medical/surgical procedure, or trauma within 
4 weeks prior to initiation of administration of study product(s). 
7. History of any psychiatric condition that has required hospitalization in the last 12 months or subject is 
considered psychologically unstable by the investigator. 
8. History of any substance use disorder or positive urine drug screening (UDS) test for illicit substances 
listed in Protocol v4.0 Section 8.1 at Screening or Check-in (Day -1)1. 
• Note 1: Any approved medical use of amphetamines, barbiturates, benzodiazepines, cannabis, 
tricyclic antidepressants and opiates will not be acceptable. 
9. History of alcoholism or of binge1 or heavy alcohol drinking2 at any time in the 6 months before study 
product administration or positive urine alcohol test at Screening or Check-in (Day -1). 
• Note 1: Binge drinking is defined as 5 or more drinks during a single occasion if male, or 4 or more 
if female. 
• Note 2: Heavy drinking of alcohol is defined as consumption of more than 14 drinks of alcohol per 
week if male, or more than 7 drinks if female. 
10. History of ≥10 pack-years of nicotine product1 consumption in the 5-year period before screening, or 
positive urine cotinine screen at Check-in (Day -1)2. 


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• Note 1: Nicotine products include cigarettes, e-cigarettes, pipe, cigar, chewing tobacco, nicotine 
patch. 
• Note 2: Positive urine cotinine at Screening is allowed if negative at Check-in (Day -1). 
11. Body mass index (BMI) ≤ 18 kg/m2 or ≥ 32 kg/m2, or weight ≤ 100 lbs at Screening. 
12. Prior exposure to SLV213 or K777 or K11777. 
13. Use of any prohibited prescription or non-prescription medication within 14 days or 5 half-lives of the 
drug, whichever is longer, prior to study Check-in. (See Section 4.4.7) 
14. Use of any investigational drug product within 30 days or 5 half-lives (whichever is longer) before 
investigational product administration in this study. 
15. Planned participation in a clinical research study that requires treatment with a study drug, blood draws 
or other invasive assessments during the study period (screening until final visit). 
16. Blood or plasma donation of 500 mL within 3 months or more than 100 mL within 30 days before 
signing informed consent or planned donation prior to completion of this trial. 
17. Positive viral serology tests for Human Immunodeficiency Virus (HIV), hepatitis B virus, or hepatitis 
C virus (HCV) at screening1 (See Protocol v4.0 Section 8.1) with one exception2: 
• Note 1: Viral serology tests include HIV 1 and HIV 2 antibodies, Hepatitis B virus surface antigen 
(HBsAg), and HCV antibodies. 
• Note 2: Do not exclude participants with HCV antibodies who have been successfully treated for 
Hepatitis C, do not take any treatment medications currently, do not use prohibited medications, 
have normal transaminases and are generally healthy. 
18. Positive SARS-CoV-2 (COVID-19) molecular diagnostic test (Cue Care™ test) at Check-in (Day -1). 
4.3.2.1. 
Exclusion of Specific Populations 
Because the effects on the fetus are not known, pregnant women will not be eligible for the trial. Women of 
childbearing potential must utilize a highly effective method of contraception and will be required to have a 
negative urine pregnancy test on Check-in (Day -1) (within 24 h prior to initiation of study drug 
administration). 
Children will not be included in this trial as presently there are no safety or efficacy data in adults. Should the 
outcome of this trial be deemed acceptable, additional trials may be initiated, including those in other 
populations. 
4.4. 
Treatments 
4.4.1. 
Treatments Administered 
Study intervention: 
• SLV213 capsules containing 100 mg of a refined powder of drug substance K777 hydrochloride. 
• Matching placebo capsules containing 62.5 mg microcrystalline celluloid. 
Each participant will be randomly assigned to receive SLV213 or placebo (SLV213:placebo ratio 2:1) by 
mouth as follows: 4 capsules Q12h in Cohort 1, 6 capsules Q12h in Cohort 2, and 8 capsules Q12h in 


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Cohort 3. The SLV213 dose will be 400 mg Q12h, 600 mg Q12h and 800 mg Q12h for participants in 
Cohorts 1, 2 and 3, respectively, for 7 days. 
This study was terminated after Cohort 1 and will not proceed with sequential cohorts. 
4.4.2. 
Identity of Investigational Product(s) 
In this SAP, the term “study drug” refers to all or any of the drugs defined below: 
Product 1: SLV213 in 100 mg capsules 
SLV213 drug substance (K777) is 4-methylpiperazine-1-carboxylic acid [1-(3-benzenesulfonyl-1-phenethyl-
allycarbamoyl)-2-phenylethyl]-amid) as hydrochloride salt. SLV213 is a white to tan powder of the drug 
substance without excipients or stabilizer that will be packed into Swedish orange opaque size 1 capsules. It is 
an investigational drug product that is being used to accordance with approved labeling. 
 
Drug Substance Characteristics 
Molecular weight 
611.19 (574.73 free base) 
Molecular formula 
C32H39C1N4O4S 
Calculated pKa 
7.02 
 
Product 2: Matched Placebo 
Placebo for SLV213 drug product is manufactured as microcrystalline cellulose in a size 1 orange hard gelatin 
capsule. 
4.4.3. 
Method of Assigning Participants to Treatment Groups (Randomization) 
Participants in each cohort will be randomized 2:1 to drug versus placebo before dosing on Day 1 and receive 
assigned treatment at each dose. 
4.4.4. 
Selection of Doses in the Study 
Selva has conducted a Phase 1 randomized double-blind placebo-controlled SAD study in healthy volunteers 
to evaluate the safety, tolerability, and PK of SLV213 following oral administration (Study SLV213-01). 
Following randomization, 5 cohorts of 8 participants each (6 active, 2 placebo) received a single dose of the 
active compound SLV213 or placebo at 50 mg, 100 mg, 200 mg, 400 mg, or 800 mg PO daily (QD). A SRC 
evaluated the blinded results of each successive cohort before proceeding to dose the next cohort. Although a 
clinically significant episode of orthostatic hypotension was observed 30 minutes (min) after dosing in one 
participant at the 200 mg dose level, this was not seen in this participant at subsequent time points, nor in any 
other participant at the 400 mg or 800 mg dose levels. The SRC therefore concluded that no dose limiting 
toxicity (DLT) had been seen at any of the dose levels. PK analyses demonstrated dose dependent Cmax and 
AUC. Preliminary modeling of 400 mg and 800 mg BID using predicted blood levels showed exposures 
comparable to concentrations measured in preclinical efficacy models. It is therefore concluded that 400 mg 
Q12h, 600 mg Q12h and 800 mg Q12h dosing should be well tolerated. Further description of the results of 
the SLV213-01 study is provided in the investigator’s brochure (IB). 


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This study was terminated after Cohort 1 (400 mg) and will not proceed with sequential cohorts (600 mg and 
800 mg). 
4.4.5. 
Selection and Timing of Dose for Each Participant 
Participants will take their study drug prior to morning and evening meals in the fasted state with at least 240 
mL (8 fluid ounces) or more of tap or bottled water under the supervision of the site staff. Participants will not 
be re-dosed outside of the standard schedule of events. A list of study products by cohort is available in 
Table 1. 
Dose modifications are not planned unless mandated by the SMC. 
4.4.6. 
Blinding 
The study will be double-blinded, placebo-controlled. Placebo capsules are made to mimic study drug to 
avoid unblinding. Study drug and placebo are in matched bottles with matched capsule sizes. Administration 
of drug and placebo is controlled by the CTU as designated on the Delegation of Authority Log. 
The investigational drug blind shall not be broken by the investigator unless information concerning the 
investigational drug is essential for the medical treatment of the participant. If possible, the DMID Medical 
monitor should be contacted before the investigational drug blind is broken to discuss the need for unblinding. 
For unblinding a participant, the investigational drug blind can be obtained by contacting the dispensing 
pharmacist. The emergency unblinding information will be obtained from the statistical and data coordinating 
center (SDCC). The sponsor (investigational new drug [IND] holder) must be notified as soon as possible if 
the investigational drug blind is broken. The date, time, and reason the blind is broken must be recorded in the 
source documents. Details will be presented in the study-specific manual of procedures (MOP). 
4.4.7. 
Prior and Concomitant Therapy 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the Case Report Form (CRF) are 
concomitant prescription medications, and supplements. 
Information about prior medications, including hormonal contraceptives, taken by the participant in the 
30 days prior to initiation of dosing with study product(s) will be recorded on the appropriate CRF. 
Concomitant medications include all medications (prescription and over-the-counter [OTC] medications, 
supplements, and vaccines), except study products, taken by the participant from the time of the first dose of 
study product(s) to the end of the study. At each study visit following dosing, including telephone calls, 
participants will be queried about new ConMeds and changes to existing medications. The following 
medications are prohibited during the study: 
• No medications are allowed after enrollment until completion of all study assessments with the 
exception of up to 1,000 mg acetaminophen daily for up to 3 days for the relief of common, temporary 
symptoms (headache, musculoskeletal pain, etc.) if approved by the site PI or authorized clinician. 
• Any medications known to be strongly metabolized by CYP3A4 or CYP2D6, or strongly inhibit or 
induce these enzymes might interfere with the evaluation of the investigational product and should not 
be used by the participant for 14 days or 5 half-lives of the drug, whichever is longer, prior to and 
during the study. (See Protocol v4.0 Appendix C for a partial list). 


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• Participant should refrain from OTC supplements, such as vitamins and herbal supplements 
(e.g., Saint John’s Wort), for 14 days or 5 half-lives of the supplement, whichever is longer, prior to 
and for the duration of the trial. 
In the event medical conditions dictate the use of medications during the in-patient period, appropriate 
treatment may be prescribed by authorized/licensed clinician. For events during the out-patient period, 
participants are encouraged to notify the investigator or, if they seek care by their personal healthcare 
provider, to comply with the course of therapy as prescribed and inform the study investigator as soon as 
practical. 
Any drug or vaccine used or received by the participant during the trial should be recorded on the appropriate 
CRF. 
For additional lifestyle restrictions, see Protocol v4.0 Section 5.4. 
4.4.8. 
Treatment Compliance 
Participants will be directly observed at the time of dosing by a member of the clinical research team who is 
licensed and authorized to administer the study product (PI, sub-investigator or licensed clinician listed in 
Form 1572, or staff listed in the study Delegation of Authority Log). Each dose of study product will be 
administered by a member of the clinical research team that is delegated to administer the study product. 
Study product administration date and time will be documented on site source document and recorded on the 
appropriate eCRF. 
4.5. 
Safety and Pharmacokinetic Variables 
The following section describes the safety and PK variables of the study. As this study is a Phase 1 clinical 
trial in healthy adult participants, there will be no assessment of drug efficacy. 
4.5.1. 
Safety Variables 
Venipuncture schedule and blood volumes are shown in schedule of assessments (Table 3). The following 
safety endpoints will be assessed: 
• Chemistry (CHEM), Hematology (HEM), Coagulation (COAG), and Urinalysis (UA) clinical 
laboratory result safety parameters will be collected at Screening, Day -1, and prior to the morning 
dose on Days 2, 4, and 6, and on Day 8 or at early termination. 
o CHEM parameters: Electrolytes (sodium, potassium, total carbon dioxide [CO2]), calcium, 
chloride, creatinine, blood urea nitrogen (BUN), fasting glucose, total protein, albumin, total 
bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase 
(ALP), amylase, lipase, magnesium, and inorganic phosphorus. 
 Note 1: Estimate glomerular flow rate (eGFR) and direct bilirubin will be collected but not 
graded. 
o HEM parameters: Hemoglobin, platelets, white blood cells (WBC), neutrophils, lymphocytes, 
monocytes, basophils, and eosinophils. 
 Note 1: Red blood cells (RBC) will be collected but not graded. 
o COAG parameters: Prothrombin time and activated partial thromboplastin time (aPTT). 


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 Note 1: Prothrombin time international normalized rate (PT INR) will be collected but not 
graded. 
o UA parameters: Nitrite, urine protein, and urine glucose via dipstick. 
 Note 1: pH, specific gravity, bilirubin, and occult blood will be collected but not graded. 
 Note 2: If urine dipstick is abnormal for blood, protein, glucose, and nitrites, urine microscopy 
will be performed (for WBC, RBC, and bacteria), and the results will supersede those of the 
dipstick UA. 
• Vital signs (VS) will be collected at Screening, Day -1, within 30 minutes before and 2 hours 
(± 10 minutes) after each dose on Day 1 through Day 7, and the mornings of Days 8 and 9. 
o Supine VS parameters: Body temperature (oral), systolic blood pressure (SBP), diastolic 
BP (DBP), pulse, and respiratory rate. 
 Note 1: BP will be taken after at least 5 minutes of resting. 
o Orthostatic VS parameters: SBP, DBP, and pulse 
 Note 1: Orthostatic parameters will be measured 1 minute ± 15 seconds and 3 minutes ± 15 
seconds after standing. 
• Electrocardiogram (ECG) results will be collected at Screening, Day -1, and prior to the morning dose 
on Day 4, and Day 8 (before 12h PK timepoint after Day 7 evening dose) or at early termination. 
o ECG parameters: PR interval, QRS interval, QT interval, QT interval corrected for heart rate using 
Fridericia’s formula (QTcF correction), RR interval, and ventricular rate. 
Incidence, relatedness, and severity of TEAEs and SAEs will be recorded from the time of dosing to the final 
visit on the appropriate eCRF. All AEs will be graded for severity and relationship to the study product by a 
trained and qualified member of the study team. All AEs and SAEs will be considered unsolicited events. 
Abnormal clinical assessments should be submitted in the appropriate AE form. If a participant had an event 
with graded severity after enrollment on Day -1 but before dosing on Day 1, then the event will be reported in 
an updated medical history (MH) form and will be considered an AE only if it increases in severity grade after 
dosing. 
4.5.2. 
PK Variables 
Blood (plasma) samples for PK analysis will be collected according to the schedule of assessment (Table 3). 
Plasma concentrations of SLV213 will be quantitated using validated assays and study drug concentration 
data will be transferred to SDCC (Emmes) from the bioanalytical lab, KCAS, for reporting and PK analysis. 
PK parameters to be estimated for single dose and multiple dose plasma samples are described in Section 10. 
 


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5. 
SAMPLE SIZE CONSIDERATIONS 
The sample size chosen of a total of 36 participants (12 per cohort: 8 to receive active drug and 4 placebo) is 
considered to be sufficient for evaluation of safety, tolerability and PK data for this study; the sample size was 
not based on statistical power considerations (Table 4). 
Participants will be replaced if they withdraw or are withdrawn prior to Day 1 of treatment. The replacement 
participant would receive the same treatment that the participant would have received. 
Participants who withdraw or are withdrawn from this study after receiving at least one dose of study product 
and prior to Day 9 for reasons not related to TEAEs or study drug intolerance may be replaced, at the 
recommendation of the Site PI and concurrence by the DMID MO, with a participant who will receive the 
same treatment as the withdrawn participant, and an effort will be made to also be of the same gender as the 
participant who is replaced. The SDCC must be contacted prior to enrolling any replacement participants. 
 


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6. 
GENERAL STATISTICAL CONSIDERATIONS 
6.1. 
General Principles 
All continuous variables will be summarized using the following descriptive statistics: n (non-missing sample 
size), mean, standard deviation, median, maximum, and minimum. The frequency and percentages (based on 
analysis population sample size, unless otherwise stated) of observed levels will be reported for all categorical 
measures. In general, all data will be listed, sorted by treatment group, participant, parameter, and time point 
as applicable. 
The Safety Population will be the primary population used for summaries of safety endpoints. The PK 
Analysis Population will be used for summaries of PK endpoints. Analyses of primary and secondary 
endpoints will be done for each dose of SLV213 and compared with a placebo group. 
6.2. 
Timing of Analyses 
The primary clinical database for this study will consist of safety data including unsolicited events, and 
abnormal laboratory values, as well as baseline/demographic data. Once the last participant has completed the 
final visit, the primary clinical database will be cleaned, monitored, and locked. After clinical database lock 
and receipt of secondary endpoint data, a set of topline tables will be generated, including summaries of 
clinical safety and secondary PK data. The topline report will be made available to the study team for 
planning subsequent trials and may be presented in a public forum or used for publication in collaboration 
with the lead PI. These analyses will be considered final and will be included in the Clinical Study Report 
(CSR). 
Interim Analysis 
Blinded safety and tolerability data will be periodically reviewed by DMID and the site PI or authorized study 
clinician (listed on FDA Form 1572) to assess whether rules for halting progression to the next study cohort 
have been met. An ad hoc SMC meeting will review safety data if halting criteria have been met. The SMC 
will receive data in aggregate. The SMC may request to receive data by study product vs. placebo in a closed 
session. The SMC may also request that the blind be broken for individual participants, as needed, to assess 
safety issues. The SMC will be asked to recommend early termination or modification only when there is 
clear and substantial evidence of a treatment difference. More details about the interim analyses are described 
below, as well as in a separate guidance document for the SMC. 
Interim Safety Analyses 
Interim safety analysis is not planned. Safety data may be summarized for ad hoc review as requested by the 
SMC. Top level safety parameters will be assessed between cohorts as needed. 
After one participant experienced a moderate allergic reaction, further dosing was discontinued in four 
participants. As a result, four replacement participants were added at the advice of the SMC. One of these 
replacement participants also had a moderate allergic reaction to the study product. After meeting a halting 
rule criterion, the study was halted, and the SMC reviewed data of the two participants who reported a 
moderate allergic reaction. Under the advisement of the SMC, the study will not proceed with Cohort 2 and 
Cohort 3. 


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Interim Pharmacokinetics, Pharmacodynamic, Microbiological Activity, or Efficacy Review 
An interim PK and pharmacodynamics (PD) analysis is not planned. If concentration versus time or PK data 
are available, top-level concentration versus time curves or PK parameters will be assessed between cohorts 
as needed. 
Final Analyses 
Final analysis will be completed after study completion and database lock. No formal study data will be 
provided prior to this final analysis. 
6.3. 
Analysis Populations 
6.3.1. 
Full Analysis Population 
The Full Analysis population will include all randomized participants, including replacement participants, and 
analyzed according to the treatment as randomized. This population is analogous to an intent-to-treat 
population. 
6.3.2. 
Modified Intention-to-Treat (mITT) Population 
The mITT population will include all randomized participants, including replacement participants, who meet 
eligibility criteria and receive at least one dose of any study treatment. Participants will be excluded from the 
mITT population, if they fail to meet eligibility criteria or if they do not receive any study treatment. Analysis 
will be performed according to the treatment as randomized. 
6.3.3. 
Safety Population 
The Safety population will include all randomized participants, including replacement participants, who 
received at least one dose of any study treatment, and analysis will be performed according to the treatment 
actually received. 
6.3.4. 
Pharmacokinetics (PK) Population 
The PK population will include all randomized participants, including replacement participants, who received 
at least one dose of study treatment and have at least one quantifiable post-dosing plasma concentration to use 
for the PK analysis. 
6.4. 
Covariates and Subgroups 
The protocol does not define any formal subgroup analyses, and the study is not adequately powered to 
perform subgroup analyses. 
6.5. 
Handling of Missing Data, Outliers, and BQL Data 
6.5.1. 
Missing Data 
All attempts will be made to collect all data per protocol. No imputation will be performed for missing values. 
6.5.2. 
Outliers 
Outliers will not be excluded from the primary analyses. Outliers identified during the PK analysis will be 
discussed in the analysis report. Outliers will be defined as any values of plasma concentration for a given 


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treatment group that fall outside the interquartile fences of their respective distribution. Given an interquartile 
range (IQR) of Q3-Q1, where Q3 is the 75th percentile and Q1 is the 25th percentile, outliers will be those that 
are greater than Q3 + (1.5 x IQR) or those less than Q1 – (1.5 x IQR). 
6.5.3. 
BQL Data 
PK sample concentrations below the quantitative limit (BQL) will be imputed as zero if they did not come 
after a PK sample concentration that is above the lower limit of quantitation (LLOQ). The first PK sample 
that’s BQL will be imputed as ½ LLOQ if it came after a PK sample concentration above LLOQ and all PK 
samples after are also BQL. Otherwise, PK sample concentrations that are BQL will be imputed as missing. 
6.6. 
Interim Analyses and Data Monitoring 
Refer to Section 6.2. 
6.7. 
Multicenter Studies 
This is a single-site study. 
6.8. 
Multiple Comparisons/Multiplicity 
The objectives of the study are to obtain safety data and plasma PK data for 3 escalating doses of SLV213 
administered PO daily Q12h for seven days. There are no formal hypotheses being tested in this Phase 1 trial. 
This study was terminated after Cohort 1 (400 mg) and will not proceed with sequential cohorts (600 mg and 
800 mg). 
 


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7. 
STUDY SUBJECTS 
7.1. 
Disposition of Participants 
The composition of analysis populations, including reasons for participant exclusion, by treatment group, is 
presented in Table 11. 
The disposition of participants in the study will be tabulated by treatment group (Table 10). The table shows 
the total number of participants enrolled, included in Safety Population (receiving at least 1 dose), received all 
planned doses, included in the mITT population, included in PK population (having at least one quantifiable 
post dose plasma concentration), completed all PK blood draws, and completed follow-up. 
A flowchart showing the disposition of study participant will be included (Figure 2). This figure will present 
the number of participants screened, enrolled, dosed, completed the study and/or lost to follow-up, and 
analyzed by treatment group. 
A listing of participants who discontinued dosing or terminated from study follow-up and the reason will be 
included in Listing 2. A listing of participants who were excluded from certain analysis populations and the 
reasons are included in Listing 5. 
7.2. 
Protocol Deviations 
A summary of participant-specific protocol deviations will be presented by the reason for the deviation, the 
deviation category, and treatment group for all participants in the Safety Population (Table 5). All participant-
specific protocol deviations and non-participant specific protocol deviations will be included in Appendix 3 
as data listings (Listing 3 and Listing 4 respectively). 
 


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8. 
EFFICACY EVALUATION 
There are no efficacy endpoints for this trial. 
 


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9. 
SAFETY EVALUATION 
All safety analyses will be performed using the Safety Population and will be presented by Treatment Group. 
TEAEs will be presented in listings and summarized. Individual results of laboratory tests, VS, and ECGs will 
be listed and baseline, post dose, and changes from baseline to post dose laboratory, VS, and ECG data will 
be summarized. 
In general, TEAEs, including abnormal laboratory values, will be graded according to the FDA Guidance: 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials (https://www.fda.gov/media/73679/download). Grading scales are provided for AEs (Table 6), supine 
vital signs (Table 7), clinical laboratory results (Table 8), and ECG results (Table 9). Abnormal PE findings 
will be presented in data listings (Listing 18). 
Clinical laboratory tests and VS at Screening Visit and Check-in (Day -1) should be within site normal 
reference range with exceptions as allowed per Section 4.3.1, inclusion criterion #4 and outlined in the 
Manual of Procedures (MOP). Grade 1 measurements acceptable at baseline will only be considered a TEAE 
post-baseline if condition worsened. 
All TEAEs will be summarized using frequency counts and percentages. The following summaries will be 
presented for TEAEs and SAEs: 
• Overall (i.e., regardless of severity or relationship to treatment). 
• By severity grade (mild, moderate, severe, or life-threatening). 
• By relationship to study drug. 
• By MedDRA level hierarchy (system organ class [SOC], higher level group term [HLGT], and 
preferred term [PT]). 
Unless otherwise specified, at each level of participant summarization in reporting the incidence of TEAEs, a 
participant will be counted once if the participant reported one or more TEAEs. If more than one occurrence 
of a TEAE is reported, the TEAE of the worst severity or the worst-case relationship assessment will be 
summarized. 
9.1. 
Demographic and Other Baseline Characteristics 
Summaries of sex, gender assigned at birth, ethnicity, and race and of age, height, weight, and BMI will be 
presented by treatment group (Table 12 and Table 13 respectively). Ethnicity is categorized as Hispanic or 
Latino, or Not Hispanic or Latino. In accordance with NIH reporting policy, participants may self-designate 
as belonging to more than one race or may refuse to identify a race, the latter reflected in the CRF as “No” to 
each racial option. 
Individual participant listings (Appendix 3) will be presented for all demographics, including weight, height, 
and BMI (Listing 6), pre-existing medical conditions (Listing 7), and concomitant medications (Listing 21). 
9.1.1. 
Prior and Concurrent Medical Conditions 
All current illnesses and pre-existing medical conditions will be Medical Dictionary for Regulatory Activities 
(MedDRA) coded using MedDRA dictionary version 24.1 or higher. 
Individual participant listings will be presented for all medical conditions (Listing 7). 


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9.1.2. 
Prior and Concomitant Medications  
All medications will be coded to the Anatomical Therapeutic Classification (ATC) using the current version 
of the World Health Organization (WHO) Drug Dictionary. 
Individual participant listings will be presented for all concomitant medications (Listing 21). 
9.2. 
Measurements of Treatment Compliance 
Information on whether a participant missed a dose and reason, if provided, for missing a dose are included in 
Listing 8. 
9.3. 
Adverse Events 
All AEs collected will be considered unsolicited. Unsolicited AEs collected after receiving the first dose will 
be considered TEAEs. 
An overall summary of TEAEs by treatment group will be presented in Table 22 including number and 
percentage of participants who experienced at least one TEAE and at least one SAE. The number and 
percentage of participants and the number of events will be presented for SAEs and AEs in Table 23. 
The following summaries of AEs will be presented by treatment group, SOC, HLGT, and PT: 
• The number and percentage of participants, its corresponding 95% Confidence Interval (CI), and the 
number of events will be presented in Table 24. The 95% CI will be calculated using exact Clopper-
Pearson methodology. 
• The number and percentage of participants will be presented by the maximum severity of each 
relationship to the study treatment (related or not related) in Table 25. 
• The frequency and incidence of related TEAEs are presented graphically in Figure 9 and Figure 10, 
respectively. 
Individual participant listings will be presented for all TEAEs (Listing 12). 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events 
A complete listing of SAEs will be presented in Table 26. Other non-serious, unsolicited, moderate or greater 
severity TEAEs are listed in Table 27. A listing of adverse events of special interest (AESIs), medically 
attended adverse events (MAAEs), and unanticipated problems (UPs) will be presented in Table 28. 
9.5. 
Pregnancies 
Individual data listings of pregnancy reports will be provided if a pregnancy occurs post dosing: 
• Maternal information will be presented in Listing 22. 
• Gravida and para information will be presented in Listing 23. 
• Live birth outcomes will be presented in Listing 24, and still birth outcomes will be presented in 
Listing 25. 
• Spontaneous, elective, or therapeutic abortion outcomes will be presented in Listing 26. 


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9.6. 
Clinical Laboratory Evaluations 
Venipuncture schedule and blood volumes are shown in schedule of assessments (Table 3). Unscheduled 
clinical laboratory evaluations will be included in listings of all clinical laboratory results but will be excluded 
from tabular and graphical summaries by time point, except when calculating the maximum severity post 
baseline. All clinical laboratory results will be listed for each participant from time of screening to last study 
visit. Any abnormal laboratory result at Screening or Check-in (Day -1) (baseline) with values in the Grade 1 
range but deemed acceptable for enrollment per Section 4.3.1, inclusion criterion #4, will be presented in 
listings but will only be reported as a TEAE if severity worsens. Clinical laboratory parameters that have 
grading criteria for both decreases (result lower than normal range) and increases (result higher than normal 
range) will be summarized separately by direction. 
Laboratory results will be presented for chemistry, hematology, coagulation, and urinalysis separately. All 
safety laboratory results, severity, and change from baseline will be listed for each participant by treatment 
group, parameter, and time point in Listing 13, Listing 14, Listing 15, and Listing 16. Abnormal laboratory 
results (laboratory results outside the site normal range) will be presented in Table 29, Table 30, Table 31, 
and Table 32. Laboratory results outside of normal range but not within toxicity grading ranges will be listed 
as “ONR” (out of normal range) for severity. 
The sort order for CHEM parameters will be as follows: Sodium, Potassium, Total Carbon Dioxide, Calcium, 
Chloride, Creatinine, eGFR, Blood Urea Nitrogen, Fasting Glucose, Total Protein, Albumin, Total Bilirubin, 
Direct Bilirubin, Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, Amylase, 
Lipase, Magnesium, and Inorganic Phosphorus. 
The sort order for HEM parameters will be as follows: Hemoglobin, Platelets, Red Blood Cells, White Blood 
Cells, Neutrophils, Lymphocytes, Monocytes, Basophils, and Eosinophils. 
The sort order for COAG parameters will be as follows: PT INR, Prothrombin Time, and aPTT. 
The sort order for UA parameters will be as follows: pH, Specific Gravity, Bilirubin, Nitrite, Urine Protein, 
Urine Glucose, Occult Blood, White Blood Cell Count, Red Blood Cell Count, and Bacteria. 
Laboratory results will be summarized for baseline, Day 2, Day 4, Day 6, and Day 8 in tables and figures: 
• Number and percentage of participants with none, mild, moderate, severe, or life-threatening 
laboratory results both low (decrease) and high (increase) by parameter, time point, and treatment 
group for CHEM (Table 33), HEM (Table 34), COAG (Table 35), and UA (Table 36). 
9.7. 
Vital Signs and Physical Evaluations 
Unscheduled supine or orthostatic VS measurements will be included in listings but will be excluded from 
tabular and graphical summaries by time point, except when calculating the maximum severity post baseline. 
If VS measurements are repeated due to technical errors, the initial measurements made in error will not be 
used for analysis but will be listed. The following rules will be used to determine which supine VS 
measurement to use for analyses if repeat measurements occur: 
1. If the first replicate is normal, then it will be used for analysis. 
2. If the first and second replicates are both abnormal, then the replicate with the higher severity will be 
used for analysis. 
3. If the first replicate is abnormal, the second replicate is normal, and the third replicate was not 
performed, then the first replicate will be used in the analysis. 


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4. If the first replicate is abnormal, the second replicate is normal, and the third replicate is normal, then 
the second replicate will be used in the analysis. 
5. If the first replicate is abnormal, the second replicate is normal, and the third replicate is abnormal, then 
the abnormal replicate with the higher severity will be used for analysis. 
Any supine VS assessment at Screening or Check-in (Day -1) with values in the Grade 1 range but deemed 
acceptable for enrollment per Section 4.3.1, inclusion criterion #4, will be presented in listings but will only 
be reported as a TEAE if severity worsens. VS assessments that have grading criteria for both decreases 
(result lower than normal range) and increases (result higher than normal range) will be summarized 
separately by direction. 
The sort order for VS will be as follows: Oral Temperature, SBP, DPB, Pulse, and Respiratory Rate. 
Supine VS results will be summarized in tables: 
• Number and percentage of participants with mild, moderate, severe, or life-threatening VS results both 
low (decrease) and high (increase) by parameter, time point, dose (morning or evening), and treatment 
group (Table 37). 
Following supine measurements, orthostatic measurements of blood pressure and heart rate (pulse) were taken 
at 1 min (±15s) and 3 min (±15s) after standing. These measurements were evaluated relative to the supine 
measurements that were taken before standing up. The criteria for an abnormal VS orthostatic response 
include the following: 
• Orthostatic hypotension, defined as an SBP decrease of at least 20 mm/Hg and/or a DBP decrease of 
at least 10 mm/Hg from supine baseline, 
• And an increase in orthostatic pulse defined as an increase of at least 30 beats/min above supine 
baseline or any time there was there was tachycardia with a pulse above 120 beats/min. 
Abnormal VS orthostatic response meeting these criteria will be summarized as a TEAE. Orthostatic BP and 
HR are not included in VS tables. If orthostatic measurements were repeated, then supine measurements were 
repeated first. 
All supine and orthostatic VS measurements will be presented in Listing 17. 
Abnormal physical exams will be submitted and counted as an AE. A listing of abnormal physical exams will 
be presented in Listing 18. 
9.8. 
Concomitant Medications 
Refer to Section 9.1.2. 
9.9. 
Other Safety Measures 
9.9.1. 
12-Lead Standard Electrocardiogram 
Unscheduled ECG measurements will be included in listings but will be excluded from tabular and graphical 
summaries by time point, except when calculating the maximum severity post baseline. Baseline is defined in 
Section 3.1. Individual interval measurements and overall interpretations will be presented in Listing 19 and 
Listing 20, respectively. 


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The sort order for ECG interval measurements will be as follows: PR Interval, QRS Interval, QT Interval, 
QTcF Interval, RR Interval, and Ventricular Rate. 
12-lead standard ECG results will be summarized in tables and figures: 
• Summary of 12-lead standard ECG change in overall interpretation from baseline will be shown by 
treatment group and time point (Table 38). 
• Number and percentage of participants with mild, moderate, severe, or life-threatening ECG results by 
parameter, time point, and treatment group (Table 39). 
9.9.2. 
Tolerability 
Tolerability to study product is summarized by treatment group in Table 14. The table includes number and 
percentage of participants who (1) were terminated early or withdrawn due to TEAE related to study product; 
(2) had at least one TEAE; (3) had at least one Grade 3 abnormal lab test, VS measurement, or ECG 
parameter; (4) completed all oral medication doses. 
 


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10. 
PHARMACOKINETICS 
The PK Analysis Population will be used when summarizing plasma drug concentrations and will be used to 
conduct noncompartmental analysis (NCA). Concentrations collected that are BQL before the first 
measurable PK concentration above the LLOQ will be treated as 0 for plotting and for all calculations 
including NCA and concentration summary statistics. The first BQL concentration after the last measurable 
PK concentration will be imputed as ½ LLOQ. Otherwise, BQL concentrations will be imputed as missing. 
Otherwise, PK sample concentrations that are BQL will be imputed as missing. 
There will be no imputation for missing concentrations. The geometric mean (GM) of concentrations will be 
calculated using non-missing values after imputations. 
Collection of plasma samples outside of the protocol defined time window for the time point, determined by 
exact rather than nominal time of collection, will not result in exclusion of the sample result from NCA. 
Plasma samples collected out of window will be evaluated on a case-by-case basis. Results from PK plasma 
samples that were collected substantially outside of the protocol-defined time window will be excluded from 
concentration summary statistics by nominal time points and plots of mean concentration by nominal time 
point. Substantially out-of-window samples will be defined as twice the size of the protocol-defined windows. 
Plasma will be drawn at the following time points to measure the concentration of SLV213 and analyze PK 
parameters: 
• On Day 1 MORNING DOSE: Within 30 min before the morning dose (t=0), and at 0.5h (±5 min), 
1h (±5 min), 2h (±5 min), 4h (±5 min), 6h (±10 min), 8h (±10 min), and 12h (±15 min) after the 
morning dose. (The 12h time point is the same as the pre-dose time point (t=0) before the evening 
dose on Day 1) 
• On Day 1 EVENING DOSE: Before (t=0) and 12h (±15 min) after the evening dose. (The 12h time 
point is the same as the pre-dose time point before the morning dose on Day 2). 
• On Days 2 to 6: Within 30 min before the morning and evening doses (t=0) and at 12h (±15 min) after 
the morning and evening doses on each day. (The PK time point before each dose on Days 2 to 6 is the 
same as the 12h time point of the previously received dose.) 
• On Day 7 MORNING DOSE: Within 30 min before the morning dose (t=0), and 12h (±15 min) after 
the morning dose. (The 12h time point is the same as the pre-dose time point (t=0) before the evening 
dose on Day 7) 
• On Day 7 EVENING DOSE: Within 30 min before the evening dose (t=0), and at 0.5h (±5 min), 
1h (±5 min), 2h (±5 min), and 4h (±5 min) after the evening dose on Day 7. 
• On Day 8: At 6h (±10 min), 8h (±10 min), 12h (±15 min) and 24h (±15 min) after the evening dose 
on Day 7. 
• On Day 9: At 36h (±15 min) and 48h (-2 hours) after the evening dose on Dose 7. 
If the exact time of plasma PK sample collection is not recorded, then the collection time will be imputed as 
the planned time for analysis, as long as it is not known that the sample was collected outside of the protocol-
defined window. Rationale for excluding results from analysis will be described in the CSR. Results from 
samples with imputed collection times will be indicated in listing of PK sample concentrations. 
Participant-level SLV213 concentration listings will include separate columns for concentrations reported by 
the lab and concentrations used for analysis (Listing 9). The lab reported concentrations may include codes 


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such as “BQL” or “QNS” (Quantity Not Sufficient), while the analysis concentrations will contain numeric 
data only, including imputed values such as 0 for pre-dose time points and BQL samples prior to the first 
quantifiable sample. Listing will also indicate nominal time (i.e., planned time point) and actual time post 
dose in hours and minutes (e.g., 12H 10M). The listing will also indicate sample times that were collected out 
of window or imputed. 
Individual concentrations for all participants in the PK population will be presented in tables and figures: 
1. Summary statistics of SLV213 concentrations in plasma are presented for each nominal time point on 
Day 1 (morning dose) (Table 15 and [by sex] Table 16), Day 1 (evening dose) to Day 7 (morning dose) 
(Table 17 and [by sex] Table 18), and Day 7 (evening dose) to Day 9 (Table 19 and [by sex] Table 20). 
2. Individual SLV213 concentrations in plasma profiles are presented graphically for Day 1 (morning dose) 
(Figure 3) and Day 7 (evening dose) (Figure 4). 
3. Individual trough SLV213 concentrations in plasma profiles are presented for Day 1 (morning dose) 
through Day 7 (evening dose) (Figure 5). 
4. Semi-log individual SLV213 concentrations in plasma profiles are presented for Day 1 (morning dose) 
(Figure 6) and Day 7 (evening dose) (Figure 7). 
5. Semi-log individual trough SLV213 concentrations in plasma profiles are presented for Day 1 
(morning dose) to Day 7 (evening dose) (Figure 8). 
10.1. 
Noncompartmental Analysis 
PK parameters from plasma PK data will be estimated through NCA using version 8.3.4 or higher of Phoenix 
WinNonlin®. Actual post dose times will be used for estimation of plasma PK parameters instead of nominal 
time. In case of imputed sample collection times, the imputed time will be included in NCA. Any outliers 
identified in the PK analysis will be discussed in the analysis report. Outliers will not be excluded from the 
noncompartmental PK analysis. 
All estimable participant-specific PK parameters for single-dose and multiple dose are included in Listing 10 
and Listing 11, respectively. 
Summary statistics for SLV213 PK parameters are presented by Day 1, Single Dose and Day 7, Multiple 
Dose for the 400 mg SLV213 treatment group (Table 21) for participants in the PK population with a 
measurable Ke (terminal elimination rate constant) at the given dose. 
The definition of coefficient of variation (CV%) is described below: 
For an independent identically distributed random sample {x1, x2,…, xn} from a log-normal distribution, let s2 
be the sample variance statistic of the natural log-transformed values of the sample. The CV% will be defined 
as: 
CV% = ඥexp(s2) −1 × 100% 
Phoenix WinNonlin® NCA will use the following settings to compute parameters from plasma PK data: 
• Linear Up Log Down calculation method 
• Uniform weighting 
• Ke Acceptance Criteria 
o Rsq_adjusted > 0.90 


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o Includes at least 3 time points after Tmax 
10.1.1. 
Single-Dose Plasma PK Parameters 
These parameters will be computed (if estimable) from the plasma drug concentration-time data over the 
12-hours following Dose 1 (Day 1, morning dose) for each study drug: 
Cmax 
Cmax is defined as the maximum drug or metabolite concentration observed in plasma over all PK sample 
concentrations. It will be obtained from the Cmax parameter calculated by WinNonlin®. If there is no 
measurable concentration in the participant’s PK profile, then Cmax will be missing for that participant. Cmax 
will be reported in units of ng/mL. The dose-normalized parameter Cmax/Dose will also be reported from 
Cmax_D in WinNonlin®. 
Cmin 
Cmin is defined as the observed minimum concentration at the end of the dosing interval. It will be obtained 
from the Clast parameter calculated by WinNonlin®. 
Tmax 
Time of maximum concentration (Tmax) is defined as the time at which the Cmax occurs. It will be obtained 
from the Tmax parameter calculated by WinNonlin®. If there is no measurable Cmax in the participant’s PK 
profile, then Tmax will be missing for that participant. Tmax will be reported in units of h. 
Ke 
The terminal phase elimination rate constant (Ke) is defined as the first-order rate constant describing the rate 
of decrease of drug or metabolite concentration in the terminal phase (defined as the terminal region of the PK 
curve where drug or metabolite concentration follows first-order elimination kinetics). Ke will be computed 
as the slope of a terminal region consisting of > 3 points in the plot of log-transformed concentration data 
versus time. Ke will be estimated using uniform weighting. 
Time points used in the estimation of Ke will be initially selected using the WinNonlin® automatic algorithm. 
Manually chosen time points may be used at the discretion of the PK analyst after examination of the 
automatically chosen points in the context of the semi-log profile to improve estimation of Ke on a case-by-
case basis. The set of points chosen must contain only time points after Tmax, include at least 3 time points, 
and satisfy the Ke Acceptance Criteria described above. Otherwise, the elimination rate constant and all 
derived parameters (apparent terminal elimination half-life [t1/2], AUC Extrapolated to Infinity [AUC0-∞], total 
clearance [CLT], and apparent volume of distribution during terminal phase [Vd]) will be treated as missing. 
This parameter will be represented by the Lambda_z parameter calculated by WinNonlin®. Ke will be 
reported in units of 1/h. 
t1/2 
The t1/2 is defined as the time required for the drug or metabolite concentration to decrease by a factor of one-
half in the terminal phase. The t1/2 can be estimated as ln(2)/ Ke. It will be obtained from the HL_Lambda_z 
parameter calculated by WinNonlin®. Terminal half-life will be reported in units of h. 


