PRIMARY OBJECTIVE: 
 To investigate the ability of Ifenprodil (20 mg TID) to improve lung function in patients infected with COVID-19
SECONDARY OBJECTIVES: 
 To investigate the effects of Ifenprodil (20 mg TID) on symptoms and biomarkers associated with infection with COVID-19
 To investigate the effects of Ifenprodil (20 mg TID) on lung function and health status in patients infected with COVID-19 

SAFETY OBJECTIVES: 
 To study the safety of Ifenprodil (20 mg TID) in patients infected with COVID-19


 Ifenprodil was discovered by a genome wide RNAi assay to uncover gene targets associated with cytoprotective activity against highly pathogenic H5N1 influenza, specifically by preserving cell viability in vitro. When tested in a murine model of H5N1, the drug at clinically relevant doses: (1) improved survivability from 0% at day 6 to 40% at day 14 post-infection, (2) the drug significantly reduced edemaand lung injury score and (3) reduced infiltrating T cells and NK cells and attenuated the ‘cytokine storm’. The mortality rate of H5N1 in humans is >50%, whereas the mortality rate of COVID-19 infectedpatients is < 5%, and both viruses cause acute lung injury and share similar pulmonary pathologies.   
 Ifenprodil has also been shown to mediate anti-inflammatory responses and reduce pulmonary fibrosisin a murine model of idiopathic pulmonary fibrosis, a complication which can occur after a respiratory virus infection.  
Since H5N1 has a significantly higher mortality rate than COVID-19 but these share similar lung pathologies, Algernon Pharmaceuticals believes Ifenprodil could reduce lung injury associated with COVID-19 infection, thereby improving lung function and accelerating patient recovery.
The purpose of this proof-of-concept trial is to determine the efficacy of Ifenprodil in improving lung function in patients with COVID-19 infection with severe pneumonia.

Treatment

Treatment Group:  
IP (Ifenprodil) plus Standard of Care (SOC) (N=20) 
Control Group:   
Standard of Care (SOC) (N=20) 

TREATMENT:  
Test Product:  Ifenprodil, 20 mg TID for up to 4 weeks, in conjunction with SOC   
Duration of patient participation: Up to 5 weeks 

The chemical name of Ifenprodil is (1RS,2SR)-4-[2-(4-Benzylpiperidin-1-yl)-1-hydroxypropyl] phenol hemi-(2R,3R)-tartrate. The drug is more commonly referred to as ifenprodil. Ifenprodil will be provided as white, round, biconvex, film-coated tablets containing 20 mg of the active ingredient. 

Treatment Administration and Schedule 

Tablets will be taken by mouth TID in the in the morning (AM, upon rising), in the afternoon (PM, 6-10 hours following first dose), and evening (PM, 6-10 hours before the next day’s anticipated first dose).
Best efforts should be made to keep the three doses approximately 8 hours apart. The length of dosing for the study is up to 4 weeks.
The first dose of study medication will be taken on day 1 at the first visit, following randomization.
In cases where the patient is unable to swallow tablets the use of a nasogastric/stomach tube is permitted. Crushing and administration of tablets should follow local practices/SOPs. Study drug administration should continue until the end of week 4, or hospital discharge, whichever comes first.

Arm Label

Target Number of Participant

Arm Type

Arm Description

Test Product:  Ifenprodil, 20 mg TID for up to 4 weeks, in conjunction with SOC   
Duration of patient participation: Up to 5 weeks

Tablets will be taken by mouth TID in the in the morning (AM, upon rising), in the afternoon (PM, 6-10 hours following first dose), and evening (PM, 6-10 hours before the next day’s anticipated first dose).
Best efforts should be made to keep the three doses approximately 8 hours apart. The length of dosing for the study is up to 4 weeks.
The first dose of study medication will be taken on day 1 at the first visit, following randomization.

Arm Label

Target Number of Participant

Arm Type

Arm Description

Standard of Care (SOC) :   up to 4 weeks of SOC  
Duration of patient participation: Up to 5 weeks

