Clinical trial NCT04389671
Conditions: COVID-19 Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS)
Sponsor: Windtree Therapeutics
Start date: 2021-01-05; Completion date: 2022-02-20
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a multicenter, single-treatment study. Subjects will consist of adults with COVID-19 associated acute lung injury who are being cared for in a critical care environment.

Detailed description:
This is a multicenter, single-treatment study. Subjects will consist of adults with COVID-19 associated acute lung injury who are being cared for in a critical care environment.

Lucinactant is a synthetic surfactant that, in its liquid form (SURFAXIN®), is approved by the United States Food and Drug Administration (NDA 021746) for the prevention of respiratory distress syndrome (RDS) in premature infants at high risk for RDS.

It has been studied in over 2000 children and adults. Preliminary data from animal and adult human studies indicate that lucinactant may be able to benefit those with acute respiratory distress syndrome (ARDS) in the context of COVID-19 infection, improving oxygenation and lung compliance. When given to intubated patients, Lucinactant could potentially decrease the duration of ventilation.

Lucinactant has an extensive safety profile in different patient populations for different indications.

It is hypothesized that lucinactant may improve the respiratory status of patients suffering from COVID-19.

Arms: arm 1: Lyophilized Lucinactant reconstituted with sterile water for injection
Interventions: intervention 1: Lucinactant
Intervention descriptions: intervention 1: Lucinactant administered as a liquid at a dose of 80 mg total phospholipids (TPL)/kg lean body weight delivered

Protocol documents:
ICF_002.pdf: 
Protocol 02-CL-2001a 
- CONFIDENTIAL - 
Windtree Therapeutics, Inc. 
Master Informed Consent Form 
Version 2.1, 18 June2021 
 
 
Page 1 of 11 
INFORMATION for POTENTIAL PARTICIPANTS 
 
Name of Study: 
A Multicenter, Single-Treatment Study to Assess the 
Safety and Tolerability of Lyophilized Lucinactant in 
Adults with COVID-19 Associated Acute Lung Injury 
Study Number: 
02-CL-2001a 
Study Sponsor: 
Windtree Therapeutics, Inc. 
2600 Kelly Road, Suite 100 
Warrington, PA 18976 
USA 
Study Doctor (Investigator): 
[Investigator Name] 
[Site Address] [Office Hours Tel] [Out of Hours Tel] 
Institutional Review Board or Ethics 
Committee 
[IRB/EC Name] 
[IRB/EC Address] [Office Hours Tel] 
[Out of Hours Tel] 
 
Why are you receiving this information? 
You are being asked to consider whether you (or the person you represent) would like to participate 
in a clinical research study. The following information describes the study and your role as a 
possible volunteer. You have the right to know all the details about this research. When you 
understand these details, including all the possible risks, hazards, or benefits, you may then decide 
whether you (or the person you represent) would like to participate in this study. Please read this 
information carefully and do not hesitate to ask the study doctor any questions you may have about 
the study. 
You or the person you represent have been asked to take part because you have been diagnosed 
with COVID-19 associated acute lung injury and are being cared for in a critical care unit in the 
hospital. 
What is the purpose of this clinical research study? 
The coronavirus that was first detected in China in 2019 and which has been detected in over 190 
countries on every continent, has infected over 150 million people worldwide (including 
approximately 3 million deaths), including approximately 35 million in the United States (including 


Protocol 02-CL-2001a 
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Version 2.1, 18 June2021 
 
 
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over 600,000 deaths). The virus has been named “SARS-CoV-2” and the disease it causes has been 
named “coronavirus disease 2019” (abbreviated “COVID-19”). 
This virus is part of a large family of viruses that are common in people and many different types of 
animals, including camels, cattle, cats, and bats. Rarely, animal coronaviruses can infect people and 
then spread between people such as with MERS-CoV or SARS-CoV, and now with this new virus.  
While the information we have so far indicates that most COVID-19 illness is mild, early experience 
suggests serious illness occurs in approximately 16% of people infected with the coronavirus. This 
study includes patients who are seriously ill with COVID-19. 
Surfactant is a naturally occurring substance in the lungs. It works to keep the air sacs in the lung 
open and to decrease the amount of work required to breathe. Surfactant can be damaged or stop 
working by infection and inflammation. This can make breathing difficult and decrease the ability 
of the lungs to get oxygen to the body. In COVID-19, the cells in the lungs that make surfactant are 
affected by the virus and this may limit their ability to make surfactant. 
Lucinactant is a man-made surfactant that has been tested in many studies and is approved by the 
United States Food and Drug Administration (FDA) for the prevention of respiratory distress 
syndrome in premature infants at high risk for RDS (NDA 021746). Preliminary data from animal 
and adult human studies indicate that lucinactant could potentially benefit those with a type of lung 
injury known as acute respiratory distress syndrome (ARDS). It would do this by improving oxygen 
levels in the blood and lessening lung damage. Also, lucinactant could possibly lead to less time 
needed on the breathing machine (mechanical ventilation).  
Many studies have found that damage to surfactant and too little surfactant contribute to the 
development of ARDS. Several studies in adult ARDS have shown that lucinactant can be safely 
given to critically ill patients and may refill the surfactant pool. A study among patients with ARDS 
caused by a direct lung injury, such as pneumonia, found that those who received surfactant may 
have a higher survival rate than those who received standard therapy. In fact, more oxygen in the 
blood was found across the entire population of patients who received surfactant. Some side effects 
were observed in these studies, which are described in detail later in this document. 
Lucinactant has been safely administered to over 1000 patients for different diseases. In almost all 
cases, there were no safety signals of concern with rates of side effects being similar to control groups 
(placebo and active).  


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Version 2.1, 18 June2021 
 
 
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The purpose of this study is to evaluate the safety and tolerability of lucinactant in patients with 
COVID-19 and who are on a breathing machine being treated in a critical care unit in a hospital. 
What makes this different from the usual treatment? 
Lung surfactant is affected by conditions in the inflamed lung in a way that could lead to the 
surfactant being inactivated or destroyed. Since some of the major breathing consequences of ARDS 
may be directly impacted by the lack of surfactant, treatment with lucinactant is potentially effective 
in treating ARDS. Additionally, lucinactant has been shown to be more resistant to inflammation 
and to reduce the inflammatory response in lab tests of lung injury when compared to animal-derived 
surfactants. These lab results indicate that lucinactant treatment may result in reduced inflammation-
related lung damage  
How long will I be in the trial? 
The duration of the study treatment will be approximately 1-2 days. Health information will be 
collected while in the hospital or until you or the person you represent have been in the study for 30 
days (whichever is sooner). If the hospital discharge is before the 30th day of the study, you may be 
contacted by someone at the hospital to enquire about your health at that time. 
What are the treatments and how are they assigned? 
If you or the person you represent meet the requirements for the study and you provide consent, you 
or the person you represent will be enrolled at the site. All patients will be receiving the 
investigational medicine in this study; there is no control or placebo.  
• Up to 30 patients will be administered lyophilized lucinactant (160 ml [~80 mg/kg lean 
body weight]), reconstituted with sterile water and delivered as a liquid in 4 equal parts 
into the airways  
If you continue to have trouble breathing after receiving lucinactant, you may receive additional 
doses of lucinactant. You can receive up to 3 additional doses no sooner than 6 hours apart from 
completion of previous dose. 
What if I decide to participate or allow participation? 
If you decide to participate or allow participation in this study, you will be required to sign this 
Informed Consent Form. The medical records and medical history will be reviewed to ensure that 
you or the person you represent are a good candidate for the study. 


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A physical exam will be done to see if you qualify to be in the study. In order to be considered for 
this study, you or the person you represent must be supported by mechanical ventilation for no longer 
than 7 days.  
The following procedures will be conducted for those who qualify: 
1) Participants will receive lucinactant, a surfactant, as a liquid into the airways. 
2) Before, during, and after each treatment of study drug, vital signs, oxygen and carbon dioxide 
levels in your blood and breathing machine settings will be checked and documented. These 
assessments are part of the routine hospital care. 
3) Vital signs will be documented every 12 hours for 5 days. 
4) The last day of the study is 30 days after study entry . Oxygen and carbon dioxide levels in 
your blood will be checked at this time. 
What will happen at the end of the study? 
At the end of the study (30 days after enrollment or sooner if you decide to withdraw from the study), 
final measurements and information about your health will be collected. 
What are the potential risks and discomforts? 
People suffering from COVID-19 are at risk of complications, including death. The degree of risk is 
different for each person and depends on many factors. People who have COVID-19 may require 
placing a tube in their windpipe and connecting that tube to a breathing machine. These risks are 
present whether you participate in this study or not. Your doctor or the study doctor can talk to you 
about these risks. 
Lyophilized lucinactant is an investigational drug that is being tested in humans. This means there 
may be unknown risks to you. It also means it is not known whether this drug will be of any benefit 
to you or make your problem worse.  
In previous studies, lucinactant, given as a liquid into a tube in the windpipe, was found to be 
generally safe; however, it should be noted that in one study with lucinactant, the rates of dying were 
21% and 14% in the lucinactant-treated patients and the untreated group, respectively. The majority 
of deaths were due to non-respiratory causes and the overall rate of dying for the untreated patients 
was on the lower end of anticipated number of deaths for ARDS trials at that time.  


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Version 2.1, 18 June2021 
 
 
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Previous research has shown that when lucinactant is delivered as a liquid through a tube in the 
windpipe, side effects may include: a decrease in the oxygen level in the blood for a short period of 
time, apnea (stopping breathing for a few seconds), a slowing of the heart, and regurgitation, which 
might occur when the drug first goes into the large airways of the lung. In a study of lucinactant for 
ARDS in adults, 45% of those who received lucinactant reported a treatment-related adverse event, 
and 40% of the patients experienced a serious adverse event related to treatment. The most 
commonly reported side effects were anemia, airway obstruction, pneumothorax (air in the chest 
cavity), hypotension (low blood pressure), and decreased oxygen saturation. Pneumothorax was 
identified as a significant side effect and was observed in a total of 22% patients receiving lucinactant 
and 14% patients receiving standard care. The number of pneumothoraces seen was similar to the 
number usually seen in ARDS patients.  
Overall, side effects for the lucinactant treated patients were not significantly different to the 
comparison group (standard of care), and, in general, the procedure was considered safe and well 
tolerated given the severity of illness. Although there were short episodes of low oxygen levels, low 
blood pressure and a need to adjust breathing machine during the treatment delivery procedure, most 
subjects completed the procedure. However; if these events or others happen during this study, may 
require your doctor and/or the study doctor to stop giving the study drug. Treatment may be stopped 
at any time if it is in your best interest.  
One important feature of this study, and a significant difference with the current study, is the dosing 
procedure. The early lucinactant study used a technique known as bronchopulmonary segmental 
lavage. This procedure carries some risk in intubated patients. Additionally, the procedure takes time 
to perform. The degree to which this dosing procedure contributed to the results of the study, if at 
all, cannot be determined and will be avoided in future investigations. Regardless, the same 
procedure will not be used in this study and lucinactant will be given as a liquid in the airway. 
You will be closely watched by your doctor and health care staff during the study. From the time of 
starting the study to the end of the study, all of those enrolled will be monitored for all possible side 
effects, and especially for signs that the breathing problem is getting worse. An independent safety 
committee (also known as a Data Monitoring Committee or Data Safety Monitoring Board) will also 
oversee this study safety. This committee, comprised of doctors who are specialists in this field and 
those experienced in clinical study safety, are not employed by Windtree Therapeutics, Inc. (the 
Sponsor). This committee will advise the Sponsor about the safety of study subjects and will also 
evaluate the ongoing scientific strength of the study. 


Protocol 02-CL-2001a 
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Windtree Therapeutics, Inc. 
Master Informed Consent Form 
Version 2.1, 18 June2021 
 
 
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What are the advantages and disadvantages of participation in the study? 
As with any investigational product, there is no guarantee this treatment will help anyone 
participating in the study. New information about the benefits and safety of lucinactant will be 
obtained from your participation in this study. This new information may benefit others in the future 
if lucinactant is shown to be safe and effective for those suffering from COVID-19 who require 
mechanical ventilation. 
Are there any alternative treatments? 
If you do not wish to take part in this research, you will be provided with the established standard 
treatment available at this hospital, which may include drugs like remdesivir or steroids. In addition, 
there are new therapies being studied for those suffering from COVID-19 including antivirals and 
vaccines. 
Will you be informed if new information becomes available during the study? 
The study doctor will inform you in a timely manner of any new information learned during the 
study that may affect your willingness to continue your participation. 
Who can you contact with further questions? 
You may ask questions about this consent form or the study at any time (before or during the course 
of the study). If you have additional questions, or if you experience a research-related injury, contact 
the study doctor using the details provided in the table on the first page of this informed consent. 
If you have a complaint or question about your rights as a research subject, you may contact the 
institutional review board using the details provided in the table on the first page of this informed 
consent. This is a group of scientific and non-scientific individuals who review research studies with 
the safety and welfare of research subjects in mind. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
US Law, and the International Clinical Trial Registrations Platform. These websites will not include 
information that can identify you. At most, the websites will include a summary of the results. You 
can search these websites at any time. These websites only show data in English, but you can request 
information from the study staff at any time and have access to data that are publicly available. 


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Windtree Therapeutics, Inc. 
Master Informed Consent Form 
Version 2.1, 18 June2021 
 
 
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What happens if you change your mind? 
Participation in this study is voluntary. You or the person you represent do not have to take part, and 
you may discontinue your participation at any time. There will be no penalty or loss of benefits to 
which you are otherwise entitled or affect your treatment or your rights at this center in any way. If 
you enroll in this study and then later withdraw from this study, any information obtained while in 
the study may be used to evaluate the safety and tolerability of lucinactant. 
If you decide to stop study before you have completed the study, tell the study doctor and follow 
their instructions. It may be helpful if you could explain your reasons. You may also be asked to 
allow end of study procedures (such as a final medical examination and laboratory tests) to be 
completed, for safety.  
In addition, the study doctor or the Sponsor may withdraw you from the study for his or her own 
safety, even if you wish to continue to participate. Reasons that the Sponsor may withdraw you from 
the study include: 
• If you need additional medication 
• If you experience a study-related injury 
• If you or the study site do not follow the study rules 
Are there any costs if I decide to participate? 
Study drugs will be made available to you at no charge and you will not be required to pay for any 
study procedures. You or your insurance company may be billed for any standard medical care that 
is not required for the research study. 
Is there a payment if I decide to participate? 
You will not receive payment for participating in this study, but the study drugs will be made 
available to you at no charge and you will not be required to pay for any study procedures. 
Will I receive compensation if I become injured because of the study? 
If you are injured because of your participation in this study, treatment for the injury will be made 
available through [name of physician] and [institution]. Windtree Therapeutics, Inc. will pay the 
costs of this treatment not paid by your medical insurance. No other payment is available from the 
Sponsor or the study doctor in the event of injury. You are not waiving any legal rights by signing 
this form, accepting medical care, or accepting payment for medical expenses. 


Protocol 02-CL-2001a 
- CONFIDENTIAL - 
Windtree Therapeutics, Inc. 
Master Informed Consent Form 
Version 2.1, 18 June2021 
 
 
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Will the personnel involved in the study receive any payment? 
The [institution] receives payment from Windtree Therapeutics, Inc., who is the Sponsor of this 
study for study-related activities. 
What will happen to my data? 
• 
For sites located in California, the HIPAA authorization must be separate from the ICF (at 
the end of the ICF document) with a separate signature and 14-point font under 
California’s medical privacy laws. 
This research study may be performed only by collecting and using your medical information. Your 
study records will be kept as confidential as possible. Only a number will be used to identify you 
and you will not be identified in any reports or publications that may result from this research study. 
Under data protection laws (the Health Insurance Portability and Accountability Act in the US or 
Law 25326 in Argentina) your study site shall be responsible for ensuring that your personal 
information is safeguarded. 
Because of the research goals of this study, however, your study records cannot be kept completely 
confidential. The study personnel, the Sponsor, and its agents will need to review the medical 
information collected from you for use in this study to accurately record information for this study. 
In addition, to review the study findings, personnel from ethics committees, the US FDA, or 
ANMAT may review your medical records. The following sections provide a specific description of 
how your information will be used and disclosed if you consent to participate in this research study. 
By signing this consent form, you are authorizing such access. If you do not sign this form to 
authorize access, you will not be able to participate in this study. 
The medical information that will be collected from you if you participate in the study includes: 
• 
Information obtained from procedures to determine your eligibility to participate in the 
study, including a routine medical history, physical exam, and blood and breathing tests. 
• 
Information that is created or collected from you during your participation in the study, 
including the results of the tests included in the previous bullet point and any other 
procedures performed during the study. 
• 
Information contained in your medical records about to your medical history and treatment. 
The above information may identify you by name, address, telephone number, social security 
number, health plan number, study number, date of birth, dates relating to various medical 
procedures, and/or other identifying information. 


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Version 2.1, 18 June2021 
 
 
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If you sign this form to participate in the study, the study personnel will be authorized to use the 
information described above to carry out the purposes of the research study. The study personnel 
will also be authorized to disclose the relevant information described above to the following parties 
involved in the research study: 
• 
The Sponsor or other agents designated by the Sponsor to collect or review study data for 
verification of study procedures and/or adverse event reporting. 
• 
The Institutional Review Board (IRB)/Ethics Committee (EC) that oversees the research 
study at your site. 
• 
Government regulatory agencies including the FDA. 
Once your information is disclosed to the Sponsor, its agents, the IRB/EC, or government agencies 
as described above, there is a potential that your medical information will be re-disclosed and will 
no longer be protected by U.S. federal privacy regulations. 
The study data may be transferred to other countries for processing, including countries not covered 
by data protection legislation. The laws of your state may provide further protection. 
While the study is in progress, your access to your study records will be temporarily suspended. You 
will be able to access your information when the research study is completed. You have the right to 
see and copy the medical information collected from you during the study for as long as that 
information is maintained by the study personnel and other entities subject to federal privacy 
regulation. 
• 
Edit the expiration date in the 2nd sentence of this paragraph if a specific date of 
expiration is required by state law (e.g., CA, MN, IL) 
Study data, including your coded medical information, may be used and shared for research purposes 
related to this study. This consent has no expiration date. In signing this form, you allow the use and 
disclosure of your information for purposes of the study at any time in the future. 
Will I be photographed or filmed? 
Your treatment may be filmed for review of treatment procedures (to ensure proper procedures are 
followed) and possibly for training purposes. Your identity will be obscured by putting a light cloth 
over a portion of your face while the filming is occurring. If you sign this document, you give 
permission to [site name] and affiliates to film your treatment and to transmit this video to the 


Protocol 02-CL-2001a 
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Windtree Therapeutics, Inc. 
Master Informed Consent Form 
Version 2.1, 18 June2021 
 
 
Page 10 of 11 
sponsor. Not agreeing to the use of Photography/Videography does not affect your ability to be 
included in the study. 
You have a right to revoke my consent to be photographed, recorded, or to have other images taken 
in writing at any time. 
You may request cessation of photography, video or other imaging during the recording process. If 
you wish to revoke this consent, it will apply to the use of my images in the future but will not apply 
to previously made publications or presentations. Photographs, videos, or other images will be 
maintained in a protected and secure manner as part of your confidential research record. 
_____  (Participant Initials) I will allow photographs, recordings, or other images 
taken of me. 
_____ (Participant Initials) I do not want photographs, videotaped images, or other 
images taken of me. 
Withdrawal of Consent: 
You may withdraw your consent at any time by sending a written request to [insert name of 
responsible study personnel] at [insert address]. If you withdraw your consent, data collected prior 
to your withdrawal may still be processed along with other data collected as part of the study. 
Normally, no new information will be collected for the study database unless you specifically 
authorize that. However, the law does require that any side effects you may have suffered are 
documented and reported. To complete the study findings, your long-term health status may also be 
obtained from public sources. 
 