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AUC 
AUC0-last is defined as the area under the concentration-time curve from dosing (t=0) to the time of the last 
measured concentration. AUC0-last will be estimated using the Linear Up Log Down calculation method and 
obtained from the AUClast parameter calculated by WinNonlin®. 
AUC0-∞is defined as the total area under the concentration-time curve from dosing (t=0) taken to the limit as 
the end time becomes arbitrarily large. AUC0-∞ can be calculated by adding AUC0-last to an extrapolated value 
equal to the last measured concentration greater than the LLOQ divided by Ke: 
AUC0−∞ = AUC0−last + Clast
 Ke  
Where Clast is the last measured concentration > LLOQ. AUC0-∞ will be obtained from the AUCINF_obs 
parameter calculated by WinNonlin®. 
%AUCex is defined as percentage of AUC0-∞ obtained by extrapolation from time of the last measured 
concentration to infinity. %AUCex can be calculated by dividing AUC from time of the last measured 
concentration to infinity by AUC0-∞: 
%AUC𝑒𝑒𝑒𝑒= AUC0−∞−AUC0−last
AUC0−inf
, 
If %AUCex is >20%, the estimated AUC0-∞ will be excluded from statistical summaries of PK parameter 
estimates and downstream calculations. %AUCex will be obtained from the AUC_%Extrap_obs parameter 
calculated by WinNonlin®. 
AUC0-12 will be calculated as the AUC extrapolated to 12 h after dosing. This will be obtained from the 
WinNonlin® AUC0_12 parameter. 
AUC0-tau will be calculated as the AUC to the end of the dosing interval. The dose-normalized parameter 
AUC0-tau/Dose will also be reported. These parameters will be obtained from the AUC_tau and AUC_tau_D 
parameters in WinNonlin®, respectively. 
All AUCs will be reported in units of ng*h/mL. 
CLT 
Total clearance (CLT) will be obtained from Dose/AUC∞. If %AUCex is >20%, the estimated CLT value will 
be excluded from statistical summaries of parameter estimates and downstream calculations. CLT will be 
obtained from the CL_F_obs parameter calculated by WinNonlin®. Clearance will be reported in units of L/h. 
Vd 
Apparent volume of distribution (Vd) will be calculated as (CLT)/ Ke. If %AUCex is >20%, the estimated Vd 
value will be excluded from statistical summaries of parameter estimates and downstream calculations. Vd 
will be obtained from Vz_F_obs calculated by WinNonlin®. Volume will be reported in units of L. 
10.1.2. 
Multiple-Dose Plasma PK Parameters 
These parameters will be computed (if estimable) from the plasma drug concentration-time data over the 48-
hour dosing interval following Dose 14 (Day 7, evening dose) for each study drug. Note that these parameter 
estimates assume that steady state has been achieved. 


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Cmax,ss 
Cmax,ss is the observed maximum concentration at steady state. This will be obtained from the Cmax parameter 
calculated by WinNonlin® for Dose 14. 
Cmin,ss 
Cmin,ss is the observed minimum concentration at the end of the dosing interval at steady state. This will be 
obtained from the Clast parameter calculated by WinNonlin® for Dose 14. 
Cavg 
Cavg is the calculated average concentration during the dosing interval. It is calculated as AUC0-tau,ss/tau. This 
will be obtained from the Cavg parameter calculated by WinNonlin® for Dose 14. 
Tmax,ss 
Tmax,ss is the time of maximum concentration (Cmax) at steady state. This will be obtained from the Tmax 
parameter calculated by WinNonlin® for Dose 14. 
Tmin 
Tmin is the time to minimum concentration (Cmin). This will be obtained from the Tlast parameter calculated by 
WinNonlin® for Dose 14. 
Ke 
Ke is the first-order rate constant describing the rate of decrease of drug or metabolite concentration in the 
terminal phase (see Section 10.1.1 for additional details). This will be obtained from the Lambda_z parameter 
calculated by WinNonlin® for Dose 14. 
AUC(0-48),ss 
AUC(0-48),ss is calculated as the area under the plasma concentration - time curve extrapolated to 48 h after 
dosing (see Section 10.1.1 for additional details). 
AUC(0-tau),ss 
AUC(0-tau),ss is calculated as the area under the plasma concentration-time curve to the end of the dosing 
interval at steady state. 
t1/2 
t1/2 will be obtained from the HL_Lambda_z parameter calculated by WinNonlin® for Dose 14 (see 
Section 10.1.1 for additional details). 
CLT 
CLT will be obtained from the CL_F_obs parameter calculated by WinNonlin® (see Section 10.1.1 for 
additional details). 
Vd,ss 
Vd,ss is the volume of distribution at steady state. It will be obtained from Vz_F_obs in WinNonlin®. 
Linearity Index 
The Linearity Index is calculated as AUC(0-tau),ss (Dose 14 [Day 7 Evening Dose]) / AUC(0-∞) (Dose 1 [Day 1 
Morning Dose]). 


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RAUC 
RAUC is the accumulation ratio for AUC, which is estimated as AUC(0-tau),ss (Dose 14 [Day 7 Evening Dose]) 
/ AUC(0-tau) (Dose 1 [Day 1 Morning Dose]) where AUC(0-tau),ss (Dose 14 [Day 7 Evening Dose]) and 
AUC(0-tau) (Dose 1 [Day 1 Morning Dose]) are taken from the 0-12h interval on their respective days. 
RCmax 
RCmax is the accumulation ratio for Cmax, which is estimated as Cmax (Dose 14 [Day 7 Evening Dose]) / Cmax 
(Dose 1 [Day 1 Morning Dose]). 
 


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11. 
IMMUNOGENICITY 
Not applicable. 
 


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12. 
OTHER ANALYSES 
Not applicable. 
 


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13. 
REPORTING CONVENTIONS 
P-values >0.001 and <0.999 will be reported to 3 decimal places; p-values less than 0.001 will be reported as 
“<0.001” The mean, standard deviation, and other statistics will be reported to 1 decimal place greater than 
the original data. The minimum and maximum will use the same number of decimal places as the original 
data. Proportions will be presented as 2 decimal places; values greater than zero but <0.01 will be presented 
as “<0.01”. Percentages will be reported to the nearest whole number; values greater than zero but “<1” will 
be presented as “<1”; values greater than 99% but less than 100% will be reported as “>99”. Estimated 
parameters, not on the same scale as raw observations (e.g. regression coefficients) will be reported to 
3 significant figures. 
 


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14. 
TECHNICAL DETAILS 
SAS version 9.4 or above and R versions 3.2 or above will be used to generate tables, figures, and listings. PK 
parameters will be estimated through NCA using Phoenix® WinNonlin® version 8.3.4 or later. 
 


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15. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES 
If there are any changes to the planned analyses prior to final data lock and after finalization of the SAP, they 
may be added to the SAP as an addendum. The SAP will not be amended after final data lock. 
Changes from Protocol v4.0: 
The study did not continue enrollment after Cohort 1 (See Section 6.2). This SAP provides shells for an 
abbreviated CSR that will assess 400 mg SLV213 and placebo treatment groups from Cohort 1 only. 
 


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16. 
REFERENCES 
1. ICH Harmonised Tripartite Guideline. Structure and Content of Clinical Study Reports E3. 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. 1995. Retrieved from: 
https://database.ich.org/sites/default/files/E3_Guideline.pdf. 
2. ICH Harmonised Tripartite Guideline. General Considerations for Clinical Trials E8. 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. 1997. Retrieved from: 
https://database.ich.org/sites/default/files/E8_Guideline.pdf. 
3. ICH Harmonised Tripartite Guideline. Statistical Principles for Clinical Trials E9. International 
Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for 
Human Use. 1998. Retrieved from: https://database.ich.org/sites/default/files/E9_Guideline.pdf. 
4. American Statistical Association Guideline. Ethical Guidelines for Statistical Practice. American 
Statistical Association. 2022. Retrieved from: https://www.amstat.org/docs/default-source/amstat-
documents/ethicalguidelines.pdf?sfvrsn=bdeeafdd_3. 
5. Royal Statistical Association Guideline. Code of Conduct. The Royal Statistical Association. 
2014. Retrieved from: https://rss.org.uk/RSS/media/File-library/About/2019/RSS-Code-of-
Conduct-2014.pdf. 
 


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17. 
LISTING OF TABLES, FIGURES, AND LISTINGS  
Table, figure, and listing shells are presented in Appendix 1, Appendix 2, and Appendix 3, respectively. 
 


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APPENDICES 
 


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APPENDIX 1. TABLE MOCK-UPS 
 
LIST OF TABLES 
Table 1: 
Dosing and Administration .........................................................................................................51 
Table 2: 
Schedule of Assessments ............................................................................................................52 
Table 3: 
Laboratory Samples and Estimated Total Blood Volume (mL) .................................................55 
Table 4: 
Sample Size .................................................................................................................................56 
Table 5: 
Distribution of Protocol Deviations by Category, Type, and Treatment Group, Full Analysis 
Population ...................................................................................................................................57 
Table 6: 
Adverse Event Grading Scale .....................................................................................................59 
Table 7: 
Vital Sign Grading Scale ............................................................................................................59 
Table 8: 
Laboratory Adverse Event Grading Scale ..................................................................................60 
Table 9: 
ECG Adverse Event Grading Scale ............................................................................................62 
Table 10: 
Participant Disposition by Treatment Group, Full Analysis Population ....................................63 
Table 11: 
Analysis Populations by Treatment Group, Full Analysis Population .......................................64 
Table 12: 
Summary of Categorical Demographic and Baseline Characteristics by Treatment Group, 
Full Analysis Population .............................................................................................................65 
Table 13: 
Summary of Continuous Demographic and Baseline Characteristics by Treatment Group, 
Full Analysis Population .............................................................................................................66 
Table 14: 
Tolerability by Treatment Group, Safety Population .................................................................67 
Table 15: 
Summary Statistics for SLV213 Concentrations in Plasma, 400 mg SLV213 PK Population – 
Day 1, Morning Dose (Single Dose) ..........................................................................................68 
Table 16: 
Summary Statistics for SLV213 Concentrations in Plasma by Sex, 400 mg SLV213 PK 
Population – Day 1, Morning Dose (Single Dose) .....................................................................68 
Table 17: 
Summary Statistics for SLV213 Concentrations in Plasma by Time Point and Dose, 400 mg 
SLV213 PK Population – Day 1, Evening Dose to Day 7, Morning Dose ................................69 
Table 18: 
Summary Statistics for SLV213 Concentrations in Plasma by Sex, Time Point, and Dose, 
400 mg SLV213 PK Population – Day 1, Evening Dose to Day 7, Morning Dose ...................70 
Table 19: 
Summary Statistics for SLV213 Concentrations in Plasma, 400 mg SLV213 PK Population – 
Day 7, Evening Dose to Day 9 (Multiple Doses) .......................................................................71 
Table 20: 
Summary Statistics for SLV213 Concentrations in Plasma by Sex, 400 mg SLV213 PK 
Population – Day 7, Evening Dose to Day 9 (Multiple Doses) ..................................................71 
Table 21: 
Summary Statistics for SLV213 PK Parameters by Dose, 400 mg SLV213 PK Population .....72 
Table 22: 
Overall Summary of Adverse Events, Safety Population ...........................................................74 


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Table 23: 
Serious Adverse Events and Adverse Events by MedDRA System Organ Class and Preferred 
Term, and Treatment Group, Safety Population .........................................................................75 
Table 24: 
Summary of Treatment Emergent Adverse Events by MedDRA System Organ Class, High 
Level Group Term, Preferred Term, and Treatment Group, Safety Population .........................76 
Table 25: 
Treatment Emergent Adverse Events by MedDRA System Organ Class, High Level Group 
Term, Preferred Term, Maximum Severity, Relationship, and Treatment Group, Safety 
Population ...................................................................................................................................77 
Table 26: 
Listing of Serious Adverse Events ..............................................................................................78 
Table 27: 
Listing of Non-Serious, Unsolicited, Moderate or Greater Severity Adverse Events ................79 
Table 28: 
Listing of Adverse Events of Special Interest, Medically Attended Adverse Events, and 
Unanticipated Problems ..............................................................................................................80 
Table 29: 
Listing of Abnormal Laboratory Results – Chemistry ...............................................................82 
Table 30: 
Listing of Abnormal Laboratory Results – Hematology ............................................................83 
Table 31: 
Listing of Abnormal Laboratory Results – Coagulation.............................................................84 
Table 32: 
Listing of Abnormal Laboratory Results – Urinalysis ................................................................85 
Table 33: 
Chemistry Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment 
Group, Safety Population ............................................................................................................86 
Table 34: 
Hematology Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Group, Safety Population ..........................................................................................89 
Table 35: 
Coagulation Laboratory Results by Parameter, Maximum Severity, Time Point, and 
Treatment Group, Safety Population ..........................................................................................90 
Table 36: 
Urinalysis Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment 
Group, Safety Population ............................................................................................................91 
Table 37: 
Supine Vital Signs by Assessment, Maximum Severity, Time Point, and Treatment Group, 
Safety Population ........................................................................................................................92 
Table 38: 
Summary of Post Dose Electrocardiograms Change in Overall Interpretations from Baseline 
by Treatment Group and Time Point, Safety Population............................................................95 
Table 39: 
ECG Results by Parameter, Severity, Treatment Group, and Time Point, Safety Population ...96 
 


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9.1 
Overall Study Design and Plan Description 
Table 1: 
Dosing and Administration 
Cohort 
Product Name 
Dose 
Route 
Frequency of 
Administration 
Duration of 
Treatment 
1 
SLV213 
400 mg 
(4x 100 mg capsules) 
Oral 
Q12 hours 
7 Days 
Matched Placebo 
4 capsules 
2 
(not 
enrolled) 
SLV213 
600 mg 
(6x 100 mg capsules) 
Oral 
Q12 hours 
7 Days 
Matched Placebo 
6 capsules 
3 
(not 
enrolled) 
SLV213 
800 mg 
(8x 100 mg capsules) 
Oral 
Q12 hours 
7 Days 
Matched Placebo 
8 capsules 
Note: The study was terminated prior to enrollment to Cohorts 2 and 3 
 


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9.5.1 Immunogenicity and Safety Measurements Assessed and Flow Chart 
Table 2: 
Schedule of Assessments 
 
Screening Period 
In-patient at the CTU 
Out-patient 
 
Procedures 
Screening 
Check-in/ 
Enrollment  
Randomization/ 
Drug 
Administration 
and Monitoring 
Drug 
Administration 
and Monitoring 
Drug 
Administration 
and Monitoring 
Monitoring Discharge 
Interim and 
Closeout Visits 
(by phone)(t) 
Unscheduled 
visit(s)(w) 
Early 
Termination 
Study Day 
Day -28 to Day -2 
Day -1 
Day 1 
Day 2- Day 6 
Day 7: 
Day 8: 
Day 9 
Days 15, 
21, 28 (each ± 
2 days) 
Informed Consent(a) 
x 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
Eligibility confirmation(b) 
x 
x (b) 
x (b) 
 
 
 
 
 
 
 
Medical History (MH)(c) 
x(c) 
x(c) 
x(c) 
 
 
 
 
 
 
 
Prior and Concomitant 
Medication(d) 
x 
x 
x 
x 
x 
x 
x 
x 
x(w) 
x 
Complete Physical Examination 
(PE)(e) 
x 
x 
 
 
 
 
x 
 
 
x 
Focused PE(f)  
 
 
x 
x 
x 
x 
 
 
x(w) 
 
Height and Weight and Body 
Mass Index (BMI) 
x 
 
 
 
 
 
 
 
 
 
Body weight 
 
x 
 
 
 
 
 
 
 
 
Vital Signs (VS)(g) 
x 
x 
x 
x 
x 
x 
x 
 
x(w) 
x 
Pregnancy Test(h)  
x 
x 
 
 
 
 
 
 
 
 
Follicle-stimulating hormone 
(FSH) in post-menopausal 
women(i) 
x 
 
 
 
 
 
 
 
 
 
Urine Drug Screen (UDS) and 
alcohol test(j) 
x 
x 
 
 
 
 
 
 
 
 
Cotinine test in urine(k)  
x 
x 
 
 
 
 
 
 
 
 
HIV(1 and 2) and Hepatitis B and 
C Serology tests(l) 
x 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 (COVID-19) test(m) 
 
x 
 
 
 
 
 
 
 
 
Blood (serum) Clinical 
Laboratory Assessments(n)  
x 
x 
 
x 
 
x 
 
 
x(w) 
x 
Urinalysis (UA)(o) 
x 
x 
 
x 
 
x 
 
 
x(w) 
x 


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Screening Period 
In-patient at the CTU 
Out-patient 
 
Procedures 
Screening 
Check-in/ 
Enrollment  
Randomization/ 
Drug 
Administration 
and Monitoring 
Drug 
Administration 
and Monitoring 
Drug 
Administration 
and Monitoring 
Monitoring Discharge 
Interim and 
Closeout Visits 
(by phone)(t) 
Unscheduled 
visit(s)(w) 
Early 
Termination 
Study Day 
Day -28 to Day -2 
Day -1 
Day 1 
Day 2- Day 6 
Day 7: 
Day 8: 
Day 9 
Days 15, 
21, 28 (each ± 
2 days) 
ECG(p) 
x 
x 
 
x 
 
x 
 
 
x(w) 
x 
Enrollment / Randomization(q) 
 
x 
x 
 
 
 
 
 
 
 
Record time of last meal 
consumed before initiation of 
predose fasting  
 
x 
x 
x 
x 
 
 
 
 
 
Drug Administration(r) 
 
 
x 
x 
x 
 
 
 
 
 
Adverse Events(s) 
 
 
x 
x 
x 
x 
x 
x 
x(w) 
x 
Telephone Call(t) 
 
 
 
 
 
 
 
x 
 
 
PK Assessments and Future 
tests(u) 
 
 
x 
x 
x 
x 
x 
 
 
x 
Check patency of IV blood draw 
line – replace if needed 
 
 
x 
x 
x 
x 
x 
 
 
 
Counselling(v) 
x 
x 
x 
x 
x 
x 
x 
x 
 
X 
 
(a) Informed consent to occur and informed consent form (ICF) signed prior to any study related procedures. 
(b) Eligibility for Admission in the CTU confirmed on Day-1 after review of assessments and for Dosing on Day 1 before administration of the first dose. 
(c) MH obtained at Screening and updated on Day-1 and before dosing on Day 1. 
(d) Prior Medications include any medications used prior to first dose. Concomitant medications include any new medications taken only after initiation of first dose on Day 1. 
(e) Complete PE includes assessments described in Protocol v4.0 Section 8.1.1. It will be completed at Screening, Check-in (Day -1) and on Day 9. 
(f) Focused PE is a symptom directed PE performed as needed to assess new symptoms reported from the time of Admission on Day-1 to before the first dose, and after first dose on Day 1 to the end 
of the study to assess treatment-emergent AEs as needed, except on Day 9 when a complete PE is performed. 
(g) VS include blood pressure (BP), heart rate (HR), respiratory rate (RR) and temperature (T) and assessed resting supine at Screening, Day-1, within 30 min before and 2 h (± 10 min) after each 
dose on Days 1 to 7, and once daily in the morning on Day 8 and on Day 9, or ET (See Protocol v4.0 Section 8.1.1 and Section 8.3.1). Orthostatic blood pressure and heart rate are also assessed in 
the standing position for 1 minute ± 15 seconds and 3 minutes ± 15 seconds. NOTE: VS are taken before drawing blood for safety lab tests, plasma PK, and serum for future research if 
consented. Supine VS are taken before orthostatic BP and HR. 
(h) Serum pregnancy test at Screening and Urine pregnancy test on Day-1 (See Protocol v4.0 Section 8.1.2). 
(i) FSH to confirm menopause in women with amenorrhea of 12 or more months at Screening. 
(j) UDS screening for illicit drugs described in Protocol v4.0 Section 8.1.2 and urine alcohol test. 
(k) Urine cotinine test for nicotine use at Screening and Day-1. 
(l) HIV antibody (HIV 1 and HIV 2), Hepatitis B virus surface antigen (HBsAg) and Hepatitis C virus antibody (HCV) tests at Screening Visit (see Protocol v4.0 Section 8.1.2). 
(m) SARS-CoV-2 (Covid-19) molecular diagnostic Cue Care™ test at Check-in Visit (Day-1) (see Protocol v4.0 Section 8.1.2). 
(n) Clinical laboratory tests at Screening, Day-1, before the first (morning) dose on dosing Days 2, 4 and 6, and on Day 8, or ET. (See Protocol v4.0 Section 8.1.2 and Section 8.3.2). 


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(o) UA by dipstick at Screening, Day-1, and on Days 4 and 8, or ET. If abnormal for blood, protein, glucose and nitrites, a microscopic UA will be done. The results of microscopic UA will supersede 
the results of dipstick UA. UA will be postponed in a menstruating female (See Protocol v4.0 Section 8.1.2 and Section 8.3.2).  
(p) 12-lead ECGs at Screening, Day-1, before the morning dose on Day 4 and at Day 8 (before the 12h PK timepoint after evening dose on Day 7), unscheduled as indicated or ET (See Protocol v4.0 
Section 8.1.1 and Section 8.3.1). 
(q) Enrollment will occur on Day-1 after eligibility is confirmed. NOTE: Randomization will occur before administration of the morning dose on Day 1. 
(r) Dose administration Q12h (±15 min) for all doses following Day 1 first dose on Day 1 to Day 7. Each dose is ingested with approximately 240 mL (8 oz) or more of tap or bottled water in the 
fasted state. See Protocol v4.0 Section 6.2.5 for the duration of fast and restriction of fluid intake before and after dosing. Meals to be scheduled to accommodate dosing schedule and restrictions. 
(s) Treatment-emergent adverse events (TEAEs) and serious AEs (SAEs) will be reported and followed from the first dose (Day 1) to the last visit (Day 28 ± 2 days). (See Protocol v4.0 Section 8.5 
for AE and SAE definition, evaluation, and reporting.). NOTE: Monitoring for AEs starts upon ingestion of the first capsule on Day 1. 
(t) The interim and close-out outpatient visits on Day 15 (± 2 days), 21 (± 2 days) and 28 (± 2 days) may be conducted by phone to collect information about new AEs and SAEs and medication use 
since the previous visit. (See footnote (v) for unscheduled visits during the outpatient period)  
(u) Blood will be drawn at the following timepoints to measure the concentration of study drug and analyze PK parameters (plasma PK) and, if consented, secondary future research (serum) (See 
Protocol v4.0 Section 8.3.4). NOTE: Start recording time for PK collections after ingestion of the last capsule at each dose daily. Collect blood after measurement of VS and ECG 
recording. 
• 
On Day 1 MORNING DOSE: Within 30 min before the morning dose (t=0), and at 0.5h (±5 min), 1h (±5 min), 2h (±5 min), 4h (±5 min), 6h (±10 min), 8h (±10 min), and 12h (±15 min) 
after the morning dose. (The 12h timepoint after the morning dose on Day 1 is the same as the predose timepoint before the evening dose on Day 1). 
• 
On Day 1 EVENING DOSE: Before the evening dose (t=0), and 12h (±15 min) after the evening dose. (The 12h timepoint after the evening dose on Day 1 is the same as the predose 
timepoint before the morning dose on Day 2). 
• 
On Days 2 to 6: Within 30 min before the morning and evening doses and 12h (±15 min) after the morning and evening doses. (The PK timepoint before each dose on Days 2 to 6 is the same 
as the 12h timepoint of the previously received dose.). 
• 
On Day 7 MORNING DOSE: Within 30 min before the morning dose and at 12h (±15 min) after the morning dose. (The 12h timepoint is the same as the predose timepoint before the 
evening dose on Day 7). 
• 
On Day 7 EVENING DOSE: Within 30 min before the evening dose (t=0), and at 0.5h (±5 min), 1h (±5 min), 2h (±5 min), and 4h (±5 min) after the evening dose on Day 7. 
• 
On Day 8: At 6h (±10 min), 8h (±10 min), 12h (±15 min), and 24h (±15 min) after the evening dose on Day 7. 
• 
On Day 9: At 36h (±15 min) and 48h (-2 hours) after the evening dose on Day 7. 
(v) Participant counseled to avoid prohibited lifestyle activities and prescription and non-prescription medications and use recommended contraception methods after Screening and, if enrolled and 
dosed, for the duration of study. Before or at discharge from the in-patient phase on Day 9, participants must be counseled to use recommended contraception and avoid pregnancy for at least 30 
days after the last study dose. Male participants must be counseled to avoid donating sperm for 30 days after the last dose received in the study. 
(w) An unscheduled visit to the CTU may be initiated by study staff after each outpatient follow up by phone call for evaluation of any new AEs assessed as moderate or above or SAEs or AESIs by 
the study PI or authorized clinician. The evaluation will consist of a history of the AE, any ConMeds taken, focused PE and, as needed, clinical laboratory tests, ECG and other tests as indicated. 
Any ongoing AEs after discharge from the CTU on Day 9 may also be followed with as needed assessments during unscheduled visits. 
 
 


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Table 3: 
Laboratory Samples and Estimated Total Blood Volume (mL) 
Study Periods 
Out-patient 
In-patient 
In-patient Period (Days 1 – 9) 
 
Study Visit 
Screen 
Check-in 
Dosing 
In-patient FU 
Discharge 
ET 
Study Day a 
-28 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
HEMATOLOGY 1 
4 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
COAGULATION 1 
2.7 
2.7 
 
2.7 
 
2.7 
 
2.7 
 
2.7 
 
2.7 
CHEMISTRY 1  
8.5 
8.5 
 
8.5 
 
8.5 
 
8.5 
 
8.5 
 
8.5 
Serum β-HCG and FSH 1,2 
0 
 
 
 
 
 
 
 
 
 
 
 
Viral Serology (HIV, HBsAg, HCV) 3 
8.5 
 
 
 
 
 
 
 
 
 
 
 
PK (plasma) 4 
 
 
48 
12 
12 
12 
12 
12 
36 
24 
12 
6 
Future research (serum)5 
 
 
28 
7 
7 
7 
7 
7 
21 
14 
7 
3.5 
Total blood volume/visit 
23.7 
15.2 
76 
34.2 
19 
34.2 
19 
34.2 
57 
53.2 
19 
24.7 
Cumulative total blood volume 
23.7 
38.9 
114.9 
149.1 
168.1. 
202.3 
221.3 
255.5 
312.5 
365.7 
384.7 
 
a Study Days shown correspond to days in each study period. For a view of the cumulative numbering of study days, please refer to Protocol Section 8.1. 
1 Clinical Safety blood tests (HEM, CHEM, COAG) are drawn at Screening Visit, on Day -1, pre-dose on Days 2, 4 and 6, on Day 8, and ET if needed. The CHEM test includes serum β-HCG and 
FSH at Screening. 
2 Serum pregnancy test (β-HCG) in all women at Screening. FSH at Screening only in post-menopausal women. 
3 Viral serology tests are drawn at Screening. 
4 PK (plasma) samples (6 mL total blood per sample) are drawn on: 
• 
On Day 1: MORNING DOSE: Within 30 min before the dose (t=0), and at 0.5h (±5 min), 1h (±5 min), 2h (±5 min), 4h (±5 min), 6h (±10 min), 8h (±10 min), and 12h (±15 min) after the 
morning dose. And EVENING DOSE: Before and 12h (±15 min) after the dose.  
o 
NOTE: Starting with the Evening Dose on Day 1, the timepoint before each dose is the same as the 12h timepoint after the previous dose. 
• 
On Days 2 to 6: Within 30 min before the morning and evening doses and 12h (±15 min) after the morning and evening doses. 
• 
On Day 7 MORNING DOSE: Within 30 min before the morning dose (t=0), and at 12h (±15 min) after the morning dose. 
• 
On Day 7 EVENING DOSE: Within 30 min before the evening dose (t=0), and at 0.5h (±5 min), 1h (±5 min), 2h (±5 min), and 4h (±5 min) after the evening dose. 
• 
On Day 8: At 6h (±10 min) 8h (±10 min), 12h (±15 min), and 24h (±15 min) after the evening dose on Day 7. 
• 
On Day 9: At 36h (±15 min) and 48h (-2 hours) after the evening dose on Day 7. 
5 Future research (serum) samples (3.5 mL total blood per sample) are drawn if subject consented to their collection at the same timepoints as PK (plasma) samples from Day 1 to Day 9. 
 


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9.7.1 Sample Size 
Table 4: 
Sample Size  
Study Treatment Group 
No. of Participants 
400 mg SLV213 
6 
600 mg SLV213 (not enrolled) 
6 
800 mg SLV213 (not enrolled) 
6 
Placebo 
18 
Note: The sample size chosen was not based on statistical power considerations. 
The study was terminated prior to enrollment of 600 mg SLV213 and 800 mg SLV213 treatment groups and their associated placebo groups. 
 


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10.2 
Protocol Deviations 
Table 5: 
Distribution of Protocol Deviations by Category, Type, and Treatment Group, 
Full Analysis Population 
[Implementation Note: If no participants experienced the deviation type, then that row will be omitted. If there 
is only one deviation type within a category, then “Any type” row will be omitted. All categories should be 
present. If there are no deviation types within a category, then only the “Any type” row will be present for the 
category.] 
Category 
Deviation Type 
400 mg SLV213  
(N=X) 
Placebo 
(N=X) 
No. of 
Part. 
No. of 
Dev. 
No. of 
Part. 
No. of 
Dev. 
Major Deviation 
Eligibility/enrollment 
Any type 
 
 
 
 
Did not meet inclusion criterion 
x 
x 
x 
x 
Met exclusion criterion 
 
 
 
 
ICF not signed prior to study procedures 
 
 
 
 
Other 
 
 
 
 
Treatment administration schedule 
Any type 
 
 
 
 
Out of window visit 
 
 
 
 
Missed visit/visit not conducted 
 
 
 
 
Missed treatment administration 
 
 
 
 
Delayed treatment administration 
 
 
 
 
Other 
 
 
 
 
Follow-up visit schedule 
Any type 
 
 
 
 
Out of window visit 
 
 
 
 
Missed visit/visit not conducted 
 
 
 
 
Other 
 
 
 
 
Protocol procedure/assessment 
Any type 
 
 
 
 
Incorrect version of ICF signed 
 
 
 
 
Blood not collected 
 
 
 
 
Urine not collected 
 
 
 
 
Stool not collected 
 
 
 
 
Other specimen not collected 
 
 
 
 
Too few aliquots obtained 
 
 
 
 
Specimen result not obtained 
 
 
 
 
Required procedure not conducted 
 
 
 
 
Required procedure done incorrectly 
 
 
 
 


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Table 5: Distribution of Protocol Deviations by Category, Type, and Treatment Group (continued) 
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Category 
Deviation Type 
400 mg SLV213  
(N=X) 
Placebo 
(N=X) 
No. of 
Part. 
No. of 
Dev. 
No. of 
Part. 
No. of 
Dev. 
Study product temperature excursion 
 
 
 
 
Specimen temperature excursion 
 
 
 
 
Other 
 
 
 
 
Treatment administration 
Any type 
 
 
 
 
Required procedure done incorrectly 
 
 
 
 
Study product temperature excursion 
 
 
 
 
Other 
 
 
 
 
Blinding policy/procedure 
Any type 
 
 
 
 
Treatment unblinded 
 
 
 
 
Other 
 
 
 
 
[Repeat for Minor Deviations] 
Note: N = Number of participants randomized (Full Analysis Population). 
 


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12.2.2 Displays of Adverse Events 
Adverse events will be graded per FDA Guidance (https://www.fda.gov/media/73679/download) unless 
otherwise specified. 
Table 6: 
Adverse Event Grading Scale 
Parameter 
Grade 1/Mild 
Grade 2/Moderate 
Grade 3/Severe 
Grade 4/ 
Potentially Life-
Threatening 
Clinical adverse 
event NOT identified 
elsewhere in the 
grading table 
Mild symptoms causing 
no or minimal 
interference with usual 
social & functional 
activities with 
intervention not indicated 
Moderate symptoms 
causing greater than 
minimal interference with 
usual social & functional 
activities with 
intervention indicated 
Severe symptoms causing 
inability to perform usual 
social & functional 
activities with 
intervention or 
hospitalization indicated 
Potentially life-threatening 
symptoms causing inability 
to perform basic self-care 
functions with intervention 
indicated to prevent 
permanent impairment, 
persistent disability, or death  
The functional table below should be used to grade the severity of an AE that is not specifically identified in the grading table. In 
addition, all deaths related to an AE are to be classified as Grade 5. 
 
Table 7: 
Vital Sign Grading Scale 
Parameter 
Grade 1/Mild 
Grade 2/Moderate 
Grade 3/Severe 
Grade 4/ 
Potentially Life-
Threatening 
Supine (at rest) 
Fever1 (°C) 
 
(°F) 
38.0 – 38.4 
100.4 – 101.1 
38.5 – 38.9 
101.2 – 102.1 
39.0 – 40 
102.1 – 104 
> 40 
> 104 
Tachycardia – bpm 
101 – 115 
116-130 
> 130 
ER visit or hospitalization 
for arrhythmia 
Bradycardia2 – bpm, 
when baseline HR 60-100 bpm 
50 – 54 
45 – 49 
< 45 
ER visit or hospitalization 
for arrhythmia 
Sinus Bradycardia2 – bpm, 
when baseline HR <60 bpm 
45 – 49  
40 – 44  
<40  
Life-threatening 
consequences, urgent 
intervention indicated 
Hypertension (diastolic) – mmHg 
91 – 95 
96 – 100 
> 100 
ER visit or hospitalization 
for malignant 
hypertension 
Hypertension (systolic) – mmHg 
141 – 150 
151 – 155 
> 155 
ER visit or hospitalization 
for malignant 
hypertension 
Hypotension (systolic) – mmHg 
85 – 89 
80 – 84 
< 80 
ER visit or hospitalization 
for hypotensive shock 
Respiratory Rate – BPM 
17 – 20 
21 – 25 
> 25 
Intubation 
1 Oral temperature; no recent hot or cold beverages or smoking. 
2 Use clinical judgement when characterizing bradycardia among some healthy participant populations (e.g., conditioned athletes). 
Note: Isolated/individual abnormalities of VS would not be considered toward halting criteria. Abnormalities of VS will be described as 
“increased X” or “decreased X” (X = HR, BP, RR, temperature) if asymptomatic, transient, and not associated with a systemic or organ-specific 
disorder and coded by MedDRA within the System Organ Class (SOC) “Investigations.” These abnormalities will be graded per criteria in this 
table, but not considered in determining whether study stopping criteria have been met. On the other hand, abnormalities of VS that are either 
secondary to systemic or organ-specific clinical syndrome or primary disorders will be coded in the appropriate SOC (e.g., “cardiac disorders”, 
“respiratory disorders”, “immunological disorders”, etc.). These abnormalities will be considered in determining whether stopping criteria have 
been met. 
 


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12.4.1 Individual Laboratory Measurements and Abnormal Laboratory Values 
Table 8: 
Laboratory Adverse Event Grading Scale 
Parameter 
Grade 1/Mild 
Grade 2/Moderate 
Grade 3/Severe 
Grade 4/ 
Potentially Life-
Threatening 
Chemistry 
Sodium increase – mmol/L 
144 – 145 
146 – 147 
148 – 150 
> 150 
Sodium decrease – mmol/L 
132 – 134 
130 – 131 
125 – 129 
< 125 
Potassium increase – mmol/L 
5.1 – 5.2 
5.3 – 5.4 
5.5 – 5.6 
> 5.6 
Potassium increase – mmol/L 
3.5 – 3.6 
3.3 – 3.4 
3.1 – 3.2 
< 3.1 
Carbon Dioxide increase – mEq/L 
32.1 – 36.0 
36.1 – 40.0 
> 40.0 
Intervention indicated 
Carbon Dioxide decrease – mEq/L 
17.0 – 21.9 
14.0 – 16.9 
< 14.0 
Metabolic acidosis 
Invention indicated 
Calcium increase – mg/dL 
10.5 – 11.0 
 11.1 – 11.5 
 11.6 – 12.0 
 > 12.0 
Calcium decrease – mg/dL 
8.0 – 8.4  
7.5 – 7.9  
7.0 – 7.4  
< 7.0 
Creatinine increase – mg/dL 
1.50 – 1.79 
1.80 – 2.00 
2.01 – 2.50 
> 2.50 
BUN increase – mg/dL 
23 – 26  
27 – 31  
> 31 
Requires dialysis 
Glucose (fasting) increase – mg/dL 
100 - 110 
111 - 125 
>125 
Insulin requirements 
or hyperosmolar coma 
Glucose (fasting) decrease – mg/dL 
65 – 69 
 55 – 64  
45 – 54 
 < 45 
Total Protein decrease – g/dL 
5.5 – 6.0 
 5.0 – 5.4  
< 5.0 
 -- 
Albumin decrease – g/dL 
2.8 – 3.1 
 2.5 – 2.7  
< 2.5 
 -- 
Total Bilirubin increase – mg/dL, 
when LFT1 normal 
1.5 – 2.1  
2.2 – 2.7  
2.8 – 4.2  
> 4.2  
Total Bilirubin increase – mg/dL, 
when LFT1 increased 
1.5 – 1.6  
1.7 – 2.1  
2.2 – 2.4 
> 2.4  
Alanine Aminotransferase (SPGT/ALT) 
increase – U/L, 
female 
male 
44 – 100 
60 – 137 
101 – 200 
138 – 275 
201 – 400 
276 – 550 
> 400 
> 500 
Aspartate Aminotransferase 
(SGOT/AST) increase – U/L, 
female 
male 
38 – 87 
55 – 125 
88 – 175 
126 – 250 
176 – 350 
251 – 500 
> 350 
> 500 
Alkaline Phosphatase (ALP) increase – 
U/L, 
female 
male 
114 – 208 
141 – 258 
209 – 312 
259 – 387 
313 – 1040 
388 – 1290 
> 1040 
> 1290 
Amylase increase – U/L 
110 – 150  
151 – 200 
201 – 500 
> 500 
Lipase increase – U/L 
66 – 90 
91 – 201 
121 - 300 
> 300 
Magnesium decrease – mg/dL 
1.30 – 1.50  
1.10 – 1.29 
0.90 – 1.09  
< 0.90 
Phosphorus (inorganic) decrease – mg/dL 
2.3-2.5 
2.0 – 2.2  
1.6 – 1.9  
< 1.6 
Hematology 
Hemoglobin decrease – g/dL, 
female 
male 
11.0 – 12.0 
12.5 – 13.5 
9.5 – 10.9 
10.5 – 12.4 
8.0 – 9.4 
8.5 – 10.4 
< 8.0 
< 8.5 
Hemoglobin decrease – g/dL, 
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 


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Table 8: Laboratory Adverse Event Grading Scale (continued) 
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Parameter 
Grade 1/Mild 
Grade 2/Moderate 
Grade 3/Severe 
Grade 4/ 
Potentially Life-
Threatening 
change from baseline  
Platelets decrease – x103/µL 
125 – 140 
100 – 124 
25 – 99 
< 25 
Leukocytes (WBC) increase – x103/µL 
10.80 – 15.00 
15.01 – 20.00 
20.01 – 25.00 
> 25.00 
Leukocytes (WBC) decrease – x103/µL 
2.50 – 3.50 
1.50 – 2.49 
1.00 – 1.49 
< 1.00 
Lymphocytes decrease – x103/µL 
0.75 – 1.00 
0.50 – 0.74 
0.25 – 0.49 
< 0.25 
Monocytes increase – x103/µL 
1.01 – 2.00 
2.01 – 3.00 
> 3.00 
Intervention indicated 
Basophils increase – x103/µL 
0.16 – 0.50 
0.51 – 0.80 
> 0.80 
Intervention indicated 
Eosinophils increase – x103/µL 
0.65 – 1.50 
1.51 – 5.00 
> 5.0 
Hyper-eosinophilic 
Neutrophils decrease – x103/µL 
1.50 – 2.00 
1.00 – 1.49 
0.50 – 0.99 
< 0.50 
Coagulation 
Prothrombin Time – sec  
11.2 – 12.3 
12.4 – 13.4 
13.5 – 14.0 
> 14.0 
Activated Partial Thromboplastin Time 
(aPTT) – sec 
35.0 – 42.0 
42.1 – 49.0 
49.1 – 52.5 
> 52.5 
Urine Dipstick 
Nitrite 
1+ 
2+ 
>2+ 
 -- 
Urine Protein 
Trace  
1+  
2+ 
Hospitalization or 
dialysis 
Urine Glucose 
Trace  
1+  
2+ 
Hospitalization for 
hyperglycemia 
Urine Microscopy2 
White blood cells (WBC) per HPF 
0 – 10 
11 – 50 
> 50 or gross 
Hospitalization of 
intervention 
Red blood cells (RBC) per HPF 
1 – 10 
11 – 50 
> 50 or gross 
Hospitalization or 
packed red blood cells 
(PRBC) transfusion 
Bacteria (microscopic) 
Few 
Moderate 
Many 
Hospitalization or 
intervention 
1 Liver function tests (LFT) include ALT and AST. 
2 Urine microscopy was only performed if urine dipstick was abnormal for blood, protein, glucose, and nitrites. The results of the urine microscopy 
would supersede the results of the urine dipstick. 
 