Gender

Age

Description

INCLUSION CRITERIA: 
1. Male and female patients aged 19-85 years of age, inclusive, as of baseline/screening visit
2. Confirmed coronavirus infection based on possessing at least one of the following etiological
evidence: 
a. Positive real-time fluorescence polymerase chain reaction of the patient’s respiratory or
blood specimens for COVID-19 nucleic acid 
b. Viral gene sequences in respiratory or blood specimens that are highly homologous to
COVID-19 
c. Any other diagnostic test accepted by local regulatory authorities 
3. Presence of severe pneumonia as evidenced by any of the following: 
a. Respiratory distress with RR >=30 breaths/minute
b. SpO2 <90% on room air and at rest
c. PaO2/FiO2 =< 250 mmHg (1mmHg = 0.133kPa)  
4. Chest imaging (x-ray [XR] or computerized tomography [CT]) confirms severe pneumonia AND
shows evidence of inflammatory exudation or pleural effusion 
5. Female patients of childbearing potential who are sexually active with a non-sterilized male
partner must use at least 1 highly effective method of contraception from the time of screening
and must agree to continue using such precautions for 90 days after the final dose of study
drug(s) 
6. Non-sterilized males who are sexually active with a female partner of childbearing potential must
use condom plus spermicide from day 1 through 90 days after receipt of the last dose of study
drug(s) 
Patients (or their legal designates), must have the capacity to understand, sign and date a voluntary
written, informed consent form and any required authorization prior to initiation of any study
procedure.

EXCLUSION CRITERIA: 
1. Patients with vasodilatory shock, orthostatic hypotension, hypotension, or tachycardia at
screening or baseline 
2. Patients experiencing cerebral hemorrhage or cerebral infarction at baseline
3. Patients with galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption
4. Patients taking drugs that increase risk of bleeding (e.g. anti-coagulants, anti-platelet)
5. Patients taking droxidopa
6. ALT/AST > 5 times the upper limit of normal at baseline
7. Stage 4 severe chronic kidney disease or requiring dialysis (i.e. eGFR < 30) at baseline
8. Presence of other disease that may interfere with testing procedures or which in the judgement
of the Investigator may interfere with trial participation or may put the patient at risk when
participating in this trial
9. Pregnant and lactating women and those planning to get pregnant
10. Known or suspected allergy to the trial drug or the relevant drugs given in the trial
11. Patients who have participated in any other clinical trial/s, including a COVID-19 trial, within the
past 3 months
12. The participant is, in the opinion of the PI, unlikely to comply with the clinical study protocol or
is unsuitable for any other reason

Effect on the rate of change of partial pressure of oxygen (PaO2) and PaO2/FiO2 ratio taken at baseline and measured twice daily up to 4 weeks of treatment in IP versus control group patients

at baseline and measured twice daily up to 4 weeks

Changes in the extent of dyspnea from baseline, using a Likert scale, at 24 hours, 72 hours, 7 days and 14 days in IP versus control group Likert scale: The patient grades his current breathing compared to when he first started the drug (from -3 to 3). "0" = no change, "1" =minimally better, "2" =moderately better, "3" =markedly better, "-1" =minimally worse, "-2" =moderately worse, "-3" =markedly worse

using a Likert scale, at 24 hours, 72 hours, 7 days and 14 days in IP versus control group Likert scale

Rate of all-cause mortality in IP group versus control group patients

from the time the patient signs informed consent until completion of the final Safety Follow-up Visit

Rate of mechanical ventilation in IP group versus control group patients

Measurements at Baseline till the last day of Visit

Time to hospital discharge for IP group versus control group patients

Measurements at Baseline till the last day of Visit

Type, frequency, severity, and relationship of AEs to investigational product (IP).

from the time the patient signs informed consent until completion of the final Safety Follow-up Visit

Number of patients who discontinue IP due to any AE.

from the time the patient signs informed consent until completion of the final Safety Follow-up Visit

Frequency of clinically significant changes in vital signs and/or laboratory findings.

from the time the patient signs informed consent until completion of the final Safety Follow-up Visit

Rate of change to patient’s experience of cough (Visual analog scale [VAS]) at 24 hours, 72 hours, 7 days and 14 days in IP versus control group VAS: The patient draws a horizontal line on an axial graph (from 0 to 100) to show the degree of how he/she feels about coughing. The number "100" equals the worst coughing the patient has ever felt and the number "0" equals the best he/she has felt since the day of hospital admission.

At 24 hours, 72 hours, 7 days and 14 days

The area of lung lesions on Chest XR at 7 days and 14 days in IP group versus control group patients

At 7 days and 14 days

The degree of lung exudation on Chest XR at 7 days and 14 days in IP group versus control group patients

At 7 days and 14 days

Effect on CRP, cardiac troponin, IL-6, myoglobin and ferritin at 72 hours, 7 days and 14 days between IP group versus control group patients in IP group versus control group patients

At 72 hours, 7 days and 14 days

Time on mechanical ventilation in IP group versus control group patients

Measurements at Baseline till the last day of Visit