 


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Master Informed Consent Form 
Version 2.1, 18 June2021 
 
 
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Statement of Consent 
• 
I have read and understand the statements in this informed consent form. 
• 
I have had the opportunity to ask questions and I am satisfied with the explanations 
provided. 
• 
I voluntarily agree to take part in this study or agree on behalf of the patient as the legally 
authorized representative. 
• 
I understand that I and/or my legal representative will receive a copy of this signed and 
dated written consent form. 
• 
I additionally consent, or agree on behalf of the patient, to the use of my coded medical 
information for future medical or drug company research. 
 
 
_____________________________ 
________________________________ 
___________ 
Subject/Legal Representative Name 
Signature 
Date 
 
 
_____________________________ 
_______________________________ 
___________ 
Witness (if applicable) Name 
Signature 
Date 
 
• 
I have presented the study and answered the subject’s questions. 
• 
I will give the subject and/or legal representative a copy of this signed and dated informed 
consent. 
 
 
_____________________________ 
_______________________________ 
___________ 
Presenter (Investigator/Delegate) 
Signature 
Date 

Prot_000.pdf: 
This confidential information about an investigational product is provided for the exclusive use of investigators of 
this product and is subject to change at any time. The information in this document contains trade secrets and 
commercial information that are privileged or confidential and may not be disclosed unless such disclosure is 
required by federal or state law or regulations. In any event, persons to whom the information is disclosed must 
be informed that the information is privileged or confidential and may not be further disclosed by them. These 
restrictions on disclosure will apply equally to all future information supplied to you which is indicated as 
privileged or confidential. 
 
TITLE PAGE 
A MULTICENTER, SINGLE-TREATMENT STUDY TO ASSESS THE SAFETY AND 
TOLERABILITY OF LYOPHILIZED LUCINACTANT IN ADULTS WITH 
COVID-19 ASSOCIATED ACUTE LUNG INJURY 
Protocol Number: 02-CL-2001a 
 
Version Number: 2.1 
Date: 18 June 2021 
Development Phase: 
2 
Investigational Product: 
Lyophilized Lucinactant 
IND Number: 
149624 
ClinicalTrials.gov No.: 
NCT04389671 
Sponsor Name: 
Windtree Therapeutics, Inc.  
Sponsor’s Medical Officer: 
Steven G. Simonson, MD, MHS 
Senior Vice President, Chief Medical Officer 
Address: 
2600 Kelly Road 
Suite 100 
Warrington, PA 18976 
USA 
Phone No.: 
(215) 488-9300  
Fax No.: 
(215) 488-9301 
Coordinating Investigator: 
Yuh-Chin T. Huang, M.D., M.H.S. 
Professor of Medicine, Pulmonary and Critical Care Medicine 
Duke University Medical Center 
 


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A Multicenter, Single-Treatment Study to Assess the Safety and Tolerability of Lyophilized 
Lucinactant in Adults with COVID-19 Associated Acute Lung Injury 
Author 
Approver 
Name: Phillip D. Simmons 
Name: Steven G. Simonson 
Title: Exec. Director, Biostatistics & Data Mgmt. 
Title: Sr. Vice President, Chief Medical Officer 
Signature/Date 
Signature/Date 
 
 
Approver 
Approver 
Name: Carlos Guardia 
Name: Catherine Kacprzycki 
Title: Senior Medical Director 
Title: Senior Director, Clinical Operations 
Signature/Date 
Signature/Date 
 
 
 


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STATEMENT OF COMPLIANCE 
This study will be conducted in accordance with International Conference on Harmonisation (ICH) 
Guideline for Good Clinical Practice (ICH E6[R2]), applicable United States Code of Federal 
Regulations (CFR), Title 21, as well as all applicable local, state, and federal regulations and 
guidelines regarding the conduct of clinical studies. In addition, this study will be conducted in 
accordance with the ethical principles included in the World Medical Assembly (WMA) 
Declaration of Helsinki, Ethical Principles for Medical Research Involving Human Subjects 
adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended most 
recently by the 64th WMA General Assembly, Fortaleza, Brazil, October 2013. 
Throughout this protocol, the term “Clinical Investigator” or “Investigator” will be defined, in 
accordance with 21 CFR 54, as any listed or identified principal investigator (PI) or 
subinvestigator who is directly involved in study dosing or evaluation of research subjects. PIs or 
subinvestigators must be listed on Form FDA 1572 and documented as appropriate on the 
delegation of authority signature log. The PI will assure that no deviation from or changes to the 
protocol will take place without prior agreement from the Investigational New Drug (IND) sponsor 
and documented approval from the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC), except where necessary to eliminate an immediate hazard(s) to the trial 
participants. All personnel involved in the conduct of this study will have completed Human 
Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB/IEC for review and approval. Approval of both the protocol and the 
consent form must be obtained before any participant is enrolled. All changes to the consent form 
will be IRB/IEC approved; a determination will be made regarding whether a new consent needs 
to be obtained from participants who provided consent using a previously approved consent form. 
 


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PROTOCOL AGREEMENT 
I have read the protocol specified below and agree that it contains all necessary details for 
carrying out this study. I will conduct the study as outlined herein and will complete the study 
within the time designated. I will provide copies of the protocol and all pertinent information to 
all individuals responsible to me who assist in the conduct of this study. I will discuss this 
material with them to ensure they are fully informed regarding the study drug and the conduct of 
the study. 
 
I will use only the informed consent form approved by the Institutional Review Board (IRB)/ 
Independent Ethics Committee (IEC) and Windtree Therapeutics, Inc. (Windtree), and will fulfill 
all responsibilities for submitting pertinent information to the IRB/IEC responsible for the study. 
 
I further agree that regulatory agencies (eg, US Food and Drug Administration), Windtree, or 
their designees shall have access to any source document from which case report form 
information may have been generated. 
 
I agree that I and all sub-investigators listed on the delegation of authority form and/or Form 
FDA 1572 shall inform Windtree of any equity interest in the company prior to participating in 
this study. I further agree that I and all sub-investigators listed will consult with Windtree before 
acquiring any financial interest in the company during the study and for one year after the 
study’s completion. 
 
 
 
 
Investigator Signature  
 
Date 
 
Print Name and Title 
Site #: 
 
 
Site Name: 
 
Address: 
 
 
 
 
 
 
 
Phone Number: 
 
 


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1 
PROTOCOL 02-CL-2001a 
1.1 Summary 
Protocol Number 
02-CL-2001a 
Title: 
A Multicenter, Single-Treatment Study to Assess the Safety and 
Tolerability of Lyophilized Lucinactant in Adults with COVID-19 
Associated Acute Lung Injury 
Phase: 
2a 
US IND Number: 
149624 
Sponsor: 
Windtree Therapeutics, Inc. (Windtree), Warrington, PA, USA 
ClinicalTrials.gov No.: 
NCT04389671 
Committees: 
DMC 
Study Drug: 
Lyophilized lucinactant reconstituted with sterile water for injection 
and administered at a dose of 160 ml (~80 mg total phospholipids 
(TPL)/kg lean body weight), delivered as a liquid. 
Rationale: 
The coronavirus that was first detected in China in 2019 and which 
has been detected in over 190 countries on every continent, has 
infected over 150 million people worldwide (including approximately 
3 million deaths), including approximately 35 million in the United 
States (including over 600,000 deaths). The virus has been named 
“SARS-CoV-2” and the disease it causes has been named 
“coronavirus disease 2019” (abbreviated “COVID-19”). 
Coronaviruses are a large family of viruses that are common in people 
and many different species of animals, including camels, cattle, cats, 
and bats. Rarely, animal coronaviruses can infect people and then 
spread between people such as with MERS-CoV, SARS-CoV, and 


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now with this new virus. The SARS-CoV-2 virus is a betacoronavirus, 
like MERS-CoV and SARS-CoV. All three of these viruses have their 
origins in bats. The viral sequences from U.S. patients are similar to 
the one that China initially posted, suggesting a likely single, recent 
emergence of this virus from an animal reservoir. 
Surfactants, specifically lucinactant, have been studied in acute 
hypoxemic respiratory failure and in acute lung injury. It is 
hypothesized that lucinactant may improve the respiratory status of 
patients suffering from COVID-19. 
Lucinactant is a synthetic surfactant that is approved by the US FDA 
(NDA 021746) for the prevention of respiratory distress syndrome 
(RDS) in premature infants at high risk for RDS. It has been safely 
administered to over 1000 children and adults. Preliminary data from 
animal and human adult studies indicate that lucinactant could benefit 
those with acute respiratory distress syndrome (ARDS) in the context 
of COVID-19 infection, improving oxygenation and lessening lung 
damage. When given after intubation, lucinactant could potentially 
decrease the duration of ventilation or extracorporeal membrane 
oxygenation (ECMO).  
ARDS, as a consequence of COVID-19 infection, seems to have a 
significant negative impact on surfactant related lung function. SARS-
CoV-2 uses the SARS-coronavirus receptor, angiotensin-converting 
enzyme 2 (ACE2) for entry into the host cells. ACE2 is a surface 
molecule on alveolar Type 2 cells of lung. Type 2 cells are the source 
of surfactant in the lung and if they are damaged surfactant production 
is impaired, resulting in decreased lung compliance. This appears to 
occur early in the course of COVID-19 lung injury. This increases the 
likelihood of the need for mechanical ventilation, which may further 
damage the lungs. Recent publications suggest that lung fibrosis and 
severe interstitial changes occur in COVID-19 patients who developed 
ARDS.  
In addition to the direct lung injury caused by COVID-19, there is a 
subsequent damage to the lung through triggering and activation of the 
inflammatory cascade, similar to that involved in the development of 


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bronchopulmonary dysplasia (BPD). There is data supporting benefit 
of lucinactant to decrease the incidence and severity of BPD, 
supporting the rationale for use of exogenous surfactant in the 
treatment of pulmonary disease caused by COVID-19. 
Lucinactant significantly reduced mortality in a related pre-clinical 
model of H5N1 in ferrets infected with highly pathogenic avian 
influenza. Results showed 
that surfactant treatment 
significantly 
improved 
survival, as well as viral- 
and inflammation-related 
lung damage.  
Clinical 
evidence 
in 
patients with acute lung 
injury 
(ALI) 
showed 
potentially 
beneficial 
results 
in 
children 
on 
mechanical ventilation due 
to severe respiratory syncytial virus (RSV) infection, including 
pneumonia. Many studies in clinical ARDS have substantiated that 
damage to surfactant and inadequate quantities of functioning 
surfactant contribute to the pathophysiology of ARDS. Several studies 
in adult ARDS have established that lucinactant can be safely 
administered to critically ill patients and potentially replenish the 
surfactant pool.  
In many animal models, surfactant replacement therapy of pneumonia 
has been studied showing decreased intrapulmonary bacterial 
proliferation, decreased bacterial growth, and improved pulmonary 
function with increased pulmonary compliance. Clinical studies of 
surfactant in subjects with pneumonia have shown improvements in 
oxygenation and mean airway pressure, with one study showing a 
reduced need for ECMO. A series of in vitro studies have shown that 
a synthetic surfactant containing KL4 peptide tends to be more 
resistant to inhibition by four serum components (fibrinogen, C-


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reactive protein, platelet activating factor, lyso-phospatidylcholine) 
known to inhibit surfactant activity when compared with an animal 
derived surfactant.  
A study on recombinant surfactant protein C–based surfactant, 
indicated that among patients with ARDS caused by a direct lung 
injury, those who received surfactant tended to have a higher survival 
rate than those who received standard therapy. In fact, an oxygenation 
benefit was found across the entire population of patients who 
received surfactant. 
Lucinactant has an extensive safety profile and has been safely 
administered to over 1000 subjects in different patient populations 
(adults, infants, toddlers) for different indications (eg, respiratory 
distress syndrome of the newborn (RDS), acute hypoxemic respiratory 
failure (AHRF), ARDS). In almost all cases, there were no safety 
signals of concern with rates of adverse events (AEs) being similar to 
control (placebo and active). An increase in AEs was noted in one 
study when using bronchoalveolar lavage to administer SURFAXIN; 
however, bronchoalveolar lavage is no longer used and lyophilized 
lucinactant has a much lower viscosity then SURFAXIN, which also 
should minimize any temporary airway obstruction. 
It is hypothesized that lucinactant may improve the respiratory status 
of patients suffering from COVID-19. 
Study Description: 
This is a multicenter, single-treatment study. Subjects will consist of 
adults with COVID-19 associated acute lung injury who are being 
cared for in a critical care environment. 
See Section 1.2, Schedule of Activities (SOA). 
Study Objective: 
To evaluate the safety and preliminary efficacy of lyophilized 
lucinactant, as assessed by oxygenation index (OI) through 12 hours 
post initiation of dosing and other physiological and outcome 
measurements through 24 hours or through Day 30. 


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Endpoints: 
Primary Endpoints: 
• Safety and Tolerability of reconstituted lyophilized lucinactant 
given as a bolus to patients with COVID-19. 
• Change from baseline in OI at 12 hours post initiation of dosing. 
OI is defined as Paw×FiO2×100/PaO2. 
 
Secondary Efficacy Variables: 
• Change from baseline through 24 hours post dosing initiation: 
o FiO2; 
o PaO2; 
o SpO2; 
o OI; 
o PaCO2; 
o ETCO2; 
o P/F and or S/F ratios, defined as PaO2 or SpO2 divided by 
FiO2; 
o Plateau pressure and peak inspiratory pressure (PIP) measured 
on the ventilator; 
o Ventilation Index (VI). VI is defined as [RR×(PIP − PEEP)× 
PaCO2]/1000; 
o Lung compliance; 
o Pressure-volume loops if ventilator technology permits. 
• Through 30 days: 
o Daily lung compliance (static) on ventilator; 
o Ventilator-free days; 
o Days in the intensive care unit (ICU); 
o Days in the hospital; 
o Incidence of all-cause mortality; 
o Organ failure free days. 


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Safety Variables: 
• All-cause mortality; 
• Peri-dosing adverse events (desaturation, bradycardia, ET reflux, 
hypotension) 
• AEs and serious AEs (SAEs). SAEs that are ongoing at Day 30 
will be followed for an additional 30 days; 
• Air leaks as AEs of special interest; 
• Assessments of vital signs. 
Study Population: 
The study population will be comprised of adults 18-75 (inclusive) 
who are positive for SARS-CoV-2, are exhibiting symptoms of severe 
COVID-19 infection, who are intubated and are receiving mechanical 
ventilation in a critical care environment. 
The objective of the pilot safety study is to evaluate the safety and 
feasibility of lucinactant administration in COVID-19 patients. A 
small number of patients should be sufficient to provide evidence that 
liquid lucinactant can be safely delivered as an intratracheal bolus. A 
total of up to 30 study subjects will be enrolled (see “Treatment 
Group” section). 
Description of Sites: 
Approximately 15 study sites in the United States and Argentina. 
Description of Study 
Intervention: 
Reconstituted lyophilized lucinactant will be given at a dose of 160 ml 
(30 mg TPL/ml), delivered as a liquid in the trachea through the 
endotracheal tube. Lyophilized lucinactant has the following four 
active ingredients:  
• sinapultide (a synthetic peptide), consisting of amino acid 
residues lysine (K) and leucine (L), according to the sequence 
KLLLLKLLLLKLLLLKLLLLK (KL4); 
• dipalmitoyl-phosphatidylcholine (DPPC); 
• palmitoyloleoyl-phosphatidylglycerol, sodium salt (POPG, Na); 
and 
• palmitic acid (PA). 


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Inclusion Criteria: 
Each subject must meet all inclusion criteria to be enrolled in this 
study: 
1. Signed and dated ICF (electronically or in ink) by the subject 
or legally authorized representative; 
2. Age 18-75 (inclusive); 
3. Assay positive for SARS-CoV-2 virus, preferably by 
polymerase chain reaction (PCR); 
4. Endotracheal intubation and MV within 7 days of initial 
intubation; 
5. In-dwelling arterial line; 
6. P/F ratio < 300; 
7. Mean blood pressure ≥ 65 mmHg, immediately before 
enrollment; 
8. Bilateral infiltrates seen on frontal chest radiograph. 
Exclusion Criteria: 
 
 
Subjects meeting any exclusion criteria must not be enrolled in this 
study: 
1. Life expectancy < 48 hours or do not resuscitate orders; 
2. Severe lung disease (home O2, FEV1 < 2 liters) not likely to 
respond to therapy or profound hypoxemia (ie, OI ≥ 25 or P/F 
< 100); 
3. Severe renal impairment (creatinine clearance < 30 mL/min); 
4. Within the last 6 months has received, or is currently receiving, 
immunosuppression therapy (azathioprine, cyclophosphamide 
or methotrexate) or any transplant recipient; 
5. Clinically significant cardiac disease that adversely effects 
cardiopulmonary function: 
a. Acute coronary syndromes or active ischemic heart 
disease (as assessed by the PI using troponin and ECG) 
b. Cardiac ejection fraction < 40% (if known); 
c. Need for multiple-dose vasopressors to support blood 
pressure 
(single 
dose 
vasopressors, 
such 
as 
Levophed™ ≤ 0.1 mcg/kg/min are allowed); 
d. Cardiogenic pulmonary edema as the etiology of the 
current respiratory distress; 
e. Evidence of myocarditis or pericarditis; 
6. Neuromuscular disease; 
7. Neutropenia (ANC < 1000);  


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8. Active malignancy that impacts treatment decisions or life 
expectancy related to this trial; 
9. Suspected concomitant bacterial or other viral lung infection. 
Bacterial infection defined as WBC > 15k and positive blood/ 
urine/sputum culture results within 72 hours. 
Treatment Group: 
Up to 30 enrolled subjects will be administered an investigational drug 
product, reconstituted lyophilized lucinactant. Prior to administration, 
lyophilized lucinactant will be reconstituted with sterile water for 
injection then delivered as a liquid into the trachea in quarter doses. 
Lucinactant 
Lyophilized lucinactant 160 ml (~80 mg TPL/kg 
lean body weight of 30 mg/ml suspension)   
 
Up to 3 repeat study treatments of the same dose 
volume may be given if criteria are met. 
Enrollment should occur as soon as possible once it has been 
confirmed that the subject has met all inclusion criteria and has not 
met any exclusion criteria within 7 days of initial intubation. 
Treatment initiation is to begin within 6 hours of enrollment. If the 
subject does not tolerate one of the 40 ml quarter doses, the dosing for 
that dose may be terminated at that time. It is recommended that the 
other quarter doses remain 40 ml; however, a lower dose may be 
administered for the remaining aliquots at the Investigator’s 
discretion. 
Up to 3 retreatment doses are allowed no sooner than 6 hours apart 
(from completion of previous dose). Subjects are eligible for 
retreatments if they remain on MV, there is no evidence of 
pneumothorax, the P/F ratio is under 300 (or S/F ratio is under 315, if 
no arterial line is present), and there are no safety concerns that would 
prevent retreatment (in the opinion of the investigator). Retreatments 
are given at the discretion of the investigator. 
Retreatment should be performed in the same manner as the initial 
treatment. 