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Table 9: 
ECG Adverse Event Grading Scale 
ECG interval abnormality 
Grade 1/Mild 
Grade 2/Moderate 
Grade 3/Severe 
Grade 4/ 
Potentially Life-
Threatening 
QTcF interval  
prolonged (msec): 
• 
Male 
• 
Female 
Asymptomatic, 
QTcF 
• 
451 – 479 msec 
• 
471 – 479 msec 
Asymptomatic, 
QTcF 480 – 500 msec 
OR 
increase in interval  
30 – 59 msec above 
baseline 
Asymptomatic, 
QTcF >500 msec 
OR 
Increase in interval  
>60 msec above 
baseline 
QTcF >500msec, 
Life threatening signs 
or symptoms (e.g., 
arrhythmia, 
hypotension, 
syncope); Torsade de 
pointes 
PR interval prolonged (msec) 
211 – 250 msec 
>250 msec 
Type II 2nd degree AV 
block 
OR 
Ventricular pause >3.0 
msec 
Urgent Intervention 
indicated 
 


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14.1 
Description of Study Participants 
14.1.1 Disposition of Participants 
Table 10: 
Participant Disposition by Treatment Group, Full Analysis Population 
Participant 
Disposition  
400 mg SLV213 
(N=X) 
Placebo 
(N=X) 
n 
% 
n 
% 
Enrolled/Randomized 
x 
100 
x 
100 
Included in Safety Population 
(Received at least One Dose of Study Product) 
x 
xx 
x 
xx 
Included in the mITT Population 
(Received at least One Dose of Study Product and Meet 
Eligibility Criteria) 
 
 
 
 
Received All Planned Doses of Study Producta 
x 
xx 
x 
xx 
Included in the PK Populationb 
(Had at least One Quantifiable Post-Dosing Plasma 
Concentration) 
 
 
 
 
Completed all PK Blood Draws 
(Study Day 1 through Study Day 9) 
 
 
 
 
Completed Follow-up 
(Study Day 28)a 
 
 
 
 
Note: A total of X participants were screened from [study start date] to [date last enrollment]. 
N = Number of participants randomized (Full Analysis Population); n = Number of participants meeting the disposition criteria. 
a Refer to Listing 2: 16.2.1 Early Terminations or Discontinued Participants for reasons participants discontinued or terminated early. 
b Refer to Listing 5: 16.2.3 Participants Excluded from Analysis for reasons participants are excluded from the analysis populations. 
 


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Table 11: 
Analysis Populations by Treatment Group, Full Analysis Population 
[Implementation Note: Participants can be counted for more than one reason. If no participants were excluded 
for the given reason, then that row will be omitted. If there is only one reason within a category, then “Any 
reason” row will be omitted. All analysis populations should be present. If there are no reasons within an 
analysis population, then only the “Any reason” row will be present for the category.] 
Analysis Populations 
Reason Participants Excluded 
400 mg SLV213  
(N=X) 
Placebo  
(N=X) 
n 
% 
n 
% 
Safety Population  
Did not receive study product 
x 
xx 
x 
xx 
mITT Population 
Any Reason 
 
 
 
 
Exclusion from Safety Population 
 
 
 
 
PK Analysis Population 
Any Reason 
 
 
 
 
Exclusion from Safety Population 
 
 
 
 
No quantifiable post-dosing plasma concentration 
 
 
 
 
Note: N = Number of participants randomized (Full Analysis Population); n = Number of participants excluded entirely from the specified analysis 
population for the given reason. 
 


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14.1.2 Demographic Data by Study Group 
Table 12: 
Summary of Categorical Demographic and Baseline Characteristics by Treatment 
Group, Full Analysis Population 
[Implementation Note: If there are no records of “Other”, “Not Reported”, “Decline to State”, and 
“Unknown”, then the characteristics will be omitted, respectively.] 
Variable 
Characteristic 
400 mg SLV213 
(N=X) 
Placebo 
(N=X) 
n 
% 
n 
% 
Sex  
Male 
x 
xx 
x 
xx 
Female 
 
 
 
 
Sex Assigned at Birth 
Male 
 
 
 
 
Female 
 
 
 
 
Intersex 
 
 
 
 
Gender Identity 
Cisgender Man 
 
 
 
 
Cisgender Woman 
 
 
 
 
Genderqueer 
 
 
 
 
Gender Non-binary 
 
 
 
 
Gender Non-conforming 
 
 
 
 
Transgender Man 
 
 
 
 
Transgender Woman 
 
 
 
 
Other 
 
 
 
 
Decline to State 
 
 
 
 
Ethnicity  
Not Hispanic or Latino 
x 
xx 
x 
xx 
Hispanic or Latino 
 
 
 
 
Not Reported 
 
 
 
 
Unknown 
 
 
 
 
Race  
American Indian or Alaska Native 
x 
xx 
x 
xx 
Asian 
 
 
 
 
Native Hawaiian or Other Pacific Islander 
 
 
 
 
Black or African American 
 
 
 
 
White 
 
 
 
 
Multi-Racial 
 
 
 
 
Unknown 
 
 
 
 
Note: N = Number of participants randomized (Full Analysis Population); n = Number of participants with the given characteristic. 
 


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Table 13: 
Summary of Continuous Demographic and Baseline Characteristics by Treatment 
Group, Full Analysis Population 
Variable 
Statistic 
400 mg SLV213 
(N=X) 
Placebo 
(N=X) 
Age (years) 
Mean (SD) 
xx.x 
xx.x 
Median 
xx.x 
xx.x 
Minimum, Maximum 
xx, xx 
xx, xx 
Weight (kg) 
Mean (SD) 
xx.xx 
xx.x 
Median 
xx.xx 
xx.x 
Minimum, Maximum 
xx.x, xx.x 
xx, xx 
Height (cm) 
Mean (SD) 
xx.xx 
xx.x 
Median 
xx.xx 
xx.x 
Minimum, Maximum 
xx.x, xx.x 
xx, xx 
BMI (kg/m2) 
Mean (SD) 
xx.xx 
xx.x 
Median 
xx.xx 
xx.x 
Minimum, Maximum 
xx.x, xx.x 
xx, xx 
Note: N = Number of participants randomized (Full Analysis Population). 
SD = Standard Deviation. 
 


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14.2 
Tolerability Data 
Table 14: 
Tolerability by Treatment Group, Safety Population 
Participants who: 
400 mg SLV213 
(N=X) 
Placebo 
(N=X) 
n 
% 
n 
% 
Terminated early or withdrawn due to TEAE related to study product 
x 
xx 
xx 
xx 
Have at least one TEAE 
 
 
 
 
Met Grade 3 abnormal criteria at least once post-dose for 
 
 
 
 
 Safety laboratory tests 
 
 
 
 
 VS measurements 
 
 
 
 
 Safety ECG parameters 
 
 
 
 
Completed all oral medication doses 
 
 
 
 
Note: N = Number of participants in the Safety Population; n = Number of participants meeting each tolerability category criteria. 
 


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14.3 
Pharmacokinetic Data 
Table 15: 
Summary Statistics for SLV213 Concentrations in Plasma, 400 mg SLV213 PK 
Population – Day 1, Morning Dose (Single Dose) 
[Implementation Note: SLV213 plasma concentrations will be summarized for Study Day 1 for 400 mg 
SLV213 treatment group. Nominal time points are t=0, 0.5, 1, 2, 4, 6, 8, and 12 hours post morning dose.] 
Statistic 
Nominal Timea (h) 
0 
0.5 
1 
2 
4 
6 
8 
12 
n 
x 
x 
x 
x 
x 
x 
x 
x 
Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
Geometric Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
CV% 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Minimum, 
Maximum 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
Note: Concentrations are reported in units of ng/mL. Time points where data was not collected are denoted by “-”. Time points 
where data was not estimable are denoted by “NE”. 
BQL values were imputed as 0 if they did not come after a PK sample concentration that is above the LLOQ. The first BQL value 
after the last PK sample concentration that is above the LLOQ is imputed as ½ LLOQ. All other BQL values are treated as 
missing. 
n = Number of data points used to compute summary statistics. 
SD = Standard Deviation; CV = Coefficient of Variance. 
a Times are relative to time of dosing. Time 0 concentrations are drawn within 30 minutes prior to dosing.  
Tables with similar format: 
Table 16: 
Summary Statistics for SLV213 Concentrations in Plasma by Sex, 400 mg SLV213 PK 
Population – Day 1, Morning Dose (Single Dose) 
[Implementation Note: Row headers will be included labeled as “Male” and “Female”.] 
 
 


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Table 17: 
Summary Statistics for SLV213 Concentrations in Plasma by Time Point and Dose, 400 
mg SLV213 PK Population – Day 1, Evening Dose to Day 7, Morning Dose 
[Implementation Note: SLV213 plasma concentrations will be summarized for each study day from Day 1 
(evening dose) to Day 7 (morning dose) for 400 mg SLV213 treatment group, and each dosing period 
(morning and evening). Nominal time points are t=0 and 12 hours post morning dose and evening dose. The 
12-hour time point is the same as the pre-dose time point of the previously received dose. Thus only t=12 
hours will be shown for each dose except for Day 1 (evening dose), which will also show t=0 hours.] 
Time Point 
Dosea 
Statistic 
 
400 mg SLV213 
(N=X) 
Day 1 
Evening (0 h) 
n 
x 
 
 
Mean (SD) 
xx.x (xx.x) 
 
 
Geometric Mean 
xx.x 
 
 
CV% 
xx.x 
 
 
Median 
xx.x 
 
 
Minimum, Maximum 
xx, xx 
 
Evening (12 h) 
n 
 
 
… 
… 
 
Day 2 
Morning (12 h) 
n 
x 
 
 
Mean (SD) 
xx.x (xx.x) 
 
 
CV% 
xx.x 
 
 
Median 
xx.x 
 
 
Minimum, Maximum 
xx, xx 
 
Evening (12 h) 
n 
x 
 
 
… 
 
Day 3 
Morning (12 h) 
n 
 
… 
… 
… 
 
Day 7 
Morning (12 h) 
n 
 
 
 
… 
 
Note: Concentrations are reported in units of ng/mL. Time points where data was not collected are denoted by “-”. Time points where data was 
not estimable are denoted by “NE”. 
BQL values were imputed as 0 if they did not come after a PK sample concentration that is above the LLOQ. The first BQL value after 
the last PK sample concentration that is above the LLOQ is imputed as ½ LLOQ. All other BQL values are treated as missing. 
n = Number of data points used to compute summary statistics. 
SD = Standard Deviation; CV = Coefficient of Variance. 
a Times are relative to time of dosing. Time 0 concentrations are drawn within 30 minutes prior to dosing. The 12-hour time point is the same as 
the pre-dose time point of the next received dose. 
 


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Tables with similar format: 
Table 18: 
Summary Statistics for SLV213 Concentrations in Plasma by Sex, Time Point, and Dose, 
400 mg SLV213 PK Population – Day 1, Evening Dose to Day 7, Morning Dose 
[Implementation Note: Row headers will be included labeled as “Male” and “Female”.] 
 


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Table 19: 
Summary Statistics for SLV213 Concentrations in Plasma, 400 mg SLV213 PK Population – Day 7, Evening Dose to Day 9 
(Multiple Doses) 
[Implementation Note: SLV213 plasma concentrations will be summarized for Study Day 7 (evening dose) for 400 mg SLV213 treatment group. 
Nominal time points are t=0, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, and 48 hours post evening dose.] 
Statistic 
Nominal Timea (h) 
0 
0.5 
1 
2 
4 
6 
12 
24 
36 
48 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
SD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
CV% 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Minimum, Maximum 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
n 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
n 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
Note: Concentrations are reported in units of ng/mL. Time points where data was not collected are denoted by “-”. Time points where data was not estimable are denoted by “NE”. BQL values were 
imputed as 0 if they did not come after a PK sample concentration that is above the LLOQ. 
The first BQL value after the last PK sample concentration that is above the LLOQ is imputed as ½ LLOQ. All other BQL values are treated as missing. 
n = Number of data points used to compute summary statistics. 
SD = Standard Deviation; CV = Coefficient of Variance. 
a Times are relative to time of dosing. Time 0 concentrations are drawn within 30 minutes prior to dosing. 
 
Tables with similar format: 
Table 20: 
Summary Statistics for SLV213 Concentrations in Plasma by Sex, 400 mg SLV213 PK Population – Day 7, Evening Dose to Day 9 
(Multiple Doses) 
[Implementation Note: Row headers will be included labeled as “Male” and “Female”.] 
 


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Table 21: 
Summary Statistics for SLV213 PK Parameters by Dose, 400 mg SLV213 PK Population 
[Implementation Note: PK parameters will only be summarized for participants with a measurable Ke at the 
specified dosing day.] 
PK Parameter (Units) 
N 
Mean (SD) 
GM (CV%) 
Median 
Minimum, 
Maximum 
Day 1, Single Dose 
Cmax (ng/mL) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
Cmax/Dose (ng/mL/mg) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
Cmin (ng/mL) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
Tmax (h) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
AUC(0-t) (ng*h/mL) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
AUC(0-∞) (ng*h/mL) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
AUC(0-12) (ng*h/mL) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
AUC(0-last) (ng*h/mL) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
AUC(0-tau) (ng*h/mL) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
AUC(0-tau)/Dose (ng*h/mL/mg) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
t1/2 (h) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
CLT (L/h) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
Ke (1/h) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
Vd (L) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
Day 7, Multiple Doses 
Cmax,ss (ng/mL) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
Cmax/Dose (ng/mL/mg) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
Cmin,ss (ng/mL) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
Cavg (ng/mL) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
RCmaxa  
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
Tmax,ss (h) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
Tmin (h) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
AUC(0-48),ss (ng*h/mL) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
AUC(0-tau),ss (ng*h/mL) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
AUC(0-tau)/Dose (ng*h/mL/mg) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
Linearity Indexb 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 


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PK Parameter (Units) 
N 
Mean (SD) 
GM (CV%) 
Median 
Minimum, 
Maximum 
RAUCc 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
t1/2 (h) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
CLT (L/h) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
Vd,ss (L) 
x 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
xx, xx 
Note: Single-dose parameters are calculated over the 12-hour period following the morning dose (Dose 1) on Day 1. Multiple-dose parameters 
are calculated over the 48-hour period following the evening dose (Dose 14) on Day 7. 
N = Number of participants with an estimable Ke for the given dose used to calculate summary statistics. 
SD = Standard Deviation; GM = Geometric Mean; CV = Coefficient of Variance. 
a RCmax is defined as the accumulation ratio for Cmax estimated as Cmax (Day 7, Evening Dose)/Cmax (Day 1, Morning Dose). 
b Linearity index is estimated as AUC(0-tau),ss (Day 7, Evening Dose)/AUC(0-∞) (Day 1, Morning Dose) 
c RAUC is defined as the accumulation ratio for AUC estimated as AUC(0-tau) (Day 7)/AUC(0-tau) (Day 1). 
 


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14.4 
Safety Data 
14.4.1 Displays of Adverse Events 
Table 22: 
Overall Summary of Adverse Events, Safety Population 
[Implementation Note: An “adverse event” includes laboratory AEs, ECG AEs, TEAEs, and other unsolicited 
AEs.] 
Participantsa with 
400 mg SLV213 
(N=X) 
Placebo 
(N=X) 
All 
Participants 
(N=X) 
n 
% 
n 
% 
n 
% 
At least one adverse event 
x 
xx 
x 
xx 
x 
xx 
At least one related adverse event 
x 
xx 
x 
xx 
x 
xx 
 
Mild (Grade 1) 
x 
xx 
x 
xx 
x 
xx 
 
Moderate (Grade 2)  
x 
xx 
x 
xx 
x 
xx 
 
Severe (Grade 3)  
x 
xx 
x 
xx 
x 
xx 
At least one severe (Grade 3) adverse event 
x 
xx 
x 
xx 
x 
xx 
 
Related  
x 
xx 
x 
xx 
x 
xx 
 
Unrelated 
x 
xx 
x 
xx 
x 
xx 
At least one serious adverse eventb 
x 
xx 
x 
xx 
x 
xx 
At least one related, serious adverse event 
x 
xx 
x 
xx 
x 
xx 
At least one adverse event leading to early terminationc  
x 
xx 
x 
xx 
x 
xx 
At least one adverse event of special interest 
 
 
 
 
 
 
At least one medically attended adverse event 
x 
xx 
x 
xx 
x 
xx 
At least one unanticipated problem 
 
 
 
 
 
 
Note: N = Number of participants in the Safety Population. 
a Participants are counted once for each category regardless of the number of events. 
b Refer to Listing of Serious Adverse Events. 
c As reported on the Adverse Event eCRF. 
 


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Table 23: 
Serious Adverse Events and Adverse Events by MedDRA System Organ Class and Preferred Term, and Treatment Group, Safety 
Population 
[Implementation Note: If there is only one PT within a given SOC, then “Any PT” row will be omitted. An “adverse event” includes laboratory AEs, 
ECG AEs, TEAEs, and other unsolicited AEs. Serious adverse events will be displayed regardless of percentage of participants.] 
MedDRA  
System Organ Class 
MedDRA  
Preferred Term 
400 mg SLV213 
(N=X) 
Placebo 
(N=X) 
All Participants 
(N=X) 
 
 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
Serious Adverse Events 
Any SOC 
Any PT 
x 
xx 
x 
x 
xx 
x 
x 
xx 
x 
[SOC 1] 
Any SOC 
x 
xx 
x 
x 
xx 
x 
x 
xx 
x 
 
[PT 1] 
x 
xx 
x 
x 
xx 
x 
x 
xx 
x 
 
[PT 2] 
x 
xx 
x 
x 
xx 
x 
x 
xx 
x 
 
… 
 
 
 
 
 
 
 
 
 
[SOC 2] 
Any SOC 
x 
xx 
x 
x 
xx 
x 
x 
xx 
x 
 
[PT 1] 
x 
xx 
x 
x 
xx 
x 
x 
xx 
x 
… 
… 
x 
xx 
x 
x 
xx 
x 
x 
xx 
x 
[Repeat for Other (non-serious) Adverse Events] 
Note: N = Number of participants in the Safety Population (number of participants at risk). 
n = Number of participants reporting event. 
Events = Total frequency of events reported. 
 


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14.3.1.2 
Treatment-Emergent Adverse Events 
Table 24: 
Summary of Treatment Emergent Adverse Events by MedDRA System Organ Class, High Level Group Term, Preferred Term, 
and Treatment Group, Safety Population 
[Implementation Note: If there is only one PT within a given SOC and HLGT, then “Any PT” row will be omitted. Similarly, if there is only one HLGT 
within a given SOC, then “Any HLGT” row will be omitted.] 
Treatment Group 
MedDRA  
System Organ Class 
MedDRA  
High Level Group Term 
MedDRA  
Preferred Term 
n (%) 
95% CIa 
Number of Events 
400 mg SLV213 (N=X) 
Any SOC 
Any HLGT 
Any PT 
x (xx) 
xx, xx 
x 
 
[SOC 1] 
Any HLGT 
Any PT 
x (xx) 
xx, xx 
x 
 
 
[HLGT 1] 
Any PT 
x (xx) 
xx, xx 
x 
 
 
 
[PT 1] 
x (xx) 
xx, xx 
x 
 
[SOC 2] 
Any HLGT 
Any PT 
x (xx) 
xx, xx 
x 
 
 
[HLGT 1] 
Any PT 
x (xx) 
xx, xx 
x 
 
 
 
[PT 1] 
x (xx) 
xx, xx 
x 
Placebo (N=X) 
… 
… 
… 
x (xx) 
xx, xx 
x 
 
… 
… 
… 
x (xx) 
xx, xx 
x 
All Participants (N=X) 
… 
… 
… 
x (xx) 
xx, xx 
x 
 
… 
… 
… 
x (xx) 
xx, xx 
x 
Note: N = Number of participants in the Safety Population in the specified treatment group. 
n = Number of participants reporting adverse events within each SOC/HLGT/PT. 
A participant is only counted once per PT. 
a Exact Clopper-Pearson Confidence Interval. 
 


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Table 25: 
Treatment Emergent Adverse Events by MedDRA System Organ Class, High Level Group Term, Preferred Term, Maximum 
Severity, Relationship, and Treatment Group, Safety Population 
[Implementation Note: If there is only one PT within a given SOC and HLGT, then “Any PT” row will be omitted. Similarly, if there is only one HLGT 
within a given SOC, then “Any HLGT” row will be omitted. Life-threatening severity will only be included as applicable. The highest severity for each 
relationship status will be reported, e.g., a participant may be counted for Mild Related and Severe Not Related for the same PT.] 
Treatment Group 
MedDRA 
System Organ Class 
MedDRA 
High Level Group Term 
MedDRA 
Preferred Term 
Severity 
Relationship to Study Treatment 
Related 
n (%) 
Not Related 
n (%) 
400 mg SLV213 (N=X) 
Any SOC 
Any HLGT 
Any PT 
Any Severity 
x (xx) 
x (xx) 
 
 
 
 
Mild 
x (xx) 
x (xx) 
 
 
 
 
Moderate 
x (xx) 
x (xx) 
 
 
 
 
Severe 
x (xx) 
x (xx) 
 
 
 
 
Life-Threatening 
x (xx) 
x (xx) 
 
[SOC 1] 
Any HLGT 
Any PT 
Any Severity 
x (xx) 
x (xx) 
 
 
 
 
… 
x (xx) 
x (xx) 
 
 
[HLGT 1] 
Any PT 
Any Severity 
x (xx) 
x (xx) 
 
 
 
 
… 
x (xx) 
x (xx) 
 
 
 
[PT 1] 
Any Severity 
x (xx) 
x (xx) 
 
 
 
 
… 
x (xx) 
x (xx) 
Placebo (N=X) 
… 
… 
… 
 
x (xx) 
x (xx) 
 
… 
… 
… 
 
x (xx) 
x (xx) 
All Participants (N=X) 
… 
… 
… 
 
x (xx) 
x (xx) 
 
… 
… 
… 
 
x (xx) 
x (xx) 
Note: N = Number of participants in the Safety Population in the specified treatment group. 
n = Number of participants reporting adverse events within each SOC/HLGT/PT with the specified maximum severity. 
A participant is only counted once per PT. A participant highest reported severity for each relationship to study treatment is reported. 
 


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14.3.2 Listing of Deaths, Other Serious and Significant Adverse Events 
Table 26: 
Listing of Serious Adverse Events 
[Implementation Note: If the event is ongoing (i.e., no stop date), indicate “ongoing” for “Duration”. If there are no comments, then indicate “None” for 
“Comments”. Listing should be sorted by Treatment Group, Participant ID, and AE Number.] 
Adverse 
Event 
Associated 
with Dose 
No. 
No. of 
Days Post 
Associated 
Dose 
(Duration) 
No. of 
Days Post 
Dose the 
Event 
Became 
Serious 
Reason 
Reported 
as an 
SAE 
Severity 
Relationship 
to Study 
Treatment 
If Not 
Related, 
Alternative 
Etiology 
Action 
Taken 
with Study 
Treatment 
Participant 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System 
Organ 
Class 
MedDRA 
High 
Level 
Group 
Term 
MedDRA 
Preferred 
Term 
Treatment Group: , Participant ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
Treatment Group: , Participant ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 


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Table 27: 
Listing of Non-Serious, Unsolicited, Moderate or Greater Severity Adverse Events 
[Implementation Note: If the event is ongoing (i.e., no stop date), indicate “ongoing” for “Duration”. If there are no comments, then indicate “None” for 
“Comments”. Listing should be sorted by Treatment Group, Participant ID, and AE Number.] 
Adverse 
Event 
Associated 
with Dose 
No. 
No. of 
Days Post 
Associated 
Dose 
(Duration) 
Severity 
Relationship 
to Study 
Treatment 
If Not 
Related, 
Alternative 
Etiology 
Action 
Taken 
with 
Study 
Treatment 
Participant 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System Organ 
Class 
MedDRA High 
Level Group 
Term 
MedDRA 
Preferred Term 
Treatment Group: , Participant ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
Treatment Group: , Participant ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 


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Table 28: 
Listing of Adverse Events of Special Interest, Medically Attended Adverse Events, and Unanticipated Problems 
[Implementation Note: This table is for any AESIs, MAAEs, and UPs. If the event is ongoing (i.e., no stop date), indicate “ongoing” for “Duration of 
Event”. If there are no comments, then indicate “None” for “Comments”. Listing should be sorted by Treatment Group, Participant ID, and AE Number.] 
Adverse Event 
Associated 
with Dose No. 
No. of Days 
Post 
Associated 
Dose  
Duration of 
Event 
Severity 
MedDRA 
System Organ 
Class 
AESI? 
MAAE? 
UP? 
Relationship 
Outcome 
Treatment Group: , Participant ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
Comments: 
Treatment Group: , Participant ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 


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14.3.3 Narratives of Deaths, Other Serious and Significant Adverse Events 
(not included in SAP, but this is a placeholder for the CSR) 
 


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14.3.4 Abnormal Laboratory Value Listings (by Participant) 
Table 29: 
Listing of Abnormal Laboratory Results – Chemistry 
[Implementation Note: This listing is for any chemistry lab result outside of normal range, including ONRs and graded events. Listing will be sorted by 
Treatment Group, Participant ID, Laboratory Parameter, and Planned Time Point. Refer to Section 9.6 for parameter sort order.] 
Treatment 
Group 
Participant 
ID 
Sex 
Age 
(years) 
Planned 
Time Point 
Actual 
Study Day 
Laboratory 
Parameter 
(Units) 
Result 
(Severity) 
Relationship to 
Treatment 
If Not Related, 
Alternate 
Etiology 
Action Taken 
with Study 
Treatment 
Participant 
Discontinued Due 
to Result? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 30: 
Listing of Abnormal Laboratory Results – Hematology 
[Implementation Note: This listing is for any hematology lab result outside of normal range, including ONRs and graded events. Listing will be sorted by 
Treatment Group, Participant ID, Laboratory Parameter, and Planned Time Point. Refer to Section 9.6 for parameter sort order.] 
Treatment 
Group 
Participant 
ID 
Sex 
Age 
(years) 
Planned 
Time Point 
Actual 
Study Day 
Laboratory 
Parameter 
(Units) 
Result 
(Severity) 
Relationship to 
Treatment 
If Not Related, 
Alternate 
Etiology 
Action Taken 
with Study 
Treatment 
Participant 
Discontinued Due 
to Result? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 31: 
Listing of Abnormal Laboratory Results – Coagulation 
[Implementation Note: This listing is for any coagulation lab result outside of normal range, including ONRs and graded events. Listing will be sorted by 
Treatment Group, Participant ID, Laboratory Parameter, and Planned Time Point. Refer to Section 9.6 for parameter sort order.] 
Treatment 
Group 
Participant 
ID 
Sex 
Age 
(years) 
Planned 
Time Point 
Actual 
Study Day 
Laboratory 
Parameter 
(Units) 
Result 
(Severity) 
Relationship to 
Treatment 
If Not Related, 
Alternate 
Etiology 
Action Taken 
with Study 
Treatment 
Participant 
Discontinued Due 
to Result? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 32: 
Listing of Abnormal Laboratory Results – Urinalysis 
[Implementation Note: This listing is for any urinalysis lab result outside of normal range, including ONRs and graded events. Listing will be sorted by 
Treatment Group, Participant ID, Laboratory Parameter, and Planned Time Point. Refer to Section 9.6 for parameter sort order.] 
Treatment 
Group 
Participant 
ID 
Sex 
Age 
(years) 
Planned 
Time Point 
Actual 
Study Day 
Laboratory 
Parameter 
(Units) 
Result 
(Severity) 
Relationship to 
Treatment 
If Not Related, 
Alternate 
Etiology 
Action Taken 
with Study 
Treatment 
Participant 
Discontinued Due 
to Result? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14.3.5 Displays of Laboratory Results 
14.3.5.1 
Chemistry Results 
Table 33: 
Chemistry Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Group, Safety Population 
[Implementation Note: Chemistry results will be presented for Check-In (Day -1)(baseline), 2, 4, 6, and 8 and for each treatment group. 
If there are no life-threatening/grade 4 chemistry results reported, then the rows will be omitted. If there is not at least one graded event for a treatment 
group within a parameter, then only “None” row will be shown. If there are more than one graded event within a parameter for a specified time point, 
then report the maximum severity. 
If the grade is zero counts, then populate the cell with “-”. 
Parameters will be shown in the following order: Any Chemistry Parameter, Sodium, Potassium, Total Carbon Dioxide, Calcium, Creatinine, Blood 
Urea Nitrogen, Fasting Glucose, Total Protein, Albumin, Total Bilirubin, Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, 
Amylase, Lipase, Magnesium, and Inorganic Phosphorus. 
Parameters will specify increase or decrease. If a parameter can both increase and decrease, then the parameter decrease will be listed first. 
The following parameters may decrease: Sodium, Potassium, Total Carbon Dioxide, Calcium, Total Protein, Albumin, Magnesium, and Inorganic 
Phosphorus. 
The following parameters may increase: Sodium, Potassium, Total Carbon Dioxide, Calcium, Creatinine, Blood Urea Nitrogen, Fasting Glucose, Total 
Bilirubin, Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, Amylase, and Lipase.] 
Severity 
Treatment Group 
 
Day -1 
(Baseline) 
Day 2 
Day 4 
Day 6 
Day 8 
Any Time  
Post Baseline 
n/N 
% 
n/N 
% 
n/N 
% 
n/N 
% 
n/N 
% 
n/N 
% 
Any Chemistry Parameter 
None 
400 mg SLV213 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
x/x 
xx 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
All Participants 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
 


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Severity 
Treatment Group 
 
Day -1 
(Baseline) 
Day 2 
Day 4 
Day 6 
Day 8 
Any Time  
Post Baseline 
n/N 
% 
n/N 
% 
n/N 
% 
n/N 
% 
n/N 
% 
n/N 
% 
Moderate 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Life-Threatening 
400 mg SLV213 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Sodium, Decrease 
None 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Mild 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate 
400 mg SLV213 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Severe 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Life-Threatening 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 33: Chemistry Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Group, Safety Population (continued) 
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Severity 
Treatment Group 
 
Day -1 
(Baseline) 
Day 2 
Day 4 
Day 6 
Day 8 
Any Time  
Post Baseline 
n/N 
% 
n/N 
% 
n/N 
% 
n/N 
% 
n/N 
% 
n/N 
% 
Sodium, Increase 
None 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
 
[Repeat for each chemistry parameter] 
Note: The “Any Time Post Baseline” column indicates the maximum severity experienced by each participant at any time point post baseline, including unscheduled assessments. 
Abnormal laboratory events were only considered an adverse event if the graded severity worsened from baseline. 
N = Number of participants in the Safety Population with the laboratory result assessed at the respective time point; n = Number of participants with the maximum grade experienced 
for the specified parameter and time point. 
 


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14.3.5.2 
Hematology Results 
Table 34: 
Hematology Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Group, Safety Population  
[Implementation Note: This table will be a similar format to Table 33. 
Parameters will be shown in the following order: Any Hematology Parameter, Hemoglobin, Platelets, White Blood Cells, Neutrophils, Lymphocytes, 
Monocytes, Basophils, and Eosinophils. 
The following parameters may decrease: Hemoglobin, Platelets, White Blood Cells, Neutrophils, and Lymphocytes. 
The following parameters may increase: Hemoglobin, White Blood Cells, Monocytes, Basophils, and Eosinophils.] 
 


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14.3.5.2 
Coagulation Results 
Table 35: 
Coagulation Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Group, Safety Population  
[Implementation Note: This table will be a similar format to Table 33. 
Parameters will be shown in the following order: Any Coagulation Parameter, Prothrombin Time, and Activated Partial Thromboplastin Time (aPTT).] 
 


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14.3.5.3 
Urinalysis Results 
Table 36: 
Urinalysis Laboratory Results by Parameter, Maximum Severity, Time Point, and Treatment Group, Safety Population  
[Implementation Note: This table will be a similar format to Table 33. Urinalysis will be presented for Days -1 (baseline), 4, and 8 and for each 
treatment group. Headers will not be split into Low and High, e.g., “Mild/Grade 1”. 
Parameters will be shown in the following order: Any Urinalysis Parameter, Bilirubin, Nitrite, Urine Protein, Urine Glucose, White Blood Cell Count, 
Red Blood Cell Count, and Bacteria. 
Urine microscopy parameters (WBC Count, RBC Count, and Bacteria) were only collected conditionally and thus will only be included if at least 
5 participants reported a graded event. Otherwise refer to Table 32.] 
 


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14.3.6 Displays of Vital Signs 
Table 37: 
Supine Vital Signs by Assessment, Maximum Severity, Time Point, and Treatment Group, Safety Population 
[Implementation Note: Vital signs will be presented for Days 1 (pre-dose 1)(baseline) through Day 9 for each treatment group. Dosing days (Days 1 
through 7) will be separated by pre- and post- Morning and Evening dose. Follow-up assessments and Maximum Post Baseline will be Any Time. 
If there are no life-threatening/grade 4 vital signs reported, then the columns will be omitted. If there is not at least one graded event for a treatment 
group within a parameter, then only “Max Severity Post Baseline” will be shown. If there are more than one graded event within a parameter for a 
specified time point, then report the maximum severity. 
For grading not applicable to the specified parameter, then populate the cell with “N/A”. Otherwise, if the grade is zero counts, then populate the cell 
with “-”. Assessments will be shown in the following order: Any Vital Sign Assessment, Oral Temperature, Systolic Blood Pressure, Diastolic Blood 
Pressure, Pulse, and Respiratory Rate. 
Assessments will specify low or high. If an assessment can be both high and low, then the low assessment will be listed first. 
The following assessments may be low: Systolic Blood Pressure, Diastolic Blood Pressure, and Pulse. 
All assessments may be high.] 
Time Point 
Dose 
Treatment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Life-Threatening/ 
Grade 4 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any Vital Sign Assessment 
Day 1 
Pre-Morning (Baseline) 
400 mg SLV213 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
All Participants 
 
 
 
 
 
 
 
 
 
 
 
 
Post-Morning 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-Evening 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Post-Evening 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 


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Time Point 
Dose 
Treatment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Life-Threatening/ 
Grade 4 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 2 
Pre-Morning 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Post-Morning 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-Evening 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Post-Evening 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
… 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
Day 8 
N/A 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Day 9 
N/A 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Max Severity Post 
Baseline 
Any Time 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Oral Temperature 
Day 1 
Pre-Morning (Baseline) 
400 mg SLV213 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
Day 9 
N/A 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 


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Table 37: Supine Vital Signs by Assessment, Maximum Severity, Time Point, and Treatment Group, Safety Population (continued) 
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Time Point 
Dose 
Treatment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Life-Threatening/ 
Grade 4 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Max Severity Post 
Baseline 
Any Time 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Systolic Blood Pressure, Low 
Day 1 
Pre-Morning (Baseline) 
400 mg SLV213 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
Day 9 
N/A  
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Max Severity Post 
Baseline 
Any Time 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
[Repeat for all vital sign assessments] 
Note: The “Max Severity Post Baseline” rows indicate the maximum severity experienced by each participant at any time point post baseline, including unscheduled assessments. 
N = Number of participants in the Safety Population with the laboratory result assessed at the respective time point; n = Number of participants with the maximum grade experienced 
for the specified assessment and time point. 
Vital signs were collected prior to and after each dose (morning and evening) on Days 1 through Day 9 and collected in the morning during follow-up visits (Day 8 and Day 9). 
 


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14.3.7 Displays of 12-Lead Standard Electrocardiograms 
Table 38: 
Summary of Post Dose Electrocardiograms Change in Overall Interpretations from 
Baseline by Treatment Group and Time Point, Safety Population 
Change from Baseline in ECG Interpretation 
400 mg SLV213 
(N=X) 
Placebo 
(N=X) 
All Participants 
(N=X) 
n 
% 
n 
% 
n 
% 
Day 4 
Normal at Both Times 
x 
xx 
x 
xx 
x 
xx 
Normal to Abnormal, NCS 
 
 
 
 
 
 
Normal to Abnormal, CS 
 
 
 
 
 
 
Day 8 
Normal at Both Times 
x 
xx 
x 
xx 
x 
xx 
Normal to Abnormal, NCS 
 
 
 
 
 
 
Normal to Abnormal, CS 
 
 
 
 
 
 
Note: N = Number of participants in the Safety Population with ECG measurements; n = Number of participants with the change from baseline 
interpretations. 
NCS = Not clinically significant; CS = Clinically significant. 
 


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Table 39: 
ECG Results by Parameter, Severity, Treatment Group, and Time Point, Safety Population 
[Implementation Note: ECGs will be presented for Days -1 (baseline), 4, and 8 for each treatment group. 
If there are no life-threatening/grade 4 vital signs reported, then the columns will be omitted. If there is not at least one graded event for a treatment 
group within a parameter, then only “Max Severity Post Baseline” will be shown. If there are more than one graded event within a parameter for a 
specified time point, then report the maximum severity. 
Parameters will be shown in the following order: Any ECG Parameter, PR Interval, and QTcF Interval.] 
Time Point 
Treatment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Life-Threatening/ 
Grade 4 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any ECG Parameter 
Day -1 (Baseline) 
400 mg SLV213 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
All Participants 
 
 
 
 
 
 
 
 
 
 
 
Day 4 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Day 8 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Max Severity Post Baseline 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PR Interval  
Day -1 (Baseline) 
400 mg SLV213 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
All Participants 
 
 
 
 
 
 
 
 
 
 
 
Day 4 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 


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Table 39: ECG Results by Parameter, Severity, Treatment Group, and Time Point, Safety Population (continued) 
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Time Point 
Treatment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Life-Threatening/ 
Grade 4 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 8 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Max Severity Post Baseline 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QTcF Interval  
Day -1 (Baseline) 
400 mg SLV213 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Day 4 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Day 8 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Max Severity Post Baseline 
400 mg SLV213 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each participant at any time point post baseline, including unscheduled assessments. 
N = Number of participants in the Safety Population with the laboratory result assessed at the respective time point; n = Number of participants with the maximum grade experienced for the specified 
parameter and time point. 
 


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APPENDIX 2. FIGURE MOCK-UPS 
 
LIST OF FIGURES 
Figure 1: 
Schematic of Study Design .........................................................................................................99 
Figure 2: 
CONSORT Flow Diagram ........................................................................................................100 
Figure 3: 
Individual SLV213 Concentration in Plasma Profiles – Day 1, Morning Dose .......................101 
Figure 4: 
Individual SLV213 Concentration in Plasma Profiles – Day 7, Evening Dose ........................101 
Figure 5: 
Individual Trough SLV213 Concentration in Plasma Profiles – Day 1 to Day 7, All Doses ...101 
Figure 6: 
Semi-Log Individual SLV213 Concentration in Plasma Profiles – Day 1, Morning Dose ......102 
Figure 7: 
Semi-Log Individual SLV213 Concentration in Plasma Profiles – Day 7, Evening Dose.......102 
Figure 8: 
Semi-Log Trough SLV213 Concentration in Plasma Profiles – Day 1 to Day 7, All Doses ...102 
Figure 9: 
Frequency of Related Adverse Events by MedDRA System Organ Class and Severity ..........103 
Figure 10: 
Incidence of Related Adverse Events by MedDRA System Organ Class and Maximum 
Severity .....................................................................................................................................104 
 
 


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9.5.1 Safety Measurements Assessed and Flow Chart 
Figure 1: 
Schematic of Study Design 
[Implementation Note: Pulled from Protocol v4.0 Section 1.3.] 
 