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Early Discontinuation 
of Treatment: 
The administration of study treatment may be discontinued at any time 
prior to the completion of dosing based on the clinical judgment of the 
PI. Reasons for discontinuation of study treatment include, but are not 
limited to the following:  
1. An AE which places subject at risk occurs (eg, severe bradycardia, 
hypotension, cardiac arrest)  
2. If, in the PI’s best medical judgment, initiating or continuing the 
subject’s exposure to study treatment is not in the best interest of 
the subject’s safety. 
Subjects whose treatment is discontinued based on the PI’s judgment 
will continue in the study. Subjects whose treatment is discontinued 
based on the subject’s request may continue in the study; however, if 
a subject withdraws consent, the subject will be withdrawn from the 
study and no further data collection will be done. 
Study Duration: 
Subject participation will be from enrollment to 30 days after 
enrollment unless they have an ongoing SAE (to be followed for an 
additional 30 days).  
Overall, study enrollment will be completed in approximately 7 to 8 
months, with the last subject last visit approximately 8 to 9 months 
from the time the first subject enrolled. 
Statistical Analysis: 
The statistical analysis will be based on all enrolled subjects.  
For the efficacy analysis, populations of all enrolled subjects who 
received any treatment (modified intent-to-treat [mITT]) will be 
evaluated. For the safety analysis, all enrolled subjects who received 
any lucinactant (including partial doses) will be evaluated.  
All efficacy and safety parameters will be evaluated using summary 
statistics. For continuous variables, n, mean, standard deviation, 
median, min, and max will be presented; for discrete variables, 
frequency and percent will be presented. 


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All deaths will be summarized using frequency and percent, overall 
and by type of death (respiratory or not respiratory) and included as 
part of the assessment of safety. Also, the deaths will be listed by 
subject and narratives for each death will be included.  
 
1.2 Schedule of Activities (SOA) 
 
 
Primary Phase Through Day 30 
Measurement/Procedure 
Screening 
Treatment 
Period 
(Day 1) 
Post-Treatment 
Period  
(Days 2-5) 
Final Period 
(Days 6 to 30) 
Informed consent 
X 
 
 
 
Inclusion/exclusion Criteria 
X 
 
 
 
Demographics 
X 
 
 
 
Medical history 
X 
 
 
 
Physical examination 
X 
 
 
 
Enrollment 
 
X 
 
 
Study treatment administration 
 
X 
 
 
Vital signs 
X 
X 
X2 
X 
ABG (PaO2, PaCO2, pH) 
 
X1 
X 
X 
FiO2, SpO2, Paw, EtCO2 
 
X1 
X 
X 
Ventilator parameters (rate, peak and 
plateau pressure, lung compliance) 
 
X2 
X2 
 
Respiratory support parameters 
X 
X 
X 
X 
Pressure volume loops 
 
X3 
 
 
AEs/SAEs 
 
X 
X 
X5 
Concomitant medications 
X 
X 
X 
X 
Final Visit/Discharge 
 
 
 
X4 
Note: Day 1 for all subjects is the day of enrollment. 
1 Time 0 (study treatment), 1, 2, 4, 8, 12, 18, 24 hours after treatment  
2 Recorded every 12 hours at 08:00 and 20:00 through Day 5. 
3 Recorded every 2 hours through 24 hours. 
4 Occurs at Day 30, withdrawal from the study, or death (whichever occurs first). 
5 AEs ongoing at Day 30 will be followed for an additional 30 days or until stop date/time (whichever occurs first). 


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  TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................................. I 
STATEMENT OF COMPLIANCE ............................................................................................ 3 
PROTOCOL AGREEMENT ...................................................................................................... 4 
1 
PROTOCOL 02-CL-2001A.................................................................................................. 5 
1.1 
Summary ............................................................................................................................ 5 
1.2 
Schedule of Activities (SOA) .......................................................................................... 14 
TABLE OF CONTENTS ........................................................................................................... 15 
2 
INTRODUCTION............................................................................................................... 19 
2.1 
Study Rationale ............................................................................................................... 19 
2.2 
Background ..................................................................................................................... 19 
2.2.1 Unmet Medical Need in Treatment of COVID-19 Associated ARDS ......................... 21 
2.2.2 Lucinactant .................................................................................................................... 21 
2.3 
Clinical Experience with Lucinactant ........................................................................... 23 
2.4 
Risk/Benefit Assessment ................................................................................................. 28 
2.4.1 Known Potential Risks .................................................................................................. 28 
2.4.2 Known Potential Benefits ............................................................................................. 29 
2.4.3 Assessment of Potential Risks and Benefits ................................................................. 29 
3 
OBJECTIVES AND ENDPOINTS ................................................................................... 30 
4 
STUDY DESIGN ................................................................................................................. 32 
4.1 
Overall Design ................................................................................................................. 32 
4.2 
Scientific Rationale for Study Design ............................................................................ 32 
4.3 
Justification for Dose ...................................................................................................... 32 
4.4 
End of Study Definition .................................................................................................. 34 
5 
STUDY POPULATION ..................................................................................................... 35 
5.1 
Inclusion Criteria ............................................................................................................ 35 
5.2 
Exclusion Criteria ........................................................................................................... 35 


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5.3 
Lifestyle Considerations ................................................................................................. 36 
5.4 
Screen Failures ................................................................................................................ 36 
5.5 
Strategies for Recruitment and Retention .................................................................... 36 
6 
STUDY DOSING AND ADMINISTRATION ................................................................. 37 
6.1 
Treatments Administered .............................................................................................. 37 
6.1.1 Study Intervention Description ..................................................................................... 37 
6.1.2 Dosing and Administration ........................................................................................... 37 
6.2 
Preparation/Handling/Storage/Accountability ............................................................ 39 
6.2.1 Acquisition and Accountability .................................................................................... 39 
6.2.2 Formulation, Appearance, Packaging and Labeling ..................................................... 39 
6.2.3 Product Storage ............................................................................................................. 39 
6.2.4 Preparation .................................................................................................................... 40 
6.3 
Measures to Minimize Bias: Randomization and Blinding......................................... 40 
6.4 
Study Intervention Compliance ..................................................................................... 40 
6.5 
Concomitant Therapy ..................................................................................................... 40 
6.5.1 Rescue Medicine or Therapy ........................................................................................ 40 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................................. 41 
7.1 
Discontinuation of Study Intervention .......................................................................... 41 
7.2 
Participant Discontinuation/Withdrawal from the Study .......................................... 41 
7.3 
Lost to Follow-Up ............................................................................................................ 41 
8 
STUDY ASSESSMENTS AND PROCEDURES ............................................................. 42 
8.1 
Screening Process ............................................................................................................ 42 
8.1.1 Demographics and Baseline Characteristics ................................................................. 42 
8.1.2 Medical History ............................................................................................................ 42 
8.1.3 Physical examination .................................................................................................... 42 
8.1.4 Respiratory Support Parameters ................................................................................... 42 
8.1.5 Enrollment..................................................................................................................... 42 
8.2 
Treatment Period ............................................................................................................ 43 
8.2.1 Gas Exchange Parameters and Arterial Blood Gases ................................................... 43 
8.2.2 Vital signs ..................................................................................................................... 43 
8.2.3 Respiratory Support Parameters ................................................................................... 43 
8.2.4 Pressure Volume Loops ................................................................................................ 44 


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8.2.5 Readmissions and death ................................................................................................ 44 
8.3 
Safety and Other Assessments ....................................................................................... 44 
8.4 
Adverse Events and Serious Adverse Events ............................................................... 45 
8.4.1 Definition of Adverse Events........................................................................................ 45 
8.4.2 Definition of Serious Adverse Events........................................................................... 45 
8.4.3 Classification of an Adverse Event ............................................................................... 45 
8.4.4 Time Period and Frequency for Event Assessment and Follow-Up ............................. 47 
8.4.5 Adverse Event Reporting .............................................................................................. 47 
8.4.6 Serious Adverse Event Reporting ................................................................................. 48 
8.4.7 Reporting Events to Subjects ........................................................................................ 50 
8.4.8 Events of Special Interest.............................................................................................. 50 
8.4.9 Reporting of Pregnancy ................................................................................................ 50 
9 
STATISTICAL CONSIDERATIONS .............................................................................. 51 
9.1 
Statistical Hypothesis ...................................................................................................... 51 
9.2 
Sample Size Determination ............................................................................................ 51 
9.3 
Populations for Analyses ................................................................................................ 51 
9.4 
Statistical Analyses.......................................................................................................... 51 
9.4.1 General Approach ......................................................................................................... 51 
9.4.2 Analysis of the Primary Efficacy Endpoint(s) .............................................................. 51 
9.4.3 Analysis of the Secondary Endpoint(s)......................................................................... 52 
9.4.4 Safety Analyses ............................................................................................................. 52 
9.4.5 Baseline Descriptive Statistics ...................................................................................... 52 
9.4.6 Planned Interim Analyses ............................................................................................. 52 
9.4.7 Sub-Group Analyses ..................................................................................................... 53 
9.4.8 Tabulation of Individual Participant Data..................................................................... 53 
9.4.9 Exploratory Analyses .................................................................................................... 53 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 54 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ......................................... 54 
10.1.1 
Informed Consent Process ........................................................................................ 54 
10.1.2 
Study Discontinuation and Closure .......................................................................... 55 
10.1.3 
Confidentiality and Privacy ...................................................................................... 55 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 56 
10.1.5 
Key Roles and Study Governance ............................................................................ 56 
10.1.6 
Safety Oversight........................................................................................................ 56 
10.1.7 
Clinical Monitoring ................................................................................................... 57 
10.1.8 
Quality Assurance and Quality Control .................................................................... 59 


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10.1.9 
Data Handling and Record Keeping ......................................................................... 60 
10.1.10 Protocol Deviations ................................................................................................... 62 
10.1.11 Publication and Data Sharing Policy ........................................................................ 62 
10.1.12 Conflict of Interest Policy ......................................................................................... 63 
10.2 
List of Abbreviations ...................................................................................................... 64 
11 REFERENCES .................................................................................................................... 66 
 


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2 
INTRODUCTION 
2.1 Study Rationale 
The coronavirus that was first detected in China in 2019 and which has been detected in over 190 
countries on every continent, has infected over 150 million people worldwide (including 
approximately 3 million deaths), including approximately 35 million in the United States 
(including over 600,000 deaths). The virus has been named “SARS-CoV-2” and the disease it 
causes has been named “coronavirus disease 2019” (abbreviated “COVID-19”). 
Coronaviruses are a large family of viruses that are common in people and many different species 
of animals, including camels, cattle, cats, and bats. Rarely, animal coronaviruses can infect people 
and then spread between people such as with MERS-CoV, SARS-CoV, and now with this new 
virus. The SARS-CoV-2 virus is a betacoronavirus, like MERS-CoV and SARS-CoV. All three of 
these viruses have their origins in bats. The sequences from U.S. patients are similar to the one 
that China initially posted, suggesting a likely single, recent emergence of this virus from an animal 
reservoir. 
Surfactants, specifically lucinactant, have been studied in acute hypoxemic respiratory failure and 
in acute lung injury. It is hypothesized that lucinactant may improve the respiratory status of 
patients suffering from COVID-19.  
Lucinactant is a synthetic surfactant that is approved by the US FDA (NDA 021746) for the 
prevention of respiratory distress syndrome (RDS) in premature infants at high risk for RDS. It 
has been safely administered to over 1000 children and adults. Preliminary data from animal and 
human adult studies indicate that lucinactant could benefit those with acute respiratory distress 
syndrome (ARDS) in the context of COVID-19 infection, improving oxygenation and lessening 
lung damage. When given after intubation, lucinactant could potentially decrease the duration of 
ventilation or extracorporeal membrane oxygenation (ECMO).  
2.2 Background 
COVID-19 is the 3rd serious coronavirus outbreak since 2002. At this time, the mortality rate 
associated with COVID-19 is approximately 5%. This is lower than the 10% and 36% fatality rates 
seen during the SARS and MERS coronavirus outbreaks, respectively. The characterization of 
COVID-19 is still evolving. COVID-19 has some similarity to SARS including that it may be able 
to use the ACE2 receptor in the lung. However, the spread of infection appears to be more rapid 
with COVID-19 compared to SARS (over 150 million cases in 15 months for COVID-19 vs 8098 
cases in 8 months for SARS). Most reported cases have been in adults and most hospitalized 


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patients have pneumonia. Many patients develop an ARDS-like clinical presentation, some 
develop a secondary infection, and many require intensive care for respiratory support including 
mechanical ventilation and ECMO. The fatality rate for COVID-19 patients hospitalized with 
pneumonia is 7-10% (from CDC June 20, 2020). 
COVID-19 uses the SARS-coronavirus receptor, angiotensin-converting enzyme 2 (ACE2) for 
entry into the host cells. ACE2 is a surface molecule highly expressed in AT2 cells of lung, along 
with esophageal upper epithelial cells and absorptive enterocytes from ileum and colon which 
indicated digestive system along with respiratory systems is a potential route for COVID-19 
infection (1). AT2 cells are the cells that produce surfactant in the lung. It stands to reason that if 
they are damaged by COVID-19, that surfactant production would be impaired. Recent 
publications suggest that lung fibrosis and severe interstitial changes occur in COVID-19 patients 
who developed ALI/ARDS. These changes resemble those seen in premature infants who are 
initially ventilated due to RDS and later develop BPD, which also presents with similar lung 
interstitial and fibrotic changes (2,3,4). These observations may support the of use of exogenous 
surfactant in the treatment of ALI/ARDS caused by COVID-19. 
Lucinactant significantly reduced mortality in a related pre-clinical model of H5N1 in ferrets 
infected with highly pathogenic avian (H5N1) influenza. Results showed that surfactant treatment 
significantly improved survival, as well as viral- and inflammation-related lung damage (Figure 
2-1).  
 
Figure 2-1. H5N1 in Ferrets 
 


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2.2.1 
Unmet Medical Need in Treatment of COVID-19 Associated ARDS 
Currently, when patients’ breathing deteriorates, they are placed on a mechanical ventilator (MV) 
to help them breathe while they are symptomatic. However, MV cannot correct the underlying 
issue involved with breathing difficulties, known as acute respiratory distress syndrome (ARDS), 
and in many cases cannot prevent death. 
ARDS is a sudden, progressive pulmonary disorder characterized by lung inflammation and non-
cardiogenic pulmonary edema in association with refractory hypoxemia, decreased lung 
compliance, and diffuse pulmonary infiltrates on the chest radiograph (5). It may occur as a direct 
result of injury to the lung such as with gastric content aspiration, pneumonia (both bacterial and 
viral), toxin inhalation or it may be associated with a wide variety of systemic processes such as 
sepsis, non-thoracic trauma, acute pancreatitis, multiple blood transfusions, fat embolism or shock 
(6). The pathophysiology of ARDS involves injury to the alveolar-capillary barrier, atelectasis, 
intrapulmonary shunting of blood flow and surfactant dysfunction. Despite advances in medical 
management in intensive care units, mortality from ARDS can be as high as 40%, and current 
therapy remains entirely supportive with no therapies having been demonstrated safe and 
efficacious and receive regulatory approval (7,8,9,10,11,12,13). 
The primary goal of ARDS treatment is to identify and correct the underlying etiology. For 
coronavirus this is supportive care until the virus is cleared by the immune system. Prevention of 
potential adverse effects of mechanical ventilation such as barotrauma and volutrauma is also 
critical. Using mechanical ventilatory support as safely as possible and improving lung compliance 
can contribute to avoiding these complications.   
There is an unmet medical need for a therapy that will improve the patients’ respiratory status and 
potentially reduce the time on mechanical ventilators. 
2.2.2 
Lucinactant  
Since the initial report of ARDS by Ashbaugh et al. (14), abnormalities of the surfactant system 
have been recognized. In subsequent studies, Petty and colleagues reported both qualitative and 
quantitative alterations in surfactant obtained from patients with ARDS (15,16). It is now widely 
accepted that surfactant abnormalities play a major role in the pathophysiology of ARDS, favoring 
alveolar collapse, ventilation/perfusion mismatch, and increased pulmonary shunt fraction 
(17,18,19,20). Not only have these chemical and functional changes been described in patients 


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with established ARDS, but similar alterations have been described in patients at-risk to develop 
ARDS (20,21).  
Degradation of native surfactant by inflammatory mediators and reactive oxygen species, and 
inhibition of surfactant functional activity plasma proteins have been implicated in impairment of 
alveolar surfactant. One of the hallmarks of ARDS is damaged alveoli and airways that are filled 
with fluid containing inflammatory cells, protein, inflammatory mediators and other debris. In 
addition, damage to the epithelial type II cells may result in decreased production and/or release 
of altered surfactant.  
The biophysical change in the surfactant system that occurs with ARDS is an increase in minimum 
surface tension (20), while the biochemical changes in the surfactant system that occur with ARDS 
include: 
1) a decrease in the total phospholipid content (20),  
2) an alteration in the phospholipid profile as demonstrated by a decrease in the percentage 
of phosphatidylcholine (PC), dipalmitoyl phosphatidylcholine (DPPC), and 
phosphatidylglycerol (PG) (17,18,19,20),  
3) an alteration in the fatty acid composition of the phospholipids (17,22), 
4) a reduction in large surfactant aggregates (23,24), and 
5) a decrease in the surfactant associated proteins SP-A, SP-B, and SP-D (20,21,23). 
Since many of the major pulmonary consequences of ARDS may be directly influenced by 
surfactant dysfunction, replacement treatment with exogenous surfactant is potentially efficacious 
in this disorder. In addition, damaged alveoli and airways are filled with fluid containing 
inflammatory cells, protein, inflammatory mediators and other debris. 
In a series of in vitro studies, liquid lucinactant for intratracheal instillation (SURFAXIN®) has 
been shown to be more resistant than natural lung surfactant and exogenous, commercially 
available animal-derived surfactant to the inhibitory effects of plasma proteins (including 
fibrinogen (25,26)), and inactivation by hypochlorous acid and reactive oxygen species (27). This 
is especially relevant in the milieu of the inflamed lung that leads to natural surfactant inactivation 
and degradation. 
Additionally, lucinactant has been shown to modulate the inflammatory response in various 
models of lung injury. In addition to studies in a murine H1N1 influenza model, we have also 
generated data showing that lucinactant administration significantly attenuates protein leak and 
neutrophil migration into the alveolar space in a hyperoxic and LPS lung injury model in mice 