 
Consent
Screening
Study Start, Randomization/Enrollment
By Cohort
• Study Identification Number assigned
• Collection of baseline data/labs
Cohort #1
• Placebo (n=4)
• SLV213 400mg PO Q12 hours (n=8)
Cohort #2
• Placebo (n=4)
• SLV213 600mg PO Q12 hours (n=8)
Cohort #3
• Placebo (n=4)
• SLV213 800mg PO Q12 hours (n=8)
SRC Review
SRC Review
SMC Review


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10.1 
Disposition of Participants 
Figure 2: 
CONSORT Flow Diagram 
[Implementation Note: Treatment groups will be 400 mg SLV213 and Placebo. “Reasons for Exclusion” and the associated footnote will only be listed if 
at least one participant was excluded from the specified population for the specified reason in the given treatment group. ‘x’ will be replaced with the 
number of participants that meet the criteria. If any participants received the incorrect dose at any point in time, a footnote will be attached to 
“Completed all dosesa” of the given treatment group and the following footnote will be added: “a X participants received at least one incorrect dose.” The 
asterisks will be updated to footnote (b), if applicable. A footnote will be added before footnotes (a) and (b): “Note: The study was terminated prior to 
enrollment to Cohorts 2 (600 mg SLV213) and 3 (800 mg SLV213).”] 
 


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14.2.2 
Pharmacokinetics 
Figure 3: 
Individual SLV213 Concentration in Plasma Profiles – Day 1, Morning Dose 
[Implementation Note: The figure will consist of individual concentrations at each nominal time point: t=0 
(pre-dose), 1h, 2h, 4h, 6h, 8h, and 12h. The y-axis will be labeled “Concentration in Plasma (ng/mL)” with 
the maximum concentration as the max and the minimum concentration as the min. The x-axis will be labeled 
“Time (h)” with tick marks at each nominal time point. Data points should represent actual time of 
collection.] 
 
Figures with similar format: 
Figure 4: 
Individual SLV213 Concentration in Plasma Profiles – Day 7, Evening Dose 
[Implementation Note: Dose 14 nominal time points are t=0 (pre-dose), 1h, 2h, 4h, 6h, 8h, 12h, 24h, 36h, and 
48h.] 
Figure 5: 
Individual Trough SLV213 Concentration in Plasma Profiles – Day 1 to Day 7, All Doses 
[Implementation Note: Trough concentrations are defined as concentrations collected 12 hours after each 
morning and evening dose. Note, 12 hours post dose will also be considered as t=0 (pre-dose) for the 
proceeding dose. The x-axis label will be “Doses” with a tick mark for each dose number.] 
 


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Figure 6: 
Semi-Log Individual SLV213 Concentration in Plasma Profiles – Day 1, Morning Dose 
[Implementation Note: The figure will consist of individual concentrations at each nominal time point: t=0 
(pre-dose), 1h, 2h, 4h, 6h, 8h, and 12h. The y-axis will be in the log-10 scale and labeled “Concentration in 
Plasma (ng/mL)” with the maximum concentration as the max and the minimum concentration as the min. 
The x-axis will be labeled “Time (h)” with tick marks at each nominal time point. Data points should 
represent actual time of collection.] 
 
Figures with similar format: 
Figure 7: 
Semi-Log Individual SLV213 Concentration in Plasma Profiles – Day 7, Evening Dose 
[Implementation Note: Dose 14 nominal time points are t=0 (pre-dose), 1h, 2h, 4h, 6h, 8h, 12h, 24h, 36h, and 
48h.] 
Figure 8: 
Semi-Log Trough SLV213 Concentration in Plasma Profiles – Day 1 to Day 7, All Doses 
[Implementation Note: Trough concentrations are defined as concentrations collected 12 hours after each 
morning and evening dose. Note, 12 hours post dose will also be considered as t=0 (pre-dose) for the 
proceeding dose. The x-axis label will be “Doses” with a tick mark for each dose number.] 
 


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14.3.1.2 Unsolicited Adverse Events 
Figure 9: 
Frequency of Related Adverse Events by MedDRA System Organ Class and Severity 
[Implementation Note: This figure will include serious and non-serious unsolicited adverse events deemed 
related to the study product. It will be paneled by treatment group: 400 mg SLV213 and Placebo. The SOCs 
will be sorted by descending frequency with “Any SOC” at the top.] 
 
 


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Figure 10: 
Incidence of Related Adverse Events by MedDRA System Organ Class and Maximum 
Severity 
[Implementation Note: This figure will include serious and non-serious unsolicited adverse events deemed 
related to the study product. It will be paneled by treatment group: 400 mg SLV213 and Placebo. The SOCs 
will be sorted by descending incidence with “Any SOC” at the top.] 
 
 


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APPENDIX 3. LISTINGS MOCK-UPS 
 
LISTINGS 
Listing 1: 
16.1.6: Listing of Participants Receiving Investigational Product ...........................................106 
Listing 2: 
16.2.1: Early Terminations or Discontinued Participants .........................................................107 
Listing 3: 
16.2.2.1: Participant-Specific Protocol Deviations ...................................................................108 
Listing 4: 
16.2.2.2: Non-Participant-Specific Protocol Deviations...........................................................109 
Listing 5: 
16.2.3: Participants Excluded from Analysis Populations ........................................................110 
Listing 6: 
16.2.4.1: Demographic Data .....................................................................................................111 
Listing 7: 
16.2.4.2: Pre-Existing and Concurrent Medical Conditions .....................................................112 
Listing 8: 
16.2.5: Compliance Data...........................................................................................................113 
Listing 9: 
16.2.6.1: Participant-Level SLV213 Concentrations in Plasma ...............................................114 
Listing 10: 16.2.6.2: Participant-Specific Single-Dose SLV213 Plasma PK Parameters ...........................115 
Listing 11: 16.2.6.3: Participant-Specific Multiple-Dose SLV213 Plasma PK Parameters .......................116 
Listing 12: 16.2.7.3: Treatment Emergent Adverse Events ........................................................................117 
Listing 13: 16.2.8.1: Clinical Laboratory Results – Chemistry...................................................................118 
Listing 14: 16.2.8.2: Clinical Laboratory Results – Hematology ...............................................................118 
Listing 15: 16.2.8.2: Clinical Laboratory Results – Coagulation ................................................................118 
Listing 16: 16.2.8.3: Clinical Laboratory Results – Urinalysis ...................................................................118 
Listing 17: 16.2.9.1: Vital Signs..................................................................................................................119 
Listing 18: 16.2.9.2: Abnormal Physical Exam Findings ...........................................................................120 
Listing 19: 16.2.10: Electrocardiogram Interval Measurements .................................................................121 
Listing 20: 16.2.10: Electrocardiogram Overall Interpretations and Comments ........................................122 
Listing 21: 16.2.11: Concomitant Medications ...........................................................................................123 
Listing 22: 16.2.12.1: Pregnancy Reports – Maternal Information.............................................................124 
Listing 23: 16.2.12.2: Pregnancy Reports – Gravida and Para ...................................................................124 
Listing 24: 16.2.12.3: Pregnancy Reports – Live Birth Outcomes .............................................................125 
Listing 25: 16.2.12.4: Pregnancy Reports – Still Birth Outcomes ..............................................................125 
Listing 26: 16.2.12.5: Pregnancy Reports – Spontaneous, Elective, or Therapeutic Abortion Outcomes .125 
 


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Listing 1: 
16.1.6: Listing of Participants Receiving Investigational Product 
[Implementation Note: Listing will be sorted by Treatment Group, Participant ID, Date, and Time.] 
Treatment Group 
Participant ID 
Study Day 
(Dose) 
Date 
Time 
 
 
Day 1 (Morning) 
ddMMMyyyy 
hh:mm 
 
 
 
 
 
 


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16.2 
Database Listings by Participant 
16.2.1 Discontinued Participant 
Listing 2: 
16.2.1: Early Terminations or Discontinued Participants 
[Implementation Note: Listing will be sorted by Treatment Group, Participant ID, Category, and Study Day.] 
Treatment Group 
 Participant ID 
Category 
Reason for Early Termination or Treatment Discontinuation 
Study Day 
 
 
 
 
 
 
 


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16.2.2 Protocol Deviations 
Listing 3: 
16.2.2.1: Participant-Specific Protocol Deviations 
[Implementation Note: Listing will be sorted by Treatment Group, Participant ID, and DV Number.] 
Treatment 
Group 
Participant 
ID 
DV Number 
Deviation 
Deviation 
Category 
Study 
Day 
Reason for 
Deviation 
Deviation 
Resulted 
in AE? 
Deviation 
Resulted in 
Participant 
Termination? 
Deviation 
Affected 
Product 
Stability? 
Deviation 
Classification 
Deviation 
Resolution 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 4: 
16.2.2.2: Non-Participant-Specific Protocol Deviations 
[Implementation Note: Listing will be sorted by Site, Start Date, and Deviation.] 
DV 
Number 
Deviation 
Deviation 
Category 
Start Date 
End Date 
Reason for 
Deviation 
Deviation 
Resulted in 
Participant 
Termination? 
Deviation 
Affected 
Product 
Stability? 
Deviation 
Classification 
Deviation 
Resolution 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.3 Participants Excluded from the Safety and/or PK Analysis 
Listing 5: 
16.2.3: Participants Excluded from Analysis Populations 
[Implementation Note: This listing should be congruent with “Analysis Populations by Treatment Group” (Table 11). Only participants who were 
excluded from at least one analysis population will be included in this listing. Participants who were excluded from multiple analysis populations will 
have a separate line per analysis population excluded from in the listing. 
Listing will be sorted by Treatment Group, Participant ID, Analyses Included, and Analyses Excluded.] 
Treatment Group 
Participant ID 
Analyses in which 
Participant is Included 
Analyses from which  
Participant is Excluded 
Results Available? 
Reason Participant Excluded 
 
 
[e.g., Full Analysis, Safety, mITT, 
PK] 
[e.g., Safety, mITT, PK (All Visits)] 
 
Safety: Did not receive study 
product 
mITT, PK: Excluded from Safety 
Population 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: “Yes” in the “Results available” column indicates that available data were removed from the analysis. “No” indicates that no data were available for inclusion in the analysis. 
 


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16.2.4 Demographic Data 
Listing 6: 
16.2.4.1: Demographic Data 
[Implementation Note: If the participant is multi-racial, in the “Race” column, note “Multiple: (list races, separated by a comma).” 
Listing will be sorted by Treatment Group and Participant ID.] 
Treatment 
Group 
Participant ID 
Sex 
Sex Assigned at 
Birth 
Gender 
Ethnicity 
Race 
Age 
 (years) 
Weight 
(kg) 
Height 
(cm) 
BMI 
(kg/m2) 
 
 
Male 
 
Man/Cisgender 
Man 
Not Hispanic or 
Latino 
Multiple: Asian, 
White 
20 
85.5 
180.1 
26.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 7: 
16.2.4.2: Pre-Existing and Concurrent Medical Conditions 
[Implementation Note: “Condition Start Day” and “Condition End Day” are relative to enrollment (which is Day 1, day before enrollment is Day -1). 
Rather than use exact study days, categorize as follows: 
• 5 years prior to enrollment 
• 1-5 years prior to enrollment 
• 1-12 months prior to enrollment 
• Within 1 month of enrollment 
• During study 
• If ongoing, display “Ongoing” in the “Condition End Day” column 
It may be appropriate to add another category, based on exclusion criteria that restrict conditions within a particular time period (e.g., within 3 years prior 
to enrollment). 
Listing will be sorted by Treatment Group, Participant ID, and MH Number.] 
Treatment 
Group 
 Participant 
ID 
MH Number 
Medical History Term 
Condition Start Day  
Condition End Day 
MedDRA System Organ Class 
MedDRA Preferred Term 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.5 Compliance and/or Drug Concentration Data (if available) 
Listing 8: 
16.2.5: Compliance Data 
[Implementation Note: Only participants who missed at least one dose will be included in this listing. Each dose missed will be its own row. If no 
reason/comment was provided for the dose being missed, then fill “Reasons for Missing” with “Reason not given”. 
Listing will be sorted by Treatment Group and Participant ID.] 
Treatment Group  
Participant ID  
Dose Missed 
Reasons for Missing 
 
 
[e.g., Day 3, Day 3 (Morning), etc.] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.6 Pharmacokinetics 
Listing 9: 
16.2.6.1: 
Participant-Level SLV213 Concentrations in Plasma 
[Implementation Note: Units of nominal time and actual time may vary by time point and will be provided for each time rather than in the column 
header. “Laboratory Reported Concentrations” will give the verbatim value reported by the lab (with minimal formatting, as needed) and will use the 
character value such as PC.PCORRES. “Analysis Concentrations” will report the value actually used for analysis and will use a numeric variable such as 
ADNCA.AVAL. If one or more samples are excluded from NCA, two additional columns will be provided in the PK report listing: “Excluded from 
NCA (Yes/No)” and “Reason for Exclusion from NCA”. 
In the actual time column, mark out-of-window times with one asterisk (*), substantially out of window visits with two asterisks (**), and imputed times 
with three asterisks (***). If there are no out-of-window times or imputed values, remove their respective footnotes. 
Listing will be sorted by Treatment Group, Participant ID, Study Day, and Nominal Time.] 
Treatment Group 
Participant ID 
Study Day 
(Dose) 
Nominal Time 
Actual Time 
Laboratory Reported 
Concentrations (ng/mL) 
Analysis Concentrations 
(ng/mL) 
 
 
Day 1 
(Morning) 
0 
0 
0 
0 
 
 
Day 1 
(Morning) 
30M 
28M 
BQL 
0 
 
 
Day 1 
(Morning) 
1H 
1H 12M* 
207 
207 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Out-of-window collection time. 
**Substantially out-of-window collection time. 
***Imputed time. 
 


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Listing 10: 
16.2.6.2: 
Participant-Specific Single-Dose SLV213 Plasma PK Parameters 
[Implementation Note: This listing will include all estimable PK parameters regardless of Ke. Listing will be sorted by Treatment Group and Participant 
ID.] 
Treatment 
Group 
Participant 
ID 
Cmax 
(ng/mL) 
Cmax/Dose 
(ng/mL/mg) 
Cmin 
(ng/mL) 
Tmax 
(h) 
Tmin 
(h) 
AUC(0-t) 
(ng*h/mL) 
AUC(0-∞) 
(ng*h/mL) 
AUC(0-12) 
(ng*h/mL) 
AUC(0-last) 
(ng*h/mL) 
AUC(0-tau) 
(ng*h/mL) 
AUC(0-tau)/Dose 
(ng*h/mL)/mg) 
t1/2 
(h) 
CLT 
(L/h) 
Ke 
(1/h) 
Vd 
(L) 
  
  
  
  
  
 
 
  
  
 
 
 
 
  
  
  
  
  
  
  
  
  
 
 
  
  
 
 
 
 
  
  
  
  
  
  
  
  
  
 
 
  
  
 
 
 
 
  
  
  
  
  
  
  
  
  
 
 
  
  
 
 
 
 
  
  
  
  
 


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Listing 11: 
16.2.6.3: Participant-Specific Multiple-Dose SLV213 Plasma PK Parameters 
[Implementation Note: This listing will include all estimable PK parameters regardless of Ke. Listing will be sorted by Treatment Group and Participant 
ID.] 
Treatment 
Group 
Participant 
ID 
Cmax,ss 
(ng/mL) 
Cmax,ss/ 
Dose 
(ng/mL)/ 
mg) 
Cmin,ss 
(ng/mL) 
Cavg 
(ng/mL) 
Tmax,ss 
(h) 
Tmin 
(h) 
AUC(0-48),ss 
(ng*h/ 
mL) 
AUC(0-tau),ss 
(ng*h/ 
mL) 
AUC(0-tau),ss/ 
Dose 
(ng*h/mL)/ 
mg) 
t1/2 
(h) 
CLT 
(L/h) 
Ke 
(1/h) 
Vd,ss 
(L) 
Linearity 
Index 
RAUC 
RCmax 
  
  
  
  
  
 
  
  
 
 
 
 
  
 
  
  
 
  
  
  
  
  
  
 
  
  
 
 
 
 
  
 
  
  
 
  
  
  
  
  
  
 
  
  
 
 
 
 
  
 
  
  
 
  
  
  
  
  
  
 
  
  
 
 
 
 
  
 
  
  
 
  
 


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16.2.7 Adverse Events 
Listing 12: 
16.2.7.3: Treatment Emergent Adverse Events 
[Implementation Note: Listing will be sorted by Treatment Group, Participant ID, and AE Number.] 
Adverse 
Event 
Associated 
with Dose 
No. 
No. of Days 
Post 
Associated 
Dose 
(Duration) 
Severity 
SAE? 
TEAE? 
Relationship 
to Study 
Treatment 
If Not 
Related, 
Alternative 
Etiology 
Action 
Taken with 
Study 
Treatment 
Participant 
Discontinued 
Due to AE? 
Outcome 
MedDRA 
System 
Organ 
Class 
MedDRA 
Preferred 
Term 
Treatment Group: , Participant ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
Treatment Group: , Participant ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
Note: For additional details about SAEs, see Listing of Serious Adverse Events. 
 


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16.2.8 Individual Laboratory Measurements 
[Implementation Note: These listings (for hematology, chemistry, coagulation, and urinalysis) include all laboratory results, scheduled and unscheduled. 
These listings are not color-coded, but the severity should be included in parentheses after the result for abnormal results, e.g., 16.2 (Mild). 
Measurements outside the reference range but are not graded should show “ONR” for “Severity Grade”. Change from Baseline column will be blank for 
non-numeric parameters and a dash (-) for baseline time point. 
Refer to Section 9.6 for sort order of laboratory parameters. 
Listing will be sorted by Treatment Group, Participant ID, Parameter, Time Point, and Assessment Time. Refer to Section 9.6 for parameter sort orders.] 
Listing 13: 
16.2.8.1: Clinical Laboratory Results – Chemistry 
Treatment 
Group 
Participant ID 
Time Point 
Assessment 
Date 
Assessment 
Time 
Sex  
Age 
(years) 
Laboratory 
Parameter  
(Units) 
Result  
(Severity Grade) 
Reference 
Normal 
Range Low 
Reference 
Normal 
Range High 
Change 
from 
Baseline 
400 mg SLV213 
ABC.00101 
Baseline 
ddMMMyyyy 
hh:mm 
Male 
22 
Sodium (mmol/L) 
138 
133 
145 
- 
 
 
Day 2 
ddMMMyyyy  
hh:mm 
Male 
22 
Sodium (mmol/L) 
134 (Mild) 
133 
145 
-4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listings with similar format: 
Listing 14: 
16.2.8.2: Clinical Laboratory Results – Hematology 
Listing 15: 
16.2.8.2: Clinical Laboratory Results – Coagulation 
Listing 16: 
16.2.8.3: Clinical Laboratory Results – Urinalysis 
[Implementation Note: The Change from Baseline column will not be included. A column will be added between Age and Laboratory Parameter 
columns and will be labelled as “Methodology”. Options for this column include dipstick and microscopy.] 
 


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16.2.9 Vital Signs and Physical Exam Findings 
Listing 17: 
16.2.9.1: Vital Signs 
[Implementation Note: This includes all vital sign assessments, scheduled and unscheduled. This listing is not color-coded, but the severity should be 
included in parentheses after the result for abnormal supine results, e.g., 141 (Mild). 
Listing will be sorted by Treatment Group, Participant ID, Study Day, and Planned Time Point.] 
Treatment 
Group 
Participant 
ID 
Study Day 
(Dose) 
Planned 
Time 
Point 
Actual 
Time 
Point 
Temperature 
(°C) 
Systolic Blood Pressure 
(mmHg) 
Diastolic Blood Pressure 
(mmHg) 
Pulse 
(beats/min) 
Respiratory 
Rate 
(breaths/min) 
Supine 
Standing
(1 min) 
Standing
(3 min) 
Supine 
Standing
(1 min) 
Standing
(3 min) 
Supine 
Standing
(1 min) 
Standing
(3 min) 
 
 
Day 1 
(Morning) 
-30M 
-32M 
36 (None) 
120 
(None) 
116 
112 
60 (None) 
68 
57 
60 (None) 
68 
70 
12 (None) 
 
 
Day 1 
(Morning) 
2H 
2H 5M 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 8 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 9 
- 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Systolic blood pressure, diastolic blood pressure, and pulse standing measurements that meet the criteria for an abnormal orthostatic response are graded according to Adverse Event Grading Scale 
and are included in Listing 12: 16.2.7.3 Treatment Emergent Adverse Events. 
Time point refers to the amount of time before or after the associated dose that supine vital signs were collected. Standing vital signs were collected 1 min (±15 s) and 3 min (±15 s) after supine vital 
signs were collected. 
 


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Listing 18: 
16.2.9.2: Abnormal Physical Exam Findings 
[Implementation Note: Listing will be sorted by Treatment Group, Participant ID, Planned Time Point, and AE Number.] 
Treatment 
Group 
Participant ID 
Planned Time 
Point 
Actual Study 
Day 
Body System 
Abnormal Finding 
Reported as an AE? 
(AE Description; Number) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.10 12-Lead Electrocardiogram 
Listing 19: 
16.2.10: Electrocardiogram Interval Measurements 
[Implementation Note: This included all ECG assessments, scheduled and unscheduled. These listings are not color-coded, but the severity should be 
included in parentheses after the result for abnormal results, e.g., 16.2 (Mild). 
Refer to Section 9.1.1 for sort order of ECG parameters. 
Listing will be sorted by Treatment Group, Participant ID, Parameter, Time Point, and Assessment Time. Refer to Section 9.1.1 for parameter sort 
order.] 
Treatment 
Group 
Participant ID 
Sex 
Parameter 
Time Point 
Assessment Date 
Assessment Time 
Result (Severity) 
Change from 
Baseline 
 
 
 
 
Baseline 
ddMMMyyyy 
hh:mm 
 
 
 
 
 
 
Day 4 
ddMMMyyyy  
hh:mm 
 
 
  
  
  
  
 
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
 
  
  
  
  
 


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Listing 20: 
16.2.10: Electrocardiogram Overall Interpretations and Comments 
[Implementation Note: Listing will be sorted by Treatment Group, Participant ID and Time Point.] 
Treatment 
Group 
Participant 
ID 
Sex 
Time Point 
Assessment Date 
Interpretation 
Change from 
Baseline 
Morphological 
Abnormalities 
Present? 
If Abnormal CS, 
AE No. 
Comments 
 
 
Male 
Baseline 
ddMMMyyy 
Normal NCS 
- 
No 
- 
Sinus Bradycardia 
 
 
Male 
Day 4 
ddMMMyyy 
Abnormal NCS 
NCB 
Yes 
- 
Sinus Bradycardia 
  
  
  
  
  
  
 
 
 
  
  
  
  
  
  
  
 
 
 
  
  
  
  
  
  
  
 
 
 
  
Note: NCS = Not clinically significant; CS = Clinically significant. 
NCB = No change from baseline; NSB = Not clinically significant, change from baseline; CSB = Clinically significant change from baseline. 
 


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16.2.10 Concomitant Medications 
Listing 21: 
16.2.11: Concomitant Medications 
[Implementation Note: Listing will be sorted by Treatment Group, Participant ID, and CM Number.] 
Treatment 
Group 
Participant 
ID 
CM 
Number 
Medication 
Medication Start 
Day 
Medication End 
Day 
Indication 
Taken for an AE? 
(AE Description; 
Number) 
Taken for a condition on 
Medical History? 
(MH Description; 
Number) 
ATC Level 1  
(ATC Level 2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.12 Pregnancy Reports 
[Implementation Note: Listings will be sorted by Treatment Group (as applicable), Participant ID, and Pregnancy Number or Fetus Number.] 
Listing 22: 
16.2.12.1: Pregnancy Reports – Maternal Information 
Treatment 
Group  
Participant 
ID  
Pregnancy 
Number 
Study Day 
Corresponding 
to Estimated 
Date of 
Conception 
Source of 
Maternal 
Information 
Pregnancy 
Status 
Mother’s 
Pre-
Pregnancy 
BMI 
Mother’s 
Weight 
Gain 
During 
Pregnancy 
Tobacco, 
Alcohol, or 
Drug Use 
During 
Pregnancy? 
Medications 
During 
Pregnancy? 
Maternal 
Complications 
During 
Pregnancy? 
Maternal 
Complications 
During Labor, 
Delivery, or 
Post-Partum? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Maternal Complications are included in the Adverse Event listing. Medications taken during pregnancy are included in the Concomitant Medications Listing. 
 
Listing 23: 
16.2.12.2: Pregnancy Reports – Gravida and Para 
 
 
 
Live Births 
 
 
 
 
 
Participant 
ID 
Pregnancy 
Number 
Gravida 
Extremely 
PBa 
Very 
Early 
PBa 
Early 
PBa 
Late 
PBa 
Early 
TBb 
Full 
TBb 
Late 
TBb 
Post 
TBb 
Still 
Births 
Spontaneous 
Abortion/ 
Miscarriage 
Elective 
Abortions 
Therapeutic 
Abortions 
Major 
Congenital 
Anomaly 
with 
Previous 
Pregnancy? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Gravida includes the current pregnancy, para events do not. 
a Preterm Birth 
b Term Birth 
 
 


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Listing 24: 
16.2.12.3: Pregnancy Reports – Live Birth Outcomes 
Participant 
ID 
Pregnancy 
Number 
Fetus 
Number 
Pregnancy 
Outcome 
(for this 
Fetus) 
Fetal 
Distress 
During 
Labor and 
Delivery? 
Delivery 
Method 
Gestational 
Age at Live 
Birth  
Size for 
Gestational 
Age 
Apgar 
Score, 1 
minute 
Apgar 
Score, 5 
minutes 
Cord pH 
Congenital 
Anomalies? 
Illnesses/ 
Hospitalizations 
within 1 Month 
of Birth? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Congenital Anomalies are included in the Adverse Event listing. 
 
Listing 25: 
16.2.12.4: Pregnancy Reports – Still Birth Outcomes 
Participant 
ID 
Date of 
Initial 
Report 
Fetus 
Number 
Pregnancy 
Outcome 
(for this 
Fetus) 
Fetal 
Distress 
During 
Labor and 
Delivery? 
Delivery 
Method 
Gestational 
Age at Still 
Birth 
Size for 
Gestational 
Age 
Cord pH 
Congenital 
Anomalies? 
Autopsy 
Performed? 
If Autopsy, 
Etiology for Still 
Birth Identified? 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 26: 
16.2.12.5: Pregnancy Reports – Spontaneous, Elective, or Therapeutic Abortion Outcomes 
Participant 
ID 
Date of Initial 
Report 
Fetus Number 
Pregnancy Outcome 
(for this Fetus) 
Gestational Age at 
Termination 
Abnormality in Product of Conception? 
Reason for Therapeutic 
Abortion 
 
 
 
 
 
 
 
 

Prot_001.pdf: 
Protocol 22-0027 
Version 4.0 
Multiple Ascending Dose Safety and PK of SLV213  
27 March 2024 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 1 of 84 
A Randomized, Double Blind, Placebo-Controlled, Multiple 
Ascending Dose, Phase 1 Study of SLV213 in Healthy Volunteers 
DMID Protocol Number: 22-0027 
 
 
IND Sponsor: Division of Microbiology and Infectious Diseases (DMID), 
National Institute of Allergy and Infectious Diseases (NIAID), 
National Institutes of Health (NIH) 
 
 
 
Version Number: 4.0 
27 March 2024 
Pharmaceutical Support: Selva Therapeutics, Inc. 
 
 


Protocol 22-0027 
Version 4.0 
Multiple Ascending Dose Safety and PK of SLV213  
27 March 2024 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 2 of 84 
STATEMENT OF COMPLIANCE 
Each institution engaged in this research will hold a current Federalwide Assurance (FWA) issued 
by the Office of Human Research Protection (OHRP) for federally funded research. The 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) must be registered with 
OHRP as applicable to the research.  
The study will be carried out in accordance with the following as applicable: 
• United States Code of Federal Regulations (CFR) 45 CFR Part 46: Protection of Human 
Subjects 
• Food and Drug Administration (FDA) Regulations: 21 CFR Part 50 (Protection of Human 
Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical Investigators), 21 CFR Part 56 
(Institutional Review Boards), 21 CFR Part 11 (Electronic Records and Electronic 
Signatures), and 21 CFR Part 312 (Investigational New Drug Application), and/or 
21 CFR 812 (Investigational Device Exemptions) 
• The International Council for Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use (ICH) E6(R2) Good Clinical Practice (GCP), and the 
Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects 
of Research, Report of the National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research 
• The policies and procedures of National Institutes of Health (NIH) Office of Extramural 
Research and the Division of Microbiology and Infectious Diseases (DMID) 
• The National Institute of Allergy and Infectious Diseases (NIAID) Terms of Award 
• Any additional Federal, State, and Local Regulations and Guidance 
The signature below provides the necessary assurance that this study will be conducted according 
to all stipulations of the protocol including statements regarding confidentiality, and according to 
local legal and regulatory requirements, US federal regulations, and ICH E6(R2) GCP guidelines. 
Site Principal Investigator Signature: 
 
 
Signed: 
 
Date: 
 
 
Martin Kankam, MD, PhD, MPH, FAPCR  
Medical Director, Altasciences 
 
 
 
 


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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ................................................................................................ 2 
TABLE OF CONTENTS ................................................................................................................ 3 
LIST OF TABLES .......................................................................................................................... 6 
LIST OF FIGURES ........................................................................................................................ 6 
1. 
PROTOCOL SUMMARY ....................................................................................................... 7 
1.1 
Synopsis .......................................................................................................................... 7 
1.2 
Schedule of Assessments (SOA) .................................................................................. 10 
1.3 
Study Schema................................................................................................................ 13 
2. 
INTRODUCTION ................................................................................................................. 13 
2.1 
Study Rationale ............................................................................................................. 13 
2.2 
Background ................................................................................................................... 14 
2.3 
Risk/Benefit Assessment .............................................................................................. 15 
2.3.1 
Known Potential Risks .......................................................................................... 15 
2.3.2 
Known Potential Benefits ..................................................................................... 16 
2.3.3 
Assessment of Potential Risks and Benefits ......................................................... 17 
3. 
OBJECTIVES AND ENDPOINTS ....................................................................................... 18 
4. 
STUDY DESIGN .................................................................................................................. 20 
4.1 
Overall Design .............................................................................................................. 20 
4.2 
Dose Escalation ............................................................................................................. 20 
4.3 
Scientific Rationale for Study Design ........................................................................... 20 
4.4 
Justification for Dose .................................................................................................... 21 
5. 
STUDY POPULATION ........................................................................................................ 21 
5.1 
Inclusion Criteria .......................................................................................................... 21 
5.2 
Exclusion Criteria ......................................................................................................... 23 
5.2.1 
Exclusion of Specific Populations ........................................................................ 25 
5.3 
Inclusion of Vulnerable Participants ............................................................................. 25 
5.4 
Lifestyle Considerations ............................................................................................... 25 
5.5 
Screen Failures .............................................................................................................. 26 
5.6 
Strategies for Recruitment and Retention ..................................................................... 26 
5.6.1 
Recruitment ........................................................................................................... 26 
5.6.2 
Retention ............................................................................................................... 27 
5.6.3 
Compensation Plan for Participants ...................................................................... 27 
5.6.4 
Costs ...................................................................................................................... 27 
6. 
STUDY PRODUCT .............................................................................................................. 27 
6.1 
Study Product(s) and Administration ........................................................................... 27 
6.1.1 
Study Product Description .................................................................................... 27 
6.1.2 
Dosing and Administration ................................................................................... 28 
6.1.3 
Dose Modifications ............................................................................................... 28 
6.1.4 
Criteria for Redosing............................................................................................. 28 
6.2 
Preparation/Handling/Storage/Accountability .............................................................. 28 
6.2.1 
Acquisition ............................................................................................................ 28 


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6.2.2 
Accountability ....................................................................................................... 29 
6.2.3 
Formulation, Appearance, Packaging, and Labeling ............................................ 30 
6.2.4 
Product Storage and Stability................................................................................ 31 
6.2.5 
Preparation ............................................................................................................ 31 
6.3 
Measures to Minimize Bias: Randomization and Blinding .......................................... 32 
6.3.1 
Treatment Assignment Procedures ....................................................................... 32 
6.3.2 
Randomization ...................................................................................................... 32 
6.3.3 
Blinding and Masking Procedures ........................................................................ 32 
6.4 
Study Intervention Compliance .................................................................................... 32 
6.5 
Concomitant Therapy.................................................................................................... 33 
6.5.1 
Rescue Medicine ................................................................................................... 33 
6.5.2 
Non-Research Standard of Care ............................................................................ 33 
7. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................. 34 
7.1 
Halting Criteria and Discontinuation of Study Intervention ......................................... 34 
7.1.1 
Study Halting Criteria ........................................................................................... 34 
7.1.2 
Individual Halting Criteria .................................................................................... 34 
7.1.3 
Follow Up for Participants Who Discontinued Study Intervention ...................... 35 
7.2 
Participant Withdrawal from the Study and Replacement ............................................ 35 
7.2.1 
Participant Withdrawal from the Study ................................................................ 35 
7.2.2 
Participant Replacement ....................................................................................... 36 
7.3 
Lost to Follow-Up ......................................................................................................... 36 
8. 
STUDY ASSESSMENTS AND PROCEDURES ................................................................. 37 
8.1 
Screening Procedures .................................................................................................... 37 
8.1.1 
Clinical Procedures and Evaluations .................................................................... 37 
8.1.2 
Laboratory Evaluations ......................................................................................... 39 
8.1.3 
Evaluation of Screening Data ............................................................................... 41 
8.1.4 
Procedures to be Followed in the Event of Abnormal Clinical Laboratory Test 
Values or Abnormal Clinical Findings During Screening .................................................... 41 
8.2 
Efficacy Assessments .................................................................................................... 42 
8.2.1 
Efficacy Evaluations ............................................................................................. 42 
8.2.2 
Exploratory Assessments ...................................................................................... 42 
8.3 
In-Patient and Follow up Procedures ............................................................................ 43 
8.3.1 
Clinical Procedures and Evaluations .................................................................... 43 
8.3.2 
Laboratory Evaluations ......................................................................................... 44 
8.3.3 
Procedures to be Followed in the Event of Abnormal Clinical Laboratory Test 
Values or Abnormal Clinical Findings During Conduct of the Trial ................................... 44 
8.3.4 
Blood sampling for Plasma SLV213 Assay during the In-patient Period and 
Serum for Future Research ................................................................................................... 45 
8.3.5 
Total Blood Volume Drawn .................................................................................. 47 
8.3.6 
Disposition of Plasma Samples ............................................................................. 47 
8.4 
Study Drug Administration ........................................................................................... 47 
8.5 
Adverse Events and Serious Adverse Events ............................................................... 48 


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8.5.1 
Definition of Adverse Events (AE) ....................................................................... 48 
8.5.2 
Definition of Serious Adverse Events (SAE) ....................................................... 48 
8.5.3 
Definition of Medically-Attended Adverse Events (MAAE) ............................... 49 
8.5.4 
Classification of an Adverse Event ....................................................................... 49 
8.5.5 
Time Period and Frequency for Event Assessment and Follow up ...................... 50 
8.5.6 
Adverse Event Reporting ...................................................................................... 50 
8.5.7 
Serious Adverse Event Reporting ......................................................................... 51 
8.5.8 
Reporting Events to Participants ........................................................................... 52 
8.5.9 
Adverse Events of Special Interest (AESI) ........................................................... 52 
8.5.10 
Reporting of Pregnancy ........................................................................................ 53 
8.6 
Unanticipated Problems ................................................................................................ 53 
8.6.1 
Definition of Unanticipated Problems .................................................................. 53 
8.6.2 
Unanticipated Problem Reporting ......................................................................... 54 
8.6.3 
Reporting Unanticipated Problems to Participants ............................................... 54 
9. 
STATISTICAL CONSIDERATIONS .................................................................................. 55 
9.1 
Statistical Hypotheses ................................................................................................... 55 
9.2 
Sample Size Determination ........................................................................................... 55 
9.3 
Statistical Analyses ....................................................................................................... 55 
9.3.1 
General Methodology ........................................................................................... 55 
9.3.2 
Timing of Analyses ............................................................................................... 55 
9.3.3 
Populations for Analyses ...................................................................................... 56 
9.3.4 
Baseline Characteristics and Participant Disposition ........................................... 57 
9.3.5 
Efficacy Analyses ................................................................................................. 57 
9.3.6 
Safety Analyses ..................................................................................................... 57 
9.3.7 
Pharmacokinetic Analysis ..................................................................................... 58 
9.3.8 
Missing Values and Outliers ................................................................................. 60 
9.3.9 
Multiple Comparisons / Multiplicity .................................................................... 60 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........ 60 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ............................................ 60 
10.1.1 
Informed Consent Process .................................................................................... 61 
10.1.2 
Study Termination and Closure ............................................................................ 62 
10.1.3 
Confidentiality and Privacy .................................................................................. 63 
10.1.4 
Secondary Use of Stored Specimens and Data ..................................................... 64 
10.1.5 
Key Roles and Study Governance ........................................................................ 64 
10.1.6 
Safety Oversight.................................................................................................... 64 
10.1.7 
Clinical Monitoring ............................................................................................... 65 
10.1.8 
Quality Assurance and Quality Control ................................................................ 65 
10.1.9 
Data Handling and Record Keeping ..................................................................... 66 
10.1.10 
Protocol Deviations ............................................................................................... 67 
10.1.11 
Publication and Data Sharing Policy .................................................................... 68 
10.1.12 
Conflict of Interest Policy ..................................................................................... 68 
10.2 
Additional Considerations ............................................................................................ 68 
10.2.1 
Research Related Injuries ..................................................................................... 68 


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10.3 
Abbreviations ................................................................................................................ 69 
10.4 
Protocol Amendment History ....................................................................................... 73 
11. REFERENCES ...................................................................................................................... 78 
12. APPENDICES ....................................................................................................................... 79 
Appendix A: Adverse Events Toxicity Grading Criteria .............................................................. 80 
Appendix B: Blood Volume Withdrawn During the Trial ........................................................... 82 
Appendix C: Strong Inhibitors, Inducers, and Sensitive Substrates of CYP3A4 and CYP2D6 ... 83 
 
LIST OF TABLES 
Table 1: Drug Substance Characteristics ...................................................................................... 30 
Table 2: Matched Placebo Composition ....................................................................................... 31 
Table 3: Laboratory Samples and Estimated Total Blood Volume (mL) ..................................... 82 
 
LIST OF FIGURES 
Figure 1: Study Schema ................................................................................................................ 13 
Figure 2: Structure of K777 .......................................................................................................... 30 
Figure 3: Structure of Matched Placebo ....................................................................................... 31 
 
 


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1. 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Rationale  
The outbreak of COVID-19, which is caused by the severe acute respiratory syndrome-related 
coronavirus 2 (SARS-CoV-2) has been declared a pandemic and represents a great threat to public 
health (CDC 2020). Well over 625 million individuals have been infected globally and more than 
6.5 million confirmed deaths have been reported, numbers that are likely to continue to grow 
(Our World in Data 2020). Confirmed US cases have exceeded 102 million, with over 1 million 
deaths to date. Selva Therapeutics, Inc. is developing SLV213, 4-methylpiperazine-1-carboxylic 
acid [1-(3- benzenesulfonyl- 1- phenethylallyl-carbamoyl)-2-phenylethyl]-amide, a vinyl sulfone 
cysteine protease inhibitor for the treatment of subjects infected with SARS-CoV-2, to address an 
urgent medical need for the treatment of COVID-19. 
SLV213 is an oral formulation (drug substance powder in capsules without excipients or 
stabilizers) of the drug substance K777 hydrochloride, which has been demonstrated to exhibit 
broad inhibitory properties against host cathepsins (e.g., Cathepsin L), which represent one of two 
types of proteases known to activate or “prime” the spike protein of coronaviruses. Priming by 
host Cathepsin L in the endosome is required to initiate the conformational change of the spike 
protein necessary to begin viral entry into host cells. This mechanism of entry is required for 
coronaviruses (e.g., SARS-CoV-2, Middle East respiratory syndrome coronavirus, Human 
coronavirus NL63) (Zhou, Vedantham et al. 2015). Crucially, due to SLV213’s broad mechanism 
of action against host cathepsins as well as the conservation of the priming mechanism for 
coronaviruses, there is potential for SLV213 to be effective against future coronavirus outbreaks 
(Mellott, Tseng et al. 2021) 
Study Design  
The proposed study will evaluate the safety, tolerability, and pharmacokinetics (PK) of multiple 
ascending doses (MAD) of SLV213 in healthy male and female participants, 18-65 years of age. 
This study will help to select the most likely suitable dose (e.g., at Maximum Tolerated Dose 
[MTD]) for the treatment of patients with COVID-19 in a pivotal study. This double blind, 
placebo-controlled study will consist of three sequential cohorts of 12 participants each (8 SLV213 
and 4 placebo), at doses of 400 mg every 12 hours (Q12h), 600 mg Q12h, and 800 mg Q12h 
administered orally (PO) for 7 days. After each cohort, a Safety Review Committee (SRC) will 
evaluate the safety of the regimen before proceeding to dose the next cohort.  
Randomization will occur into the respective cohorts as above. Upon meeting the 
Inclusion/Exclusion criteria, subjects will begin treatment with SLV213 or placebo per their 
assigned cohort. Participants will take their study drug in the fasted state prior to morning and 
evening meals and will remain as in-patient in the clinical trial unit (CTU) during all treatments 
and for approximately 48 hours (h) after the last dose for monitoring. After discharge from the 
CTU, participants will be monitored by CTU staff by telephone to assess for new adverse events 
(AEs) and use of concomitant medications (ConMeds) since the last visit or contact, approximately 


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weekly for three weeks. Participants will be asked to return to the CTU for further assessment of 
moderate or severe AEs. (For further information on study drug administration see Section 6.1.2. 
List of assessments from Screening to last study visit can be found in the Schedule of Assessments 
(SOA), Section 1.2, and in Section 8.1 and Section 8.3).  
Objectives 
• Primary: To evaluate the safety and tolerability of multiple ascending doses of SLV213 for 
7 days in healthy participants. 
• Secondary: To characterize the multiple dose PK of SLV213 in healthy participants. 
Outcomes / Endpoints 
• Primary:  
o Safety: Type, incidence, severity, and relatedness to study drug of all treatment-
emergent systemic, laboratory and electrocardiographic (ECG) adverse events (AEs) 
and serious adverse events (SAEs) in each treatment cohort from the first dose (Day 1) 
through the last visit (Day 28 ± 2 days). 
o Tolerability: Proportion of participants experiencing any treatment-emergent AEs 
assessed as related to study drug vs. placebo.   
• Secondary: PK parameter estimates and calculated exposure measures in plasma SLV213 
following a single initial dose on Day 1 and after multiple Q12h dose administration for 
7 days. 
For a full list of Objectives and Outcomes/Endpoints, see Section 3. 
Inclusion Criteria 
See inclusion criteria in Section 5.1. 
Exclusion Criteria 
See exclusion criteria in Section 5.2. 
Study Phase (if applicable) 
Phase 1 
Study Population 
36 ambulatory healthy participants, age 18-65 years of age inclusive at the time of dosing.  
Sites 
One clinical site located in the United States.  
 