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(28), decreases cytokine levels (including IL-6 and IL-8) in a preterm mechanically ventilated 
lamb model of RDS (as well in airway cell culture systems) (29), and ameliorates lung injury in a 
hydrochloric acid ALI model in spontaneously breathing pigs when delivered both as an 
intratracheal liquid instillate or as an aerosol (30,31).  
2.3 Clinical Experience with Lucinactant 
Several studies in adult ARDS have established that surfactant can be safely administered to 
critically ill patients. In addition, clinical evidence in children with acute hypoxic respiratory 
failure (AHRF) showed potentially beneficial results of lucinactant in a group of patients with mild 
to moderate RSV infections, including pneumonia. 
Windtree 
has 
completed 
13 
clinical 
studies 
with 
lucinactant 
for 
intratracheal 
administration: 4 studies 
in 
adult 
subjects 
with 
ARDS 
(Studies 
KL4-ARDS-01, 
KL4-ARDS-02, KL4-ARDS-03, and KL4-ARDS-04), 1 study in children up to 2 years of age with 
acute hypoxemic respiratory failure (AHRF) (Study KL4-AHRF-01), 1 study in premature 
neonates with RDS (Study KL4-IRDS-01 [CP-1/CP-2]), 3 studies in premature neonates at risk 
for developing RDS (Studies KL4-IRDS-02, KL4-IRDS-05, and KL4-IRDS-06), 1 study in very 
low birth weight (VLBW) premature neonates for the prevention of BPD (Study KL4-BPD-01), 
and 3 studies in full-term neonates with MAS (Studies KL4-MAS-01, KL4-MAS-02, and KL4-
MAS-03). Additionally three clinical studies with lucinactant for inhalation (reconstituted 
lyophilized lucinactant delivered via an investigational medical device) have been completed in 
preterm neonates with RDS (Studies 03-CL-1201, 03-CL-1401 and 03-CL-1202). There is 1 
ongoing clinical study with lucinactant for inhalation (Study 03-CL-1702) for premature neonates 
with RDS. Enrollment for this study has been terminated but data analysis is ongoing. 
A summary of selected studies is presented below. 
1. 
The KL4-ARDS-02 study was a phase 1b safety trial in adult ARDS patients that  first 
attempted to utilize bronchopulmonary segmental surfactant lavage of the entire lung to 
treat ARDS (32). Bronchoscopic administration of dilute (2.5 mg/mL and 10 mg/mL) 
concentrations of lucinactant, when administered as two or three 30 mL aliquots followed 
by suctioning of all 19 bronchopulmonary segments, was safe and well tolerated in all 
12 patients tested. A similar safety profile was observed in 4 of the 12 patients who 
received retreatment of the three 30 mL aliquot dosing regimen of lucinactant 6-24 hours 
later. A second, similar trial was performed in 14 patients with ARDS. Nine of these 


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received bronchoscopic administration of lucinactant. In these patients, the therapy was 
safe and well-tolerated.  
2. 
The KL4-ARDS-03 study was a phase 2, open-label, controlled, multi-center, 
international study of surfactant lavage for the treatment of ARDS in adults. Patients 
were randomized to receive either surfactant administered in low concentrations and 
large volumes via a bronchoscopic segmental lavage technique (lung wash), or the 
current standard of care (SOC), which is MV and other supportive therapies. Surfactant 
was delivered with a bronchoscope to each of the 19 segments of the lung and was 
intended to cleanse and remove inflammatory substances and debris from the lung, while 
leaving sufficient amounts of surfactant behind to help re-establish an adequate lung 
function and capacity to absorb oxygen. The primary efficacy endpoint was the incidence 
of patients alive and off mechanical ventilation for ≥ 48 hours at the end of Day 28. 
Secondary efficacy endpoints included mortality rate at the end of Day 28 and number 
of days alive and off mechanical ventilation for ≥ 48 hours through the end of Day 28. 
Results suggest that a transient increase in oxygenation occurred in both of the 
lucinactant treatment groups during the dosing period. This increase in oxygenation 
appeared to be more sustained in the higher lucinactant dose group compared to the lower 
lucinactant dose group. 
3. 
The KL4-ARDS-04 study was a phase 2, multicenter, randomized, open-label controlled 
study designed to assess the tolerability, safety, and efficacy of lucinactant delivered via 
bronchopulmonary segmental lavage to adult patients with ARDS. The study population 
consisted of adult patients between the ages of 16.4 and 76.4 years (inclusive) who were 
intubated and required mechanical ventilation and who met the criteria for a diagnosis of 
ARDS. 
The study was conducted in 2 parts: Part A was designed to evaluate the safety and 
tolerability of 4 lucinactant treatment regimens; Part B was designed to evaluate the 
safety and effectiveness of 2 lucinactant treatment regimens from part A of the study 
compared to standard of care. An Independent Safety Review Committee evaluated the 
safety and tolerability data from each treatment regimen in Part A of the study. 
The key results of the trial showed that surfactant lavage exhibited a positive 
pharmacologic effect manifested as improved oxygenation. This was demonstrated by an 
acute increase in the PaO2/FiO2 (P/F) ratio after patients received surfactant lavage. 


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Clinically and statistically significant increases were observed in the P/F ratio at 24 hours 
after surfactant lavage, compared with SOC. 
All-cause mortality at the end of Day 28 was not different between the lucinactant groups 
and SOC (14.3%; 23.7%; 13.9%, respectively). The mean number of days that subjects 
were alive and off mechanical ventilation through Day 28 was slightly less for subjects 
in lucinactant Group B.2 (10.6 days) compared with lucinactant Group B.1 (14.4 days) 
and SOC (13.9 days). 
There were no meaningful differences noted in the clinical outcomes in patients classified 
as having direct or indirect ARDS. 
4. 
The KL4-AHRF-01 study was a phase 2, multicenter, masked, placebo-controlled trial 
in 165 infants up to 2 years-of-age. Infants were randomized to receive either lucinactant 
or placebo (33). For the primary outcome, duration of MV through 14 days, there was no 
difference in the duration of MV between subjects treated with lucinactant and placebo 
treatment. There were no significant differences in other efficacy endpoints: ventilator 
free days, duration of intensive care unit (ICU) stay, duration of supplemental oxygen or 
duration of hospitalization through 14 days post randomization. Similarly, there were no 
significant differences in fraction of inspired oxygen, P/F ratio and oxygenation index 
(OI) at any time point. There was a trend for improved oxygenation with lucinactant 
based on improvement in P/F from eligibility to 48 hours post dose. Subjects with milder 
disease seemed to respond better to lucinactant treatment, and statistically fewer 
lucinactant subjects required a second treatment; however, more lucinactant subjects 
required reintubation compared to placebo. 
Safety evaluations included assessment of adverse events during dosing (peri-dosing 
events), adverse events associated with endotracheal intubation and MV, and any other 
adverse event that occurred throughout the duration of the study. As expected, peri-
dosing events were more frequent in the lucinactant-treated subjects, since placebo 
subjects only received sham air. In general, peri-dosing events were transient and 
resolved when lucinactant instillations were slowed. There were no significant difference 
in overall mortality between groups. All deaths were deemed to be not related to study 
treatment by the Principal Investigators. In summary, in this study in ventilated infants 
with AHRF, treatment with intratracheal lucinactant appeared to be generally safe and 
well-tolerated despite the expected transient peri-dosing events observed. An 
improvement in oxygenation and the observation that significantly less requirement for 


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retreatment was needed in the lucinactant-treated infants suggests a pharmacologic 
effect. 
5. 
The KL4-IRDS-02 (CP1/CP2) study was  a phase 1/2 clinical trial in premature neonates 
demonstrated that lucinactant is effective in the treatment of RDS in such patients (34). 
A total of 47 pre-term neonates (750-1750 g birth weight) were enrolled within the first 
four hours of life. All enrolled patients were treated with a bolus intratracheal injection 
of lucinactant (133 mg/kg or 200 mg/kg). 
Treatment with lucinactant rapidly improved oxygenation, improved lung expansion as 
demonstrated radiographically, and reduced ventilation support. The fraction of inspired 
oxygen (FiO2) fell in conjunction with a rise in the ratio of the partial pressure of oxygen 
in arterial blood compared to the alveoli (a/A O2). There were no deaths related to RDS 
among the study neonates, although two of 47 (4.3%) died of unrelated abnormalities: 
aortic atresia and sequelae of extreme immaturity. 
6. 
The KL4-MAS-01/KL4-MAS-02 study was a multicenter, randomized, controlled phase 
1/2 trial comparing the safety and efficacy of lucinactant lavage to standard of care for 
treatment of MAS in full-term newborn neonates was performed (35). Results indicated that 
the procedure was well tolerated in the 15 patients treated with lucinactant. There were two 
serious adverse events (SAEs) related to the drug: one report of hypoxia which was 
considered by the investigator to be probably related to the drug and one report of 
hypotension which was considered by the investigator to be possibly related to the drug. 
The neonates lavaged with lucinactant exhibited more rapid and sustained improvement in 
oxygenation compared to control neonates. Moreover, the lavaged neonates were 
disconnected from mechanical ventilation (MV) an average of three days sooner than 
control neonates. 
7. 
The KL4-IRDS-06 study was a phase 3, pivotal, multinational, multicenter, randomized, 
masked, controlled, event-driven, prophylaxis study in premature neonates that 
demonstrated  lucinactant is significantly superior to colfosceril palmitate (Exosurf®) in 
preventing and ameliorating RDS, reducing death due to RDS, and keeping neonates 
alive and without BPD, and  lucinactant is generally safe and well tolerated compared 
with colfosceril palmitate and beractant (Survanta®) (36). In this study, a total of 1294 
neonates less than 32 weeks of gestational age and weighing between 600 and 1250 
grams at birth were randomized at 50 study centers, 527 to the lucinactant group, 509 to 
the colfosceril palmitate group, and 258 to the beractant group. Efficacy analyses were 


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based on the intent-to-treat population (all randomized neonates). Safety analyses were 
based on all treated neonates (n=1288). 
Lucinactant was significantly superior to colfosceril palmitate in the primary outcomes 
and associated clinically important complications of prematurity and mechanical 
ventilation. Compared with colfosceril palmitate treated neonates, significantly fewer 
lucinactant treated neonates had RDS at 24 hours (39.1% vs. 47.2% p=0.005) or died 
from an RDS-related death within 14 days of birth (4.7% vs. 9.4% p=0.002). All-cause 
mortality rates at 36 weeks post conceptual age (PCA) for lucinactant, colfosceril 
palmitate and beractant were 21.1%, 23.8% and 26.4% respectively.  
The incidence of adverse experiences in the study were those expected in this population 
and did not differ from those observed with colfosceril palmitate or beractant. 
8. 
The KL4-IRDS-02 study was a phase 3, supportive, masked, multicenter, randomized, 
controlled study comparing lucinactant to poractant alfa (Curosurf®), lucinactant was 
shown to be non-inferior to poractant alfa for the endpoint of alive and not having BPD 
at 28 days of age in neonates with birth weight between 600 and 1250 grams, and 24 to 
< 29 weeks gestational age (37). All-cause mortality rates throughout the course of the 
study were consistently lower in the lucinactant group but did not reach statistical 
significance. Lucinactant event rates for other key secondary outcome measures were 
similar to those in the poractant-treated group. 
Adverse events (AEs) and SAEs were reported generally with the same frequency in both 
treatment groups. Although significantly more instances of transient peri-dosing events 
were reported with lucinactant compared with poractant alfa, they did not appear to lead 
to excess deaths, air-leak, or other neonatal complications. Interruption of administration 
of study drug in those neonates was very infrequent and no neonates discontinued 
lucinactant because of an AE. 
9. 
The KL4-BPD-01 study was a phase 2, multicenter, masked, placebo-controlled trial (38) 
assessing safety and efficacy of lucinactant, in very low birth weight neonates at risk for 
developing bronchopulmonary dysplasia (BPD) randomized 136 premature neonates to 
receive either lucinactant standard dose (175 mg/kg), lucinactant low dose (90 mg/kg), 
or sham air as a control. 


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For the primary endpoint, a lower incidence of death or BPD in neonates receiving the 
standard 175 mg/kg lucinactant dosing compared with controls (57.8% vs. 65.9%, 
respectively) was observed. This study also showed a higher survival rate through 36 
weeks post-menstrual age (PMA) in neonates receiving the standard 175 mg/kg 
lucinactant dosing compared with controls (88.9% vs. 84.1%, respectively) and a 
reduction in duration of mechanical ventilation (approximately four less days) and need 
for supplemental oxygen in neonates receiving the standard 175 mg/kg lucinactant dosing 
compared with controls. 
Lucinactant therapy was generally safe and well tolerated with generally no differences 
between the lucinactant treatment groups and the control group in common complications 
of prematurity. There were no differences noted in tolerability of drug between the 
lucinactant standard dose of 175 mg/kg (given at a volume of 5.8 ml/kg) and the 
lucinactant low dose of 90 mg/kg (given at a volume of 3.0 ml/kg). 
2.4 Risk/Benefit Assessment 
2.4.1 
Known Potential Risks  
Risks for this study must be considered within the context of treating adults with COVID-19, 
which carries with it substantial risk of morbidity and mortality. Intratracheal instillation of 
surfactant into the lung requires endotracheal intubation, often with concomitant positive pressure 
MV. However, patients in this trial will have been intubated to treat their underlying condition. 
MV is associated with morbidities such as ventilator-associated lung injury and 
volutrauma/barotrauma resulting in air leak syndromes such as pneumothorax and/or pulmonary 
interstitial emphysema (PIE). Surfactant instilled intratracheally has been associated with peri-
dosing events such as transient hypoxemia, bradycardia, and hypotension. These are usually not 
severe, are transient, and typically resolve within 30 minutes. 
Studies in adults with ARDS administered lucinactant using bronchopulmonary surfactant lavage 
of each segment of the lungs to attempt to remove alveolar debris and effectively deposit functional 
surfactant. Safety results show that this procedure was generally safe and well tolerated; however, 
this procedure was more invasive than other delivery methods and required more time and skill to 
complete dosing and may have contributed to the increased treatment-emergent AE in the 
lucinactant-treated subjects. A total of 44 of 110 lucinactant patients (40%) and 14 of 42 standard 
of care patients (33%) experienced an SAE. A total of 15 of 88 lucinactant patients (17%) in KL4-
ARDS-04 had an SAE that was considered to be related to study treatment (patients receiving 


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standard of care had all AEs and SAEs defined as not study-treatment related). A total of 28 deaths 
were observed in the ARDS studies. In the KL4-ARDS-04 Study, all-cause mortality at the end of 
Day 28 was numerically, but not statistically significantly, higher in lucinactant Group B.2 (24%) 
compared with lucinactant Group B.1 and SOC (14% in each). 
2.4.2 
Known Potential Benefits  
All subjects enrolled in this study will receive surfactant therapy. Since many of the major 
pulmonary consequences of ARDS may be directly influenced by surfactant dysfunction, 
replacement treatment with exogenous surfactant is potentially efficacious in this disorder. 
Surfactant administration in adults with ARDS has been associated with improvements in 
oxygenation and is known to provide clinical benefits to preterm neonates, including a reduction 
in the risk of developing RDS or having RDS-related death. There is a potential that lucinactant 
may reduce lung inflammation and lessen the work of breathing. Nonetheless, the hypothesis that 
SRT can provide benefit in acute lung injury has not been definitively answered. Windtree believes 
that with the appropriate dose and delivery technique, there is significant potential benefit for 
lucinactant to minimize lung injury in COVID-19 and to protect and support the lungs until 
endogenous surfactant is functional and the underlying pathological process is reversed. 
2.4.3 
Assessment of Potential Risks and Benefits  
Adults in this study will be given lyophilized lucinactant, an investigational medicinal product 
that, once reconstituted with sterile WFI, is chemically and physically comparable to the liquid 
formulation of the approved product, SURFAXIN. As this is a single-treatment study, all subjects 
will be subject to the same risks and benefits. Lyophilized lucinactant is expected to generally safe 
and well tolerated. 
Previous results from KL4-ARDS-04 where lucinactant was delivered via bronchopulmonary 
lavage have been taken into consideration in the design of the proposed study. Dosing will occur 
by a far less invasive procedure. Close safety review has been incorporated to monitor the safety 
profile and identify any findings that might merit a change to the study. The program is designed 
to be a rigorous, iterative process.  
We believe this plan provides an appropriate risk/benefit for the 02-CL-2001a clinical trial. 
 


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3 
OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
The primary objective of this 
study is to evaluate the safety and 
feasibility of lucinactant SRT in 
treating COVID-19, as assessed by 
OI at 12 hours post dosing and 
other physiological and outcome 
measurements through 24 hours or 
through Day 30. 
Change from baseline in OI at 12 hours 
post initiation of dosing. OI is defined 
as Paw×FiO2×100/PaO2. OI is defined as 
Paw×FiO2×100/PaO2 
Improvements in 
oxygenation should be 
an indicator of surfactant 
physiological activity on 
gas exchange and 
compliance that should 
underly improvement in 
clinical parameters. 
Secondary Efficacy 
 
 
To assess other measures of 
efficacy to ensure consistency of 
results across multiple endpoints. 
• 
Change from baseline through 24 
hours post dosing initiation: 
o FiO2; 
o PaO2; 
o SpO2; 
o OI; 
o PaCO2; 
o ETCO2; 
o P/F and or S/F ratios; 
o Change in plateau pressure and 
PIP measured on the ventilator; 
o Ventilation Index (VI). VI is 
defined as [RR×(PIP − PEEP)× 
PaCO2]/1000; 
o Lung compliance; 
o Pressure-volume loops, if 
ventilator technology permits. 
• 
Through 30 days: 
o Daily lung compliance (static) 
on ventilator; 
o Ventilator free days; 
o Duration of ECMO 
o Days in the ICU; 
These endpoints 
represent endpoints that 
are appropriate given the 
trial design. 


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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
o Days in the hospital; 
o All-cause mortality; 
o Organ failure free days. 
Safety 
 
 
To ensure that administration of 
lucinactant does not lead to safety 
concerns. 
• 
All-cause mortality; 
• 
Peri-dosing adverse events 
(desaturation, bradycardia, ET 
reflux, hypotension); 
• 
AEs and SAEs. SAEs that are 
ongoing at Day 30 will be followed 
for an additional 30 days; 
• 
Assessments of vital signs. 
Standard measurements 
of safety. 