 


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Study intervention: 
• SLV213 capsules containing 100 mg of a defined powder of drug substance K777 
hydrochloride. The chemical structure, characteristics and formulation of SLV213 are 
provided in Section 6.1.1 and Section 6.2.3, and in Figure 2 and Table 1. 
• Matching placebo capsules containing 62.5 mg microcrystalline celluloid. The chemical 
structure, characteristics and formulation are provided in Section 6.1.1 and Section 6.2.3, 
and in Figure 3 and Table 2 
Each participant will be randomly assigned to receive SLV213 or placebo (SLV213: placebo ratio 
2:1) orally (PO) as follows: 4 capsules Q12h in Cohort 1, 6 capsules Q12h in Cohort 2, and 
8 capsules Q12h in Cohort 3 daily for 7 days. The SLV213 dose will be 400 mg Q12h, 600 mg 
Q12h and 800 mg Q12h for participants in Cohorts 1, 2 and 3, respectively, for 7 days.  
Study Duration 
Screening can occur up to 28 days before the start of dosing. Dosing commences over a period of 
7 days at the study site. Participants are followed for 28 (± 2) days after the first dose is 
administered. The study is expected to complete in 6 months.  
Participant Duration 
There will be a Screening period of 27 days (Day-28 to Day-2) to determine eligibility and a check-
in visit (Day-1) to confirm eligibility for admission. Eligible participants will be monitored as in-
patients in the CTU for 9 days, 7 days (Day 1 to Day 7) during active dosing, and for 2 days after 
dosing (Days 8 and 9) for in-patient follow-up, discharged on Day 9, and followed up to 21 days 
as out-patients after the last dose, on Days 15 (±2 days), 21 (±2 days) and 28 (±2 days) by phone, 
and as needed at the CTU for the evaluation of AEs/SAEs. The total participant duration including 
the screening and post-dosing periods would be up to 56 (±2 days). 
Safety Monitoring 
This protocol will utilize a safety monitoring committee (SMC) and a safety review committee 
(SRC).  
The SMC will consist of independent experts and will advise the sponsor (Division of 
Microbiology and Infectious Diseases [DMID]) on the safety of the study. The SMC will have an 
organizational meeting and will conduct a review of safety data for dose escalation if a halting rule 
is met, as defined by the protocol, or if the internal SRC requests a review of the data, or ad hoc 
when requested by the sponsor, investigators, or SMC. The SMC will review the safety, 
tolerability, trial progress and final PK data at the conclusion of the trial to provide a 
recommendation on the dose of SLV213 to be used in a Phase 2 clinical trial.  
The SRC will review combined safety data to study Day 15 in each cohort and recommend dose 
escalation if halting criteria are not met. The SRC will consist of a DMID Medical Monitor (MM), 
a DMID Medical Officer (MO), the clinical site principal investigator (PI) and the Pharmaceutical 
(Selva) MO. (See Section 10.1.6 for further details on safety oversight.)  


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1.2 
Schedule of Assessments (SOA) 
 
Screening Period 
In-patient at the CTU 
Out-patient 
 
Procedures 
Screening 
Check-in/ 
Enrollment  
Randomization
/ Drug 
Administration 
and Monitoring 
Drug 
Administration 
and Monitoring 
Drug 
Administration 
and Monitoring 
Monitoring Discharge
Interim and 
Closeout 
Visits (by 
phone)(t) 
Unscheduled 
visit(s)(w) 
Early 
Termination 
Study Day 
Day -28 to Day -2 
Day -1 
Day 1 
Day 2- Day 6 
Day 7: 
Day 8: 
Day 9 
Days 15, 
21, 28 (each 
± 2 days) 
Informed Consent(a) 
x 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
Eligibility confirmation(b) 
x  
x (b) 
x (b) 
 
 
 
 
 
 
 
Medical History (MH)(c) 
x(c) 
x(c) 
x(c) 
 
 
 
 
 
 
 
Prior and Concomitant 
Medication(d) 
x 
x 
x 
x 
x 
x 
x 
x 
x(w) 
x 
Complete Physical 
Examination (PE)(e)   
x 
x 
 
 
 
 
x 
 
 
x 
Focused PE(f)  
 
 
x 
x 
x 
x 
 
 
x(w) 
 
Height and Weight and Body 
Mass Index (BMI) 
x 
 
 
 
 
 
 
 
 
 
Body weight 
 
x 
 
 
 
 
 
 
 
 
Vital Signs (VS)(g) 
x 
x 
x 
x 
x 
x 
x 
 
x(w) 
x 
Pregnancy Test(h)  
x  
x 
 
 
 
 
 
 
 
 
Follicle-stimulating hormone 
(FSH) in post-menopausal 
women(i) 
x 
 
 
 
 
 
 
 
 
 
Urine Drug Screen (UDS) and 
alcohol test(j) 
x 
x 
 
 
 
 
 
 
 
 
Cotinine test in urine(k)  
x 
x 
 
 
 
 
 
 
 
 
HIV(1 and 2) and Hepatitis B 
and C Serology tests(l) 
x 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 (COVID-19) 
test(m) 
 
x 
 
 
 
 
 
 
 
 
Blood (serum) Clinical 
Laboratory Assessments(n)  
x 
x 
 
x 
 
x 
 
 
x(w) 
x 
Urinalysis (UA)(o) 
x 
x 
 
x 
 
x 
 
 
x(w) 
x 
ECG(p) 
x 
x 
 
x  
 
x 
 
 
x(w)  
x 
Enrollment / Randomization(q) 
 
x 
x 
 
 
 
 
 
 
 


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Record time of last meal 
consumed before initiation of 
predose fasting  
 
x 
x 
x 
x 
 
 
 
 
 
Drug Administration(r) 
 
 
x 
x 
x 
 
 
 
 
 
Adverse Events(s) 
 
 
x 
x 
x 
x 
x 
x 
x(w)  
x 
Telephone Call(t) 
 
 
 
 
 
 
 
x 
 
 
PK Assessments and Future 
tests(u) 
 
 
x 
x 
x 
x 
x 
 
 
x 
Check patency of IV blood 
draw line – replace if needed 
 
 
x 
x 
x 
x 
x 
 
 
 
Counselling(v) 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
(a) Informed consent to occur and informed consent form (ICF) signed prior to any study related procedures. 
(b) Eligibility for Admission in the CTU confirmed on Day-1 after review of assessments and for Dosing on Day 1 before administration of the first dose. 
(c) MH obtained at Screening and updated on Day-1 and before dosing on Day 1.  
(d) Prior Medications include any medications used prior to first dose. Concomitant medications include any new medications taken only after initiation of first dose on Day 1. 
(e) Complete PE includes assessments described in Section 8.1.1 It will be completed at Screening, Check-in (Day -1) and on Day 9. 
(f) Focused PE is a symptom directed PE performed as needed to assess new symptoms reported from the time of Admission on Day-1 to before the first dose, and after first 
dose on Day 1 to the end of the study to assess treatment-emergent AEs as needed, except on Day 9 when a complete PE is performed. 
(g) VS include blood pressure (BP), heart rate (HR), respiratory rate (RR) and temperature (T) and assessed resting supine at Screening, Day-1, within 30 min before and 2 h 
(± 10 min) after each dose on Days 1 to 7, and once daily in the morning on Day 8 and on Day 9, or ET (See Section 8.1.1 and Section 8.3.1. Orthostatic blood pressure and 
heart rate are also assessed in the standing position for 1 minute ± 15 seconds and 3 minutes ± 15 seconds. NOTE: VS are taken before drawing blood for safety lab 
tests, plasma PK, and serum for future research if consented. Supine VS are taken before orthostatic BP and HR. 
(h) Serum pregnancy test at Screening and Urine pregnancy test on Day-1 (See Section 8.1.2. 
(i) FSH to confirm menopause in women with amenorrhea of 12 or more months at Screening. 
(j) UDS screening for illicit drugs described in Section 8.1.2 and urine alcohol test. 
(k) Urine cotinine test for nicotine use at Screening and Day-1. 
(l) HIV antibody (HIV 1 and HIV 2), Hepatitis B virus surface antigen (HBsAg) and Hepatitis C virus antibody (HCV) tests at Screening Visit (see Section 8.1.2). 
(m) SARS-CoV-2 (Covid-19) molecular diagnostic Cue Care™ test at Check-in Visit (Day-1) (see Section 8.1.2). 
(n) Clinical laboratory tests at Screening, Day-1, before the first (morning) dose on dosing Days 2, 4 and 6, and on Day 8, or ET. (See Section 8.1.2 and Section 8.3.2. 
(o) UA by dipstick at Screening, Day-1, and on Days 4 and 8, or ET. If abnormal for blood, protein, glucose and nitrites, a microscopic UA will be done. The results of 
microscopic UA will supersede the results of dipstick UA. UA will be postponed in a menstruating female Section 8.1.2 and Section 8.3.2).  
(p) 12-lead ECGs at Screening, Day-1, before the morning dose on Day 4 and at Day 8 (before the 12h PK timepoint after evening dose on Day 7), unscheduled as indicated or 
ET (See Section 8.1.1 and Section 8.3.1). 
(q) Enrollment will occur on Day-1 after eligibility is confirmed. NOTE: Randomization will occur before administration of the morning dose on Day 1. 
(r) Dose administration Q12h (±15 min) for all doses following Day 1 first dose on Day 1 to Day 7. Each dose is ingested with approximately 240 mL (8 oz) or more of tap or 
bottled water in the fasted state. See Section 6.2.5 for the duration of fast and restriction of fluid intake before and after dosing. Meals to be scheduled to accommodate 
dosing schedule and restrictions. 
(s) Treatment-emergent adverse events (TEAEs) and serious AEs (SAEs) will be reported and followed from the first dose (Day 1) to the last visit (Day 28 ± 2 days). (See 
Section 8.5 for AE and SAE definition, evaluation, and reporting.). NOTE: Monitoring for AEs starts upon ingestion of the first capsule on Day 1.   
(t) The interim and close-out outpatient visits on Day 15 (± 2 days), 21 (± 2 days) and 28 (± 2 days) may be conducted by phone to collect information about new AEs and 
SAEs and medication use since the previous visit. (See footnote (v) for unscheduled visits during the outpatient period)  
(u) Blood will be drawn at the following timepoints to measure the concentration of study drug and analyze PK parameters (plasma PK) and, if consented, secondary future 
research (serum) (See Section 8.3.4). NOTE: Start recording time for PK collections after ingestion of the last capsule at each dose daily. Collect blood after 
measurement of VS and ECG recording. 


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• 
On Day 1 MORNING DOSE: Within 30 min before the morning dose (t=0), and at 0.5h (±5 min), 1h (±5 min), 2h (±5 min), 4h (±5 min), 6h (±10 min), 8h (±10 min), 
and 12h (±15 min) after the morning dose. (The 12h timepoint after the morning dose on Day 1 is the same as the predose timepoint before the evening dose on 
Day 1). 
• 
On Day 1 EVENING DOSE: Before the evening dose (t=0), and 12h (±15 min) after the evening dose. (The 12h timepoint after the evening dose on Day 1 is the same 
as the predose timepoint before the morning dose on Day 2). 
 
• 
On Days 2 to 6: Within 30 min before the morning and evening doses and 12h (±15 min) after the morning and evening doses. (The PK timepoint before each dose on 
Days 2 to 6 is the same as the 12h timepoint of the previously received dose.).  
• 
On Day 7 MORNING DOSE: Within 30 min before the morning dose and at 12h (±15 min) after the morning dose. (The 12h timepoint is the same as the predose 
timepoint before the evening dose on Day 7).  
• 
On Day 7 EVENING DOSE: Within 30 min before the evening dose (t=0), and at 0.5h (±5 min), 1h (±5 min), 2h (±5 min), and 4h (±5 min) after the evening dose on 
Day 7.  
• 
On Day 8: At 6h (±10 min), 8h (±10 min), 12h (±15 min), and 24h (±15 min) after the evening dose on Day 7. 
• 
On Day 9: At 36h (±15 min) and 48h (-2 hours) after the evening dose on Day 7. 
(v) Participant counseled to avoid prohibited lifestyle activities and prescription and non-prescription medications and use recommended contraception methods after Screening 
and, if enrolled and dosed, for the duration of study. Before or at discharge from the in-patient phase on Day 9, participants must be counseled to use recommended 
contraception and avoid pregnancy for at least 30 days after the last study dose. Male participants must be counseled to avoid donating sperm for 30 days after the last dose 
received in the study. 
(w) An unscheduled visit to the CTU may be initiated by study staff after each outpatient follow up by phone call for evaluation of any new AEs assessed as moderate or above 
or SAEs or AESIs by the study PI or authorized clinician. The evaluation will consist of a history of the AE, any ConMeds taken, focused PE and, as needed, clinical 
laboratory tests, ECG and other tests as indicated. Any ongoing AEs after discharge from the CTU on Day 9 may also be followed with as needed assessments during 
unscheduled visits. 
 


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1.3 
Study Schema 
Figure 1: Study Schema 
 
2. 
INTRODUCTION 
2.1 
Study Rationale 
The outbreak of COVID-19, which is caused by SARS-CoV-2 has been declared a pandemic and 
represents a great threat to public health (CDC 2020). Well over 625 million individuals are already 
infected globally and more than 6.5 million confirmed deaths have been reported, numbers that 
are likely to continue to grow over (Our World in Data 2020). Confirmed US cases have exceeded 
102 million, with over 1 million deaths to date. 
The current standard of care for COVID-19 includes supportive care, such as oxygen therapy and 
fluid management, and the use of antiviral drugs like Remdesivir and Paxlovid. In more severe 
cases, corticosteroids are used to reduce inflammation and prevent damage to organs, such as the 
lungs. While these treatments can help manage symptoms and potentially reduce the severity of 
the disease, they do not provide a cure or prevent disease progression. Additionally, the use of 
Consent
Screening
Study Start, Randomization/Enrollment
By Cohort
• Study Identification Number assigned
• Collection of baseline data/labs
Cohort #1
• Placebo (n=4)
• SLV213 400mg PO Q12 hours (n=8)
Cohort #2
• Placebo (n=4)
• SLV213 600mg PO Q12 hours (n=8)
Cohort #3
• Placebo (n=4)
• SLV213 800mg PO Q12 hours (n=8)
SRC Review
SRC Review
SMC Review


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antivirals like Remdesivir has been associated with adverse effects, such as gastrointestinal 
problems and liver damage. Furthermore, the effectiveness of these treatments may vary 
depending on the severity of the disease and the timing of treatment. For example, corticosteroids 
may be effective in reducing inflammation and preventing damage to organs in severe cases, but 
they may not be effective in mild cases or may even exacerbate the disease in the early stages. 
There is a significant need for additional therapies that can target the underlying mechanisms of 
COVID-19 pathogenesis and reduce disease severity. For instance, host-targeted interventions that 
can block viral entry and replication could be promising therapeutic options for COVID-19 and 
other viral diseases. 
Selva has conducted a Phase 1 randomized double-blind placebo-controlled single ascending dose 
(SAD) study in healthy volunteers to evaluate the safety, tolerability, and PK of SLV213 following 
oral administration (Study SLV213-01). Following randomization, 5 cohorts of 8 participants each 
(6 active, 2 placebo) received a single dose of the active compound SLV213 or placebo PO at 
50 mg, 100 mg, 200 mg, 400 mg, or 800 mg daily (QD). A SRC evaluated the blinded results of 
each successive cohort before proceeding to dose the next cohort. Although a clinically significant 
episode of orthostatic hypotension was observed 30 minutes (min) after dosing in one participant 
at the 200 mg dose level, this was not seen in this participant at subsequent time points, nor in any 
other participant at the 400 mg or 800 mg dose levels. The SRC therefore concluded that no dose 
limiting toxicity (DLT) had been seen at any of the dose levels. Pharmacokinetic analyses 
demonstrated dose dependent peak drug concentration (Cmax) and area under the plasma 
concentration – time curve (AUC). Preliminary modeling of 400 mg and 800 mg QD suggested 
predicted blood levels were comparable to concentrations measured in preclinical efficacy models. 
It is therefore concluded that 400 mg Q12h, 600 mg Q12h, and 800 mg Q12h dosing should be 
well tolerated. Further description of the results of the SLV213-01 study is provided in the 
Investigator Brochure (IB). 
2.2 
Background 
Selva Therapeutics is developing SLV213, the oral formulation of the drug substance K777 
hydrochloride. SLV213 is a vinyl-sulfone cysteine protease inhibitor that acts as a broad antiviral 
by inhibiting cathepsin-mediated cell entry (Zhou, Vedantham et al. 2015). Such entry is required 
for infection by coronaviruses, providing a mechanism-based rationale for investigating SLV213 
as a potential treatment against COVID-19. Pharmaceutical development of SLV213 was 
previously focused on Chagas disease, and NIAID-sponsored activities have been ongoing for two 
decades, including Good Laboratory Practice (GLP) and non-GLP studies conducted primarily at 
SRI International. Due to these efforts, extensive preclinical evaluation has been completed to 
assess the PK, metabolism, and toxicity of SLV213 in rodents, dogs, and non-human primates 
(McKerrow 2018).  
A mechanism-based rationale for investigating SLV213 as a potential treatment against COVID-
19 is supported by multiple lines of evidence. Investigators at University of Texas Medical Branch, 
University of California San Diego, and the Utah State University have generated in vitro data that 
demonstrate dose-dependent antiviral effects of K777 in several SARS-CoV-2-permissive 
mammalian cell lines (Mellott, Tseng et al. 2021). Supporting evidence has also been published 


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by Hoffman et al. (Hoffmann, Kleine-Weber et al. 2020, Nie, Qian et al. 2021), which 
demonstrated that inhibition of cysteine proteases by E-64d blocks SARS-CoV-2 from cell entry, 
strongly supporting the theory that SLV213 may be a potentially effective treatment of COVID-
19.  
Additionally, investigators at Tulane Primate Research Center have completed two non-human 
primate studies in which the safety and efficacy of K777 were evaluated. Data from African Green 
monkeys inoculated with SARS-CoV-2 indicate a reduction in viral loads and a corresponding 
reduction in measures of lung pathology in treated animals compared to untreated controls (Frueh, 
Maneval et al. 2021). Histological analysis showed that treated animals were protected against 
acute respiratory distress syndrome (ARDS)-like pathology that was seen in untreated animals.  
Other clinical trials targeting other known host proteins involved in SARS-CoV-2 infection are 
ongoing; however, SLV213 represents the first opportunity to test the inhibition of host cysteine 
protease activity in humans. Evidence from the SLV213-01 Phase 1 trial, non-human primate 
studies, and emerging observations in the literature from COVID-19 patients further support the 
development of SLV213 for the treatment of COVID-19 (Nie, Qian et al. 2021). 
2.3 
Risk/Benefit Assessment 
2.3.1 
Known Potential Risks 
SLV213 
Cathepsin inhibitors have been safely used in the clinic (Drake, Clarke et al. 2017; Fuchs, Meta et 
al. 2020).  
Preclinical:  
SLV213 is the oral formulation of the drug substance, K777. All preclinical development was 
conducted with K777 (K11777). The K777 toxicology program included single-dose and repeat-
dose oral dose toxicity studies in rats and dogs. Pivotal studies included a 14-day GLP toxicity 
study in rats, a 28-day GLP toxicity study in dogs as well as standard GLP in vitro tests for 
genotoxicity. Non-GLP studies were also conducted in cynomolgus and rhesus monkeys. In 
general, K777 was well tolerated in all species after oral administration. The liver was identified 
as the target organ of toxicity. Reversible increases in transaminases (e.g., aspartate 
aminotransferase [AST], alanine aminotransferase [ALT]) were reported in all species at high 
doses. In the GLP 14-day rat toxicity study, the highest dose administered (150 mg/kg/day) 
produced mild effects on liver enzymes (2-fold elevation) that were not confirmed by 
histopathologic evaluation of the liver. In the 28-day GLP dog toxicity study, modest reversible 
elevations in serum transaminases were also observed. In addition, reversible microscopic changes 
were detected in the brain (100 mg/kg dose; females only) and in lymphoid tissues. These 
reversible changes were considered non-adverse due to lack of histopathologic, clinicopathologic, 
and clinical evidence suggestive of an organ or organismal functional impairment.  
Modest depressions in food consumption and weight gain were also observed in several studies, 
but effects were reversible and not considered adverse. Emesis was frequently reported in the dog 


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at oral K777 doses ~100 mg/kg and was also reported after intravenous (IV) dosing in a recent dog 
safety pharmacology study. Changes in hematological parameters were not typically observed or 
not considered of toxicological significance. In vitro and in vivo GLP studies did not demonstrate 
genotoxic effects of K777. 
The oral administration of K777 at doses of 15, 50, and 150 mg/kg did not induce any significant 
effects on pulmonary function or neurobehavioral responses in conscious male rats. Potential 
cardiovascular effects of K777 in vivo were further investigated in a GLP dog safety pharmacology 
study. To maximize systemic exposure of K777, conscious telemetered dogs received K777 
weekly IV at doses of 0, 5, 15, and 25 mg/kg. The IV administration of K777 did not induce any 
biologically relevant effects on blood pressure, ECG morphology, ECG measurements, or body 
temperature. Moderate increases in heart rate were observed during dosing of K777 at 15 and 
25 mg/kg, and effects were resolved immediately following dosing.  
Clinical:  
Selva has conducted a Phase 1 randomized, double-blind, placebo-controlled, SAD study to 
evaluate the safety, tolerability, and PK of SLV213 following oral administration (Study SLV213-
01). An SRC concluded that no DLT had been seen at any of the dose levels. Occasional, transient, 
mild, treatment-emergent adverse events (TEAEs) were observed at all dose levels. A clinically 
significant episode of orthostatic hypotension was observed 30 min after dosing in one participant 
at the 200 mg dose level, but this was not seen in that participant at subsequent time points, nor in 
any other participant at the 400 mg or 800mg dose levels. No SAEs were noted, and no participants 
discontinued the trial because of an AE. No clinically significant changes from participants’ 
baseline values were seen in liver function enzymes (alkaline phosphatase [ALP], ALT, AST, 
gamma-glutamyl transferase [GGT]) or in ECG parameters at any dose level. Preliminary PK 
modeling of BID dosing predicted blood levels at 400 mg BID to be well below the 800 mg single 
dose Cmax and comparable to concentrations measured in preclinical efficacy models, and 
supported the conclusion that 400 mg, 600 mg, and 800 mg Q12h dosing should be well tolerated.  
2.3.2 
Known Potential Benefits 
The participants will have no direct benefit from participating in the study.  
The development of a host-targeted therapeutic for COVID-19 would provide significant benefits 
over the current standard treatment of care. COVID-19 is a highly infectious and life-threatening 
disease that has caused a worldwide pandemic. While vaccines have been developed to prevent 
the disease, they are not entirely effective, and not all individuals can receive them. As such, the 
availability of a host-targeted therapeutic would be critical for those who contract the disease, 
particularly those at high risk of severe illness or death. 
The current standard treatment for COVID-19 involves supportive care, such as oxygen therapy 
and fluid management, and the use of antiviral drugs like Remdesivir and Paxlovid. While these 
treatments can manage symptoms and potentially reduce disease severity, they do not provide a 
cure or prevent disease progression. A host-targeted therapeutic for COVID-19 would provide a 
novel approach to improving the standard of care for the disease. Host-targeted therapies are 


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designed to target the host’s cellular pathways and processes that the virus relies on for survival 
and replication, rather than directly targeting the virus itself. This approach has the potential to 
address and reduce the underlying mechanisms of COVID-19 pathogenesis and other viral disease 
severity (Mahajan, Choudhary et al. 2021; Dwek, Bell et al. 2022).  
For example, investigators at Tulane Primate Research Center have completed two non-human 
primate studies in which the safety and efficacy of SLV213 were evaluated. Data from African 
Green monkeys inoculated with SARS-CoV-2 indicate a reduction in viral loads and a 
corresponding reduction in measures of lung pathology in treated animals compared to untreated 
controls (Frueh, Maneval et al. 2021). Histological analysis showed that treated animals were 
protected against ARDS-like pathology that was seen in untreated animals.  
Another potential advantage of host-targeted therapies is that they could be effective against 
multiple strains of the virus, including emerging variants, whereas traditional antiviral therapies 
may only target specific strains. Additionally, host-targeted therapies could reduce the potential 
for the development of drug resistance, which is a concern with traditional antiviral therapies. 
Host-targeted therapies could also be used in combination with other treatments, such as vaccines 
and antivirals, to provide a more comprehensive approach to COVID-19 treatment (Wagoner, 
Herring et al. 2022). For example, host-targeted therapies could be used in combination with 
antivirals to reduce the viral load and prevent the spread of the virus, while also targeting the host 
response to reduce inflammation and other damaging effects of the disease. 
Furthermore, host-targeted therapies could potentially address the long-term consequences of 
COVID-19, such as post-acute sequelae of SARS-CoV-2 infection or “long COVID.” These 
conditions are characterized by persistent symptoms and can have a significant impact on an 
individual’s quality of life. Host-targeted therapies could potentially target the underlying 
mechanisms of these conditions and provide relief for individuals who are experiencing prolonged 
symptoms. 
Additionally, the development of a therapeutic would help alleviate the burden on healthcare 
systems and resources that are currently overwhelmed by the number of COVID-19 cases. With 
an effective therapeutic, hospitalization rates could potentially be reduced, freeing up hospital beds 
and resources for those who need them most. The development of a host-targeted therapeutic for 
COVID-19 would be a significant advancement in the fight against this deadly disease and could 
save numerous lives. 
2.3.3 
Assessment of Potential Risks and Benefits 
• Available pre-clinical and clinical data support further clinical development of SLV213. 
The study aim is to determine the maximum tolerated dose of SLV213 after multiple doses 
in order to determine a possible therapeutic dose to test in an efficacy trial.  
• Risk will be minimized by housing the participants in a CTU and participants will be 
monitored throughout the trial by trained staff.  


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• Potential risks that were identified in animal studies were not evidenced in the Phase 1 
clinical trial. No DLTs or SAEs were noted/occurred in the Phase 1 SAD at the highest 
single dose tested (800 mg). There may be other side effects or risks that are not yet known. 
3. 
OBJECTIVES AND ENDPOINTS 
OBJECTIVE 
ENDPOINTS (OUTCOME MEASURES) 
Primary 
Primary 
To evaluate the safety and 
tolerability of multiple 
ascending doses SLV213 for 
7 days in healthy participants.  
Safety: Type, incidence, severity, and relatedness to study drug of all 
treatment-emergent systemic, laboratory and electrocardiographic 
(ECG) adverse events (AEs) and serious adverse events (SAEs) in 
each treatment cohort from the first dose (Day 1) through the last visit  
(Day 28 ± 2 days). 
Tolerability: Summarized by dose cohort and include:  
• 
Number (and percentage) of participants who: 
1) Terminate early or are withdrawn due to treatment-
emergent AEs assessed as related to intake of study 
medication.  
2) Have at least 1 treatment-emergent adverse event 
(TEAE), total and per dose level. 
3) Meet Grade 3 abnormal criteria for safety laboratory tests 
at least once post-dose. 
4) Meet Grade 3 abnormal criteria for vital sign 
measurements at least once post-dose. 
5) Meet Grade 3 criteria for safety electrocardiogram (ECG) 
parameters at least once post-dose. 
• 
Proportion of oral medication doses completed.  
Secondary 
Secondary 
To characterize the multiple 
dose pharmacokinetics (PK) 
of SLV213 in healthy 
participants. 
The following single-dose plasma PK parameters will be computed (if 
estimable) from the plasma total concentration-time data over the  
12-hour period following the morning dose on Day 1 for each cohort: 
• 
Cmax: Observed maximum concentration 
• 
Tmax: Time of maximum concentration (h) 
• 
Cmin: Observed minimum concentration at the end of the 
dosing interval 
• 
AUC(0-t): Area under the plasma concentration - time curve 
(AUC) to the last time with a concentration greater than or 
equal to the validated limit of quantitation of the assay 
• 
AUC(0-∞): Area under the plasma concentration-time curve to 
infinity 
• 
AUC(0-12): Area under the plasma concentration - time curve 
from 0h (pre-dose) to 12 h after dosing 


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OBJECTIVE 
ENDPOINTS (OUTCOME MEASURES) 
• 
AUC(0-last): Area under the plasma concentration - time curve 
from time zero to the last concentration above the lower limit 
of quantitation   
• 
AUC(0-tau): Area under the plasma concentration - time curve 
to the end of the dosing interval 
• 
t1/2: Terminal half-life 
• 
CLT: Total clearance 
• 
Ke: terminal phase elimination rate constant 
• 
Vd: Volume of distribution 
• 
Dose-normalized exposure parameters (AUC(0-tau)/Dose and 
Cmax/Dose) 
The following multiple-dose plasma PK parameters will be computed 
(if estimable) from the drug total concentration-time data over the  
48-hour dosing interval following the evening dose on Day 7 for each 
cohort. 
• 
Cmax,ss: observed maximum concentration at steady state 
• 
Cmin,ss: observed minimum concentration at the end of the 
dosing interval at steady state 
• 
Cavg: calculated average concentration during the dosing 
interval 
• 
Tmax,ss: Time of maximum concentration (Cmax) at steady state 
• 
Tmin: Time to minimum concentration (Cmin) 
• 
AUC(0-48),ss:  area under the plasma concentration - time curve 
from 0h (pre-dose) to 48 h after dosing at steady state 
• 
AUC(0-tau),ss: Area under the plasma concentration - time curve 
to the end of the dosing interval at steady state  
• 
t1/2: Terminal half-life  
• 
CLT: Total clearance 
• 
Vd,ss: Volume of distribution at steady state 
• 
Linearity Index: AUC(0-tau),ss (Day 7) / AUC(0-∞) (Day 1) 
• 
RAUC: Accumulation ratio for AUC estimated as AUC(0-tau) 
(Day 7) / AUC(0-tau) (Day 1) 
• 
RCmax: Accumulation ratio for Cmax estimated as Cmax (Day 7) 
/ Cmax (Day 1). 
• 
Dose-normalized exposure parameters (AUC(0-tau)/Dose and 
Cmax/Dose) 
Calculate trough plasma concentrations of total SLV213 at 12h after 
each morning and evening dose from Day 1 through Day 7. 
 
 
 


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4. 
STUDY DESIGN 
4.1 
Overall Design 
This Phase 1 double blind, placebo-controlled study will consist of three sequential inpatient 
cohorts of 12 healthy participants each (8 SLV213 and 4 placebo), at doses of 400 mg Q12h, 
600 mg Q12h, and 800 mg Q12h for 7 days administered PO. After each cohort has been dosed, a 
SRC will evaluate the safety of the regimen to Day 15 before proceeding to dose the next cohort. 
The study will be carried out in the US at a single clinical trial unit (CTU). Subjects who have 
consented to participate in the study, as evidenced by signing the informed consent form (ICF), 
will undergo study procedures to determine their eligibility to receive study drug.    
Upon meeting Inclusion/Exclusion criteria, participants will begin dosing with SLV213 or placebo 
per their allotted cohort. Participants will take their study drug prior to morning and evening meals. 
AEs will be noted and graded per the protocol Toxicity Grading Tables (See Appendix A). Visit 
assessments are shown in the schedule of events (Section 1.2) and Section 8.1 and Section 8.3. 
Participants will be assigned to receive their treatment according to the randomization carried out 
by the clinical site. For each dosing cohort, randomized participants will be assigned a unique 
number. Participants will be replaced if they withdraw or are withdrawn prior to Day 1 of 
treatment. The replacement participant would receive the same treatment that the participant being 
replaced would have received. A unique number will be the only participant identifier used on all 
sample collections and return of results. The site’s unblinded pharmacist or qualified designee will 
provide each participant’s study drug to blinded clinical staff at the participating site. All doses 
will be administered to the participant at the site by delegated staff under the supervision of 
licensed clinical staff authorized to administer study drug (PI, or sub-investigator or licensed 
clinicians listed on Form FDA 1572). The investigational drug blind is maintained by the 
dispensing pharmacist through a randomization schedule. 
A schematic of the study design is presented in Section 1.3. The schedule of activities is in 
Section 1.2. 
Full details about timing of analyses are found in Section 9.3.2. 
Details of the SMC oversight are found in Section 10.1.6. 
4.2 
Dose Escalation 
Participants will be enrolled in MAD cohorts. Dosing to the next cohort will be done sequentially 
only after the safety assessments to Day 15 have been completed to ensure adequate time for 
review of all available safety and tolerability data and the safety review committee (SRC) confirms 
that Halting Criteria have not been met.  
4.3 
Scientific Rationale for Study Design 
Given that the present study constitutes a follow-up to a completed SAD Phase 1 safety trial, a 
placebo control will also be utilized for the current MAD study. In light of this, healthy volunteers 


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aged 18 - 65 will be selected in a randomized fashion to constitute a representative sample of the 
broader population affected by COVID-19. Due to the MAD nature of this trial, the study will 
allow for an assessment of safety and PK of multiple doses of SLV213 over a period of 7 days.  
4.4 
Justification for Dose 
Selva has conducted a Phase 1 randomized double-blind placebo-controlled single ascending dose 
study in healthy volunteers to evaluate the safety, tolerability, and PK of SLV213 following oral 
administration (Study SLV213-01). Following randomization, five cohorts of 8 participants each 
(6 active, 2 placebo) received a single dose of the active compound SLV213 or placebo at 50 mg, 
100 mg, 200 mg, 400 mg, or 800 mg PO. A SRC evaluated the blinded results of each successive 
cohort before proceeding to dose the next cohort. Although a clinically significant episode of 
orthostatic hypotension was observed 30 min after dosing in one participant at the 200 mg dose 
level, this was not seen in this participant at subsequent time points, nor in any other participant at 
the 400 mg or 800 mg dose levels. The SRC therefore concluded that no DLT had been seen at 
any of the dose levels. Pharmacokinetic analyses demonstrated dose dependent Cmax and AUC. 
Preliminary modeling of 400 mg and 800 mg BID using predicted blood levels showed exposures 
comparable to concentrations measured in preclinical efficacy models. It is therefore concluded 
that 400 mg Q12h, 600 mg Q12h and 800 mg Q12h dosing should be well tolerated. Further 
description of the results of the SLV213-01 study is provided in the IB. 
5. 
STUDY POPULATION 
This study will enroll healthy volunteers 18-65 years old. Participants will be enrolled in an 
equitable way with best practices to balance sex and age applied to the study population. 
Recruitment of not more than 5/3 or less than 3/5 M/F ratio for each experimental group and not 
more than 3/1 or less than 1/3 M/F ratio for each placebo group may be obtained. Should a 
participant replacement be necessary within a cohort, the replacement participant will receive the 
same treatment, and attempts will be made to be of the same gender as the withdrawn participant. 
Participant Inclusion and Exclusion Criteria must be confirmed by a study clinician licensed to 
make medical diagnoses. No exemptions are granted on Participant Inclusion/Exclusion Criteria 
in DMID-sponsored studies.  
5.1 
Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
1. Provision of signed and dated informed consent form. 
2. Able to understand and willing to be available for all study visits and comply with all study 
procedures including Lifestyle Considerations (see Section 5.4) throughout the study.  
3. Male and Female individuals, age 18-65 inclusive at time of enrollment.  


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4. Good general health by medical history (MH), physical examination (PE), and vital signs 
(VS), clinical laboratory tests and ECG within normal reference range.1 
• 
Note 1: Lab exceptions include: lab test values that are within Grade 1 range per the 
Toxicity Table (Appendix A) are acceptable if not considered to be clinically 
significant by the investigator (PI, sub-investigator, or authorized clinician), with the 
exception of liver function tests (LFT) (transaminases ALT, AST, alkaline 
phosphatase (AP), total and direct bilirubin, serum creatinine, estimated glomerular 
filtration rate (eGFR) per the CKD-EPI formula, and urine protein, which must be 
within the laboratory normal reference range. 
• 
Note 2: Screening laboratory values that fall outside the laboratory normal reference 
ranges and the ranges are not listed within the Toxicity Table (Appendix A) (e.g., 
decrease aPTT) that are deemed Not Clinically Significant by the PI will be 
acceptable.  
5. Ability to take oral medication and be willing to adhere to the dosing regimen. 
6. Women of childbearing potential1 must have practiced or use true abstinence2 or use at 
least one acceptable primary form of contraception3 for specified periods4 before, during 
and after dosing.  
• Note 1: Not of childbearing potential – post-menopausal females (defined as having a 
history of amenorrhea for at least one year) or a documented status as being surgically 
sterile (hysterectomy, bilateral oophorectomy, salpingectomy, tubal ligation, or 
Essure® placement with a history of documented radiological confirmation test at least 
90 days after the procedure). 
• Note 2: True abstinence is 100% of the time without sexual intercourse (the male’s 
penis enters the female’s vagina). Periodic abstinence [e.g., calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of 
contraception). 
• Note 3: Acceptable forms of primary contraception include a monogamous relationship 
with a vasectomized partner who has been vasectomized for 180 days or more before 
the participant receiving the study product, tubal ligation, non-hormonal intrauterine 
device, and if in a monogamous relationship with a male partner who uses a barrier 
method without spermicide.  
• Note 4: Specified periods include at least 30 days prior to screening, during the period 
between screening and completion of dosing, and until at least 30 days following 
receipt of the last dose of study product.  
7. Women of childbearing potential must have a negative serum β-human chorionic 
gonadotropin (HCG) pregnancy test at screening and a negative urine HCG pregnancy test 
at check-in (Day-1) within 24 hours before receiving the initial study product. 


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8. Male participants receiving the study product must use acceptable contraception and refrain 
from donating sperm from the day of first dose until 30 days after the last dose or be 
vasectomized.1 
• Note 1: Acceptable contraception includes abstinence from intercourse with a female 
of childbearing potential or use of a male condom without spermicide when engaging 
in any activity that allows for the passage of ejaculate to a female during the 
intervention period and for at least 30 days after ending study dosing, or surgical 
sterilization for 180 days or more. 
9. Willing to avoid excessive physical exercise starting within 48 h prior to dosing and until 
discharge from the CTU on Day 9. 
10. No history of acute febrile or infectious illness for at least 7 days prior to the administration 
of study drug. 
5.2 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. Pregnant or lactating. 
2. History of any chronic disease that may increase risk to subject or interfere with endpoint 
assessment.1: 
Note 1: With the exception of stable chronic medical conditions that do not require 
prescribed oral or injectable medications (e.g., Type 2 diabetes managed by diet only). 
3. History of bradycardia, orthostatic hypotension or orthostatic tachycardia, Long COVID 
or history of dysautonomia.1 
Note 1: Exception is sinus bradycardia (HR <60 bpm) in healthy participants (e.g., 
conditioned athletes) could be enrolled per investigator’s clinical judgement. 
4. Known history of a clinically significant food or drug allergy/hypersensitivity including 
known allergy/hypersensitivity to ingredients of the study drug or placebo.  
5. Current seasonal allergies with ongoing symptoms for more than a week prior to dosing 
requiring glucocorticoids and/or frequent use of antihistamines for treatment. 
6. History of any clinically significant disease or disorder, medical/surgical procedure, or 
trauma within 4 weeks prior to initiation of administration of study product(s). 
7. History of any psychiatric condition that has required hospitalization in the last 12 months 
or subject is considered psychologically unstable by the investigator. 
8. History of any substance use disorder or positive urine drug screening (UDS) test for illicit 
substances listed in Section 8.1 at Screening or Check-in (Day -1)1. 