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4 
STUDY DESIGN  
4.1 Overall Design 
This is a multicenter, single-treatment study in adults with COVID-19, who are being cared for in 
a critical care environment. 
Subjects will be enrolled into the lucinactant treatment group if they meet all the screening criteria. 
Enrolled subjects will receive reconstituted lyophilized lucinactant (30 mg total TPL/mL) as a 
liquid at 160 ml (~80 mg TPL/kg lean body weight [~2.7 ml/kg lean body weight]). Sites from the 
US and Argentina will participate in this study. 
See Section 1.2, Schedule of Activities, for more details on study measurements and the timing of 
measurements. 
4.2 Scientific Rationale for Study Design 
Reported illnesses with COVID-19 have ranged from very mild (including some with no reported 
symptoms) to severe, including illness resulting in death. The lungs appear to be affected in nearly 
all cases, with typical symptoms including cough and shortness of breath. 
Surfactants, specifically lucinactant, have been studied in acute hypoxemic respiratory failure and 
in acute lung injury. Preliminary data from animal and adult human studies indicate that lucinactant 
could benefit those with ARDS in the context of COVID-19 infection, improving oxygenation and 
lessening lung damage. Furthermore, lucinactant, given early in the course of the disease, could 
potentially decrease the need for endotracheal intubation and mechanical ventilation.  
It is hypothesized that lucinactant may provide relief of the respiratory symptoms, allowing 
patients to recover while suffering from COVID-19. 
4.3 Justification for Dose 
SRT has been proposed to treat ARDS in children and adults. SRT was initially successful in adult 
ARDS patients (5) and later in pediatric patients (39). These studies used a dose volume of 2–4 
ml/kg.  
Survanta® (25 mg phospholipid [PL]/ml) was administered to adult ARDS patients by 
endotracheal instillation (5). Three dose groups were studied: up to 8 doses of 100 mg PL/kg (4 
ml/kg), up to 8 doses of 50 mg PL/kg (2 ml/kg), and up to 4 doses of 100 mg PL/kg (4 ml/kg). The 


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dosing strategies used were chosen on the basis of experience with animal models and the desire 
to use an incremental approach in applying this untested therapy to patients. The FiO2 at 120 hours 
after treatment began was significantly decreased only for patients who received up to 4 doses of 
100 mg PL/kg as compared with control patients (p =0.011). Mortality in the same group of 
patients was 18.8%, as compared with 43.8% in the control group (p =0.075). Intratracheal bolus 
instillation of Survanta was generally well tolerated, and no safety concerns were identified. Data 
did suggest that after 4 doses of 100 mg PL/kg, further doses were accompanied by greater reflux 
and transient increases in peak inspiratory pressure than were seen with initial doses and did not 
result in apparent improvement in measures of gas exchange. 
Infasurf® (35 mg PL/ml) was administered to children, 1 week to 21 years of age, with ARDS by 
endotracheal instillation (39). Two doses of 80 ml/m2 were administered to patients ≥ 10 kg. 
Infants < 10 kg received 3 ml/kg (equivalent to the premature infant dose). The Infasurf group 
experienced a decrease in oxygenation index from 20 to 13.9 after 12 hours compared with the 
placebo group’s decrease from 20.5 to 15.1 (p=.01). Mortality was significantly greater in the 
placebo group compared with the Infasurf group (36% vs 19.5%). No significant decrease in 
duration of ventilator therapy and ICU or hospital stay was observed. There were no differences 
in long-term complications. 
Future studies in ARDS patients switched to a lower dose volume of approximately 1 mL/kg. This 
change in dose volume resulted in a failure of SRT in adults (40,41,42). 
Venticute® (50 mg PL/ml) was administered to adult ARDS patients by endotracheal instillation 
(41). Up to 4 doses of 50 mg/kg (1 ml/kg) were administered to patients. Overall survival at 28 
days after treatment was 66% and the median number of ventilator-free days was 0. There was no 
significant difference in mortality or the need for mechanical ventilation between the Venticute 
and control groups. Patients receiving Venticute had significantly greater, improvement in blood 
oxygenation during the initial 24 hours of treatment than patients receiving standard of care. 
However, this improvement was not sustained and was not significantly different by 48 hours. 
These observations suggest the possible need for a prolonged treatment period, possibly with 
greater intervals between doses, with a larger number of doses, or with a larger dose volume. Up 
to 3 treatments (dose = 30 mg [60 mg PL/ml] per centimeter of height) were allowed if retreatment 
criteria were met. Infasurf administration was not associated with improved survival, length of 
stay or oxygenation. The authors speculated that the lack of response could be related to 
insufficient dosing of surfactant, since they choose not to administer a second dose of surfactant if 
the first was without clear benefit. They also concluded that the lack of oxygenation benefit may 


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be due to ineffective timing of instillation and/or administration technique rather than lack of 
efficacy of exogenous surfactant (40). 
Based on previous clinical studies, as well as studies in several animal models of ARDS, the 
proposed dose of lucinactant (30 mg total PL/ml) is 160 ml (80 mg/kg lbw, based on an estimated 
60 kg lbw patient similar to those enrolled in the Survanta and Venticute studies). Windtree 
believes that this dose addresses both the amount of PL required to sufficiently restore alveolar 
surface tension and the volume of lucinactant required to adequately coat the alveolar surface.  
4.4 End of Study Definition 
A subject is considered to have completed the study if he or she has completed all phases of the 
study, including the last scheduled procedure at Day 30. 
The end of the study is defined as completion of the last visit or procedure for the last subject in 
the trial (last subject/last visit). 


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5 
STUDY POPULATION  
5.1 Inclusion Criteria 
Each subject must meet all inclusion criteria to be enrolled in this study: 
1. 
Signed and dated ICF by the subject or legally authorized representative; 
2. 
Age 18-75 (inclusive); 
3. 
Assay positive for SARS-CoV-2 virus, preferably by polymerase chain reaction (PCR); 
4. 
Endotracheal intubation and MV, within 7 days of initial intubation; 
5. 
In-dwelling arterial line; 
6. 
P/F ratio < 300; 
7. 
Mean blood pressure ≥ 65 mmHg, with or without vasopressor support, immediately 
before enrollment; 
8. 
Bilateral infiltrates seen on frontal chest radiograph. 
5.2 Exclusion Criteria 
Subjects meeting any exclusion criteria must not be enrolled in this study: 
1. 
Life expectancy < 48 hours or do not resuscitate orders; 
2. 
Severe lung disease (home O2, FEV1 < 2 liters) not likely to respond to therapy  or profound 
hypoxemia (ie, OI ≥ 25 or P/F < 100); 
3. 
Severe renal impairment (creatinine clearance < 30 mL/min); 
4. 
Within the last 6 months has received, or is currently receiving, immunosuppression 
therapy (azathioprine, cyclophosphamide or methotrexate) or any transplant recipient; 
5. 
Clinically significant cardiac disease that adversely effects cardiopulmonary function: 
a. 
Acute coronary syndromes or active ischemic heart disease (as assessed by the PI 
using troponin and ECG); 
b. 
Cardiac ejection fraction < 40% (if known); 
c. 
Need for multiple-dose vasopressors to support blood pressure (single dose 
vasopressors, such as Levophed™ ≤ 0.1 mcg/kg/min are allowed); 
d. 
Cardiogenic pulmonary edema as the etiology of the current respiratory distress; 
e. 
Evidence of myocarditis or pericarditis; 
6. 
Neuromuscular disease; 
7. 
Neutropenia (ANC < 1000);  
8. 
Active malignancy that impacts treatment decisions or life expectancy related to this trial; 
9. 
Suspected concomitant bacterial or other viral lung infection. Bacterial infection defined 
as WBC > 15k and positive blood/urine/sputum culture results within 72 hours. 


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5.3 Lifestyle Considerations 
The use of lucinactant in women of childbearing potential not using contraceptive measures should 
be avoided; women of childbearing potential must have a negative pregnancy test (β-hCG) 
recorded prior to administration of lucinactant and at the end of the study. Men and premenopausal 
women will be required to use double-barrier methods of birth control from enrollment through 30 
days following discharge from the hospital. 
Subjects should not smoke or use illicit drugs, including marijuana. 
5.4 Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical trial but are not 
subsequently assigned to a study intervention or entered in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants, to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements, and to 
respond to queries from regulatory authorities. Minimal information will include the reason for 
screen failure and may include demography, eligibility criteria, and any serious adverse event 
(SAE). 
5.5 Strategies for Recruitment and Retention 
Subjects will be recruited from each institution based upon inpatient admission for COVID-19. 
Patients or their legal guardians who wish to enroll will go through the informed consent process; 
patients or their legal guardians will be reminded they may withdraw consent at any time. Informed 
consent will be administered in paper or electronic format. 
No overall recruitment strategies are planned; any strategies employed by a site must be approved 
by Windtree and their IRB/IEC and be included in their site regulatory binder (with a copy sent to 
Windtree).  


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6 
STUDY DOSING AND ADMINISTRATION 
6.1 Treatments Administered 
6.1.1 
Study Intervention Description 
Lucinactant will be provided as a lyophilized powder in a 30 ml vial. Lucinactant will be 
reconstituted with 10 ml sterile Water for Injection (WFI). Reconstituted lyophilized lucinactant 
will be given at a volume of 160 ml, delivered as a liquid in the trachea. 
Lyophilized lucinactant will be appropriately labeled with the investigational caution statements 
required by the regional health authority (eg, United States [US] Food and Drug Administration 
[FDA], the National Administration of Drugs, Foods and Medical Devices [ANMAT]) to ensure 
that users are aware that the product is limited by federal law to investigational use only. Additional 
information can be found in the investigator’s brochure and in the package insert for SURFAXIN. 
6.1.2 
Dosing and Administration 
Eligible patients will be enrolled into the study and receive lucinactant treatment. Treatment 
initiation is to begin within 6 hours of enrollment. The time of enrollment is defined as the time at 
which it has been confirmed that the subject has met all inclusion criteria and has not met any 
exclusion criteria, and a request to the pharmacy to prepare study drug has been made. Enrollment 
should occur within 7 days of endotracheal intubation and MV. 
Initial Dose  
Reconstituted lyophilized lucinactant is administered using the following instillation procedure: 
a. The ventilator will be set at an FiO2 of 1.00. 
b. To prevent cough and throat closure, the patient may receive a short-acting paralytic. 
c. Lucinactant will be administered via a number 10 French end-hole suction catheter 
positioned in the trachea at the end of the endotracheal tube. The suction catheter will be 
inserted into the ventilator’s inspiratory tubing via a side-port connector.  
d. The total dose of lucinactant will be divided into four quarter-doses (40 ml). Each 
quarter-dose will be further sub-divided into aliquots of 20 ml. Each quarter-dose will be 
instilled in one of the four positions listed below, one aliquot at a time. After each quarter 
dose, ensure the patient is stable before continuing the dosing. 


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1. Quarter-dose administered with the patient supine and positioned 45° to the right. 
Each aliquot will be followed by 1 minute of ventilation. 
2. Quarter-dose administered with the patient supine and positioned 45° to the left. Each 
aliquot will be followed by 1 minute of ventilation. 
3. Quarter-dose administered with the patient supine and positioned 45° to the right. 
Each aliquot will be followed by 1 minute of ventilation. 
4. Quarter-dose administered with the patient supine and positioned 45° to the left. Each 
aliquot will be followed by 1 minute of ventilation. 
During the administration of the lucinactant, the investigator should monitor the patient's oxygen 
saturation by pulse-oximetry. If the subject does not tolerate one of the 40 ml quarter doses, the 
dosing for that dose may be terminated at that time. It is recommended that the other quarter doses 
remain 40 ml; however, a lower dose may be administered for the remaining aliquots at the 
Investigator’s discretion. The investigator will remain with the patient during the first 10 minutes 
post-treatment. No ventilator changes are to be made during this 10-minute period unless cyanosis 
or bradycardia occur. At the end of this 10-minute period, the patient’s FiO2 should be weaned to 
the patient’s pre-treatment FiO2. The patient should not be suctioned for one hour following 
dosing. 
If, in the opinion of the investigator, the patient experiences clinically significant desaturations, 
hypoxia and/or bradycardia, the lucinactant administration should be temporally suspended to 
allow the patient to recovery. If the patient doesn’t not recovery in a reasonable time, the 
administration should be terminated. If the administration procedure is re-started and the patient 
experiences a second episode of clinically significant desaturation, hypoxia and/or bradycardia, 
the lucinactant administration should be immediately terminated. 
Retreatment Doses 
Up to 3 retreatment doses are allowed no sooner than 6 hours apart (from completion of previous 
dose). Subjects are eligible for retreatments if they remain on MV, there is no evidence of 
pneumothorax, the P/F ratio is under 300 (or S/F ratio is under 315 (43), if no arterial line is 
present), and there are no safety concerns that would prevent retreatment (in the opinion of the 
investigator). Retreatments are given at the discretion of the investigator, but it is encouraged that 
retreatments be given at the recommended time interval if the patient is still receiving MV and 
meets all retreatment criteria. 
Retreatment should be performed in the same manner as the initial treatment. 


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6.2 Preparation/Handling/Storage/Accountability 
6.2.1 
Acquisition and Accountability 
Lyophilized lucinactant will be shipped to the sites from Windtree or a supply depot. Site 
pharmacies will be stocked with an initial supply, with re-supply based on pre-set limits. 
6.2.2 
Formulation, Appearance, Packaging and Labeling 
Lyophilized lucinactant, is a sterile, white, liposomal powder consisting of a 21-amino acid 
hydrophobic synthetic peptide, (sinapultide, KL4 peptide), the phospholipids dipalmitoyl-
phosphatidylcholine (DPPC) and palmitoyloleoyl-phosphatidylglycerol, sodium salt (POPG, Na), 
and the fatty acid palmitic acid (PA). Immediately before dosing, the lyophilized product is 
reconstituted with sterile WFI at a concentration of 30 mg TPL/ml. Once reconstituted with sterile 
WFI, the product contains the same 4 APIs in the same proportions and concentrations, as 
SURFAXIN (Table 6-1). Lyophilized lucinactant contains no animal-derived materials or 
preservatives.  
Table 6-1. Drug Description 
Ingredient 
Amount (per ml) 
Sinapultide 
0.862 mg 
DPPC 
22.50 mg 
POPG, Na 
7.50 mg 
PA 
4.05 mg 
Note: amounts reflect reconstituted product at 30 mg/ml 
6.2.3 
Product Storage 
Lyophilized lucinactant must be stored in refrigerated conditions (5°C ± 3°C ) and protected from 
light. The refrigerator temperature must be monitored to ensure the viability of the drug product. 
The refrigerator temperature must be logged at least daily and will be reviewed by the CRA during 
site visits. The drug product will be shipped in insulated shippers with temperature monitors to 
ensure that appropriate temperatures were maintained during the shipping process. Instructions for 
using the temperature monitors will be included with the shipments. 


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6.2.4 
Preparation 
Details for study drug preparation can be found in the study manual. Briefly, lyophilized 
lucinactant is reconstituted immediately before use by adding 10 ml of sterile WFI to the vial of 
lucinactant, after which the vial is gently inverted to mix the suspension; no warming is necessary.  
Each vial is drawn up into a single-use syringe. The syringe should be labeled with the subject’s 
identification number.  
6.3 Measures to Minimize Bias: Randomization and Blinding 
For this study, the study drug (lyophilized lucinactant) is being delivered in an open-label manner 
and no randomization will occur; thus, no procedures to minimize bias relative to randomization 
or blinding will be employed. 
6.4 Study Intervention Compliance 
Study treatments will be administered in an in-patient setting (ie, ICU) by the PI or a person 
approved for dosing by Windtree. Completion of drug delivery for each treatment and re-treatment 
will be monitored; no other compliance measurements will be employed. 
6.5 Concomitant Therapy 
Applicable concomitant medications (sedatives, paralytics, vasopressors, anti-coagulants, 
COVID-directed antiviral and anti-inflammatory therapy) will be recorded from enrollment until 
the final subject assessment. 
6.5.1 
Rescue Medicine or Therapy 
Not applicable.  


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7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 Discontinuation of Study Intervention 
Study treatment may be interrupted at any time as circumstances dictate (eg, peri-dosing event). 
In all cases, emergent care of the subject takes precedence over study treatment; however, it is 
important to complete SRT as soon as possible. If study treatment is interrupted or stopped, the 
reason for doing so must be recorded, especially in regard to peri-dosing events (bradycardia, 
desaturation, hypotension, pallor, gagging/regurgitation/vomiting). 
Discontinuation from study treatment does not mean discontinuation from the study, and the 
remaining study procedures should be completed as indicated. If a clinically significant finding is 
identified after enrollment (including, but not limited to changes from baseline), the investigator 
or qualified designee will determine if any change in participant management is needed. Any new 
clinically relevant finding will be reported as an AE. 
7.2 Participant Discontinuation/Withdrawal from the Study 
The subject is free to withdraw consent from subject participation in the study at any time. An 
investigator may discontinue or withdraw a participant from the study if any clinical AE or other 
medical condition or situation occurs such that continued participation in the study would not be 
in the best interest of the subject. 
The reason for subject discontinuation or withdrawal from the study will be recorded on the end 
of study eCRF page. Subjects who are enrolled and subsequently withdraw, or are withdrawn or 
discontinued from the study, will not be replaced. 
7.3 Lost to Follow-Up 
All efforts should be undertaken to ensure that no subject is lost to follow-up. It is expected that 
subjects will remain in the study site until the end of study; however, if a subject is discharged 
prior to the final evaluation, the subject should be contacted for the Day 30 visit. If the subject 
cannot be reached, at least 3 additional attempts must be made (at least one contact using telephone 
and at least one using email). If the subject still cannot be reached, a certified letter should be sent 
to the subject. If contact cannot be re-established after the certified letter, the subject will be 
considered lost to follow-up.  


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8 
STUDY ASSESSMENTS AND PROCEDURES 
A table of study procedures and activities is presented in Section 1.2.  
8.1 Screening Process 
Before conducting any study-related activities, the ICF must be signed and dated by the subject or 
their legally authorized guardian and retained by the site and the subject (Section 10.1.1). 
Evaluation of the entrance criteria are performed during the screening process. 
8.1.1 
Demographics and Baseline Characteristics 
The subject’s demographic data will be recorded.  
8.1.2 
Medical History 
During Screening, medical history, and concomitant mediations will be documented. 
8.1.3 
Physical examination 
A physical examination will be conducted during Screening. Any relevant clinically significant 
abnormalities noted prior to enrollment should be recorded in the eCRF as part of the medical 
history (and not as an AE).  
8.1.4 
Respiratory Support Parameters 
During screening, information on respiratory support parameters will be captured for subjects 
receiving MV. For the initial intubation, the following must be documented: 
• Date and time support started; 
• The type of respiratory support and mode. 
Lung compliance should be recorded during screening. 
8.1.5 
Enrollment 
Eligible patients will be enrolled into the study and receive lucinactant treatment. Treatment 
initiation is to begin within 6 hours of enrollment. The time of enrollment is defined as the time at 
which  it has been confirmed that the subject has met all inclusion criteria and has not met any 


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exclusion criteria, and a request to the pharmacy to prepare study drug has been made. Enrollment 
should occur within 7 days of endotracheal intubation and MV.  
Following enrollment, dosing will proceed once the reconstituted product has been prepared (see 
the Study Manual for reconstitution and preparation instructions). Treatment initiation is to begin 
within 6 hours of enrollment. 
Just prior to dosing, vital signs (including blood pressure, mean airway pressure, weight, and body 
temperature) will be assessed. 
8.2 Treatment Period 
Reconstituted lyophilized lucinactant is administered as a liquid within 7 days of initial intubation. 
8.2.1 
Gas Exchange Parameters and Arterial Blood Gases 
Values for fraction of inspired oxygen (FiO2), oxygenation from pulse oximetry (SpO2), mean 
airway pressure (Paw), end-tidal CO2 (EtCO2), and arterial blood gases (ABGs; PaO2, PaCO2, pH) 
will be recorded from just prior to dose administration and at 1 (±0.25), 2 (±0.25), 4 (±0.5), 8 
(±0.5), 12 (±1.0), 18 (±1.0), and 24 (±1.0) hours after dose administration, daily through Day 5, 
and at Day 30.  
P/F and S/F ratios will be determined. 
8.2.2 
Vital signs 
Blood pressure, heart rate, and body temperature will be measured every 12 (±1.0) hours until 
Day 5 and at Day 30. Systolic and diastolic blood pressure should be measured using either an 
arterial line or a manual sphygmomanometer with the patient in a supine or semi-supine position.  
Weight will be measured at baseline and at Day 30.  
8.2.3 
Respiratory Support Parameters 
Information on respiratory support parameters will be captured through Day 30 or discharge, 
whichever occurs first. For each intubation and change in respiratory support, the following must 
be documented: 
• Date and time 


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• The type of respiratory support and mode 
• The reason for each intubation and change of respiratory support 
Lung compliance should be recorded every 12 (±1.0) hours through Day 5. The plateau pressure 
and peak inspiratory pressure (PIP) will be measured every 12 (±1.0) hours through Day 5. The 
ventilation index will be calculated. 
8.2.4 
Pressure Volume Loops 
Pressure volume loops will be recorded every 2 (±0.25) hours through 24 hours. 
8.2.5 
Readmissions and death 
Readmissions and death will be reported through discharge and Day 30. Hospitalization will be 
defined as any unplanned hospitalization (including admission to a hospital or any attendance in 
an acute care setting e.g. ED, or in another health care facility) of 24 hours or greater, regardless 
of whether the patient was admitted to the hospital.  
8.3 Safety and Other Assessments 
8.3.1.1 
Concomitant Medications 
Concomitant medications and therapies required for the general care of the subject are permitted, 
including remdesivir and off-label drugs. Other investigational agents or investigational medical 
devices should be avoided. Concomitant medications will be documented until the time the subject 
completes the Day 30, is discharged from the hospital, dies, or is transferred to another hospital. 
Dose, route, unit, frequency of administration, indication for administration, and dates of 
medication will be captured on the CRF. 
8.3.1.2 
Tolerability of drug administration 
During dosing, the incidence of the following will be recorded: 
o Oxygen desaturation  
o Bradycardia  
o Hypotension  
o ET tube obstruction 
In addition, information on (time, reason) and the incidence of dosing interruptions or dosing 
discontinuations will be collected. 