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• Note 1: Any approved medical use of amphetamines, barbiturates, benzodiazepines, 
cannabis, tricyclic antidepressants and opiates will not be acceptable.  
9. History of alcoholism or of binge1 or heavy alcohol drinking2 at any time in the 6 months 
before study product administration or positive urine alcohol test at Screening or Check-in 
(Day -1). 
• Note 1: Binge drinking is defined as 5 or more drinks during a single occasion if male, 
or 4 or more if female. 
• Note 2: Heavy drinking of alcohol is defined as consumption of more than 14 drinks of 
alcohol per week if male, or more than 7 drinks if female. 
10. History of ≥10 pack-years of nicotine product1 consumption in the 5-year period before 
screening, or positive urine cotinine screen at Check-in (Day -1)2. 
• Note 1: Nicotine products include cigarettes, e-cigarettes, pipe, cigar, chewing tobacco, 
nicotine patch. 
• Note 2: Positive urine cotinine at Screening is allowed if negative at Check-in  
(Day -1).  
11. Body mass index (BMI) ≤ 18 kg/m2 or ≥ 32 kg/m2, or weight ≤ 100 lbs at Screening. 
12. Prior exposure to SLV213 or K777 or K11777. 
13. Use of any prohibited prescription or non-prescription medication within 14 days or 5 half-
lives of the drug, whichever is longer, prior to study Check-in. (See Section 6.5) 
14. Use of any investigational drug product within 30 days or 5 half-lives (whichever is longer) 
before investigational product administration in this study. 
15. Planned participation in a clinical research study that requires treatment with a study drug, 
blood draws or other invasive assessments during the study period (screening until final 
visit). 
16. Blood or plasma donation of 500 mL within 3 months or more than 100 mL within 30 days 
before signing informed consent or planned donation prior to completion of this trial. 
17. Positive viral serology tests for Human Immunodeficiency Virus (HIV), hepatitis B virus, 
or hepatitis C virus (HCV) at screening1 (See Section 8.1) with one exception2: 
• Note 1: Viral serology tests include HIV 1 and HIV 2 antibodies, Hepatitis B virus 
surface antigen (HBsAg), and HCV antibodies. 
• Note 2: Do not exclude participants with HCV antibodies who have been successfully 
treated for Hepatitis C, do not take any treatment medications currently, do not use 
prohibited medications, have normal transaminases and are generally healthy. 


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18. Positive SARS-CoV-2 (COVID-19) molecular diagnostic test (Cue Care™ test) at Check-
in (Day -1).  
5.2.1 
Exclusion of Specific Populations 
Because the effects on the fetus are not known, pregnant women will not be eligible for the trial. 
Women of childbearing potential must utilize a highly effective method of contraception and will 
be required to have a negative urine pregnancy test on Check-in (Day -1) (within 24 h prior to 
initiation of study drug administration).  
Children will not be included in this trial as presently there are no safety or efficacy data in adults. 
Should the outcome of this trial be deemed acceptable, additional trials may be initiated, including 
those in other populations. 
5.3 
Inclusion of Vulnerable Participants 
Not applicable  
5.4 
Lifestyle Considerations 
During this study, participants are asked to: 
• Refrain from consumption of red wine, Seville oranges, grapefruit, or grapefruit juice, 
[pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices] from 7 days before the start 
of the study until discharge on Day 9.  
• Refrain from alcohol use 7 days before starting dosing and for the duration of the trial.  
• Refrain from using nicotine products from a week before starting dosing to discharge from 
the inpatient phase on Day 9. 
• Refrain from treatment with any prescription medications including medications known to 
be strongly metabolized by CYP3A4 or CYP2D6 or inhibit or induce both these enzymes 
for 14 days or 5 half-lives of the drug, whichever is longer, prior to starting dosing and for 
the duration of the trial. (See Appendix C for a partial list of drugs. CTU to obtain a careful 
medication history.) 
• Refrain from illicit (non-medical) use of amphetamines, barbiturates, benzodiazepines, 
cocaine, opiates, cannabis, and nicotine.  
• Any approved medical use of tricyclic antidepressants, amphetamines, barbiturates, 
benzodiazepines, opiates, and cannabis will not be acceptable.   
• Refrain from over the counter (OTC) non-prescription medications, supplements such as 
vitamins and herbal supplements (e.g., Saint John’s Wort) for at least 14 days or 5 half-
lives of the drug, whichever is longer, prior to starting dosing with study drug and for the 
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• Refrain from eating or drinking anything hot or cold within 10 minutes prior to taking oral 
temperature. 
• Refrain from consuming food or drink containing poppy seeds within 72 h of the screening 
visit and the Check-in (Day -1) visit as this could cause a false positive urine drug screen 
result. 
• Agree to Section 5.1 inclusion criteria relating to pregnancy, contraception, or sexual 
activity, and to Section 5.2, exclusion criterion relating to breastfeeding. 
• Abstain from strenuous exercise within 48 h prior to dosing, for the duration of the 7 days 
of dosing and 2 days of in-patient follow up until discharge on Day 9. Participants may 
participate in light recreational activities (e.g., watching television, reading) during those 
periods of the study. 
• After enrollment in this study (but before Day 1 of this study), the participant should notify 
study staff of their intention to enroll in any other clinical study prior to enrollment in that 
study. 
• Agree to consume food and beverages served by the CTU. Carry-out is not permitted. 
• Agree to abide by the restrictions on food and fluid intake before and after each dose. (See. 
Section 6.2.5) 
5.5 
Screen Failures 
After the screening evaluations have been completed, the PI, sub-investigator or authorized 
clinician is to review the inclusion/exclusion criteria and determine the participant’s eligibility for 
the study. 
Only the following information will be collected on screen failures: demographics (age, screen 
number, sex, ethnicity, and race) and reason(s) for ineligibility. Participants who are found to be 
ineligible will be told the reason for ineligibility. 
A participant may be rescreened if there is a transient disease status or short-term treatment with 
a medication within exclusionary window and the eligibility criteria could be met by rescreening 
at a later date. No participant may be screened more than twice due to a screening failure result as 
defined above. All other individuals who do not meet the criteria for participation in this study 
may not be rescreened for the study. (See Section 8.1.4). 
5.6 
Strategies for Recruitment and Retention 
5.6.1 
Recruitment 
Potential participants will learn about the study via Institutional Review Board (IRB)-approved 
recruitment strategies, including direct mailing, recruitment from an IRB-approved trial registry 
and local advertisements/flyers. Recruiting may begin with a brief IRB-approved telephone call 
between study staff and the potential participant. Information about the study will be presented to 


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potential participants, questions about their health and ability to comply with the study visit 
schedule will be asked of potential participants to determine eligibility. Information about the 
participant may be recorded from interviews or medical records. Appointments will be made at the 
research clinic for potential participants who are interested in further screening procedures and 
additional protocol-specific information.  
5.6.2 
Retention 
Study retention strategies will include education and explanation of the study schedule and 
procedures during screening and enrollment visits and restriction of enrollment to persons who can 
attend all study visits. Participants will be reminded of subsequent visits during each visit, and 
study staff will contact participants for follow up appointments. Study staff will contact 
participants who miss appointments to encourage them to return for completion of safety 
evaluations. 
5.6.3 
Compensation Plan for Participants  
Participants may be compensated for their participation in this trial. Compensation will be in 
accordance with local IRB requirements, and participant to IRB approval. Reimbursements will 
be disbursed at specific timepoints during the study with the amount contingent on completing 
study procedures. 
5.6.4 
Costs 
There is no cost to participants for the research tests, procedures, and study product while taking 
part in this trial. Procedures and treatment for clinical care may be billed to the participant, 
participant’s insurance or third party.  
6. 
STUDY PRODUCT 
6.1 
Study Product(s) and Administration 
6.1.1 
Study Product Description 
In this protocol, the term study drug refers to all or any of the drugs defined below: 
Product 1: SLV213 in 100 mg capsules 
SLV213 drug substance (K777) is 4-methylpiperazine-1-carboxylic acid [1- (3-benzenesulfonyl-
1-phenethyl- allylcarbamoyl)-2-phenylethyl]-amide) as a hydrochloride salt. SLV213 is a white to 
tan powder of the drug substance without excipients or stabilizer that will be packed into Swedish 
orange opaque size 1 capsules. It is an investigational drug product that is being used in accordance 
with approved labeling.  
Product 2: Matched Placebo  
Placebo for SLV213 drug product is manufactured as microcrystalline cellulose in a size 1 orange 
hard gelatin capsule. 


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6.1.2 
Dosing and Administration 
Cohort 
Product 
Name 
Dose 
Route 
Frequency of 
Administration 
Duration of 
Treatment 
1 
SLV213 
400mg 
(4x 100mg capsules) 
Oral 
Q12 hours 
7 days 
2 
SLV213 
600mg 
(6x 100mg capsules) 
Oral 
Q12 hours 
7 days 
3 
SLV213 
800mg 
(8x 100mg capsules) 
Oral 
Q12 hours 
7 days 
 
Cohort 
Product 
Name 
Dose 
Route 
Frequency of 
Administration 
Duration of 
Treatment 
1 
Matched 
Placebo 
4 capsules 
Oral 
Q12 hours 
7 days 
2 
Matched 
Placebo 
6 capsules 
Oral 
Q12 hours 
7 days 
3 
Matched 
Placebo 
8 capsules 
Oral 
Q12 hours 
7 days 
Participants will take their study drug prior to morning and evening meals in the fasted state with 
at least 240 mL (8 fluid ounces) or more of tap or bottled water under the supervision of the site 
staff.  
6.1.3 
Dose Modifications 
Dose modifications are not planned unless mandated by the SMC. 
6.1.4 
Criteria for Redosing 
Participants will not be re-dosed outside of the standard schedule of events.  
6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 
Acquisition 
Product 1: SLV213 
Will be provided by Selva Therapeutics to the DMID Clinical Materials Services (DMID CMS). 
Product 2: Matched Placebo 
Will be provided by Selva Therapeutics to the DMID CMS. 
Study products (SLV213 and placebo) from DMID CMS will be distributed to the CTU upon 
request and approval from DMID. 
DMID Clinical Materials Services Contract 
Fisher BioServices 


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20439 Seneca Meadows Parkway 
Germantown, MD 20876 
6.2.2 
Accountability 
Product 1: SLV213 
The participating site PI is responsible for study product distribution and disposition and has 
ultimate responsibility for study product accountability. The participating site PI may delegate to 
the participating site’s research pharmacist responsibility for study product accountability. The 
participating site’s research pharmacist will be responsible for maintaining complete records and 
documentation of study product receipt, accountability, dispensation, storage conditions, and final 
disposition of the study product(s).  
Study product accountability records and dispensing logs should include, but are not limited to the 
following:  
• DMID protocol number 
• Name 
• Dosage form 
• Strength of the study product 
• Capture bottle numbers assigned sequentially by the pharmacists as bottles are used 
(number uniquely, do not start over at 1 or repeat numbers) 
• Manufacturer or other source 
• Control, lot number, or other identification number 
• Expiration or retest date 
• Date of receipt of the study product 
• Quantity received from supplier; participant identification number 
• Quantity dispensed as amount or dose per participant 
• Balance of study product currently available 
• Disposition of study product if not dispensed to a study participant (e.g., retuned to supplier 
as per protocol) 
• Date of study product preparation/administration 
• Time of product administration to the participant will be recorded on the appropriate 
subject record.  
All study product(s), including the amount of SLV213, whether administered or not, must be 
documented on the appropriate study product accountability record or dispensing log. The 


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sponsor’s monitoring staff will verify the participating site’s study product accountability records 
and dispensing logs per the DMID-approved Clinical Monitoring Plan. 
Once all participant dosing is complete, the pharmacy staff should retain the remaining product 
and complete study product accountability procedures in accordance with site-specific standard 
operating procedures. This applies to unused SLV213 bottles and/or capsules. Upon completion 
of the trial or termination of the study and after the final monitoring visit, any remaining unused 
test article will be returned to Selva in accordance with the disposition plan provided by the DMID 
Clinical Project Manager.  
Product 2: Matched Placebo  
Placebo will be supplied and documented in the same manner as the study product listed above. 
6.2.3 
Formulation, Appearance, Packaging, and Labeling 
Product 1: SLV213 
SLV213 drug product is manufactured as size 1 orange hard gelatin capsules containing 100 mg 
K777. SLV213 drug product (100-mg dosage strength) is packaged at 30 capsules per bottle in 
40cc high density polyethylene (HDPE) bottles with a desiccant (silica gel pack) and secured with 
a 33 mm child-resistant closure and induction foil seal.  
Figure 2: Structure of K777 
 
 
Table 1: Drug Substance Characteristics 
Attribute 
Result 
Appearance 
White powder 
Molecular weight 
611.19 (574.73 free base) 
Molecular formula 
C32H39ClN4O4S 
Calculated pKa 
7.02 
 
Product 2: Matched Placebo  
Placebo for SLV213 drug product is manufactured as microcrystalline cellulose in a size 1 orange 
hard gelatin capsule. The capsules are packaged in 40 cc HDPE bottles closed with a 33 mm child 
resistant cap and an induction foil seal. One 0.75 g silica gel desiccant Pillowpak is added to each 
bottle. The composition of the placebo is provided in Figure 3.  


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Figure 3: Structure of Matched Placebo 
 
 
 
 
 
Table 2: Matched Placebo Composition 
Component 
Quality 
Quantity per Capsule 
Microcrystalline cellulose 
NF, Ph. Eur., JP 
62.5 mg 
Size 1 orange gelatin capsule 
Per manufacturer’s specification 
1 capsule 
6.2.4 
Product Storage and Stability 
Drug will be kept in HDPE bottles stored at the appropriate temperature listed in the storage 
conditions section before administration. 
Product 1: SLV213 
Investigational drug must be kept in a limited-access, secure place at controlled room temperature 
between (15-25°C [59-77˚F]) and protected from light until it is used or returned to the sponsor or 
designee for destruction. Investigational drug must be stored under the conditions specified on the 
label and remain in the original container until dispensed. A daily temperature log of the drug 
storage area must be maintained every working day while the drug is still in the CTU. 
Product 2: Matched Placebo 
Placebo must be kept in a limited-access, secure place at controlled room temperature between 
(15-25°C [59-77˚F]) until it is used or returned to the sponsor or designee for destruction. Matched 
placebo must be stored under the conditions specified on the label and remain in the original 
container and protected from light until dispensed. A daily temperature log of the matched placebo 
storage area must be maintained every working day while the matched placebo is still in the CTU. 
6.2.5 
Preparation 
The unblinded pharmacist will prepare each dose from the HDPE bottles. Participants will receive 
dosing Q12h daily (morning and evening) on Days 1 to 7 at the CTU. The first dose of the study 
drug will be received in the morning of Day 1 and every subsequent dose administered every 12 h 
(± 15 min). The study product will be administered orally with at least 240 mL (8 fluid ounces) of 
water by blinded delegated site staff under the supervision of the blinded PI or sub-investigator or 
authorized clinicians listed on Form FDA 1572.  
All participants are required to fast for at least 8h before and 4h after the morning dose on Day 1 
and the evening dose on Day 7, and at least 2h before dose to 1h after evening dose on Day 1, both 


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doses on Days 2-6 and the morning dose on Day 7. The meal schedule will be structured to restrict 
meals before each dose as required. Standard meals are provided at the appropriate times before 
and after drug administration and the time of last meal consumed before and after each dose will 
be recorded. Fluids will be allowed except at least 1h before and 1h after each scheduled dose.  
6.3 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1 
Treatment Assignment Procedures 
Per ICH guideline E6(R2): GCP, screening records will be kept at the participating site to 
document the reason why an individual was screened, but failed trial entry criteria. The reasons 
why individuals failed screening will be recorded in the Statistical and Data Coordinating Center’s 
(SDCC) Advantage eClinicalSM (Electronic Data Capture System). 
Consented participants who met eligibility criteria at screening and confirmed to be eligible at 
check-in (Day-1) Visit will be enrolled into the study. 
6.3.2 
Randomization 
Participants in each cohort will be randomized 2:1 to drug versus placebo before dosing on Day 1 
and receive assigned treatment at each dose.  
6.3.3 
Blinding and Masking Procedures 
The study will be double-blinded, placebo-controlled. Placebo capsules are made to mimic study 
drug to avoid unblinding. Study drug and placebo are in matched bottles with matched capsule 
sizes. Administration of drug and placebo is controlled by the CTU as designated on Delegation 
of Authority Log.   
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational drug is essential for the medical treatment of the participant. If 
possible, the DMID MM and DMID MO should be contacted before the investigational drug blind 
is broken to discuss the need for unblinding.  
For unblinding a participant, the investigational drug blind can be obtained by contacting the 
dispensing pharmacist. The emergency unblinding information will be obtained from the SDCC. 
The sponsor (DMID, the Investigational New Drug [IND] Application holder) must be notified as 
soon as possible if the investigational drug blind is broken. The date, time, and reason the blind is 
broken must be recorded in the source documents. Details will be presented in the study-specific 
Manual of Procedures (MOP).  
6.4 
Study Intervention Compliance 
Participants will be observed at the time of dosing by a member of the clinical research team who 
is licensed and authorized to administer study product (PI, sub-investigator or delegated clinicians) 
listed on Form FDA 1572. Each dose of study product will be administered by a member of the 
clinical research team that is delegated to administer the study product.  


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Study product administration date and time will be documented on site source document and 
recorded on the appropriate electronic Case Report Form (eCRF). 
6.5 
Concomitant Therapy 
For this protocol, a prescription medication is defined as a medication that can be prescribed only 
by a properly authorized/licensed clinician. Medications to be reported in the Case Report Form 
(CRF) are concomitant prescription medications, and supplements. 
Information about prior medications, including hormonal contraceptives, taken by the participant 
in the 30 days prior to initiation of dosing with study product(s) will be recorded on the appropriate 
CRF. 
Concomitant medications include all medications (prescription and OTC medications, 
supplements, and vaccines), except study products, taken by the participant from the time of the 
first dose of study product(s) to the end of the study. At each study visit following dosing, including 
telephone calls, participants will be queried about new ConMeds and changes to existing 
medications. The following medications are prohibited during the study: 
• No medications are allowed after enrollment until completion of all study assessments with 
the exception of up to 1,000 mg acetaminophen daily for up to 3 days for the relief of 
common, temporary symptoms (headache, musculoskeletal pain, etc.) if approved by the 
site PI or authorized clinician. 
• Any medications known to be strongly metabolized by CYP3A4 or CYP2D6, or strongly 
inhibit or induce these enzymes might interfere with the evaluation of the investigational 
product and should not be used by the participant for 14 days or 5 half-lives of the drug, 
whichever is longer, prior to and during the study. (See Appendix C for a partial list). 
• Participant should refrain from OTC supplements, such as vitamins and herbal supplements 
(e.g., Saint John’s Wort), for 14 days or 5 half-lives of the supplement, whichever is longer, 
prior to and for the duration of the trial. 
In the event medical conditions dictate the use of medications during the in-patient period, 
appropriate treatment may be prescribed by authorized/licensed clinician. For events during the 
out-patient period, participants are encouraged to notify the investigator or, if they seek care by 
their personal healthcare provider, to comply with the course of therapy as prescribed and inform 
the study investigator as soon as practical.  
Any drug or vaccine used or received by the participant during the trial should be recorded on the 
appropriate CRF. 
For additional lifestyle restrictions, see Section 5.4.  
6.5.1 
Rescue Medicine 
Not Applicable.  
6.5.2 
Non-Research Standard of Care 


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If at any time during the inpatient facility stay, the participant develops illness requiring medical 
care that is beyond the care available in this facility, the participant will be transferred to a hospital 
capable of providing this level of care. The hospital and physicians accepting the participant for 
care will be informed of the participant’s participation in this research study so that the participant 
can be managed according to appropriate precautions per standard of care. 
7. 
STUDY INTERVENTION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Halting Criteria and Discontinuation of Study Intervention 
7.1.1 
Study Halting Criteria 
Cohort Halting Rules 
If any of the following criteria occur, dosing of subsequent participants in the cohort will be halted 
and could resume after blinded review by the SMC at an ad hoc meeting: 
• One participant experiences a treatment-related SAE assessed as related to the 
investigational study product, with the exception of accidental injury. 
• One participant experiences a treatment-related Grade 3 or higher adverse event. 
• Two or more participants experience a Grade 2 or higher systemic AE in the same higher 
level group term (HLGT) per MedDRA classification assessed as related to the study 
product.  
• One participant develops QT prolongation on a post dose ECG, defined as a QT interval with 
Fridericia correction method (QTcF) > 500 msec (Grade 3).  
• One participant develops clinically significant abnormal liver function tests as follows: 
o ALT and/or AST > 5 × upper limit of normal (ULN) in the absence of a total bilirubin 
increase. 
o ALT and/or AST elevations > 3 × ULN in the presence of a total bilirubin increase > 2 
× ULN or an international normalized ratio (INR) > 1.5 without findings of cholestasis 
or other alternate etiology to explain the elevations (i.e., “Hy’s Law cases”). 
o Symptomatic ALT and/or AST elevations > 3 × ULN with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or 
eosinophilia (> 5% of total WBC count). 
7.1.2 
Individual Halting Criteria 
A participant will be discontinued from further dosing and the cohort dosing will be stopped for 
the SRC review or SMC ad hoc meeting if any of the following criteria are met: 


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• A participant experiences an SAE, regardless of the relationship to the study product, with 
the exception of accidental injury. 
• A participant experiences clinically significant Grade 3 or higher AE (laboratory or 
systemic) assessed as related to the study product. 
• A participant develops anaphylaxis within 24 hours after receiving the study product. 
• A participant experiences a suspected drug-related hypersensitivity AE Grade 2 or higher. 
• A participant develops QT prolongation on a post dose ECG, defined as a QT interval with 
QTcF > 500 msec (Grade 3).  
• In the opinion of the PI, further dosing would not be in the best interest of the participant. 
7.1.3 
Follow Up for Participants Who Discontinued Study Intervention 
Discontinuation from the investigational drug product does not mean discontinuation from the 
study, and remaining study procedures should be completed as indicated by the study protocol. If 
a clinically significant finding is identified (including, but not limited to changes from baseline) 
after enrollment, the PI, sub-investigator, or licensed clinician will determine if any change in 
participant management is needed. Any new clinically relevant finding will be reported as an AE. 
All other events will be monitored and collected even when drug administration has been 
discontinued. 
See SOA, Early Termination (ET) (Section 1.2) for data to be collected at the time of study 
intervention discontinuation.  
7.2 
Participant Withdrawal from the Study and Replacement 
7.2.1 
Participant Withdrawal from the Study 
Participants are free to withdraw from participation in the study at any time upon request for any 
reason.  
An investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
• Participant becomes pregnant.  
• Study non-compliance that in the opinion of the investigator poses an increased risk (i.e., 
missing safety labs), or compromises the validity of the data.  
• If any clinical, laboratory or ECG abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant. 
• If the participant met an exclusion criterion for participation in the study (either newly 
developed or not previously recognized) that precludes further study participation. 


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• Medical disease or condition, or new clinical finding(s) for which continued participation, 
in the opinion of the investigator might compromise the safety of the participant, interfere 
with the participant's successful completion of this study, or interfere with the evaluation 
of responses. 
• Participant lost to follow-up. 
Every effort should be made to encourage participants to remain in the study for the duration of 
their planned outcome assessments. Participants will be educated on the continued scientific 
importance of their data, even if they discontinue study drug. 
Unless the participant withdraws consent, those who discontinue study drug early will remain in 
the study.  
If the participant agrees, every attempt will be made to follow all AEs through resolution (return 
to baseline) or until defined as stable. 
The reason for participant discontinuation or withdrawal from the study, whether the decision was 
made by investigator or participant, and the extent of the withdrawal (i.e., whether participant 
withdrew from all components of research study or just the study intervention) will be recorded 
on the CRF.  
The investigator will inform the participant that already collected data will be retained and 
analyzed for this study even if the participant withdraws from this study. Biospecimens collected 
for the current study will still be used to analyze the study endpoints. 
7.2.2 
Participant Replacement 
Participants who withdraw or are withdrawn from this study after receiving at least one dose of 
the study product and prior to Day 9 for reasons not related to TEAEs or study drug intolerance 
may be replaced, at the recommendation of the Site PI and concurrence by the DMID MO, with a 
participant who will receive the same treatment as the withdrawn participant, and an effort will be 
made to also be of the same gender as the participant who is replaced. The SDCC must be contacted 
prior to enrolling any replacement participants.  
7.3 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she is unable to be contacted by the study 
site staff after three attempts. Extensive effort (i.e., generally three documented contact attempts 
via telephone calls, e-mail, etc., made on separate occasions) will be made to locate or recall the 
participant, or at least to determine the participant’s health status. These efforts will be documented 
in the participant’s study file. 
 
 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
Screening Procedures 
There is a small amount of risk to participants who report that they are in good health but have an 
unknown health problem at the time of screening. Screening assessments can occur up to 28 days 
before the participant’s first treatment (Day 1) and may occur in one or two visits. At the first visit, 
and prior to any other study-related activities, a delegated staff member at the participating site 
will provide the participant with detailed study information and will obtain written informed 
consent.  
Individuals will have the opportunity to ask questions. The Site PI or authorized sub-investigator 
or clinician will also be available to answer questions. The site PI will review and approve 
eligibility criteria. 
Some or all of the following assessments are performed during the Screening visit and confirmed 
at Check-in (Day -1) to determine eligibility requirements as specified in the inclusion 
(Section 5.1) and exclusion criteria (Section 5.2). Assessments are listed in the SOA (Section 1.2). 
Guidelines for documentation will be reported in the study-specific MOP and eCRF Instructions.  
8.1.1 
Clinical Procedures and Evaluations 
 
• Demographics: Demographic information (date of birth, gender, ethnicity, and race) will 
be recorded on the subject’s source documents and eCRF at Screening Visit. Name, 
address, phone number, and emergency contact information will be documented in the 
source documents only. 
• Eligibility Review: A review of study inclusion and exclusion criteria will be completed 
within 28 days before study drug dosing at the Screening and Check-in  
(Day -1) visits. Confirmation of eligibility for dosing will be performed before dosing on 
Day 1. 
Screening failures and the reason for failure to meet the study eligibility requirements will 
be documented in source documents and eCRFs.  
• Medical History (MH): A review of pertinent MH that may impact study participation 
will be obtained by direct interview of the subject. The MH will capture current disease 
processes, past disease processes, history of hospitalization, and history of surgery. 
Participants will be queried regarding a history of significant medical disorders of the head, 
eyes, ears, nose, throat (HEENT), mouth, skin, the cardiovascular, respiratory, 
gastrointestinal, renal, urological, nervous, hematological, lymphatic, endocrine, 
musculoskeletal and genital/reproductive systems. A history of allergies including allergies 
to medications, medication history, and history of substance and alcohol abuse will be 
obtained.  


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Participants will be queried about a history of orthostatic hypotension, any symptoms 
associated with position change, syncope or near syncope (i.e., dizziness, fainting), and 
symptoms related to transition from lying down to standing up (such as fast heart rate, 
dizziness, or fainting). 
The MH will be obtained at Screening Visit and updated on Day -1 (Check-in) and before 
dosing on Day 1. After start of study drug dosing, any worsening of pre-dosing MH or new 
symptoms will be evaluated and reported as TEAEs. 
• Concomitant Medications (ConMeds): Medication history will include prescription 
medication, including contraceptives, and non-prescription drugs, vitamins, supplements 
and herbal medication, and recent vaccinations including for COVID-19 used in the recent 
past, and include medications that are prohibited prior to dosing. (See Section 6.5).  
Medications history will be obtained at Screening, Check-in (Day-1) and updated prior to 
dosing on Day 1. Medications taken prior to dosing will be recorded as “Prior 
Medications”.  
• Physical Exam (PE): A Complete PE - except genital, breast, pelvic and rectal exams - 
will assess general appearance and the following body systems: (1) eyes; (2) ears, nose, 
throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) 
dermatologic system; (7) extremities; (8) musculoskeletal system; (9) lymph nodes; and 
(10) neurological/neurosensory examination.  
Any abnormal finding on a screening examination assessment must be assessed as Not 
Clinically Significant (NCS) or Clinically Significant (CS) by the investigator (PI, sub-
investigator, or authorized clinician) listed on Form FDA 1572 and recorded in the source 
document and eCRF. 
A complete PE will be performed at the Screening and Check-in (Day -1) visits. 
• Body Mass Index (BMI): Consists of weight and height measured while wearing indoor 
clothing and with shoes off. The BMI is calculated using metric units according to the 
following formula: BMI = weight (kg)/[height (m)]2. 
BMI will be measured and recorded at Screening. A subject will be excluded if BMI is 
≤ 18 kg/m2 or ≥ 32 kg/m2, or weight ≤100 lbs at Screening.  
Body weight only (i.e., not including height or recalculation of BMI) will also be measured 
on Day-1  
• Vital Signs (VS): Include body temperature (oral), BP (resting more than 5 min), RR, and 
HR. Heart rate and BP will be measured at rest with the participant supine for at least 
5 minutes.1. Repeat measurements with the participant supine may be allowed if the first 
measurement is abnormal (See Section 8.1.4) 


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Note 1: Orthostatic blood pressure and heart rate will be obtained and recorded after the 
supine VS, while a participant is in standing position with measurements taken at 1 minute 
± 15 seconds and 3 minutes ± 15 seconds after standing. 
VS will be measured before any blood draws at the Screening Visit and Check-in  
(Day -1).  
• Electrocardiogram (ECG): Standard twelve-lead ECG using an ECG machine that 
automatically calculates the HR and measures PR interval, RR interval, QRS interval, QT 
interval, and QT interval corrected by the Fridericia (QTcF) formula. QTcF may also be 
calculated manually by the site. Participants should be in a supine position and should have 
an approximate 10-minute rest period prior to the test. ECGs will be recorded before any 
blood draws. 
The ECGs will be reviewed by the PI or authorized sub-investigator or study clinician 
(listed on FDA Form 1572) for ECG interval and for morphologic abnormalities. If a 
question regarding ECG interpretation arises, the study investigators will have the ECG 
reviewed by a cardiologist. To be eligible for participation, the PR and QTcF interval must 
be within protocol reference range criteria (as shown in Appendix A) at Screening and 
Check-in (Day -1) and there must be no clinically significant ECG abnormalities. 
• ECGs will be obtained at the Screening Visit and Check-in (Day -1). 
8.1.2 
Laboratory Evaluations 
Venipuncture schedule and blood volumes are shown in Section 1.2 and Appendix B, Table 3, 
respectively.  
• Clinical Laboratory Assessments: (Hematology, Coagulation, Chemistry and 
Urinalysis): Blood and urine samples for clinical laboratory tests will be collected at the 
Screening Visit and on Check-in (Day -1) to determine eligibility.  
Participants must be fasting at least for 4h before any blood draw for clinical laboratory 
assessments. These tests will include: 
o Hematology (HEM): Complete Blood Count with absolute differential cell count (CBC 
w/Diff). The panel will include total white blood cell count (WBC), absolute count for 
neutrophils, lymphocytes, monocytes, basophils, and eosinophils, red blood cell count 
(RBC), platelet count, and hemoglobin. 
o Coagulation (COAG): INR with prothrombin time (PT), activated partial 
thromboplastin time APTT). 
o Chemistries (CHEM): Albumin, blood urea nitrogen (BUN), calcium, phosphorous 
(inorganic), creatinine, estimated glomerular filtration rate (eGFR) calculated by the 
CKD-EPI formula, electrolytes (sodium, potassium, chloride, total carbon dioxide 
[CO2]), magnesium, glucose (fasting), total bilirubin, direct bilirubin, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase 


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(ALP), total protein, amylase, and lipase. 
o Urinalysis (UA): Routine dipstick testing of clean-catch urine for occult blood, protein, 
glucose, nitrite, bilirubin, specific gravity, and pH. 
- If urine dipstick is abnormal for blood, protein, glucose, and nitrites, urine 
microscopy will be performed (for WBC, RBC, bacteria, and other cell counts), 
and the results will supersede those of the dipstick UA. 
- UA can be deferred until after the end of menses. 
Clinical laboratory tests at the Screening Visit and Check-in (Day -1) should be in the 
normal reference range with exceptions. (See Section 5.2, Inclusion Criterion #4). 
Laboratory normal reference ranges are those included in the current version of the Manual 
of Procedures (MOP).  
Other Exceptions to screening laboratory tests’ normal reference ranges are: 
a. Labs performed as part of a panel but not included among the listed tests are to be 
recorded in the source record. Examples include direct bilirubin, RBC, hematocrit, 
mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean 
corpuscular hemoglobin concentration (MCHC), red cell distribution width 
(RDW), mean platelet volume (MPV), nucleated red blood cell count (NRBC CT), 
and % white blood cells types, which are included in a CBC with WBC differential, 
INR, and specific gravity and pH resulted by dipstick urinalysis (UA). If abnormal 
per the laboratory normal reference range, they are not exclusionary and are not to 
be graded per Toxicity table individually; however, the investigator would make a 
clinical decision about their clinical significance. 
b. Menstruating females with a positive dipstick UA or microscopic UA may be 
retested following cessation of menses. Gross blood in urine that is confirmed due 
to menses is not a TEAE (but is for all other reasons). 
• Viral Serology Testing: HIV antibody test (HIV 1 & HIV 2), Hepatitis B surface Ag 
(HBsAg, Hepatitis C virus (HCV antibody, and SARS-CoV-2 molecular diagnostic test 
(Cue Care™ test) for COVID-19. 
The HIV and hepatitis tests will be performed at the Screening Visit only and all results 
must be negative for study eligibility.  
The SARS-CoV-2 test will be performed at Check-in Visit (Day -1), and the result must 
be negative for study eligibility. 
• Pregnancy Test (females of child-bearing potential only): A serum β-HCG pregnancy 
test will be done at the Screening Visit and a urine pregnancy test will be done at Check- 
in (Day -1) within 24 hours before receiving the initial study product. The results must be 
negative for determining eligibility and dosing with study drug(s). 


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• Serum follicle stimulating hormone (FSH): The test will be performed to confirm post-
menopausal status in female participants at the initial Screening Visit only. 
• Urine Drug Screen (UDS): Urine drug screen to assess for illicit (non-medical) use of 
amphetamines, cocaine metabolites, barbiturates, benzodiazepines, opiates, cannabinoids, 
tricyclic antidepressants, and phencyclidine. Urine creatinine will be measured as part of 
the profile to assess quality of collected sample. 
UDS will be performed at Screening Visit and on Day -1. Results must be negative for 
study eligibility. Participants using any of these substances for medical reasons will also 
be excluded. 
• Urine Alcohol Test: The test will be performed at Screening and Check-in (Day -1). 
Results must be negative for study eligibility. 
• Urine Cotinine Test: The test will be performed at Screening and Check-in (Day -1). A 
positive result at Screening in a participant without history of heavy consumption of 
nicotine products is acceptable. The result of test done at Check-in (Day -1) must be 
negative for study eligibility.  
8.1.3 
Evaluation of Screening Data 
The overall eligibility of the participant to participate in the study will be assessed once all 
screening values are available. The screening process can be suspended prior to complete 
assessment at any time if exclusions are identified by the study team. 
Study participants who qualify for inclusion will be contacted and scheduled for a Check-in visit 
(Day-1) to evaluate continuing eligibility for enrollment within the window for enrollment. 
8.1.4 
Procedures to be Followed in the Event of Abnormal Clinical Laboratory Test 
Values or Abnormal Clinical Findings During Screening  
During screening, if a physiologic parameter, e.g., vital signs (VS) or clinical laboratory value, is 
outside of the protocol-specified range, then the measurement may be repeated if, in the judgment 
of the investigator, the abnormality is the result of an acute, short-term, rapidly reversible condition 
(e.g., stress, anxiety, or “white coat syndrome”) or if there is a technical problem with the 
measurement caused by malfunctioning or an inappropriate measuring device (i.e., inappropriate-
sized blood pressure cuff), or error in collecting, and processing the clinical laboratory sample). 
An abnormal laboratory value may be repeated once. An abnormal vital sign should be repeated 
as described below.  
Procedure followed for Abnormal Supine Vital Signs (Screening, Day -1, pre-dose on Day 1):  
• Abnormal supine VS that are either due to technical or procedural error or the result of an 
acute, short-term condition as assessed by the PI (e.g., stress, anxiety, white coat syndrome) 
may be repeated up to twice more at rest and at least 5 min after previous measurement.  