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8.4 Adverse Events and Serious Adverse Events 
8.4.1 
Definition of Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence associated with the use of 
an intervention, whether or not considered intervention related. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of an investigational product [21 CFR 312.32(a), ICH E6(R2)]. 
8.4.2 
Definition of Serious Adverse Events 
An AE 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: death, 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 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, blood dyscrasias or convulsions that do not result in inpatient hospitalization. 
8.4.3 
Classification of an Adverse Event 
8.4.3.1 
Severity of Event 
The severity of an AE is assessed by the PI using the following definitions: 
• Mild – Events require minimal or no treatment and do not interfere with the subject’s daily 
activities.  
• Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• Severe – Events interrupt a subject’s usual activity level and may require systemic drug 
therapy or other treatment. Severe events may be potentially life-threatening or 
incapacitating. Of note, the term “severe” does not necessarily equate to “serious.” 


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8.4.3.2 
Relationship to Study Intervention 
All AEs must have their relationship to study intervention assessed by the PI, based on temporal 
relationship and his/her clinical judgment. The degree of certainty about causality will be graded 
using the categories below. In a clinical trial, the study product must always be suspect.  
• Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory 
test result, occurs in a plausible time relationship to study intervention administration, 
follows a known response pattern to the study intervention, and cannot be explained by 
concurrent disease or other drugs or chemicals. An AE that is determined to be due to the 
subject’s underlying disease state or is common for this patient population generally should 
not be considered related. 
• Possibly Related – There is some evidence to suggest a causal relationship (eg, the event 
occurred within a reasonable time after administration of the trial medication) and/or 
follows a known response pattern to the study drug. However, other factors may have 
contributed to the event (eg, the participant’s clinical condition, other concomitant events). 
Although an AE may rate only as “possibly related” soon after discovery, it can be flagged 
as requiring more information and later be upgraded to “related,” if appropriate. An AE 
that is determined to be due to the subject’s underlying disease state or is common for this 
patient population generally should not be considered possibly related. 
• Unlikely Related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (eg, the event did not occur within a reasonable time after administration of the 
study intervention) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (eg, the subject’s clinical condition, other concomitant treatments). 
• Not Related – The AE is completely independent of study intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. There should 
be an alternative, definitive etiology documented by the clinician.] 
8.4.3.3 
Expectedness 
The Windtree Medical Monitor or designee will be responsible for determining whether an AE is 
expected or unexpected. An AE will be considered unexpected if the nature, severity, or frequency 
of the event is not consistent with the risk information previously described for the study 
intervention (ie, as per the Investigator’s Brochure). 


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8.4.4 
Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an AE or SAE may come to the attention of study personnel during the study, 
or upon review by a study monitor. 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured 
on the appropriate eCRF. All AEs occurring while on study must be documented appropriately 
regardless of relationship. All AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be considered 
as baseline and not reported as an AE. However, if the study participant’s condition deteriorates 
at any time during the study, it will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the 
event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
The site will record all reportable events with start dates occurring any time after informed consent 
is obtained until 7 days after the last day of study participation or Day 30 (whichever occurs first). 
Events will be followed for outcome information until resolution or stabilization, or for 30 days 
after study participation. When possible, information collection should continue for subjects that 
withdraw or discontinue treatment early. 
8.4.5 
Adverse Event Reporting 
All AEs are to be assessed in all subjects throughout Day 30 (from enrollment to study withdrawal 
or completion) and documented in the study eCRF. Each AE should be reported spontaneously or 
in response to general, non-directed discussion with the attending nurse or physician (eg, “has 
there been any change in subject status since the last assessment period?”). For each AE, the 
investigator should obtain all information required to complete the AE page of the eCRF, in 
accordance with eCRF completion guidelines (provided separately by Windtree). 
All AEs, regardless of seriousness, severity, or relationship to study participation, must be recorded 
(using medical terminology) in the source document and on the AE page of the eCRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology. 


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All AEs must be followed until resolution or until a stable clinical end-point is reached, or for at 
least 30 days after the subject’s last day in the study if an AE is ongoing at the time the subject 
completes the study.  
Documentation of AEs in the eCRF must include the following parameters; (1) duration (time of 
onset and resolution), (2) severity or grade, (3) outcome, (4) action taken, and (5) relationship to 
study drug. AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
8.4.6 
Serious Adverse Event Reporting 
When an investigator-trained designee becomes aware of an SAE, Windtree must be notified as 
soon as possible (and no later than 24 hours after the event has occurred) by telephone, regardless 
of the relationship (or lack thereof) of the SAE to study participation. 
SAEs should be reported to Windtree’s reporting line. When reporting SAEs, the following 
information should be provided: 
1. Study identifier 
2. Study center 
3. Subject number 
4. A description of the event 
5. Date of onset 
6. Current status 
7. Clarification on whether infusion 
therapy was discontinued 
8. The reason why the event is 
classified as serious 
9. The Investigator’s assessment of the 
association between the event and 
study participation 
 
 
All reports of SAEs must be followed up within 24 hours (or sooner at the request of the medical 
monitor) by the completion of the SAE form and signature by the person who completed the form 
and the PI.  
Safety report distribution is the responsibility of Windtree or designee (ie, CRO), which 
coordinates distribution of safety reports to applicable regulatory authorities and ECs. Finalized 
safety reports are distributed by one or more individuals, “Responsible Team,” within a department 
that has responsibility to coordinate the distribution/submission activities, either directly or via a 
Local Submitting Party on behalf of Windtree. 
The Responsible Team receives finalized safety reports (eg, CIOMS-I form/MedWatch 3500A/ 
E2B file/DSUR/SUSAR Listing) and coordinates distribution to all applicable regulatory 


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authorities and ECs. Distribution will be done in accordance with project-specific documents, 
regulatory requirements, other applicable reference sources, and applicable Windtree or designee 
safety procedural documents. 
In addition, Windtree coordinates translation when required for safety reporting. Windtree also 
coordinates transcription (eg, manual transfer of information from one reporting format to another) 
when required. Project specific information is used to identify appropriate recipients. Quality 
checks will be permed on the distribution documents and recipient information for completeness 
and accuracy prior to distribution. 
The names, telephone, and fax numbers of the individuals who should be contacted regarding 
safety issues are listed below. 
FOR QUESTIONS, PLEASE CONTACT THE MEDICAL MONITOR: 
Carlos Guardia, MD (Medical Monitor) 
WhatsApp: +591 72138559 
Office: +1 (717) 300 1415 
Email: CGuardia@Windtreetx.com  
Steven G. Simonson, MD, MHS (Medical Officer) 
Office: +1 (215) 488-9474 
Email: SSimonson@Windtreetx.com  
FOR REPORTING SAEs, PLEASE CONTACT WINDTREE AT: 
Reporting Line (24/7/365): +1 833-4WINDTX 
FOR ADDITIONAL ASSISTANCE, PLEASE CONTACT YOUR CRA OR WINDTREE 
DIRECTOR OF CLINICAL OPERATIONS: 
Catherine Kacprzycki 
Director of Clinical Operations 
Office: +1 (215) 488-9478 
Cell: +1 (267) 370-3836 
Email: CKacprzycki@Windtreetx.com  


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8.4.7 
Reporting Events to Subjects 
Occurrences of AEs or SAEs that impact the risk to subjects in the study may result in a change in 
the informed consent form. Subjects who have not yet completed the study must be reconsented 
with the amended informed consent form.  
8.4.8 
Events of Special Interest 
Air leaks (eg, pneumothorax, pneumomediastinum) will be considered AEs of special interest. Air 
leaks should be reported using the reporting line within 24 hours of becoming aware of the air 
leak. 
8.4.9 
Reporting of Pregnancy 
The use of lucinactant in women of childbearing potential not using contraceptive measures should 
be avoided; women of childbearing potential must have a negative pregnancy test (β-hCG) 
recorded prior to administration of lucinactant and at the end of the study. Men and premenopausal 
women will be required to use double-barrier methods of birth control for 30 days following 
discharge from the hospital. Failure to commit to double-barrier methods will be a reason for 
screen failure. 
If a woman becomes pregnant during the study, the pregnancy will be followed until delivery or 
termination, and pertinent information about the pregnancy will be collected (eg, AEs, concomitant 
medications). 


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9 
STATISTICAL CONSIDERATIONS 
9.1 Statistical Hypothesis 
As this is an open-label study with no comparison group, no hypotheses will be used for this study. 
9.2 Sample Size Determination 
The objective of this safety pilot study is to determine if lyophilized lucinactant administration is 
safe and tolerable, and to assess the impact on oxygenation for those patients suffering with 
COVID-19. As a result, no formal sample size calculation was performed but instead enroll a 
sufficient number of subjects to provide evidence that liquid lucinactant can be safely delivered as 
an intratracheal bolus. 
Thus, up to 30 subjects (out of approximately 90 screened) will be enrolled.  
9.3 Populations for Analyses 
Populations of all enrolled subjects who received any treatment (modified intent-to-treat [mITT]) 
will be evaluated for safety and efficacy. 
9.4 Statistical Analyses 
9.4.1 
General Approach 
All efficacy and safety parameters will be evaluated using summary statistics. For continuous 
variables, n, mean, standard deviation, median, min, and max will be presented; for discrete 
variables, frequency and percent will be presented. 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) 
The primary endpoint is the change from baseline in OI through 12 hours post dosing. OI is define 
as (FiO2 × Paw × 100)/PaO2. OI will be summarized using mean, standard deviation (SD), median, 
minimum, and maximum. 


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9.4.3 
Analysis of the Secondary Endpoint(s) 
9.4.3.1 
Through 24 Hours Post Treatment 
OI, FiO2, PaO2, SpO2, PaCO2, P/F and S/F ratios, change in plateau pressure and PIP measured 
on the ventilator, VI, and lung compliance will be summarized as change from baseline at each 
time point measured using mean, SD, median, minimum, and maximum. 
9.4.3.2 
Through 30 Days 
Daily lung compliance on ventilator, ventilator free days, days in the ICU, days in the hospital, 
organ failure free days, and all-cause mortality will be summarized as was done for the primary 
endpoint. 
 
All deaths will be summarized using frequency and percent, overall and by type of death 
(respiratory or not respiratory) and included as part of the assessment of safety. Also, the deaths 
will be listed by subject and narratives for each death will be included. In this study, the secondary 
endpoint of ventilator-free days (VFD) is a mortality adjusted assessment. This issue will be dealt 
with in more detail in preparation for the next study. 
9.4.4 
Safety Analyses 
Adverse Events will be coded using MedDRA (version 22.0 or later) and will be summarized by 
treatment group using frequency and percent but will not be compared statistically. Concomitant 
medications will be classified using the WHODrug dictionary (March 2020 or later) and 
summarized using frequency and percent. All-cause mortality, physical examination and medical 
history will similarly be summarized.  
9.4.5 
Baseline Descriptive Statistics 
Demographic parameters will be summarized by treatment group and assessed qualitatively for 
homogeneity of treatment groups. For categorical data (eg, sex, race), data will be summarized 
using frequency and percent; for continuous (parametric) data, data will be summarized by n, 
mean, SD, median, minimum, and maximum. 
9.4.6 
Planned Interim Analyses 
No interim analyses are planned, other than the safety assessments performed by the DMC. 


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9.4.7 
Sub-Group Analyses 
No sub-group analyses are planned. 
9.4.8 
Tabulation of Individual Participant Data 
Datasets will be provided as CDISC-compliant standard data tabulation modules (SDTM); no 
separate individual participant data listings will be provided. 
9.4.9 
Exploratory Analyses 
Exploratory analyses may be performed based upon subject responses to treatment. 


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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Informed Consent Process 
10.1.1.1 
Consent/Assent and Other Informational Documents Provided to Participants 
The informed consent form (ICF) describes in detail the study intervention, study procedures, and 
risks. The ICF (either electronic or paper) is given to the patient and documentation of informed 
consent is required prior to starting administration of study intervention or any study-specific 
procedures that are not part of usual care.  
10.1.1.2 
Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to patient agreement to participate in the study 
and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC) approved and the patient will be 
asked to read and review the paper or electronic document. Within a maximum of 24 hours before 
administration of study medication, a medical screening will be performed on all prospective 
patients to assess suitability for the study. The investigator will explain the research study to the 
patient and answer any questions that may arise. A verbal explanation will be provided in terms 
suited to the patient’s comprehension of the purposes, procedures, and potential risks of the study 
and of the rights of research participants. Patients will have the opportunity to carefully review the 
consent form and ask questions prior to signing. The patients should have the opportunity to 
discuss the study with their family or surrogates or think about it prior to agreeing to participate. 
The patient will sign the informed consent document (in ink or electronically) prior to any 
procedures being done specifically for the study. Patients must be informed that participation is 
voluntary and that they may withdraw from the study at any time, without prejudice. A copy of 
the informed consent will be given to the patient for their records and will be retained in the site 
source documents. The informed consent process will be documented in the source document 
(including the date). The rights and welfare of the participants will be protected by emphasizing 
to the patient that the quality of their medical care will not be adversely affected if they decline to 
participate in this study. No waivers will be allowed for this study. 


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10.1.2 
Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to the principal investigator 
and regulatory authorities. If the study is prematurely terminated or suspended, the PI will 
promptly inform study participants and the IRB/IEC and will provide the reason(s) for the 
termination or suspension.  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping  
• Data that are not sufficiently complete and/or evaluable 
The study may resume once the reasons for suspension are addressed, and satisfy the sponsor, 
IRB/IEC and/or Regulatory Agency (eg, FDA or ANMAT). 
10.1.3 
Confidentiality and Privacy 
Subject confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and Windtree. The study protocol, documentation, data, and all other information generated 
will be held in strict confidence, in compliance with the Health Insurance Portability and 
Accountability Act (HIPAA) and other local privacy laws (such as Law 25326 in Argentina). No 
information concerning the study or the data will be released to any third party without prior 
written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB/IEC, 
or regulatory agencies may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records and pharmacy records for the 
participants in this study. The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB/IEC, Institutional policies, or sponsor 
requirements. 


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Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be entered into a validated Electronic Data Capture (EDC) system, and will be transmitted to 
and stored at Windtree. This will not include the participant’s contact or identifying information. 
Rather, individual participants and their research data will be identified by a unique study 
identification number. The study data entry and study management systems used by clinical sites 
and by Windtree research staff will be secured and password protected and meet the requirements 
of 21CFR11 and the General Data Protection Regulation. At the end of the study, all study 
databases will be archived at Windtree. 
10.1.4 
Future Use of Stored Specimens and Data 
No specimens will be taken for this study. 
10.1.5 
Key Roles and Study Governance 
The coordinating investigator and medical monitor are listed in Table 10-1. 
Table 10-1. Coordinating Investigator and Medical Monitor 
Coordinating Investigators 
Medical Monitor 
Yuh-Chin T. Huang, MD., MHS. 
Professor of Medicine, Pulmonary and 
Critical Care Medicine 
Duke University Medical Center  
 
Carlos Guardia, MD 
Senior Medical Director 
Windtree Therapeutics, Inc.~ 
 
 
10.1.6 
Safety Oversight 
Safety oversight will be under the direction of the medical monitor, the principal investigators, and 
a data monitoring committee (DMC). Given the open-label, single-treatment of this study, real 
time safety assessments of treated subjects will be done by the sponsor and principal investigators. 
10.1.6.1 
Data Monitoring Committee 
The DMC, made up of at least 3 experts in the field of infectious diseases, will evaluate the degree 
of risk involved in study subject participation within each treatment group and to determine if 


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study continuation in accordance with the current protocol holds the potential to institute any 
undue harm or threat to the safety and welfare of study subjects.  
During the treatment and post-dosing phases, the chair of the DMC will receive regular reports on 
SAEs and DMC members will be periodically updated on the program and trial status. An ad hoc 
meeting of the DMC will occur if the chair deems it necessary to address safety in the study. The 
DMC may recommend that study enrollment be suspended if safety concerns are identified or 
suspected. 
10.1.6.2 
Safety Reviews 
The DMC will meet after every 6 subjects have been enrolled and dosed. The DMC will continue 
to meet after every 6 enrollments and these reviews will continue until enrollment and dosing is 
complete. 
The DMC review may consist of the evaluation of (1) demographics and baseline, (2) all AEs, 
especially peri-dosing AEs and AEs of special interest, (3) case reviews of subjects with reported 
SAEs, (4) summary tables of all safety endpoints, and (5) any other available relevant data. 
Following a meeting, the DMC will provide timely recommendations to the Windtree study team. 
Recommendations may consist of, but not be limited to the following:  
• Continue the study as planned 
• Suspend study enrollment, pending additional information 
• Close study enrollment  
An independent statistician, not a member of the committee, will be responsible for the statistical 
analysis of the data. 
10.1.7 
Clinical Monitoring 
Windtree or their designee will perform on-site or remote monitoring visits as frequently as it is 
deemed necessary to ensure quality study data capture and accurate adherence to the study protocol 
as outlined in the Clinical Monitoring Plan (CMP). It is also necessary to ensure that the rights and 
well-being of trial participants are protected, and that the conduct of the trial is in compliance with 
International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) and with 
applicable regulatory requirements.  