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• If the second measurement is abnormal, it will be reported at the highest grade/value of 
severity of the two measurements and will be used for assessment of eligibility (per 
Inclusion Criterion #4).   
• If the second measurement is normal, a third measurement will be taken at least 5 minutes 
after second measurement.   
• If the third measurement is normal, the subject is eligible. If the third measurement is 
abnormal, the value with the highest grade of severity between the first and the third 
measurements will be reported and will be used for assessment of eligibility (per Inclusion 
Criterion #4). 
Re-screening: 
Rescreening is not allowed, except in the following circumstances: 
• Prospective participants may not be re-screened due to laboratory values except to verify 
accuracy of an aberrant value. 
• A participant may be re-screened if there is a transient disease status (e.g., participant 
complained of a “cold or fever” and met a temporary delaying enrollment criterion of acute 
illness or fever), or if a protocol eligibility criterion that is not met at the initial time of 
screening, will be met by rescreening at a later date (e.g., a medication taken within 
exclusionary window at the time of first screening that would not be within exclusionary 
window at a later rescreen). 
• No participant may be screened more than twice due to a screening failure result as defined 
above.  
Participants who failed screening will be provided any of their abnormal clinical laboratory results 
if requested and will be counselled to follow up with their primary healthcare provider for further 
evaluation and treatment as needed.  
8.2 
Efficacy Assessments 
Not Applicable 
8.2.1 
Efficacy Evaluations 
Not applicable 
Management of Results 
Not Applicable  
8.2.2 
Exploratory Assessments 
Not Applicable 
 
 


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8.3 
In-Patient and Follow up Procedures 
The following assessments will be performed during the In-patient Treatment Period for evaluating 
the Safety and PK objectives of the study. (See also the SOA Section 1.2). Authorized clinicians, 
who are licensed to make medical diagnoses and listed on the Form FDA 1572, will be responsible 
for all study-related medical decisions. 
8.3.1 
Clinical Procedures and Evaluations 
• Medical History (MH): After start of study drug dosing, any worsening of pre-dosing MH 
or new symptoms, including orthostatic symptoms, will be evaluated and reported as 
TEAEs. 
An interim MH will be obtained by interview of participants for evaluation of TEAEs from 
Day 1 to the last study visit, and any changes since the previous clinic visit or telephone 
call after discharge from the CTU will be noted. The interim MH should include an 
assessment for new medical conditions and symptoms suggestive of Medically- Attended 
AEs (MAAEs) (see Section 8.5.3) and protocol specified adverse events of special interest 
(AESIs) (See Section 8.5.9). 
• Assessment of TEAEs and SAEs: Unsolicited AEs will be evaluated from the time of 
initial dosing to the last study visit (Day 28 ±2 days) (See Section 8.5). During the Inpatient 
treatment period, (Day 1 to Day 9), the participants will be monitored as inpatients and 
complete scheduled assessments. Following discharge on Day 9, CTU staff will contact 
the participants by phone on Days 15 (±2 days), 21(±2 days), and 28 (±2 days) and inquire 
about their well-being, the emergence of any AEs since the last visit and the use of any 
ConMeds. Based on the information collected, participants will be asked to return to the 
CTU for evaluation.  
• Concomitant Medications (ConMeds): No medications are allowed after enrollment 
until completion of all study assessments with the exception of up to 1,000 mg 
acetaminophen daily for up to 3 days for the relief of common, temporary symptoms 
(headache, musculoskeletal pain, etc.) if approved by the site PI or authorized clinician. 
(See Section 6.5 for prohibited medications during the study). 
• Physical Examination (PE): 
o A symptom-directed (focused) PE may be performed for evaluation of new symptoms 
reported from the time of admission on Day -1 to before the first dose on Day 1 and 
assessment of TEAEs at any time after dosing on Day 1 to the last study visit, focusing 
on orthostatic vital signs and symptoms. 
o A complete PE will be performed on Day 9 prior to discharge from the CTU. (See 
Section 8.1.1)  
Any abnormal finding on a PE performed after dosing on Day 1 must be assessed as Not 
Clinically Significant (NCS) or Clinically Significant (CS) by the investigator (PI, sub-


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investigator, or authorized clinician) listed on Form FDA 1572 and recorded in the source 
document and eCRF. 
• Vital Signs (VS) inclusive of orthostatic blood pressure and heart rate: Include body 
temperature (oral), BP (resting more than 5 min), RR, and HR. Heart rate and BP will be 
measured at rest with the participant supine for at least 5 minutes. VS will be measured 
twice daily within 30 min before and 2h (± 10 min) after each dose on Days 1 to 7, once 
daily in the morning on Days 8 and 9, or at ET. Abnormal VS may also be measured at 
unscheduled visits as needed for follow up of AEs. Repeat measurements with the 
participant supine may be allowed if the first measurement is abnormal (See 
Section 8.3.3).1 
Note 1: Orthostatic blood pressure and heart rate will be obtained and recorded after the 
supine VS, while the participant is in the standing position with measurements taken at 1 
minute ± 15 seconds and 3 minutes ± 15 seconds after standing.   
• ECG: A standard 12-lead ECG will be recorded, within 30 min before the morning dose 
on Day 4, on Day 8 before the 12h blood (plasma) PK collection after the evening dose on 
Day 7, or ET. Additional ECGs may be recorded as needed for the evaluation of TEAEs. 
The participant should be in a supine position and should have an approximate 10-minute 
rest period prior to ECG recordings. 
A physician (PI or coinvestigator) or clinician who is licensed to make diagnoses (listed on 
Form FDA 1572) will evaluate the ECG for any abnormalities in ECG intervals including 
QT/QTcF, and any morphologic abnormalities for clinical significance. If a question 
regarding ECG interpretation arises, the study investigators will have the ECG reviewed 
by a cardiologist. 
8.3.2 
Laboratory Evaluations 
• Clinical Laboratory Assessments:  
o Blood for HEM, CHEM, and COAG will be collected before the morning dose on 
Days 2, 4, and 6, and on Day 8, or ET for the evaluation of the same tests listed in 
Section 8.1.2. Clinical lab tests may also be performed at unscheduled visits as needed 
for follow up of AEs. Participants must be fasting at least for 4 h before any blood draw 
for clinical laboratory assessments. 
o UA will be collected before the morning dose on Day 4 and on Day 8, or ET (See 
Section 8.1.2) 
8.3.3 
Procedures to be Followed in the Event of Abnormal Clinical Laboratory Test 
Values or Abnormal Clinical Findings During Conduct of the Trial 
All abnormal clinical findings or abnormal clinical laboratory test values post treatment will be 
considered AEs and followed up as AEs. If a physiologic parameter, e.g., VS or clinical laboratory 
value, is outside of the protocol-specified range, then the measurement may be repeated if, in the 
judgment of the participating site PI or appropriate licensed sub-investigator or clinician, the 


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abnormality is the result of an acute, short-term, rapidly reversible condition (e.g., stress, anxiety 
or “white coat syndrome”) or other source of error (e.g., a technical problem with the measurement 
caused by malfunctioning, or an inappropriate measuring device (i.e., inappropriate-sized BP cuff), 
or error in collecting or processing the clinical laboratory sample. If the repeat measure is within 
normal range, the most accurate value will be used. Any abnormal parameters will be recorded in 
the medical record. 
Once dosed with study product, lab results that are above the upper limit of normal or below the 
lower limit of normal for the baseline reference ranges but are less than Grade 1 in the toxicity 
table, will not be graded and reported as outside the normal range. Lab results that were acceptable 
for enrollment within the Grade 1 toxicity range of the FDA toxicity tables will be graded as AEs 
if the on-study values are higher or lower than the baseline value and fall within the range of AEs 
with “increased” or “decreased” values. 
Procedure followed for Abnormal Supine Vital Signs (Post Dosing On Days 1 through 9, or 
ET): 
• Any time after the start of the oral dose administration, any abnormalities in supine VS that 
occur either due to technical or procedural error or the result of an acute, short-term 
condition as assessed by the PI (e.g., stress, anxiety, white coat syndrome) may be repeated 
twice more at rest, while the participant is in the supine position and at least 5 min of each 
other. 
• If the second VS is abnormal, then the highest severity grade between the first and second 
measurements will be used for assessment of TEAE per Appendix A. 
• If the second VS is normal, then a third repeat is to be taken at least 5 min of the previous 
measurement.   
• If the third value is abnormal, the highest grade of severity between the first and third 
measurements will be used for assessment of TEAE per Appendix A. 
8.3.4 
Blood sampling for Plasma SLV213 Assay during the In-patient Period and 
Serum for Future Research 
A validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) bioanalytical 
assay method for the quantitation of total SLV213 in plasma will be performed at the bioanalytical 
lab, KCAS.  
Blood (plasma) will be drawn at the following timepoints to measure the concentration of study 
drug and analyze PK parameters:  
• On Day 1 MORNING DOSE: Within 30 min before the morning dose (t=0), and at 0.5h 
(±5 min), 1h (±5 min), 2h (±5 min), 4h (±5 min), 6h (±10 min), 8h (±10 min), and 12h 
(±15 min) after the morning dose. (The 12h timepoint is the same as the predose timepoint 
(t=0) before the evening dose on Day 1) 


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• On Day 1 EVENING DOSE: Before (t=0) and 12h (±15 min) after the evening dose. (The 
12h timepoint is the same as the predose timepoint before the morning dose on Day 2). 
• On Days 2 to 6: Within 30 min before the morning and evening doses (t=0) and at 12h 
(±15 min) after the morning and evening doses on each day. (The PK timepoint before each 
dose on Days 2 to 6 is the same as the 12h timepoint of the previously received dose.)   
• On Day 7 MORNING DOSE: Within 30 min before the morning dose (t=0), and 12h 
(±15 min) after the morning dose.  (The 12h timepoint is the same as the predose timepoint 
(t=0) before the evening dose on Day 7) 
• On Day 7 EVENING DOSE: Within 30 min before the evening dose (t=0), and at 0.5h 
(±5 min), 1h (±5 min), 2h (±5 min), and 4h (±5 min) after the evening dose on Day 7. 
• On Day 8: At 6h (±10 min), 8h (±10 min), 12h (±15 min) and 24h (±15 min) after the 
evening dose on Day 7.  
• On Day 9: At 36h (±15 min) and 48h (-2 hours) after the evening dose on Dose 7.  
Blood (serum) will be drawn at the same timepoints as PK samples for storage for secondary future 
research if the subject consented to the collection and storage. 
Blood samples will be obtained promptly after each corresponding VS assessment before each 
dose on Days 1 to 7, and on Days 8 and 9.  
Sample collections will be scheduled for the nominal time point and actual collection times 
recorded.  
Approximately 6 mL of peripheral blood will be drawn into prelabeled K2-EDTA plasma separator 
tubes for measurement of plasma concentration of SLV213 (PK samples) and 3.5 mL in serum 
separator tubes for secondary future research (if the participant has given consent) at each PK 
sampling timepoint. Details regarding the specimen preparation, handling, and storage of plasma 
PK bioanalytical samples and samples for secondary future research will be described in the 
protocol-specific MOP. 
Specimen Shipment 
Specimen shipment will occur at intervals during the trial following all applicable International 
Air Transport Association requirements and according to the specifics for storage temperature and 
documentation as detailed in the central clinical laboratory manual and protocol-specific MOP, as 
appropriate. 
All specimens for clinical screening and safety laboratory evaluations will be transported from the 
CTU to the local clinical laboratory. 
Primary and Back-up aliquots of plasma PK samples for storage will be shipped from the CTU to 
DMID CMS at: 
Fisher BioServices 


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c/o DMID Clinical Materials Services (DMID CMS) 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
Phone: 240-477-1350  
Fax: 240-477-1360 
Email: DMID.CMS@thermofisher.com  
In order to perform bioanalytical assays of PK samples within the LTS period, aliquots of plasma 
PK samples designated by the SDCC (Emmes) picklist will be shipped to the bioanalytical lab, 
KCAS, Inc., from the DMID CMS at -70°C, and assays will be performed within the LTS 
timeframe. Further information will be provided in the study-specific MOP. 
8.3.5 
Total Blood Volume Drawn  
The estimated blood volume drawn for tests at Screening and Day-1 is 38.9 mL, and for tests on 
Day 1 to Day 9 it is 325.8 mL (for safety lab tests, 60.8 mL; for plasma PK samples, 160 mL; and 
for serum for future research, if consent was provided, 105 mL). The total cumulative estimated 
blood volume drawn during the entire study is 384.7 mL. 
Venipuncture schedule and blood volumes for screening and safety lab tests and for the PK and 
future research samples are provided in Appendix B, Table 3. 
8.3.6 
Disposition of Plasma Samples 
Blood (plasma or serum) samples are collected for clinical laboratory testing, PK assays and, if 
consent was provided, for storage for future research. No genetic testing will be done on collected 
blood samples.  
Clinical laboratory samples will be destroyed after tests are completed and results are reviewed 
according to standard practices of the Site Clinical Lab. 
Plasma samples used for measurement of the concentration of study drug at the bioanalytical lab 
will be disposed of per sponsor (DMID) guidance. 
Residual plasma PK samples and additional serum samples stored at the DMID CMS (Fisher) may 
be used for secondary research if the participant provided consent to store and use these samples 
for this purpose. (See Section 10.1.4 for further information.) 
8.4 
Study Drug Administration 
Participants will receive daily dosing Q12h (morning and evening) for 7 days, with the first dose 
of the study drug administered in the morning on Day 1 and the last dose in the evening of Day 7. 
The study product will be administered orally with at least 240 mL (8 fluid ounces) or more of tap 
or bottled water.  
All participants are required to fast for the indicated periods before and after dosing as follows: 
• Day 1, Morning dose: at least 8h before and 4h after the morning dose  
• Day 1, Evening dose: at least 2h before and 1h after the evening dose 


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• Days 2-6, Both morning and evening doses: at least 2h before and 1h after each dose  
• Day 7, Morning dose: at least 2h before and 1h after the morning dose 
• Day 7, Evening dose: at least 8h before and 4h after the evening dose  
Fluids will be allowed during fasting except for at least 1h before and 1h after each scheduled 
dose. 
The meal schedule will be structured to restrict meals before and after each dose as required. 
Standard meals will be provided at appropriate times before and after each drug administration 
and the time the last meal was consumed before and after each dose on Days 1 to 7 will be recorded.  
8.5 
Adverse Events and Serious Adverse Events 
8.5.1 
Definition of Adverse Events (AE) 
An AE means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). An AE can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of medicinal (investigational) product.  
An AE is the development of an undesirable medical condition or the deterioration of a pre- 
existing medical condition following or during exposure to a pharmaceutical product, whether or 
not considered causally related to the product. In clinical studies, an AE can include an undesirable 
medical condition occurring at any time, including baseline or washout periods, even if no study 
treatment has been administered. 
Symptoms that increase in severity or frequency will be considered as AE’s and processed 
accordingly. 
Any medical condition that is present at the time the participant is screened will be considered as 
baseline and not reported as an AE. However, if the severity (i.e., grade) of any pre-existing 
medical condition increases, it should be recorded as an AE. 
Adverse events can be further divided into solicited AEs and unsolicited AEs: 
• Solicited AEs are those for which the study team will specifically query the participant 
whether they occurred. Solicited AEs are not collected in this study.  
• Unsolicited events are all AEs spontaneously reported by the participant and/or in response 
to an open question from study personnel or revealed by observation, PE or other 
procedures. All AEs collected in this study are unsolicited events. 
8.5.2 
Definition of Serious Adverse Events (SAE)  
An adverse event or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes (21 CFR 312.32 (a)):  
• Death 


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• A life-threatening adverse event* 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or  
• A congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize 
the patient or participant and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, convulsions that do not result in 
inpatient hospitalization, etc. 
* An adverse event is considered “life-threatening” if, in the view of either the investigator or 
sponsor, its occurrence places the patient or participant at immediate risk of death. It does not 
include grade 4 severity unless the adverse event might have caused death. 
8.5.3 
Definition of Medically-Attended Adverse Events (MAAE) 
MAAEs are defined as AEs with medically attended visits including hospital, emergency room, 
urgent care clinic, or other visits to or from medical personnel for any reason. Adverse events (e.g., 
abnormal vitals) identified at a routine study visit will not be considered MAAEs. 
8.5.4 
Classification of an Adverse Event 
The determination of seriousness, severity, and causality will be made by an on-site investigator 
who is qualified (licensed) to diagnose AE information, provide a medical evaluation of AEs, and 
classify AEs based upon medical judgment.  
Severity of Event 
All AEs or SAEs will be assessed for severity, according to the FDA Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, available 
at https://www.fda.gov/media/73679/download, and supplemental grading parameters are 
included in Appendix A. If the severity of any AE changes, the highest severity should be recorded. 
Relationship to Study Intervention 
For each reported adverse event or reaction, the PI or designee must assess the relationship of the 
event to the study product using the following guideline: 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. For scale of relatedness, “possibly 
related”, “probably related”, and “definitely related” map to “related”. Adverse Events when 
alternative etiology is not identified will be assessed as “related” to the study product. 


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Not Related – There is not a reasonable possibility that the administration of the study intervention 
caused the event, there is no temporal relationship between the study intervention and event onset, 
or an alternate etiology has been established. 
8.5.5 
Time Period and Frequency for Event Assessment and Follow up  
For this study: 
• Unsolicited AEs will be collected from Study Day 1 through the end of the study. 
• SAEs will be collected from Study Day 1 through the end of the study. 
• All SAEs will be followed through resolution or until the site investigator deems the event 
to be chronic or stable.  
• AEs will be followed through resolution or until the site investigator deems the event to be 
chronic or stable or has returned to baseline. 
8.5.6 
Adverse Event Reporting 
Investigator Reporting of AEs 
All clearly related signs, symptoms, and results of diagnostic procedures performed because of 
an AE should be grouped together and recorded as a single diagnosis or AE term, if available. If 
the AE is a laboratory abnormality that is part of a clinical condition or syndrome, it should be 
recorded as the syndrome or diagnosis rather than the individual laboratory abnormality. 
Each AE will also be described in terms of duration (start and stop date), severity, association 
with the study product, action(s) taken, and outcome. AEs characterized as intermittent require 
documentation of onset and duration of each episode.  
All AEs occurring during the study, whether or not they are related to the study drug, must be 
recorded on the appropriate eCRF. Information to be collected for AEs includes event term or 
description, date of onset, assessment of severity, relationship to study product and alternate 
etiology (assessed only by those with the training and authority to make a diagnosis and listed on 
the Form FDA 1572 as an investigator), date of resolution, seriousness, and outcome. AEs 
occurring during the trial collection and reporting period will be documented appropriately 
regardless of relationship.  
Laboratory AEs Evaluation and Reporting 
Once dosed with study product, lab results that are above the upper limit of normal or below the 
lower limit of normal for the baseline reference ranges, but are less than Grade 1 in the toxicity 
table, will not be graded and reported as outside the normal range. 
Laboratory values that meet the post dosing grading criteria but did not preclude the subject from 
enrolling will be entered as AEs only if the value worsens in severity. 
 
 


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8.5.7 
Serious Adverse Event Reporting 
Investigator Reporting of SAEs 
All SAEs will be recorded on the appropriate SAE form and sent to DMID Pharmacovigilance 
Group (PVG). The SAE form will collect all relevant data concerning the SAE, including event 
term or description, date of study product administration, date of onset, duration or date of 
resolution, severity, seriousness, outcome, any action taken with the study product, and 
relationship to each study product or an alternate etiology as assessed by those with the training 
and authority to make a diagnosis and listed on the Form FDA 1572 (PI, co-investigator, licensed 
clinicians). In addition, the investigator should provide relevant MH, ConMeds, laboratory or 
diagnostic results, details of any treatment for the SAE, and a narrative including all other pertinent 
medical information. 
Any AE that meets a protocol-defined serious criterion must be submitted immediately (within 
24 hours of site awareness) on an SAE form to the DMID PVG via fax or email. SAEs reported 
via the SAE Hot Line must be followed with a fax or email submission:  
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
In addition to the SAE form, select SAE data fields must also be entered into the SDCC system. 
Please see the protocol-specific MOP for details regarding this procedure.  
Other supporting documentation of the event may be requested by the DMID PVG and should be 
provided as soon as possible.  
At any time after completion of the study, if the site PI or appropriate sub-investigator becomes 
aware of an SAE that is suspected to be related to study product, the site PI or appropriate sub-
investigator will report the event to the DMID PVG. 
Regulatory Reporting of SUSARs 
The sponsor will report any Suspected Unexpected Serious Adverse Reactions (SUSAR) to the 
FDA in an IND safety report. DMID will report an AE as a suspected unexpected adverse event 
only if there is evidence to suggest a causal relationship between the study intervention and the 
AE.  
The Sponsor must ensure the event meets all three of the definitions: 
1. Suspected adverse reaction. 
2. Serious. 
3. Unexpected. 


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Both seriousness and unexpectedness are important, but the event will be reported only if there is 
evidence to suggest a causal relationship between the drug and the adverse event, such as:  
A. A single occurrence of an event that is uncommon and known to be strongly associated 
with drug exposure.  
B. One or more occurrences of an event that is not commonly associated with drug exposure 
but is otherwise uncommon in the population exposed to the drug.  
C. On review as an aggregate analysis when the occurrence is higher than the historical 
control.  
DMID will report to the FDA any unexpected fatal or life-threatening suspected adverse reaction 
as soon as possible, but in no case later than 7 calendar days after the sponsor’s initial receipt of 
the information. If the event is not fatal or life-threatening the IND safety report will be submitted 
within 15 calendar days after the sponsor determines that the information qualifies for reporting as 
specified in 21 CFR Part 312.32. Relevant follow up information to an IND safety report will be 
submitted as soon as the information is available. Upon request from FDA, DMID will submit to 
the FDA any additional data or information that the agency deems necessary, as soon as possible, 
but in no case later than 15 calendar days after receiving the request. The DMID MM is responsible 
for determining whether a SAE is a SUSAR based on the nature, severity, or frequency of the 
event. 
DMID will submit an IND safety report to the FDA and will notify all participating site PIs (i.e., 
all PIs to whom the sponsor is providing drug under its IND(s) or under any PI’s IND(s) of 
potential serious risks from clinical studies or any other source, as soon as possible. 
SAEs that are not SUSARs will be reported to the FDA at least annually in a summary format 
which includes all SAEs.  
8.5.8 
Reporting Events to Participants 
Participants have the right to be informed of any new findings of AEs or SAEs that may affect 
their safety or influence their choice to participate or continue participating in the study. Any 
information provided to the participant will be blinded with respect to study treatment. 
8.5.9 
Adverse Events of Special Interest (AESI) 
Definition of AESI 
An AESI (serious or non-serious) is one of scientific and medical concern specific to the compound 
or program, for which ongoing monitoring and rapid communication by the investigator to the 
Sponsor may be appropriate. Such clinically significant events may require further investigation in 
order to characterize and understand them and will be collected as AESIs, discussed by the SMC, 
and expanded narratives of each written as indicated. 
 
 


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Protocol-defined AESIs are:  
• All clinically significant cardiovascular Grade 3 of higher AEs including symptomatic 
cardiac arrhythmias and ECG abnormalities  
• All clinically significant Grade 3 or higher gastrointestinal AEs    
• Hepatic toxicity assessed by severe (Grade 3 or higher) based on values of liver function 
tests (LFTs  
All AESIs will be collected through study Day 28 and will be included in the safety analysis.  
All AESIs are assessed for severity and relatedness to investigational product, recorded, and 
followed as described above under AEs and SAEs. 
Reporting of AESI 
All AESIs, whether serious or non-serious, also require additional reporting to the DMID PVG 
within 24 hours of site awareness for serious AESI or within 72 hours of site awareness for non-
serious AESI. AESIs are reported on the appropriate CRF with additional reporting to DMID PVG 
using the protocol-approved SAE form. Submit AESI as follows: 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
8.5.10 
Reporting of Pregnancy 
Pregnancy is not an AE. However, any pregnancy that occurs during study participation (through 
study Day 28 should be reported to the sponsor on the appropriate CRF. Pregnancy should be 
followed to outcome. This follow-up will include pregnancy outcome (termination, pre-term birth, 
term birth) and newborn outcome (live birth, fetal demise, stillbirth; presence of any congenital 
anomalies). No in-person visits will be required for pregnancy outcome determination. 
8.6 
Unanticipated Problems  
8.6.1 
Definition of Unanticipated Problems 
The Department of Health and Human Services Office for Human Research Protections (DHHS-
OHRP) considers unanticipated problems involving risks to participants or others to include, in 
general, any incident, experience, or outcome that meets all of the following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 


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protocol and informed consent document; and (b) the characteristics of the participant 
population being studied; and 
• Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been caused 
by the procedures involved in the research); and 
• Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
Incidents arising from noncompliance with study procedures should be reported as protocol 
deviations (see Section 10.1.10). An incident that qualifies as both a unanticipated problems and a 
protocol deviation should be reported as both. 
8.6.2 
Unanticipated Problem Reporting 
The investigator will report unanticipated problems to the study sponsor (DMID), the reviewing 
IRB and to the SDCC. The unanticipated problems report will include the following information: 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• A detailed description of the event, incident, experience, or outcome;  
• An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an unanticipated problem;  
• A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the unanticipated problem. 
To satisfy the requirement for prompt reporting, unanticipated problems will be reported using the 
following timeline:   
• Unanticipated problems that are SAEs will be reported to the IRB and to the SDCC/study 
sponsor within 24 hours of the investigator becoming aware of the event.  
• Any other unanticipated problem will be reported to the IRB and to the SDCC/study 
sponsor within a timeline defined according to the relevant policies.  
• Unanticipated problems, whether they are SAEs or not, will be collected from Day 1 
through the end of the study. 
8.6.3 
Reporting Unanticipated Problems to Participants 
Participants will be informed of any unanticipated problems that will potentially influence their 
participation in this trial.  
 
 


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9. 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
The objectives of the study are to obtain safety data and plasma PK data for 3 escalating doses of 
SLV213 administered PO daily Q12h for seven days. There are no formal hypotheses being tested 
in this Phase 1 trial. 
9.2 
Sample Size Determination 
The sample size chosen of a total of 36 is considered to be sufficient for evaluation of safety, 
tolerability, and PK data of each cohort; the sample size was not based on statistical power 
considerations. 
9.3 
Statistical Analyses 
9.3.1 
General Methodology 
A Statistical Analysis Plan (SAP) will be developed and approved by the study biostatistician and 
investigative team before unblinding, and the database is locked. The SAP will present the detailed 
statistical methodology to analyze the safety, tolerability, and pharmacokinetic data from this trial. 
The SAP will also provide details for handling missing data and possible confounding variables. 
The safety set will be the primary population for safety data analysis. Analysis of primary and 
secondary endpoints will be done for each dose of SLV213 and compared with a pooled placebo 
group from all cohorts. The primary endpoint is the proportion of participants experiencing any 
TEAEs judged related to study drug vs. placebo. Frequencies and percentages of these events will 
be presented by treatment group. We will also estimate the event risks by treatment group and risk 
differences with 95% exact confidence intervals. Risk differences will be estimated for each dose 
level as compared against the pooled placebo group.  
Secondary endpoints: 
Binary endpoints will be analyzed using the same methods as described above for the primary 
endpoint.  
9.3.2 
Timing of Analyses 
The primary clinical database for this study will consist of safety data including unsolicited events, 
and abnormal laboratory values, as well as baseline/demographic data. Once the last participant 
has completed the final visit, the primary clinical database will be cleaned, monitored, and locked. 
After clinical database lock and receipt of secondary endpoint data, a set of topline tables will be 
generated, including summaries of clinical safety and secondary PK data. The topline report will 
be made available to the study team for planning subsequent trials and may be presented in a public 
forum or used for publication in collaboration with the lead PI. These analyses will be considered 
final and will be included in the Clinical Study Report. 


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A formal SAP, which will elaborate on the analyses described here and describe any changes to 
the planned analyses, will be developed and finalized before performing any of these analyses 
(with the exception of SRC/SMC reviews of descriptive safety analyses). 
Interim Analysis 
Blinded safety and tolerability data will be periodically reviewed by DMID and the site PI or 
authorized study clinician (listed on FDA Form 1572) to assess whether rules for halting 
progression to the next study cohort have been met. An ad hoc SMC meeting will review safety 
data if halting criteria have been met. The SMC will receive data in aggregate. The SMC may 
request to receive data by study product vs. placebo in a closed session. The SMC may also request 
that the blind be broken for individual participants, as needed, to assess safety issues. The SMC 
will be asked to recommend or modification only when there is clear and substantial evidence of 
a treatment difference. More details about the interim analyses are described below, as well as in 
a separate guidance document for the SMC.  
Interim Safety Analyses 
Interim safety analysis is not planned. Safety data may be summarized for ad hoc review as 
requested by the SMC. Top level safety parameters will be assessed between cohorts as needed.  
Interim Pharmacokinetics, Pharmacodynamic, Microbiological Activity, or Efficacy 
Review 
An interim PK and pharmacodynamics (PD) analysis is not planned. If concentration versus time 
or PK data are available, top-level concentration versus time curves or PK parameters will be 
assessed between cohorts as needed. 
Final Analyses  
Final analysis will be completed after study completion and database lock. No formal study data 
will be provided prior to this final analysis.  
9.3.3 
Populations for Analyses 
The following analysis sets will be used in the analysis.  
Full Analysis Set: All randomized participants and analyzed according to the treatment as 
randomized. This population is analogous to an intent-to-treat population. 
Modified Intent-To-Treat (mITT): All randomized participants who meet eligibility criteria and 
receive at least 1 dose of any study treatment. Participants will be excluded from the mITT 
population, if they fail to meet eligibility criteria or if they do not receive any study treatment. 
Analysis will be performed according to the treatment as randomized. 
Safety Set: All randomized participants who received at least 1 dose of any study treatment, and 
analysis will be performed according to the treatment actually received. 
PK Analysis Set: All randomized participants who received at least one dose of study treatment 
and have at least one quantifiable post-dosing plasma concentration to use for the PK analysis. 


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9.3.4 
Baseline Characteristics and Participant Disposition 
Details of baseline characteristics and participant disposition will be addressed in the SAP.  
9.3.5 
Efficacy Analyses 
Analysis of the Primary Efficacy Endpoint(s) 
Not Applicable.  
Analysis of the Secondary Efficacy Endpoint(s) 
Not Applicable.  
Analysis of the Exploratory Efficacy Endpoint(s) 
Not Applicable. 
9.3.6 
Safety Analyses 
AEs will be presented in listings and TEAEs will be summarized. Individual results of laboratory 
tests, VS, and ECGs will be listed and baseline, post dose, and changes from baseline to post dose 
laboratory, VS, and ECG data will be summarized. 
AEs, including abnormal laboratory values, will be graded according to the protocol Toxicity 
Tables in Appendix A. PE findings will be presented in data listings. 
All AEs occurring after study drug dosing will be summarized using frequency counts and 
percentages. The following summaries will be presented for TEAEs and SAEs: 
• Overall (i.e., regardless of severity or relationship to treatment). 
• By severity grade (mild, moderate, or severe). 
• By relationship to study drug. 
• By MedDRA level hierarchy (system organ class [SOC], higher level group term [HLGT 
and preferred term [PT]). 
Unless otherwise specified, at each level of subject summarization in reporting the incidence of 
TEAEs, a subject will be counted once if the subject reported one or more TEAEs. If more than 
one occurrence of a TEAE is reported, the TEAE of the worst severity or the worst-case 
relationship assessment will be summarized. 
Additional Safety Analyses: 
Descriptive summary statistics (mean, standard deviation [SD], median, minimum, and maximum) 
for all clinical laboratory data, 12-lead standard ECG parameters, and VS at admission and each 
applicable post-dosing visit, including changes from baseline values, will be calculated and 
presented by treatment cohort. Baseline values will be the last values recorded before initiating 
administration of study drug. For change-from-baseline summaries, participants with an undefined 
change from baseline, due to missing data, will be excluded. Clinical significance of abnormalities, 


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as assessed by the study PI or authorized study clinicians, will be indicated. The number and 
percentage of participants who meet toxicity criteria for clinical laboratory, VS and 12-lead ECG 
investigations will be listed and tabulated by treatment cohort. 
Tolerability Assessment: 
Tolerability to study product will be summarized by dose cohort and include number and 
proportion of participants with early study withdrawal or termination experiencing any  AEs 
assessed as related to study drug vs. placebo as follows: (A) Number and percentage of participants 
who:  (1) Terminate early or are withdrawn due to treatment-emergent AEs assessed as related to 
intake of study medication; (2) Have at least 1 TEAE, total and per dose level; (3) Meet Grade 3 
abnormal criteria for safety laboratory tests at least once post-dose; (4) Meet Grade 3 abnormal 
criteria for VS measurements at least once post-dose; and (5) Meet Grade 3 criteria for safety ECG 
parameters at least once post-dose, and (B) Number and percentage of oral medication doses 
completed.  
9.3.7 
Pharmacokinetic Analysis 
Plasma concentrations of SLV213 on Day 1 and Day 7 will be summarized using descriptive 
statistics (n, mean, SD, CV%, median, minimum, and maximum) for each treatment cohort, study 
day and nominal timepoint. Plasma study drug concentrations observed after each morning and 
evening dose of study drug from Day 1 through Day 7 (trough concentrations) will be summarized 
similarly for each treatment cohort and study day. 
Plasma PK parameters will be estimated by noncompartmental analysis methods using Phoenix® 
WinNonlin® version 8.0 or higher and presented by treatment cohort. PK parameters and linearity 
index and dose-normalized exposure parameters (AUC(0-tau)/Dose and Cmax/Dose) after the first 
dose on Day 1 and after the last dose on Day 7 will be analyzed and presented. 
Graphical presentations of plasma concentration vs. time profiles will be provided for SLV213 
and will include individual subject and mean concentration profiles. Semi-log concentration 
profiles will be provided for individual participants. Graphical presentation of mean and individual 
trough study drug concentrations and study drug concentrations collected 12 h after each morning 
and evening dose administered on Day 1 through Day 7 will be displayed. 
Plasma PK parameters: 
The study population and methodology used to evaluate PK parameters after first dose on Day 1 
and multiple doses on Day 7 will be described in detail in the PK Plan and is reviewed briefly 
below. 
The following single-dose plasma PK parameters will be computed (if estimable) from the plasma 
total concentration-time data over the 12-hour following the morning dose of study drug on Day 1 
in each cohort:: 
• Cmax: Observed maximum concentration 
• Tmax: Time of maximum concentration (h) 


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• Cmin: Observed minimum concentration at the end of the dosing interval 
• AUC(0-t): Area under the plasma concentration -time curve to the last time with a 
concentration greater than or equal to the validated limit of quantitation of the assay 
• AUC(0-∞): Area under the plasma concentration-time curve to infinity 
• AUC(0-12): Area under the plasma concentration - time curve from time 0 to 12h after dosing 
• AUC(0-last): Area under the plasma concentration - time curve from time zero to the last 
concentration above the lower limit of quantitation   
• AUC(0-tau): Area under the plasma concentration - time curve from time 0 to the end of the 
dosing interval 
• t1/2: Terminal half-life 
• CLT: Total clearance 
• Ke: terminal phase elimination rate constant 
• Vd: Volume of distribution 
• Dose-normalized exposure parameters (AUC(0-tau)/Dose and Cmax/Dose) 
The following multiple-dose plasma PK parameters will be computed (if estimable) from the drug 
total concentration-time data over the 48h dosing interval following the morning dose of study 
drug on Day 7 in each cohort. 
• Cmax,ss: observed maximum concentration at steady state 
• Cmin,ss: observed minimum concentration at the end of the dosing interval at steady state 
• Cavg: calculated average concentration during the dosing interval 
• Tmax,ss: Time of maximum concentration (Cmax) at steady state 
• Tmin: Time to minimum concentration (Cmin) 
• AUC(0-48),ss: Area under the plasma concentration - time curve from time 0 to 48h after 
dosing 
• AUC(0-tau),ss: Area under the plasma concentration - time curve to the end of the dosing 
interval at steady state  
• t1/2: Terminal half-life (Day 7 only) 
• CLT: Total clearance 
• Vd,ss: Volume of distribution at steady state 
• Linearity Index: AUC(0-tau),ss (Day 7) / AUC(0-∞) (Day 1) 


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• RAUC: Accumulation ratio for AUC estimated as AUC(0-tau) (Day 7) / AUC(0-tau) (Day 1) 
• RCmax: Accumulation ratio for Cmax estimated as Cmax (Day 7) / Cmax (Day 1). 
• Dose-normalized exposure parameters (AUC(0-tau)/Dose and Cmax/Dose) 
Trough plasma concentrations of total SLV213 at 12h after each morning and evening dose from 
Day 1 through Day 7 will be summarized in a tabular form and presented graphically. 
9.3.8 
Missing Values and Outliers 
All attempts will be made to collect all data per protocol. No imputation will be performed for 
missing values. Rules for identifying outliers will be described in the SAP. Outliers will not be 
excluded from the primary analyses. Outliers identified during the PK analysis will be discussed 
in the analysis report. 
9.3.9 
Multiple Comparisons / Multiplicity 
This is a small Phase 1 Study with multiple endpoints. Because analyses of endpoints are 
descriptive rather than hypothesis tests, no adjustments for multiplicity testing are planned. 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Regulatory, Ethical, and Study Oversight Considerations 
This study will be conducted in conformity with the principles set forth in The Belmont Report: 
Ethical Principles and Guidelines for the Protection of Human Subjects of Research (US National 
Commission for the Protection of Human Subjects of Biomedical and Behavioral Research; 
April 18, 1979), and the federal policy for the Protection of Human Subjects codified in 45 CFR 
Part 46, 21 CFR Part 50 (Protection of Human Subjects), and the ICH E6(R2). 
An OHRP-registered IRB will review and approve this protocol, associated informed consent 
documents, recruitment materials, and handouts or surveys intended for the participants, prior to 
the recruitment, screening, and enrollment of participants. Review shall be in accordance with 
45 CFR 46 and 21 CFR 50, 21 CFR 56 (IRBs), and other federal, state, and local regulations and 
policies, as applicable. Investigator(s) will obtain IRB approval for this protocol and any 
amendments to be conducted at his/her research site(s). Any amendments to the protocol or 
informed consent documents will be approved by the IRB before they are implemented. DMID 
must receive documentation of IRB approval prior to the recruitment, screening, and enrollment 
of participants under any IRB approvals for continuing review. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and approval will 
occur at least annually throughout the enrollment and follow-up of participants, according to 
applicable regulations and the IRB/IEC. The investigator will notify the IRB/IEC of events such 
as deviations, SAEs, etc. as applicable to the IRB/IEC policy.  


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Each institution engaged in this research will hold a current Federalwide Assurance (FWA) issued 
by the DHHS-OHRP for federally funded research and provide the FWA number to DMID. 
10.1.1 
Informed Consent Process 
For the following, “informed consent” applies to participant assent. Where appropriate, these will 
be obtained and documented for all study participants.  
Informed consent is a process that is initiated prior to an individual agreeing to participate in a trial 
and continuing throughout the individual’s trial participation. Before any study procedures are 
performed, informed consent will be obtained and documented. Participants will receive a concise 
and focused presentation of key information about the clinical trial, verbally and with a written 
consent form. Key information will include the purpose of the study, the procedures and 
experimental aspects of the study, study interventions/products, probability for random assignment 
to treatment groups, risks and discomforts, the expected duration of the participant’s participation 
in the trial, any expected benefits to the participant, and alternative treatments and procedures that 
may be available to the participant. The explanation will be organized and presented in lay 
terminology and language that facilitates understanding why one might or might not want to 
participate. 
Participants will receive an explanation as to what happens if injury occurs, including whether any 
compensation and any medical treatments are available, and, if so, what they consist of, or where 
further information may be obtained. Participants are informed of the anticipated financial 
expenses, if any. They will be informed of whom to contact (e.g., the investigator) for answers to 
any questions relating to the research project. Information will also include the foreseeable 
circumstances and/or reasons under which the participant’s participation in the trial may be 
terminated. The participants will be informed that participation is voluntary and that they are free 
to withdraw from the study for any reason at any time without penalty or loss of benefits to which 
the participant is otherwise entitled.  
Participants will be informed that records identifying the participant will be kept confidential, and, 
to the extent permitted by the applicable laws and/or regulations, will not be made publicly 
available and, if the results of the trial are published, the participant’s identity will remain 
confidential. Participants will be informed whether private information collected from this 
research and/or specimens will be used for additional research, even if identifiers are removed.  
Participants will be informed that the monitor(s), auditors(s), IRB, NIAID, and regulatory 
authority(ies) will be granted direct access to the participant’s original medical records for 
verification of clinical trial procedures and/or data without violating the confidentiality of the 
participant, to the extent permitted by the applicable laws and regulations, and that, by signing a 
written informed consent form, the participant is authorizing such access.  
Participants will be allowed sufficient time to consider participation in this research trial and have 
the opportunity to discuss this trial with their family, friends, or legally authorized representative, 
or think about it prior to agreeing to participate. 


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Informed consent forms will be IRB-approved, and participants will be asked to read and review 
the consent form. Participants will complete an informed consent form prior to starting any study 
procedures being done specifically for this trial. Once signed, a copy of the informed consent form 
will be given to the participant(s). 
New information will be communicated by the site PI to participants who consent to participate in 
this trial in accordance with IRB requirements. The informed consent document will be updated, 
and participants consented per IRB requirements, if necessary.  
Requirements for Permission by Parents/Guardians and Assent by Children (in case of a 
minor)  
Not Applicable. 
Other Informed Consent Procedures 
No human genetic testing will be conducted in this study. 
10.1.2 
Study Termination and Closure 
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or ET of the study. 
• New information or other evaluation regarding the safety or efficacy of the study drug that 
indicates a significant change in the known risk/benefit profile for the drug, such that the 
risk is no longer acceptable for participants participating in the study. 
• Significant violation of GCP guidelines that compromises the ability to achieve the primary 
study objectives or compromises participant safety. 
• Study-specific criteria for terminating the study: 
• Participants in more than one cohort have met Cohort Stopping Criteria (see Section 7.1.1). 
The study may be terminated early prior to full attainment of these criteria if warranted by safety 
data from the other participants dosed in the study to that point. 
Section 7 describes the temporary halting of the study. 
This study may be prematurely terminated if there is sufficient reasonable cause, including but not 
limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Halting criteria met and it is deemed unsafe to proceed with further dosing 
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
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• Sponsor’s determination 
If the study is prematurely terminated, the PI will promptly inform study participants and the IRB 
and regulatory authorities as applicable. Study participants will be contacted, as applicable, and be 
informed of changes to study visit schedule. The PI will assure appropriate follow-up for the 
participants, as necessary.  
The sponsor will notify regulatory authorities as applicable.  
10.1.3 
Confidentiality and Privacy 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and 
the sponsor(s) and their agents. This confidentiality is extended to cover clinical information 
relating to participants, test results of biological samples and genetic tests, and all other 
information generated during participation in the study. No identifiable information concerning 
participants will be released to any unauthorized third party. Participant confidentiality will be 
maintained when study results are published or discussed in conferences.  
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
and/or regulatory agencies may inspect all documents and records required to be maintained by 
the investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study. The clinical study site will permit access to 
such records. 
All source records including electronic data will be stored in secured systems in accordance with 
institutional policies and federal regulations.  
All study data and research specimens that leave the site (including any electronic transmission of 
data) will be coded. 
As this research is funded by the National Institutes of Health (NIH), it is covered by NIH policy 
which effectively issues the research a Certificate of Confidentiality. By this policy, researchers 
cannot be forced to disclose or provide, in any Federal, State, or local civil, criminal, 
administrative, legislative, or other proceeding, the name of such individual or any such 
information, document, or biospecimen that contains identifiable, sensitive information about the 
individual and that was created or compiled for purposes of the research, unless such disclosure or 
use is made with the consent of the individual to whom the information, document, or biospecimen 
pertains. 
The Certificate cannot be used to resist a demand for information from personnel of the United 
States Government that is used for auditing or evaluation of federally funded projects, like this 
study, or for information that must be released in order to meet the requirements of the FDA. 
A Certificate of Confidentiality does not prevent the participant from voluntarily releasing 
information about themselves or their involvement in this research. If any person or agency obtains 
a written consent to receive research information, then the researchers may not use the Certificate 
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The Certificate of Confidentiality does not cover matters that must be legally reported, including 
child and elder abuse, sexual abuse, wanting to harm themselves or others, and certain infectious 
diseases that meet the criteria for reporting. In these cases, researchers may report information that 
would identify a participant without the participant’s consent.  
The release of individual private information or specimens for other research will only occur if 
consent was obtained from the individual to whom the information, document, or biospecimen 
pertains, or for the purposes of other research that the release is in compliance with applicable 
Federal regulations governing the protection of human subjects in research.  
10.1.4 
Secondary Use of Stored Specimens and Data  
Secondary Human Participant Research is the re-use of identifiable data or identifiable 
biospecimens that were collected from some other “primary” or “initial” activity, such as the data 
and samples collected in this protocol. Participants will be informed and consent obtained if the 
participant agrees to collection of additional blood (3.5 mL per sample for 30 times) for the 
purpose of preparing and storing serum in the DMID CMS for use in other research not specified 
at this time. The “additional” samples may be released during this study or at completion of all lab 
analyses. 
Residual Research Sample:  
Remaining samples not utilized for PK analyses and stored in the DMID CMS repository will be 
reserved for future research with the participant’s consent.   
Data and residual samples from this study may be used for secondary research. All of the individual 
participant data and residual samples collected during the trial will be made available to Selva 
Therapeutics, Inc. to conduct additional research in support of their product’s development to 
include the measurement of SLV213 metabolites, the PD of SLV213, and the analysis of cytokines 
to understand the host response to SLV213. Samples and data will be coded so that the data from 
this study may be linked to an individual’s results in secondary research, however, no personal 
identifying information will be linked to the data or samples that could identify a participant. No 
genetic testing will be conducted.  
10.1.5 
Key Roles and Study Governance 
The PI is listed on the cover page. Other study team members and roles are listed in the study-
specific MOP. 
10.1.6 
Safety Oversight 
Safety Monitoring Committee (SMC) 
Safety oversight will be conducted by a SMC, a group of experts that monitors participant safety, 
reviews accumulated trial data, and advises DMID on trial safety. SMC members will be separate 
and independent of study personnel participating in this trial and should not have scientific, 
financial, or other conflict of interest related to this trial. The SMC will operate under a DMID-
approved charter or safety monitoring plan in which the procedures for review will be defined. 
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met in the review by the SRC, at the conclusion of the trial when data are available, and as needed 
during this trial.  
The SMC will conduct the following reviews: 
• Ad hoc meetings:  
o When trial-level halting criteria are met  
o At the request of DMID to review a potential safety concern identified by either the PI, 
DMID MM, DMID MO, or the Pharmaceutical (Selva) MO.  
• A final review meeting to review the cumulative unblinded safety, tolerability and trial 
progress and final PK data and provide recommendation for the dose to be used in a Phase 
2 trial.  
Additional reviews may be requested by the SMC to evaluate interim data if there are immediate 
concerns regarding participant safety observed during the course of the trial. The SMC will receive 
blinded data and may request the treatment assignment be unblinded if required for safety 
assessment. The SMC members will review grouped and unblinded data in the closed session only. 
The SMC will make a recommendation as to the advisability of proceeding with study 
interventions (as applicable), and to continue, modify, or terminate this trial. 
Safety Review Committee (SRC) 
A SRC will consist of a DMID MM, the DMID MO, the clinical site PI and the Pharmaceutical 
(Selva) MO. The SRC will review combined safety data to Day 15 after each cohort and 
recommend dose escalation if halting criteria are not met.  
The DMID MM is empowered to stop enrollment and study product administration if AEs that 
meet the halting criteria are reported.  
10.1.7 
Clinical Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants 
are protected, that the reported trial data are accurate, complete, and verifiable. Clinical Monitoring 
also ensures conduct of the trial is in compliance with the currently approved protocol / 
amendment(s), ICH, GCP, and with applicable regulatory requirement(s) and sponsor 
requirements. Clinical monitoring will also verify any critical study procedures are completed 
following specific instructions in the MOP. 
10.1.8 
Quality Assurance and Quality Control 
Each site participating in the conduct of a DMID-funded study is responsible for integrating quality 
checks throughout the lifecycle of the protocol by developing, implementing, and evaluating a 
Clinical Quality Management Plan (CQMP). Quality activities are essential to the safety of 
participants, and the reliability of study data. Quality management planning should be risk-based, 
commensurate with the risks associated with the research.  
 
 


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The CQMP will describe: 
• Routine internal quality control (QC) and quality assurance (QA) activities  
o for the purposes of measuring, documenting, and reporting study conduct, protocol 
adherence, human subjects’ protections, and reliability of the protocol-driven data 
collected; 
o independent of sponsor site monitoring. 
• 
A process for addressing data quality issues (i.e., collecting, recording, and reporting 
findings in a timely manner); systemic issues (i.e., protocol conduct, non-compliance, 
human participant protections), and implementation and evaluation of Corrective and 
Preventative Action Plan (CAPA) procedures. 
10.1.9 
Data Handling and Record Keeping 
10.1.9.1 
Data Collection and Management Responsibilities 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.  
Data collection is the responsibility of the study staff at the participating site under the supervision 
of the participating site PI. The participating site PI must maintain complete and accurate source 
documentation. The site PI is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
Clinical research data from source documentation, including, but not limited to AEs/SAEs, 
ConMeds, MH, PE, ECG, and clinical laboratory data, will be entered by the participating site into 
eCRFs via a 21 CFR Part 11-compliant internet data entry system provided by the SDCC.  
The IND sponsor is responsible for review of data collection tools and processes, and review of 
data and reports. 
At the end of the study, a copy of all datasets, including annotated CRFs and data dictionary, will 
be provided to DMID per the requirements of the funding mechanism and agreements. 
10.1.9.2 
Statistical and Data Coordinating Center (SDCC)/ Biostatistician Responsibilities 
The SDCC for this study will be responsible for data management, quality review, analysis, and 
reporting of the study data. 
Adverse events and MH will be coded according to the MedDRA dictionary. 
ConMeds will be coded according to the WHODrug dictionary.  
At the end of the study, a copy of all datasets including annotated CRFs, and data dictionary will 
be provided to DMID.  


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10.1.9.3 
Source Records 
Source data are all information, original records of clinical findings, observations, or other 
activities documented in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with ICH GCP, regulatory, and institutional requirements. Data recorded in the eCRF 
derived from source documents should be consistent with the data recorded on the source 
documents.  
For this trial, the electronic subject record utilized by the participating site is considered source 
data.  
10.1.9.4 
Data Capture Methods 
Data will be captured in the subject’s electronic source record and entered manually into the eCRF 
in the SDCC database. Clinical research data (including, but not limited to, AE/SAEs, ConMeds, 
MH, PE, VS and clinical laboratory data will be extracted from the source documentation and/or 
collected on source document worksheet by study personnel and then entered into eCRFs via a 
21 CFR Part 11-compliant internet data entry system provided by the SDCC. The data system 
includes password protection and internal quality checks, such as automatic range checks, to 
identify data that appear inconsistent, incomplete, or inaccurate. (See study-specific MOP and 
eCRF Guidelines for details.) 
10.1.9.5 
Study Record Retention 
Study related records, including the regulatory file, study product accountability records, consent 
forms, participant source documents and electronic records should be maintained for a minimum 
period of 2 years following the date a marketing application is approved for the investigational 
product for the indication for which it is being investigated; or, if no application is to be filed or if 
the application is not approved for such indication, until 3 years after the investigation is 
discontinued and FDA is notified. These documents should be retained for a longer period, 
however, if required by local policies or regulations. No records will be destroyed without the 
written consent of DMID. Consent forms with specimen retention linked to identifiable specimens 
will be maintained for as long as the specimens remain in identifiable format, and a minimum of 
three years after use of the identifiable specimens in nonexempt human subject research. 
10.1.10 
Protocol Deviations 
A protocol deviation is any noncompliance that impacts the safety of the subject or scientific 
validity with the clinical trial protocol, any process that is noted in the protocol and refers to details 
in the MOP, or GCP requirements.  
The noncompliance may be either on the part of the participant, the investigator, or the study site 
staff. Following a deviation(s), corrective actions should be developed by the site and implemented 
promptly. All individual protocol deviations will be addressed in participant study records.  
It is the responsibility of the site PI and personnel to use continuous vigilance to identify and report 
deviations within five working days of identification of the protocol deviation, or within five 


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working days of the scheduled protocol-required activity. All deviations must be promptly reported 
to DMID per the protocol deviation reporting procedures. Protocol deviations must be sent to the 
local IRB/IEC per their guidelines. The site PI and personnel are responsible for knowing and 
adhering to their IRB requirements. A completed copy of the DMID Protocol Deviation Form must 
be maintained in the Regulatory File, as well as in the participant’s chart if the deviation is 
participant specific. 
10.1.11 
Publication and Data Sharing Policy 
Data Sharing Plan 
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
• 
The NIH Public Access Policy, which ensures that the public has access to the published 
results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon 
acceptance for publication. 
As of January 2018, all clinical trials supported by the NIH must be registered on 
ClinicalTrials.gov, no later than 21 days after the enrollment of the first participant. Results of all 
clinical trials supported by the NIH, generally, need to be submitted no later than 12 months 
following the primary completion date. As part of the result posting, a copy of this protocol and a 
copy of the Statistical Analysis Plan (if applicable) will be posted on ClinicalTrials.gov. 
10.1.12 
Conflict of Interest Policy 
Investigators will file appropriate financial disclosures prior to their involvement in this study. The 
study will adhere to relevant policies with regard to conflicts of interest.  
10.2 
Additional Considerations 
10.2.1 
Research Related Injuries 
For any potential research related injury, the site PI or sub-investigator or licensed clinician listed 
in FDA Form 1572 will assess the participant. The site PI should then determine if an injury 
occurred as a direct result of the tests or treatments that are done for this trial. As needed, referrals 
to appropriate health care facilities will be provided to the participant.  
No financial compensation will be provided by the NIAID, NIH, or the US Federal 
Government to the participant, for any injury suffered due to participation in this trial.  
Public Readiness and Emergency Preparedness Act (PREP Act) 
The study treatment(s) and the efforts for this clinical trial are covered under the Public Readiness 
and Emergency Preparedness Act (PREP Act) and the Declaration issued by the Secretary of the 
U.S. Department of Health and Human Services under that Act. Under the PREP Act and the 
Declaration, covered persons (such as manufacturers, distributers, program planners, and other 
qualified persons who prescribe, administer, or dispense study product) are immune from liability 


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from the administration, or use of a covered countermeasure, such as for SLV213. The PREP Act 
provides immunity for covered persons from liability unless the injury was caused by willful 
misconduct. The Declaration invoking the PREP Act for COVID-19 covered countermeasures was 
made on March 20, 2020. 
The PREP Act also established the Countermeasures Injury Compensation Program (CICP) to 
provide compensation for serious injuries or death that occur as the direct result of the 
administration or use of certain countermeasures. Any requests for compensation must be filed 
within one year of the administration or use of the covered countermeasure. Requests for Benefits 
must be made to the Health Resources and Services Administration’s (HRSA) CICP 
(http://www.hrsa.gov/cicp/) by filing a Request for Benefits Form and all required medical records 
and supporting documentation. Additional information on filing a Request for Benefits is available 
on the CICP’s website at http://www.hrsa.gov/cicp/. Compensation may then be available for 
reasonable and necessary medical benefits, lost wages and/or death benefits to eligible individuals 
for certain injuries in accordance with regulations published by the Secretary of HHS (found at 
42 CFR Part 110). 
If an individual suffers a serious physical injury or death from the administration or use of a 
covered countermeasure in this study, the individual, the individual’s legal or personal 
representative, the administrator/executor of a deceased individual’s estate, or certain survivors 
may request benefits from the CICP. A serious physical injury means an injury that warranted 
hospitalization (whether or not the person was actually hospitalized) or that led to a significant loss 
of function or disability. The CICP is the payer of last resort. This means that it only covers 
expenses or provides benefits that other third-party payers (such as health insurance, the 
Department of Veterans Affairs, or Workers’ Compensation programs) do not have an obligation 
to pay. 
If the Secretary of HHS does not make a final determination on the individual’s request within 
240 days, or if the individual decides not to accept the compensation, the injured individual or his 
representative may pursue a tort claim in the US District Court for the District of Columbia, but 
only if the claim involves willful misconduct and meets the other requirements for suit under the 
PREP Act. Any award is reduced by any public or private insurance or worker’s compensation 
available to the injured individual. Awards for non-economic damages, such as pain, suffering, 
physical impairment, mental anguish, and loss of consortium are also limited. If the individual 
accepts compensation, or if there is no willful misconduct, then the individual does not have a tort 
claim that can be filed in a US Federal or a State court. 
10.3 
Abbreviations 
Abbreviation 
Definition 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 


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Abbreviation 
Definition 
ARDS 
Acute Respiratory Distress Syndrome 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Plasma Concentration – Time Curve 
BID 
Twice Daily 
BMI 
Body mass Index 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CHEM 
Chemistries 
CFR 
Code of Federal Regulations 
COAG 
Coagulation 
CICP 
Countermeasures Injury Compensation Program 
CMS 
Clinical Materials Services 
ConMed(s) 
Concomitant Medication(s) 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case Report Form 
CS 
Clinically Significant 
CTU 
Clinical Trial Unit 
DHHS 
Department of Health and Human Services 
DLT 
Dose-limiting Toxicity 
DMID 
Division of Microbiology and Infectious Diseases 
DVC 
DynPort Vaccine Company, LLC 
ECG 
Electrocardiogram – Also Electrocardiographic  
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
FDA 
Food and Drug Administration 
FWA 
Federalwide Assurance 
GCP 
Good Clinical Practice 
GDIT 
General Dynamics Information Technology 
GLP 
Good Laboratory Practice 
h 
Hour or Hours 
HBsAg 
Hepatitis B virus surface antigen 
HCG 
Human Chorionic Gonadotropin 
HDPE 
high density polyethylene 
HEM 
Hematology 
HR 
Heart rate 
HRSA 
Health Resources and Services Administration 
HIV 
Human Immunodeficiency Virus 
IB  
Investigator Brochure 


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Abbreviation 
Definition 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IND 
Investigational New Drug Application 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IV 
Intravenous 
LFT 
Liver Function Tests 
LTS 
Long-Term Stability 
MAAE 
Medically-Attended Adverse Events 
MAD 
Multiple Ascending Dose  
mg 
Milligram(s) 
MH 
Medical History 
min 
minutes 
mITT 
Modified Intent-To-Treat 
MM 
Medical Monitor 
MO 
Medical Officer 
MOP 
Manual of Procedures 
MTD 
Maximum Tolerated Dose 
NCS 
Not Clinically Significant 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
OTC 
Over the Counter 
PD 
Pharmacodynamic(s) 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PO 
Per os (orally) 
PREP ACT 
Public Readiness and Emergency Preparedness Act 
PVG 
Pharmacovigilance Group 
QD 
Daily 
RBC 
Red Blood Cell 
RR 
Respiratory rate 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
SARS-COV-2 
Severe Acute Respiratory Syndrome-Related Coronavirus 2 
SDCC 
Statistical and Data Coordinating Center 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Assessments 


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Abbreviation 
Definition 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
SUSAR 
Suspected Unexpected Adverse Reactions 
T 
Temperature 
TEAE 
Treatment-Emergent Adverse Event 
Q12h 
Every 12 hours 
VS 
Vital Signs 
UDS 
Urine Drug Screen 
US(A) 
United States of America 


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10.4 
Protocol Amendment History 
Version/Date 
Section # and Name 
Description of Change 
Brief Rationale 
2.0/18 December 2023 
Section 1.2, Schedule 
of Assessments 
• Added PK sampling timepoints after morning dose 
on Day 1 (Footnote u) 
• Added column for Unscheduled visits (Footnote w) – 
See also Sections 8.3.1 and 8.3.2 
• Correction 
 
• Additional information for clarification 
Section 4.1, Overall 
Design 
 
Section 5, Study 
Population  
 
Section 7.2.2, 
Participant 
Replacement 
A randomized participant will be replaced with a 
participant who will receive the same treatment and, if 
possible, of the same gender 
• Clarification  
Section 5.1, Inclusion 
Criteria 
 
Section 5.2, Exclusion 
Criteria 
• Edited inclusion criteria (IC) 2, 4, 7 and 9  
• Edited exclusion criteria (EC) 8 and 16 
• To meet CDISC requirement for 200 
characters including spaces in text of IC 
and EC excluding Notes. Notes added as 
needed 
Section 6.1.1, Study 
Product Description 
Updated study product information  
• To match latest edition of the IB 
Section 6.2.5, 
Preparation 
Staff delegated to administer DP under supervision of 
licensed PI, investigator and clinicians listed on FDA 
Form 1572 
• Clarification 
Section 6.5, 
Concomitant Therapy 
Edited format of prohibited medications and exceptions  • Clarification  
 
Section 7.1.1, Study 
Halting Criteria  
 
Section 7.1.2, 
Individual Halting 
Criteria 
• Updated Cohort halting criteria 
• Updated individual halting criteria 
• Clarification   
Section 7.2, Participant 
Withdrawal from the 
Study and Replacement 
Created separate Sections 7.2.1 (for withdrawal 
reasons) and 7.2.2 (for replacements) and updated text 
• Clarification  


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Version/Date 
Section # and Name 
Description of Change 
Brief Rationale 
Section 8.1.2, 
Laboratory Evaluations 
HIV and hepatitis serology only at Screening and rapid 
FDA approved molecular diagnostic for SARS-CoV-
test on Day-1 to replace PCR  
• Clarification 
Section 8.3.4, Blood 
sampling for Plasma 
SLV213 Assay and 
Serum for Future 
Research 
Changed volume of blood drawn for plasma PK and 
serum for future secondary research  
• Updated information 
Section 8.4, Study Drug 
Administration 
• Updated duration of fasting before and after each 
dose on Days 1-7; and 
• Entered duration of fasting before clinical labs on 
Days 2, 4 and 6.    
• Correction 
 
• Additional information   
Section 8.5.3, 
Definition of 
Medically-Attended 
Adverse Events 
(MAEE)  
Added new subsection for the definition of MAAEs 
• MAAEs will be assessed and reported 
throughout the study, not part of AESI’s  
Section 8.5.9, Adverse 
Events of Special 
Interest (AESI) 
Updated section; retained only protocol specific AESIs. 
MAAEs moved to Section 8.5.3. New-Onset Chronic 
Medical Conditions (NOCMCs) and Potentially 
Immune-Mediated Medical Conditions (PIMMCs) 
deleted.   
• Clarification 
Appendix A, Table 4, 
Toxicity Grading 
Tables – 
LABORATORY AEs 
Updated clinical reference ranges for most recent Lab 
manual and edited corresponding lab toxicity scales.  
• To ensure lab data reported match lab 
reference ranges and linked toxicity grads 
in the protocol.  
Appendix Table 6, 
Laboratory Samples 
and Estimated Total 
Blood Volume (mL) 
Updated total volume of blood drawn for PK and future 
use samples  
• Due to decreased volume of blood drawn 
for plasma PK samples  
3.0/22 February 2024 
Section 1.2 Schedule of 
Assessments 
• Removed focused PE from Day 9 
 
• Additions to footnotes "f" and “g” 
• Complete PE is performed on the same 
day 
• Clarifications 
Section 5.1 Inclusion 
Criteria 
Updated inclusion criteria 
• Updated in response to non-hold questions 
received from the FDA. 
Section 5.2 Exclusion 
Criteria 
• Updated exclusion criteria 
 
• Added “sinus” to bradycardia 
• Updated in response to non-hold questions 
received from the FDA. 


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Version/Date 
Section # and Name 
Description of Change 
Brief Rationale 
• Clarification 
Section 5.4 Lifestyle 
Considerations 
Added “or 5 half-lives of the drug, whichever is 
longer” 
• Clarification 
Section 6.2.5, 
Preparation 
Updated administration of dose that after Dose 1 
(Morning dose on Day 1), each subsequent dose will be 
administered 12 h (+/- 15 min) after previous dose. 
• Clarification  
Section 6.5 
Concomitant Therapy 
• Deleted contraceptives. 
• Added 5 half-lives or whichever is longer 
• Updated in response to non-hold questions 
received from the FDA. 
Section 7.1.1, Study 
Halting Criteria, Cohort 
Halting Rules 
• Added an additional bullet to the cohort halting 
rules for one participant experiences a treatment-
related Grade 3 or higher adverse event 
• Revised fold increase above upper limit of normal 
for ALT and/or AST in first 2 bullets 
• Added at the request of FDA 
 
 
• To align with wording in FDA 2009 
Guidance for Hepatic Toxicity 
Section 7.1.2 Individual 
Halting Criteria 
Updated criteria for discontinuation from dosing 
• Updated in response to non-hold questions 
received from the FDA. 
Section 8.1.1 Clinical 
Procedures and 
Evaluation 
• Updated Medical History, Physical Exam, and Vital 
signs to add orthostatic evaluation 
• Deleted 2nd paragraph from PE and placed in under 
Vital Signs 
• Described conditions for measuring resting VS as 
well as orthostatic BP and HR 
• Updated in response to non-hold questions 
received from the FDA. 
• Correction made 
• Clarification for supine VS assessments 
precede orthostatic 
Section 8.1.4, 
Procedures to be 
Followed in the Event 
of Abnormal Clinical 
Laboratory Test Values 
or Abnormal Clinical 
Findings During 
Screening 
• Added “supine” 
• Revised repeat vital signs at least 5 min of each 
other 
• Clarification 
• Clarification 
Section 8.3.1, Clinical 
Procedures and 
Evaluations, Physical 
Examinations 
• Medical History: Added orthostatic 
 
• Physical Examination: Added assessment of not 
clinically significant or clinically significant 
• Vital Signs: Added orthostatic 
 
• Described conditions for measuring resting VS as 
well as orthostatic BP and HR 
• Updated in response to non-hold questions 
received from the FDA  
• Additional information 
 
• Updated in response to non-hold questions 
received from the FDA 


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Version/Date 
Section # and Name 
Description of Change 
Brief Rationale 
•  Clarification for supine VS assessments 
precede orthostatic 
Section 8.3.3, 
Procedures to be 
Followed in the Event 
of Abnormal Clinical 
Laboratory Test Values 
or Abnormal Clinical 
Findings During 
Conduct of the Trial 
• Added information regarding reference ranges 
 
• Added “supine” to sub-title 
• Revised repeat vital signs at least 5 min of each 
other 
• Described reporting of abnormal labs that are 
outside reference range, but below limits of Grade 1 
• Added “supine” to subtitle for VS 
• Updated in response to non-hold questions 
received from the FDA  
• Clarification 
• Clarification 
 
• Clarification 
 
• Clarification 
Section 8.3.5, Total 
Blood Volume Drawn 
Updated total blood volume drawn 
• Correction 
Section 8.5.4 
Classification of an 
Adverse Event 
Revised to add the use of the September 2007 FDA 
Guidance: Toxicity Grading Scales for Healthy Adult 
and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials  
Updated in response to non-hold questions 
received from the FDA  
Section 8.5.6 Adverse 
Event Reporting 
• Section added to address Laboratory AE Evaluation 
and Reporting 
• Described reporting of abnormal labs that are 
outside reference range, but below limits of Grade 1 
• Added in response to non-hold questions 
received from the FDA 
• Clarification 
Section 8.5.9 Adverse 
Events of Special 
Interest 
Added “or higher” to Grade 3 AEs 
Added in response to non-hold questions 
received from the FDA 
Appendix A: Adverse 
Events Toxicity 
Grading Criteria 
• Deleted toxicity tables and replaced with a link to 
the FDA Toxicity Grading Scales for Healthy 
Volunteers 
• Added Supplemental Toxicity Tables to be used 
when needed 
 
• Added a footnote under Supplemental Vital Signs 
• Revised in response to non-hold questions 
received from the FDA 
 
• Revised in response to non-hold questions 
received from the FDA 
 
• To provided information on coding of vital 
sign AEs with or without associated 
systemic symptoms 
4.0/27 March 2024 
Section 1.2 Schedule of 
Assessments 
• Added ± 15 seconds to 1 minute and 3 minutes for 
orthostatic vital signs 
• Clarifications to add a range 
Section 5.1 Inclusion 
Criteria 
• Updated inclusion criterion #4 to include exceptions 
• Clarification to add exceptions to clinical 
laboratory tests within normal range 


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Version/Date 
Section # and Name 
Description of Change 
Brief Rationale 
Section 8.1.1, Clinical 
Procedures and 
Evaluation 
• Added ± 15 seconds to 1 minute and 3 minutes for 
orthostatic vital signs 
• Clarifications to add a range 
Section 8.1.2, 
Laboratory Evaluations 
• Deleted reference to “Appendix A” under Clinical 
Laboratory Assessments 
• Added a paragraph to state laboratory normal 
reference ranges are included in the MOP 
• There are no exceptions included in 
Appendix A 
• Clarification 
Section 8.3.1, Clinical 
Procedures and 
Evaluations, Physical 
Examinations 
• Added ± 15 seconds to 1 minute and to 3 minutes 
for orthostatic vital signs 
• Clarifications to add a range 
Section 8.3.3, 
Procedures to be 
Followed in the Event 
of Abnormal Clinical 
Laboratory Test Values 
or Abnormal Clinical 
Findings During 
Conduct of the Trial 
• Added text regarding grading the severity of lab 
AEs in subjects whose allowable baselines were in 
the FDA Grade 1 range 
• Clarification 
Appendix A: Adverse 
Events Toxicity 
Grading Criteria  
• Deleted red blood cell from supplemental tox table 
as it is included in the FDA toxicity table 
• Added “dipstick” for nitrites as these are tested by 
dipstick 
• Revised grading for bacteria (microscopic) 
• Deleted as not necessary, included in FDA 
toxicity table 
• Clarification 
 
• Clarification 


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11. 
REFERENCES 
CDC. 
(2020). 
"Human 
Coronavirus 
Types." 
Retrieved 
Mar 
18, 
2021, 
from 
https://www.cdc.gov/coronavirus/types.html. 
Drake, M. T., B. L. Clarke, M. J. Oursler and S. Khosla (2017). "Cathepsin K Inhibitors for 
Osteoporosis: Biology, Potential Clinical Utility, and Lessons Learned." Endocrine Reviews 
38(4): 325-350. 
Dwek, R. A., J. I. Bell, M. Feldmann and N. Zitzmann (2022). "Host-targeting oral antiviral drugs 
to prevent pandemics." Lancet 399 (10333): 1381-1382. 
Frueh, F. W., D. C. Maneval, R. P. Bohm, J. P. Dufour, R. V. Blair, K. Powell, P. P. Aye, N. A. 
Golden, C. J. Roy, S. Spencer, K. Russel-Lodrigue, K. S. Plante, J. A. Plante, J. McKerrow and J. 
Rappaport (2021). "An Orally Available Cathepsin L Inhibitor Protects Lungs Against SARS-
CoV-2-Induced 
Diffuse 
Alveolar 
Damage 
in 
African 
Green 
Monkeys." 
bioRxiv: 
2021.2007.2020.453127. 
Fuchs, N., M. Meta, D. Schuppan, L. Nuhn and T. Schirmeister (2020). "Novel Opportunities for 
Cathepsin S Inhibitors in Cancer Immunotherapy by Nanocarrier-Mediated Delivery." Cells 9(9). 
Hoffmann, M., H. Kleine-Weber, S. Schroeder, N. Kruger, T. Herrler, S. Erichsen, T. S. 
Schiergens, G. Herrler, N. H. Wu, A. Nitsche, M. A. Muller, C. Drosten and S. Pohlmann (2020). 
"SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven 
Protease Inhibitor." Cell 181(2): 271-280 e278. 
Mahajan, S., S. Choudhary, P. Kumar and S. Tomar (2021). "Antiviral strategies targeting host 
factors and mechanisms obliging +ssRNA viral pathogens." Bioorg Med Chem 46: 116356. 
McKerrow, J. H. (2018). "Update on drug development targeting parasite cysteine proteases." 
PLoS Negl Trop Dis 12(8): e0005850. 
Mellott, D. M., C.-T. Tseng, A. Drelich, P. Fajtová, B. C. Chenna, D. H. Kostomiris, J. Hsu, J. 
Zhu, Z. W. Taylor, K. I. Kocurek, V. Tat, A. Katzfuss, L. Li, M. A. Giardini, D. Skinner, K. Hirata, 
M. C. Yoon, S. Beck, A. F. Carlin, A. E. Clark, L. Beretta, D. Maneval, V. Hook, F. Frueh, B. L. 
Hurst, H. Wang, F. M. Raushel, A. J. O’Donoghue, J. L. de Siqueira-Neto, T. D. Meek and J. H. 
McKerrow (2021). "A Clinical-Stage Cysteine Protease Inhibitor blocks SARS-CoV-2 Infection 
of 
Human 
and 
Monkey 
Cells." 
ACS 
Chemical 
Biology 
16(4): 
642-650. 
doi: 
10.1021/acschembio.0c00875. 
Nie, X., L. Qian, R. Sun, B. Huang, X. Dong, Q. Xiao, Q. Zhang, T. Lu, L. Yue, S. Chen, X. Li, 
Y. Sun, L. Li, L. Xu, Y. Li, M. Yang, Z. Xue, S. Liang, X. Ding, C. Yuan, L. Peng, W. Liu, X. Yi, 
M. Lyu, G. Xiao, X. Xu, W. Ge, J. He, J. Fan, J. Wu, M. Luo, X. Chang, H. Pan, X. Cai, J. Zhou, 
J. Yu, H. Gao, M. Xie, S. Wang, G. Ruan, H. Chen, H. Su, H. Mei, D. Luo, D. Zhao, F. Xu, Y. Li, 
Y. Zhu, J. Xia, Y. Hu and T. Guo (2021). "Multi-organ proteomic landscape of COVID-19 
autopsies." Cell 184(3): 775-791 e714. 


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Our World in Data. (2020). "Our World in Data." Retrieved Mar 18, 2021, from 
https://ourworldindata.org/. 
Wagoner, J., S. Herring, T. Y. Hsiang, A. Ianevski, S. B. Biering, S. Xu, M. Hoffmann, S. 
Pohlmann, M. Gale, Jr., T. Aittokallio, J. T. Schiffer, J. M. White and S. J. Polyak (2022). 
"Combinations of Host- and Virus-Targeting Antiviral Drugs Confer Synergistic Suppression of 
SARS-CoV-2." Microbiol Spectr 10(5): e0333122. 
Zhou, Y., P. Vedantham, K. Lu, J. Agudelo, R. Carrion, Jr., J. W. Nunneley, D. Barnard, S. 
Pohlmann, J. H. McKerrow, A. R. Renslo and G. Simmons (2015). "Protease inhibitors targeting 
coronavirus and filovirus entry." Antiviral Res 116: 76-84 
12. 
APPENDICES 
 
 


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APPENDIX A: ADVERSE EVENTS TOXICITY GRADING CRITERIA 
The Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials will be used in this protocol, available at the following link: 
https://www.fda.gov/media/73679/download. 
Supplemental Toxicity Tables 
 
Vital Signs 
Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Sinus Bradycardia – 
when baseline HR 
<60 bpm1 
45 – 49 bpm 
40 – 44 bpm 
<40 bpm 
Life-threatening 
consequences, urgent 
intervention indicated 
1Use clinical judgement when characterizing bradycardia among some healthy subject populations (e.g., conditioned athletes). 
Note: Isolated/individual abnormalities of VS would not be considered toward halting criteria. Abnormalities of VS will be 
described as “increased X” or “decreased X” (X = HR, BP, RR, temperature) if asymptomatic, transient, and not associated with 
a systemic or organ-specific disorder and coded by MedDRA within the System Organ Class (SOC) “Investigations.” These 
abnormalities will be graded per criteria in this table, but not considered in determining whether study stopping criteria have been 
met. On the other hand, abnormalities of VS that are either secondary to systemic or organ-specific clinical syndrome or primary 
disorders will be coded in the appropriate SOC (e.g., “cardiac disorders”, “respiratory disorders”, “immunological disorders”, 
etc.). These abnormalities will be considered in determining whether stopping criteria have been met. 
 
Laboratory Parameters 
Hematology 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Monocytes increase, 
All ages – x103/µL 
1.01 – 2.00 
2.01 – 3.00 
>3.00 
Intervention indicated 
Basophils increase, 
All ages – x103/µL 
0.16 – 0.50 
0.51 – 0.80 
>0.80 
Intervention indicated 
Carbon dioxide increase, 
All ages – mEq/L 
32.1 – 36.0 
36.1 – 40.0 
>40.0 
Intervention indicated 
Carbon dioxide decrease, 
All ages – mEq/L 
17.0 – 21.9 
14.0 – 16.9 
<14.0 
Metabolic acidosis 
Invention indicated 
 
ECG Parameters 
ECG interval 
abnormality 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
QTcF interval  
prolonged (msec): 
• 
Male 
• 
Female 
Asymptomatic, 
QTcF 
• 
451 – 479 msec 
• 
471 – 479 msec 
Asymptomatic, 
QTcF 480 – 500 msec 
OR 
increase in interval  
30 – 59 msec above 
baseline 
Asymptomatic, 
QTcF >500 msec 
OR 
increase in interval  
>60 msec above 
baseline 
QTcF >500msec, 
Life threatening signs 
or symptoms (e.g., 
arrhythmia, 
hypotension, 
syncope); Torsade de 
pointes 
PR interval prolonged 
(msec) 
211 – 250 msec 
>250 msec 
Type II 2nd degree 
AV block 
OR 
Ventricular pause 
>3.0 msec 
Urgent Intervention 
indicated 
 
Urine Microscopy 
Urine Microscopy 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nitrite (dipstick) 
1+ 
2+ 
>2+ 
 
White blood cells (WBC) 
per HPF 
0 – 10 
11 – 50 
>50 or gross 
Hospitalization of 
intervention 


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Urine Microscopy 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Bacteria (microscopic) 
Few 
Moderate 
Many 
Hospitalization or 
intervention 
 
Estimating Severity Grade for Parameters Not Identified in the Grading Table 
 
The functional table below should be used to grade the severity of an AE that is not specifically 
identified in the grading table. In addition, all deaths related to an AE are to be classified as 
Grade 5. 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
Clinical adverse 
event NOT 
identified 
elsewhere in the 
grading table 
Mild symptoms 
causing no or minimal 
interference with usual 
social & functional 
activities with 
intervention not 
indicated 
Moderate symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
with intervention 
indicated 
Severe symptoms 
causing inability to 
perform usual social & 
functional activities 
with intervention or 
hospitalization 
indicated 
Potentially life-
threatening symptoms 
causing inability to 
perform basic self-care 
functions with 
intervention indicated to 
prevent permanent 
impairment, persistent 
disability, or death  
 
 


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APPENDIX B: BLOOD VOLUME WITHDRAWN DURING THE TRIAL 
Table 3: Laboratory Samples and Estimated Total Blood Volume (mL) 
Study Periods 
Out-patient 
In-patient 
In-patient Period (Days 1 – 9) 
 
Study Visit 
Screen 
Check-in 
Dosing 
In-patient FU 
Discharge 
ET 
Study Day a 
-28 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
HEMATOLOGY 1 
4 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
COAGULATION 1 
2.7 
2.7 
 
2.7 
 
2.7 
 
2.7 
 
2.7 
 
2.7 
CHEMISTRY 1  
8.5 
8.5 
 
8.5 
 
8.5 
 
8.5 
 
8.5 
 
8.5 
Serum β-HCG and FSH 1,2 
0 
 
 
 
 
 
 
 
 
 
 
 
Viral Serology (HIV, HBsAg, HCV) 3 
8.5 
 
 
 
 
 
 
 
 
 
 
 
PK (plasma) 4 
 
 
48 
12 
12 
12 
12 
12 
36 
24 
12 
6 
Future research (serum)5 
 
 
28 
7 
7 
7 
7 
7 
21 
14 
7 
3.5 
Total blood volume/visit 
23.7 
15.2 
76 
34.2 
19 
34.2 
19 
34.2 
57 
53.2 
19 
24.7 
Cumulative total blood volume 
23.7 
38.9 
114.9 
149.1 
 
168.1
202.3 
221.3 
255.5 
312.5 
365.7 
384.7 
 
a Study Days shown correspond to days in each study period. For a view of the cumulative numbering of study days, please refer to Section 8.1. 
1 Clinical Safety blood tests (HEM, CHEM, COAG) are drawn at Screening Visit, on Day -1, pre-dose on Days 2, 4 and 6, on Day 8, and ET if needed. The CHEM test includes 
serum β-HCG and FSH at Screening. 
2 Serum pregnancy test (β-HCG) in all women at Screening. FSH at Screening only in post-menopausal women. 
3 Viral serology tests are drawn at Screening. 
4 PK (plasma) samples (6 mL total blood per sample) are drawn on: 
• 
On Day 1: MORNING DOSE: Within 30 min before the dose (t=0), and at 0.5h (±5 min), 1h (±5 min), 2h (±5 min), 4h (±5 min), 6h (±10 min), 8h (±10 min), and 12h 
(±15 min) after the morning dose. And EVENING DOSE: Before and 12h (±15 min) after the dose.  
o 
NOTE: Starting with the Evening Dose on Day 1, the timepoint before each dose is the same as the 12h timepoint after the previous dose. 
• 
On Days 2 to 6: Within 30 min before the morning and evening doses and 12h (±15 min) after the morning and evening doses.     
• 
On Day 7 MORNING DOSE: Within 30 min before the morning dose (t=0), and at 12h (±15 min) after the morning dose.   
• 
On Day 7 EVENING DOSE: Within 30 min before the evening dose (t=0), and at 0.5h (±5 min), 1h (±5 min), 2h (±5 min), and 4h (±5 min) after the evening dose. 
• 
On Day 8: At 6h (±10 min) 8h (±10 min), 12h (±15 min), and 24h (±15 min) after the evening dose on Day 7. 
• 
On Day 9: At 36h (±15 min) and 48h (-2 hours) after the evening dose on Day 7.  
 
5 Future research (serum) samples (3.5 mL total blood per sample) are drawn if subject consented to their collection at the same timepoints as PK (plasma) samples from Day 1 to 
Day 9. 


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APPENDIX C: STRONG INHIBITORS, INDUCERS, AND SENSITIVE SUBSTRATES OF CYP3A4 AND 
CYP2D6 
CLASSIFICATION 
CYP3A4 
CYP2D6 
STRONG INHIBITORS1 
• 
ceritinib 
• 
clarithromycin 
• 
cobicistat 
• 
elvitegravir and ritonavir 
• 
idelalisib 
• 
indinavir and ritonavir 
• 
itraconazole 
• 
ketoconazole 
• 
lopinavir and ritonavir 
• 
nefazodone 
• 
nelfinavir 
• 
paritaprevir and ritonavir and (ombitasvir and/or dasabuvir) 
• 
posaconazole 
• 
ritonavir 
• 
saquinavir and ritonavir 
• 
telithromycin 
• 
tipranavir and ritonavir 
• 
voriconazole 
• 
bupropion 
• 
fluoxetine 
• 
paroxetine 
• 
quinidine 
• 
terbinafine 
STRONG INDUCERS2 
• 
apalutamide 
• 
carbamazepine 
• 
enzalutamide 
• 
ivosidenib 
• 
lumacaftor and ivacaftor 
• 
mitotane 
• 
phenytoin 
• 
rifampin 
• 
St. John’s wort 
• 
None 
SENSITIVE SUBSTRATES3 
• 
alfentanil 
• 
avanafil 
• 
budesonide 
• 
buspirone 
• 
conivaptan 
• 
atomoxetine 
• 
desipramine 
• 
dextromethorphan 
• 
eliglustat 
• 
nebivolol 


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CLASSIFICATION 
CYP3A4 
CYP2D6 
• 
darifenacin 
• 
darunavir6 
• 
dasatinib 
• 
dronedarone 
• 
eletriptan 
• 
eplerenone 
• 
everolimus 
• 
felodipine 
• 
ibrutinib 
• 
indinavir 
• 
isavuconazole 
• 
ivabradine 
• 
lemborexant 
• 
lomitapide 
• 
lovastatin 
• 
lurasidone 
• 
maraviroc 
• 
midazolam 
• 
mobocertinib 
• 
naloxegol 
• 
nisoldipine 
• 
quetiapine 
• 
saquinavir 
• 
sildenafil 
• 
simvastatin 
• 
sirolimus 
• 
tacrolimus 
• 
ticagrelor 
• 
tipranavir 
• 
tolvaptan 
• 
triazolam 
• 
vardenafil 
• 
venetoclax 
• 
nortriptyline 
• 
perphenazine 
• 
R-venlafaxine 
• 
tolterodine 
Source: For Healthcare Professionals: FDA’s Examples of Drugs that Interact with CYP Enzymes and Transporter Systems | FDA. Accessed at www.fda.gov. 
1Drugs that increase the AUC of sensitive index substrates of a given metabolic pathway ≥5-fold. 
2Drugs that decrease the AUC of sensitive substrates of a given metabolic pathway by ≥80%. 
3Drugs that demonstrate an increase in AUC of ≥5-fold with strong inhibitors of a given metabolic pathway.