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Monitoring will be performed as in-person/remote visits and centralized review of records. In-
person/remote visits will include source data verification to the eCRF; some source data 
verification will be performed unless otherwise specified in the CMP.  
Before enrollment, a clinical site monitor will complete a site initiation visit (SIV) at each study 
site. During SIVs, clinical site monitors will provide study training to site staff, ensure study drug 
storage is in accordance with the study protocol, and validate all other study requirements in 
accordance with the study monitoring plan.  
Clinical site monitors will schedule a study site visit as close as possible to the time of each site’s 
first enrolled study subject; periodic follow-up monitoring visits will ensure on a regularly 
scheduled basis throughout the study, in accordance with enrollment at the study site. At these 
visits, the clinical site monitor will compare the data entered into the eCRF with the hospital or 
clinic records (source documents) and check for protocol compliance. Documentation reviews will 
include but not be limited to the evaluation and confirmation of the following:  
1. A record of informed consent. 
2. Adherence to enrollment criteria. 
3. Completion of all required study assessments. 
4. Accurate and complete data capture of all AEs, concomitant medications, and safety and 
efficacy observations.  
5. Study drug storage and dispensing records maintained in accordance with study and 
regulatory requirements.  
Findings from these reviews will be discussed with the PI and study site staff. 
The dates of the monitoring visits will be recorded by the clinical site monitor in a sign-in log to 
be kept at the site. The study coordinator and PI are expected to be available for questions, have 
all source documentation readily available, and have a suitable environment provided for review 
of study-related documents. 
In accordance with ICH GCP, Windtree will select (either directly or through a subcontract with a 
company specifically trained in the monitoring of clinical studies), qualified individuals to monitor 
study sites to ensure the quality of study progress and the close adherence of study sites to the 
study protocol and all related governing documents and SOPs. 


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1. The clinical site monitor(s), before the initiation of each study site, will ensure each 
investigator and study staff understands the following: 
a) The investigational status of the study drug, placebo and the requirements for its 
accountability. 
b) The need to uphold all directives within the clinical protocol as it relates to study 
conduct and subject safety at the study site. 
c) The obligation to obtain informed consent in accordance with the Declaration of 
Helsinki and ICH GCP guidelines before enrolling each subject in the study. 
d) The obligation to obtain IRB/IEC review and approval of the study before study 
initiation at his/her clinical site, and ensure timely updates to the IRB/IEC as mandated 
by local and national regulatory requirements, and to ensure timely communications to 
Windtree of all IRB/IEC communications (to include reviews and subsequent actions) 
concerning the study. 
2. The clinical site monitor(s) will perform periodic visits to each clinical site during the 
course of the study to ensure the study protocol is being followed and that: 
a) Drug and placebo inventories are being properly maintained and documentation of vial 
usage is accurate and complete.  
b) The assignment of responsibilities log is up-to-date and that changes in personnel are 
reported to Windtree. 
c) The PI is reporting all serious or fatal AEs (Section 8.4.6) as soon as possible, and in 
no case later than 24 hours after the event, to the medical monitor or designee at 
Windtree. 
3. The clinical site monitor(s) will perform an end-of-study visit to each clinical site to ensure 
that: 
a) All drug reconciliation forms, as provided in the study manual, are accurate and 
complete. 
b) All used and unused vials of study drug have been reconciled. 
c) All eCRFs are complete and all monitoring of eCRFs has been completed. 
Details of clinical site monitoring are documented in a CMP. The CMP describes in detail who 
will conduct the monitoring, at what frequency monitoring will be done, at what level of detail 
monitoring will be performed, and the distribution of monitoring reports. 
10.1.8 
Quality Assurance and Quality Control 
Each clinical site will perform internal quality management of study conduct, data collection, and 
documentation. An individualized quality management plan will be developed to describe a site’s 
quality management. 


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Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. Following written SOPs, 
the monitors will verify that the clinical trial is conducted and data are collected, documented 
(recorded), and reported in compliance with the protocol, ICH GCP, and applicable regulatory 
requirements.  
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
10.1.9 
Data Handling and Record Keeping 
10.1.9.1 
Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. All source documents should be completed in a neat, 
legible manner to ensure accurate interpretation of data. 
Hardcopies of the study visit worksheets may be provided for use as source document worksheets 
for recording data for each participant enrolled in the study. Data recorded in the electronic case 
report form (eCRF) derived from source documents should be consistent with the data recorded 
on the source documents. Study personnel at each site will enter data from source documents into 
the protocol-specific eCRF within 5 days of the information becoming available. Subjects will not 
be identified by name in the study database or on any study documents to be collected by Windtree 
(or designee) but will instead be identified by a site and subject number. 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) will 
be entered into a 21 CFR Part 11-compliant data capture system. The data system includes 
password protection and internal quality checks, such as automatic range checks, to identify data 
that appear inconsistent, incomplete, or inaccurate.  
Members of Windtree’s Data Management department are responsible for data processing, in 
accordance with procedural documentation and a study specific Data Management Plan (DMP). 
Windtree’s Data Management will also provide eCRF Completion Guidelines; extra training will 
be provided to the study sites when necessary.  


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Clinical data will be entered directly from the source documents. After data have been entered into 
the study database, a system of computerized data validation checks will be implemented and 
applied to the database on a regular basis. Corrections for an existing eCRF record will 
automatically be recorded by the eCRF system (audit trail capturing the time, date, and the 
identification of the user who entered or updated eCRF data). Recorded corrections by the eCRF 
will create an electronic audit trail of study documentation. 
Database lock will occur once all quality assurance procedures have been completed; this will 
include but not be limited to the following: (1) all site-based study data have been entered into the 
eCRF, (2) all entered data have been reconciled and reviewed by Windtree or designee, and (3) all 
data related queries have been rendered and resolved. 
All procedures for the handling and analysis of data will be conducted using good computing 
practices meeting FDA guidelines for the handling and analysis of data for clinical trials. 
10.1.9.2 
Study Records Retention 
All records that support data entered into the eCRF of each subject must be retained in the files of 
the PI or the institution/site for a minimum of 2 years (3 years for ICF) following notification by 
Windtree that all investigations have been discontinued or that the last approval of a marketing 
application has been obtained. These documents should be retained for a longer period, however, 
if required by local regulations. No records will be destroyed without the written consent of 
Windtree. It is the responsibility of Windtree to inform the investigator when these documents no 
longer need to be retained. 
Supporting documents will include but not be limited to the following:  
1. Copies of eCRFs (given to the site on a CD)  
2. All original source documents; these may include but not be limited to the following: 
a) ICFs 
b) laboratory reports 
c) progress notes 
d) medical histories 
e) physical and diagnostic findings  
f) diagnoses  
g) dates of therapy before and during this study 
h) drug dispensing/disposition records  
 


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If the PI retires, relocates, or for other reason withdraws from the responsibility of keeping the 
study records, custody must be transferred to a person who will accept the responsibility. Windtree 
must be notified in writing of the name and address of the new custodian. 
10.1.10 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, ICH GCP, or Study 
Manual requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be developed 
by the site and implemented promptly.  
These practices are consistent with ICH GCP:  
4.5, Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
5.1, Quality Assurance and Quality Control, section 5.1.1  
5.20, Noncompliance, sections 5.20.1, and 5.20.2.  
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 10 working days of identification of the protocol deviation, or within 10 working 
days of the scheduled protocol-required activity. All deviations must be addressed in study source 
documents and reported to the site monitor. Protocol deviations must be sent to the reviewing 
IRB/IEC per their policies. The site investigator is responsible for knowing and adhering to the 
reviewing IRB/EC requirements. Further details about the handling of protocol deviations will be 
addressed in the protocol deviation process. 
10.1.11 
Publication and Data Sharing Policy 
The preparation and submittal for publication of a manuscript containing the study results shall be 
in accordance with a process determined by a mutual written agreement among Windtree and 
participating institutions.  
The publication or presentation of any study results shall comply with all applicable privacy laws, 
including but not limited to HIPAA. This trial will be registered at ClinicalTrials.gov and the 
International Clinical Trial Registration Platform (ICTRP), and results information from this trial 
will be submitted to both. In addition, every attempt will be made to publish results in peer-
reviewed journals. 


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10.1.12 
Conflict of Interest Policy 
The independence of this study from any actual or perceived influence is critical. Therefore, any 
actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, 
or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a 
perceived conflict of interest will be required to have such conflicts managed in a way that is 
appropriate to their participation in the design and conduct of this trial. The study leadership has 
established policies and procedures for all study group members to disclose all conflicts of interest 
and will establish a mechanism for the management of all reported dualities of interest. 
The FDA has issued regulations (21 CFR Part 54, Financial Disclosure by Clinical Investigators) 
that require sponsors to submit complete and accurate certification or disclosure statements to 
certify the absence of certain financial interests of clinical investigators, when clinical studies are 
submitted to FDA in support of marketing approval. These regulations are intended to ensure that 
financial interests and arrangements of clinical investigators, that could affect reliability of data 
submitted to FDA in support of marketing approval, are identified and disclosed by the sponsor. 
Clinical investigators will be asked to disclose proprietary (eg, patent, licensing agreement) and 
financial (eg, stock options, royalty) interests as they pertain to Windtree, before participating in 
the study. In addition, clinical investigators will be required to consult with Windtree before 
acquiring any financial interest in the company and must disclose any change in their proprietary 
or financial interests, if it occurs during the course of the study and for 1 year following study 
completion. The requirement for proprietary and financial disclosure also includes any ownership 
by the spouse or any dependent subject of the clinical investigator. 
If FDA determines that the financial interests of any clinical investigator raise serious questions 
about the integrity of the data, FDA will take any action it deems necessary to ensure the reliability 
of the data, including: 
1. Initiating agency audits of the data derived from the clinical investigator in question. 
2. Requesting that the sponsor submit further data analyses (eg, to evaluate the effect of the 
clinical investigator’s data on overall study outcome). 
3. Requesting that the applicant conduct additional independent studies to confirm the results 
of the questioned study. 


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4. Refusing to treat the covered clinical study as providing data that can be the basis for an 
agency action. 
If the sponsor does not include certification or disclosure, or both (as required), or does not certify 
that it was not possible to obtain the information, the FDA may refuse to file the New Drug 
Application (NDA). 
10.2 List of Abbreviations 
Abbreviation 
Description 
β-hCG 
Serum pregnancy test 
A 
A wave: peak velocity flow in late diastole caused by contraction 
AE 
Adverse event 
CFR 
Code of Federal Regulations 
CONSORT 
Consolidated standards of reporting trials 
CRF/eCRF 
Case report form/electronic CRF 
CS 
Cardiogenic shock 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HF/AHF 
Heart failure/acute heart failure 
HIPAA 
Health Insurance Portability and Accountability Act 
E 
E wave: peak velocity blood flow from LV relaxation in early diastole 
E/Ea 
Mitral Doppler inflow E velocity to annular tissue Doppler Ea wave 
velocity 
ERO 
Effective regurgitant orifice 
eGFR 
Glomerular filtration rate 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ICU 
Intensive care unit 


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Abbreviation 
Description 
IEC 
Independent ethics committee 
IRB 
Institutional review board 
IND 
Investigational new drug 
ITT 
Intent-to-Treat 
IWRS 
Interactive web response system 
LV 
Left ventricular 
MAP 
Mean arterial pressure 
NDA 
New drug application 
PAP 
Pulmonary artery pressure 
Paw 
Mean airway pressure 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SIV 
Site initiation visit 
TAPSE 
Tricuspid annular plane systolic excursion 
UP 
Unanticipated problem 
US 
United States 
WHF 
Worsening heart failure 
 
 
 


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11 REFERENCES 
1. 
Hoffmann M, Kleine-Weber H, Krüger N, Müller M, Drosten C, Pöhlmann S. bioRxiv. 
[Online].; 2020 [cited 2020 01 31. Available from: www.bioRxiv.org. 
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Bernheim A, XM, Huang M, Yang Y, Fayad ZA, Zhang N, et al. Chest CT Findings in 
Coranavirus Disease-19 (COVID-19): Relationship to Duration of Infection. Radiology. 
2020 Feb 20. 
3. 
Hosseiny M, Kooraki S, Gholamrezanezhad A, Reddy S, Myers L. Radiology Perspective 
of Coronavirus Disease 2019 (COVID-19): Lessons From Severe Acute Respiratory 
Syndrome and Middle East Respiratory Syndrome. AJR Am J Roentgenol. 2020 Feb;: p. 
1-5. 
4. 
Song F, Shi N, Shan F, Zhang Z, Shen J, Lu H, et al. Emerging 2019 Novel Coronavirus 
(2019-nCoV) Pneumonia. Radiology. 2020 Feb; 295: p. 210-217. 
5. 
Gregory TJ, Steinberg KP, Spragg R, Gadek JE, Hyers TM, Longmore WJ, et al. Bovine 
surfactant therapy for patients with acute respiratory distress syndrome. Am J Respir Crit 
Care Med. 1997 Apr; 155(4): p. 1309-1315. 
6. 
Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, et al. The American-
European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, 
and clinical trial coordination. Am J Respir Crit Care Med. 1994 Mar; 49(3 Pt 1): p. 818-
824. 
7. 
Nicholas TE, Doyle IR, Bersten AD. Surfactant replacement therapy in ARDS. White 
knight or noise in the system? Thoax. 1997; 52: p. 195-197. 
8. 
Brandstetter RD, Sharma KC, DellaBadia M, Cabreros LJ, Kabinoff GS. Adult respiratory 
distress syndrome: A disorder in need of improved outcome. Heart & Lung. 1997; 26: p. 
3-14. 
9. 
Wiedemann HP, Tai DY. Adult respiratory distress syndrome (ARDS): Current 
management, future directions. Cleve Clin J Med. 1997; 64: p. 365-372. 
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Fulkerson WJ, MacIntyre N, Stamler J, Crapo JD. Pathogenesis and treatment of the adult 
respiratory distress syndrome. Arch Intern Med. 1996; 156: p. 29-38. 
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Schuster DP, Kollef MH. Acute respiratory distress syndrome. Dis Mon. 1996 May; 42(5): 
p. 270-326. 
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Schuster DP, Kollef MH. The acute respiratory distress syndrome. New Engl J Med. 1995; 
332: p. 27-37. 
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Sachdeva RC, Guntupalli KK. Acute respiratory distress syndrome. Crit Care Clin. 1997; 
13: p. 503-521. 
14. 
Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. 
Lancet. 1967; 2: p. 319-323. 


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15. 
Petty TL, Reiss OK, Paul GW, Silvers GW, Elkins ND. Characteristics of pulmonary 
surfactant in adult respiratory distress syndrome associated with trauma and shock. Am 
Rev Respir Dis. 1977 Mar; 115(3): p. 531-536. 
16. 
Petty TL, Silvers GW, Paul GW, Stanford RE. Abnormalities in lung elastic properties and 
surfactant function in adult respiratory distress syndrome. Chest. 1979 May; 75(5): p. 571-
574. 
17. 
Hallman M, Spragg RG, Harrell JH, Moser KM, Gluck L. Evidence of lung surfactant 
abnormality in respiratory failure: Study of bronchoalveolar lavage phospholipids, surface 
activity, phospholilpase activity, and plasma myoinositol. J Clin Invest. 1982; 70: p. 673-
683. 
18. 
Pison U, Seeger W, Buchhorn R, Joka T, Brand M, Obertacke U, et al. Surfactant 
abnormalities in patients with respiratory failure after multiple trauma. Am Rev Respir 
Dis. 1989 Oct; 140(4): p. 1033-1039. 
19. 
Pison U, Obertacke U, Brand M, Seeger W, Joka T, Bruch J, et al. Altered pulmonary 
surfactant in uncomplicated and septicemia-complicated courses of acute respiratory 
failure. J Trauma. 1990 Jan; 30(1): p. 19-26. 
20. 
Gregory TJ, Longmore WJ, Moxley MA, Whitsett JA, Reed CR, Fowler AA, et al. 
Surfactant chemical composition and biophysical activity in acute respiratory distress 
syndrome. J Clin Invest. 1991 Dec; 88(6): p. 1976-1981. 
21. 
Greene KE, Wright JR, Steinberg KP, Ruzinski JT, Caldwell E, Wong WB, et al. Serial 
changes in surfactant-associated proteins in lung and serum before and after onset of 
ARDS. Am J Respir Crit Care Med. 1999 Dec; 160(6): p. 1843-1850. 
22. 
Schmidt R, Meier U, Yabut-Perez M, Walmrath D, Grimminger F, Seeger W, et al. 
Alteration of fatty acid profile in different surfactant phospholipids in acute respiratory 
distress syndrome and severe pneumonia. Am J Respir Crit Care Med. 2001 Jan; 163(1): 
p. 95-100. 
23. 
Günther A, Schmidt R, Feustel A, Meier U, Pucker C, Ermert M, et al. Surfactant subtype 
conversion is related to loss of surfactant apoprotein B and surface activity in large 
surfactant aggregates. Am J Respir Crit Care Med. 1999 Jan; 159(1): p. 244-251. 
24. 
Veldhuizen RA, McCaig LA, Akino T, Lewis JF. Pulmonary surfactant subfractions in 
patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 1995 Dec; 
152(6 Pt 1): p. 1867-1871. 
25. 
Amirkhanian JD. Inhibitory effects of oxyradicals on surfactant function utilizing in vitro 
Fenton reaction. Lun. 1998; 176: p. 63-72. 
26. 
Manalo E, Merritt TA, Kheiter A, Amirkhanian J, Cochrane C. Comparative Effects of 
Some Serum Components and Proteolytic Products of Fibrinogen on Surface Tension-
Lowering Abilities of Beractant and a Synthetic Peptide Containing Surfactant KL4. 
Pediatr Res. 1996; 39: p. 947-952. 


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27. 
Merritt T, Amirkhanian J, Helbock H, Halliwell B, Cross C. Reduction of the surface-
tension-lowering ability of surfactant after exposure to hypochlorous acid. 1993; 295(Pt 
1): p. 19-22. 
28. 
Kinniry P, Pick JSS, Jain D, Solomides C, Niven R, Segal R, et al. KL4-surfactant prevents 
hyperoxic and LPS-induced lung injury in mice. Pediatr Pulmonol. 2006; 41(10): p. 916-
928. 
29. 
Wolfson MR, Wu J, Hubert TL, Gregory TJ, Mazela J, Shaffer TH. Lucinactant attenuates 
pulmonary inflammatory response, preserves lung structure, and improves physiologic 
outcomes in a preterm lamb model of RDS. Pediatr Res. 2012 Oct; 72(4): p. 375-383. 
30. 
Zimmermann AM, Roberts KD, Lampland AL, Meyers PA, Worwa CT, Plumm B, et al. 
Improved gas exchange and survival after KL-4 surfactant in newborn pigs with severe 
acute lung injury. Pediatr Pulmonol. 2010; 45(8): p. 782-788. 
31. 
Lampland AL, Wolfson MR, Mazela J, Henderson C, Gregory TJ, Meyers P, et al. 
Aerosolized KL4 surfactant improves short‐term survival and gas exchange in 
spontaneously breathing newborn pigs with hydrochloric acid‐induced acute lung injury. 
Pediatr Pulmonol. 2014; 49(5): p. 482-489. 
32. 
Wiswell TE, Smith RM, Katz LB, Mastroianni L, Wong DY, Willms D, et al. 
Bronchopulmonary segmental lavage with Surfaxin (KL4-surfactant) for acute respiratory 
distress syndrome. Am J Respir Crit Care Med. 1999; 160(4): p. 1188-1195. 
33. 
Thomas NJ, Guardia CG, Moya FR, Cheifetz IM, Markovitz B, Cruces P, et al. A pilot, 
randomized, controlled clinical trial of lucinactant, a pepetide-containing synthetic 
surfactant, in infants with acute hypoxemic respiratory failure. Pediatr Crit Care Med. 
2012; 13(6): p. 646-653. 
34. 
Cochrane CG, Revak SD, Merritt TA, Heldt GP, Hallman M, Cunningham MD, et al. The 
efficacy and safety of KL4-Surfactant in preterm infants with respiratory distress syndome. 
Am J Respir Crit Care Med. 1996; 153: p. 404-410. 
35. 
Wiswell TE, Knight GR, Finer NN, Donn SM, Desai H, Walsh WF, et al. A multicenter, 
randomized, controlled trial comparing Surfaxin (lucinactant) lavage with standard of care 
for treatment of meconium aspiration syndrome. Pediatrics. 2002; 109(6): p. 1081-1087. 
36. 
Moya FR, Gadzinowski J, Bancalari E, Salinas V, Kopelman B, Bancalari A, Kornacka 
MK, Merritt TA, Segal R, Schaber CJ, Tsai H, Massaro J, d'Agostino R; International 
Surfaxin Collaborative Study Group. A multicenter, randomized, masked, comparison trial 
of lucinactant, colfosceril palmitate, and beractant for the prevention of respiratory distress 
syndrome among very preterm infants. Pediatrics. 2005 April; 115(4): p. 1018-1029. 
37. 
Sinha SK, Lacaze-Masmonteil T, Valls i Soler A, Wiswell TE, Gadzinowski J, Hajdu J, et 
al; Surfaxin Therapy Against Respiratory Distress Syndrome Collaborative Group. A 
multicenter, randomized, controlled trial of lucinactant versus poractant alfa among very 


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premature infants at high risk for respiratory distress syndrome. Pediatrics. 2005 April; 
115(4): p. 1030-1038. 
38. 
Laughon M, Bose C, Moya F, Aschner J, Donn SM, Morabito C, Cummings JJ, Segal R, 
Guardia C, Liu G; Surfaxin Study Group. A pilot randomized, controlled trial of later 
treatment with a peptide-containing, synthetic surfactant for the prevention of 
bronchopulmonary dysplasia. Pediatrics. 2009 Jan; 123(1): p. 89-96. 
39. 
Willson DF, Thomas NJ, Markovitz BP, Bauman LA, DiCarlo JV, Pon S, et al. Effect of 
exogenous surfactant (calfactant) in pediatric acute lung Injury: A randomized controlled 
trial. JAMA. 2005 Jan; 293(4): p. 470-476. 
40. 
Willson DF, Truwit JD, Conaway MR, Traul CS, Egan EE. The adult calfactant in acute 
respiratory distress syndrome trial. Chest. 2015 Aug; 148(2): p. 356-364. 
41. 
Spragg RG, Lewis JF, Walmrath HD, Johannigman J, Bellingan G, Laterre PF, et al. Effect 
of recombinant surfactant protein C–based surfactant on the acute respiratory distress 
syndrome. N Engl J Med. 2004; 351: p. 884-892. 
42. 
Spragg RG, Taut FJH, Lewis JF, Schenk P, Ruppert C, Dean N, et al. Recombinant 
surfactant protein C-based surfactant for patients with severe direct lung injury. Am J 
Respir Crit Care Med. 2011 April; 183(8): p. 1055-1061. 
43. 
Todd W Rice; Arthur P Wheeler; Gordon R Bernard; Douglas L Hayden; David A 
Schoenfeld; Lorraine B Ware; for the National Institutes of Health, National Heart, Lung, 
and Blood Institute ARDS Network. Comparison of the SpO2/FIO2 Ratio and the 
PaO2/FIO2 Ratio in Patients With Acute Lung Injury or ARDS. Chest. 2007; 132: p. 410-
413. 
 

SAP_001.pdf: 
WINDTREE THERAPEUTICS, INC. 
Statistical Analysis Plan 
 
A Multicenter, Single-Treatment Study to Assess the Safety and Tolerability of 
Lyophilized Lucinactant in Adults with COVID-19 Associated Acute Lung Injury 
 
 
Protocol Number: 02-CL-2001a 
Version 2.1  
 
 
 
 
 
SAP Version: 1.0 
 
01 June 2022 
 
 
 


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A Multicenter, Single-Treatment Study to Assess the Safety and Tolerability of Lyophilized 
Lucinactant in Adults with COVID-19 Associated Acute Lung Injury 
 
Statistical Analysis Plan 
 
Author/Project Biostatistician 
 
 
 
 
 
 
  
Amy Lyu 
 
Date 
Project Biostatistician 
 
 
 
By signing below, I have read through the entire statistical analysis plan and agree to implement 
the plan. 
 
 
 
 
 
 
  
Phillip D. Simmons 
 
Date 
Executive Director, Biostatistics and Data Management 
 
 
 
 
 
 
 
Carlos Guardia, MD 
 
Date 
Senior Medical Director 
 
 
 


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EXECUTIVE SUMMARY 
The primary objective of this study is to evaluate the safety and feasibility of lucinactant SRT in 
treating COVID-19, as assessed by OI at 12 hours post dosing and other physiological and outcome 
measurements through 24 hours or through Day 30. The secondary efficacy objective is to assess 
other measures of efficacy to ensure consistency of results across multiple endpoints. 
This is a multicenter, single-treatment, safety pilot study. Subjects will consist of adults 18-75 
(inclusive) with COVID-19 associated acute lung injury who are being cared for in a critical care 
environment. Up to 20 enrolled subjects will be administered an investigational drug product, 
lyophilized lucinactant. Reconstituted lyophilized lucinactant (reconstituted with sterile water for 
injection) will be delivered as a liquid into the trachea in quarter doses. Patients will be given 
injection of Lyophilized lucinactant 160 ml (~80 mg TPL/kg lean body weight of 30 mg/ml 
suspension), up to 3 repeat study treatments of the same dose volume may be given if criteria are 
met.   
The DMC, made up of at least 3 experts in the field of infectious diseases, will evaluate the degree 
of risk involved in study subject participation within each treatment group and to determine if 
study continuation in accordance with the current protocol holds the potential to institute any 
undue harm or threat to the safety and welfare of study subjects.  
During the treatment and post-dosing phases, the chair of the DMC will receive regular reports on 
SAEs and DMC members will be periodically updated on the program and trial status. An ad hoc 
meeting of the DMC will occur if the chair deems it necessary to address safety in the study. The 
DMC may recommend that study enrollment be suspended if safety concerns are identified or 
suspected. 
Repeat study treatments of the same dose volume are allowed if patients meet the criteria. Up to 3 
retreatment doses are allowed no sooner than 6 hours apart (from completion of previous dose). 
Subjects are eligible for retreatments if they remain on MV, there is no evidence of pneumothorax, 
the P/F ratio is under 300 (or S/F ratio is under 315, if no arterial line is present), and there are no 
safety concerns that would prevent retreatment (in the opinion of the investigator). Retreatments 
are given at the discretion of the investigator. 
Study Duration: 
For the treatment period (Day 1, from randomization to 24 hours after), post-treatment period 
(Days 2 to Day 5), and final period (Day 6 to Day 30), subjects will be followed for safety and 


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efficacy evaluations until the subject is is discharged, is transferred, or has died. Descriptive 
statistics (number of subjects, percent, mean, standard deviation, median, minimum, maximum) 
will be presented by treatment group, defined as the (lyophilized) lucinactant (n = 20). A final visit 
will occur at Day 30 or at the time of discharge or transfer (whichever occurs first) for all subjects. 
A subject is considered to have completed the study if he or she has completed all phases of the 
study, including the last scheduled procedure at Day 30. 
Subject participation will be from enrollment to 30 days after enrollment, unless they have an 
ongoing SAE (to be followed for an additional 30 days). Subjects will be followed up to Day 30 
at which time the subjects overall health will be assessed, a physical examination will be 
performed.  
The end of the study is defined as completion of the last visit or procedure for the last subject in 
the trial (last subject/last visit). Overall, study enrollment will be completed in approximately 3 to 
4 months, with the last subject last visit approximately 4-5 months from the time the first subject 
enrolled.  
Endpoints: 
The primary endpoints are safety and tolerability of reconstituted lyophilized lucinactant given as 
a bolus to patients with COVID-19 and change from baseline in OI at 12 hours post initiation of 
dosing. OI is defined as Paw×FiO2×100/PaO2. 
Secondary efficacy endpoints of the study includes: 
• Change from baseline through 24 hours post dosing initiation: 
o FiO2; 
o PaO2; 
o SpO2; 
o OI; 
o PaCO2; 
o ETCO2; 
o P/F and or S/F ratios, defined as PaO2 or SpO2 divided by FiO2; 
o Plateau pressure and peak inspiratory pressure (PIP) measured on the ventilator; 
o Ventilation Index (VI). VI is defined as [RR×(PIP − PEEP)× PaCO2]/1000; 
o Lung compliance; 
o Pressure-volume loops if ventilator technology permits. 
• Through 30 days: 
o Daily lung compliance (static) on ventilator; 


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o Ventilator free days; 
o Days in the intensive care unit (ICU); 
o Days in the hospital; 
o Incidence of all-cause mortality; 
o Organ failure free days. 
Safety Endpoints in the study are: 
1. All-cause mortality; 
2. Peri-dosing events (desaturation, bradycardia, ET reflux, hypotension) 
3. AEs and serious AEs (SAEs). SAEs that are ongoing at Day 30 will be followed for an 
additional 30 days; 
4. Air leaks as AEs of special interest; 
5. Assessments of vital signs. 
Analysis Populations: 
The study population will be comprised of adults 18-75 (inclusive) who are positive for SARS-
CoV-2, are exhibiting symptoms of severe COVID-19 infection, who are intubated and are 
receiving mechanical ventilation in a critical care environment 
The objective of the pilot safety study is to evaluate the safety and feasibility of lucinactant 
administration in COVID-19 patients. A small number of patients should be sufficient to provide 
evidence that liquid lucinactant can be safely delivered as an intratracheal bolus. A total of up to 
20 study subjects will be enrolled. 
 


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TABLE OF CONTENTS 
EXECUTIVE SUMMARY .......................................................................................................... 3 
TABLE OF CONTENTS ............................................................................................................. 6 
ABBREVIATIONS ....................................................................................................................... 8 
1 
OVERVIEW ........................................................................................................................ 10 
1.1 
BACKGROUND ................................................................................................................ 10 
1.1.1 Unmet Medical Need in Treatment of COVID-19 Associated ARDS ....................... 11 
1.1.2 Lucinactant ............................................................................................................... 11 
1.2 
OBJECTIVES ................................................................................................................... 13 
1.2.1 Efficacy Objective ..................................................................................................... 13 
1.2.2 Primary Endpoints .................................................................................................... 13 
1.2.3 Secondary Endpoints ................................................................................................ 13 
1.2.4 Safety Evaluations ..................................................................................................... 14 
1.3 
HYPOTHESES .................................................................................................................. 14 
2 
INVESTIGATIONAL PLAN ............................................................................................ 15 
2.1 
STUDY POPULATION ...................................................................................................... 15 
2.1.1 Inclusion criteria ....................................................................................................... 15 
2.1.2 Exclusion Criteria ..................................................................................................... 15 
2.2 
STUDY DESIGN AND RANDOMIZATION ........................................................................... 16 
2.2.1 Treatment Groups ..................................................................................................... 16 
2.2.2 Repeat Dosing ........................................................................................................... 17 
2.2.3 Sample Size Justification........................................................................................... 17 
2.2.4 Study Schedule .......................................................................................................... 18 
3 
STUDY SUBJECT CHARACTERISTICS ...................................................................... 19 
3.1 
SUBJECT DISPOSITION .................................................................................................... 19 
3.2 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ...................................................... 19 
3.2.1 Demographics ........................................................................................................... 19 
3.2.2 Medical History ........................................................................................................ 19 
3.3 
STUDY AND CONCOMITANT MEDICATION...................................................................... 20 
3.3.1 Compliance ............................................................................................................... 20 
3.3.2 Number of Doses ....................................................................................................... 20 
3.3.3 Concomitant Medication ........................................................................................... 20 
3.4 
PROTOCOL VIOLATIONS/DEVIATIONS ............................................................................ 21 
4 
EFFICACY ANALYSIS ..................................................................................................... 22 
4.1 
EFFICACY POPULATIONS ................................................................................................ 22 
4.1.1 Modified Intent-to-Treat Population ......................................................................... 22 
4.1.2 ITT Population .......................................................................................................... 22 


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4.2 
STATISTICAL ANALYSIS ................................................................................................. 22 
4.2.1 Primary Efficacy Endpoint ....................................................................................... 23 
4.2.2 Secondary Endpoints ................................................................................................ 23 
4.3 
MISSING DATA ............................................................................................................... 23 
4.4 
SUBGROUP ANALYSES ................................................................................................... 23 
4.5 
EXPLORATORY ANALYSES ............................................................................................. 24 
5 
SAFETY ANALYSES ........................................................................................................ 25 
5.1 
SAFETY POPULATION ..................................................................................................... 25 
5.2 
EXTENT OF EXPOSURE ................................................................................................... 25 
5.3 
ADVERSE EVENTS .......................................................................................................... 25 
5.3.1 Peri-Dosing AEs ....................................................................................................... 25 
5.3.2 AEs Related to Surfactant Administration (AEs of Special Interest) ........................ 26 
5.3.3 Other TEAEs ............................................................................................................. 26 
5.3.4 Serious Adverse Events ............................................................................................. 26 
5.3.5 Deaths ....................................................................................................................... 27 
5.4 
CLINICAL ASSESSMENTS OF SAFETY .............................................................................. 27 
5.4.1 Vital Signs ................................................................................................................. 27 
5.4.2 Physical Examination ............................................................................................... 27 
5.4.3 Respiratory Support and Supplemental Oxygen ....................................................... 27 
5.5 
FOLLOW-UP ................................................................................................................... 28 
6 
INTERIM ANALYSES AND DATA MONITORING .................................................... 29 
6.1 
DATA MONITORING COMMITTEE ................................................................................... 29 
6.2 
INTERIM ANALYSES/DMC MEETINGS ........................................................................... 29 
6.3 
DATA MONITORING ....................................................................................................... 30 
7 
STATISTICAL TECHNICAL ISSUES ............................................................................ 31 
7.1 
METHODS OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ....................................... 31 
7.2 
BLINDING/MASKING ...................................................................................................... 31 
7.3 
DETAILS ON STATISTICAL METHODS ............................................................................. 31 
7.4 
MULTIPLICITY ................................................................................................................ 31 
8 
GENERAL ANALYSIS DEFINITIONS .......................................................................... 32 
8.1 
BASELINE DEFINITION ................................................................................................... 32 
8.2 
WINDOWS FOR VISITS .................................................................................................... 32 
8.3 
SITE POOLING METHODS ............................................................................................... 32 
9 
REFERENCES .................................................................................................................... 33 
10 LIST OF SUMMARY TABLES, LISTINGS, AND FIGURES ..................................... 36 


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ABBREVIATIONS 
Abbreviation 
Description 
β-hCG 
Serum pregnancy test 
A 
A wave: peak velocity flow in late diastole caused by contraction 
AE 
Adverse event 
CFR 
Code of Federal Regulations 
CONSORT 
Consolidated standards of reporting trials 
CRF/eCRF 
Case report form/electronic CRF 
CS 
Cardiogenic shock 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HF/AHF 
Heart failure/acute heart failure 
HIPAA 
Health Insurance Portability and Accountability Act 
E 
E wave: peak velocity blood flow from LV relaxation in early diastole 
E/Ea 
Mitral Doppler inflow E velocity to annular tissue Doppler Ea wave 
velocity 
ERO 
Effective regurgitant orifice 
eGFR 
Glomerular filtration rate 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ICU 
Intensive care unit 
IEC 
Independent ethics committee 
IRB 
Institutional review board 
IND 
Investigational new drug 
ITT 
Intent-to-Treat 
IWRS 
Interactive web response system 
LV 
Left ventricular 


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Abbreviation 
Description 
MAP 
Mean arterial pressure 
NDA 
New drug application 
PAP 
Pulmonary artery pressure 
Paw 
Mean airway pressure 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SIV 
Site initiation visit 
TAPSE 
Tricuspid annular plane systolic excursion 
UP 
Unanticipated problem 
US 
United States 
WHF 
Worsening heart failure 
 


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1 
OVERVIEW 
This statistical analysis plan (SAP) provides a comprehensive and detailed description of strategy, 
rationale, and statistical techniques to be used to assess safety and tolerability in the 02-CL-2001a 
study of Lyophilized Lucinactant in adults with COVID-19 infection. The purpose of the SAP is 
to ensure the credibility of the study findings by pre-specifying the statistical approaches to the 
analysis of study data prior to database lock. This SAP provides additional details concerning the 
statistical analyses that are outlined in the protocol. 
1.1 
Background 
COVID-19 is the 3rd serious coronavirus outbreak since 2002. At this time, the mortality rate 
associated with COVID-19 is 5-6%. This is somewhat lower than the 10% and 36% fatality rates 
seen during the SARS and MERS coronavirus outbreaks respectively. The characterization of 
COVID-19 is rapidly evolving. Recently, transmission of COVID-19 has been confirmed from 
asymptomatic individuals. This may indicate that more people than expected have been infected 
and thus lower the overall mortality rate associated with infection. However, serious consequences 
exist for infected individuals with pneumonia. COVID-19 has some similarity to SARS including 
that it may be able to use the ACE2 receptor in the lung. However, the reported spread of infection 
appears to be more rapid with COVID-19 compared to SARS (2,085,769 cases in 4 months for 
COVID-19 vs 8098 cases in 8 months for SARS). Most reported cases have been in adults and 
most hospitalized patients have pneumonia. Many patients develop an ARDS-like clinical 
presentation, some develop a secondary infection, and many require intensive care for respiratory 
support including mechanical ventilation and extracorporeal membrane oxygenation (ECMO). 
The fatality rate for COVID-19 patients hospitalized with pneumonia is 7-10% (from CDC June 
20, 2020). 
COVID-19 uses the SARS-coronavirus receptor, angiotensin-converting enzyme 2 (ACE2) for 
entry into the host cells. ACE2 is a surface molecule highly expressed in AT2 cells of lung, along 
with esophageal upper epithelial cells and absorptive enterocytes from ileum and colon which 
indicated digestive system along with respiratory systems is a potential route for COVID-19 
infection (1). AT2 cells are the cells that produce surfactant in the lung. It stands to reason that if 
they are damaged by COVID-19, that surfactant production would be impaired. Recent 
publications suggest that lung fibrosis and severe interstitial changes occur in COVID-19 patients 
who developed ALI/ARDS. These changes resemble those seen in premature infants who are 
initially ventilated due to RDS and later develop BPD, which also presents with similar lung 
interstitial and fibrotic changes (2,3,4). These observations may support the of use of exogenous 
surfactant in the treatment of ALI/ARDS caused by COVID-19. 


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1.1.1 
Unmet Medical Need in Treatment of COVID-19 Associated ARDS 
Currently, when patients’ breathing deteriorates, they are placed on a mechanical ventilator (MV) 
to help them breathe while they are symptomatic. However, MV cannot correct the underlying 
issue involved with breathing difficulties, known as acute respiratory distress syndrome (ARDS), 
and in many cases cannot prevent death. 
ARDS is a sudden, progressive pulmonary disorder characterized by lung inflammation and non-
cardiogenic pulmonary edema in association with refractory hypoxemia, decreased lung 
compliance, and diffuse pulmonary infiltrates on the chest radiograph (5). It may occur as a direct 
result of injury to the lung such as with gastric content aspiration, pneumonia (both bacterial and 
viral), toxin inhalation or it may be associated with a wide variety of systemic processes such as 
sepsis, non-thoracic trauma, acute pancreatitis, multiple blood transfusions, fat embolism or shock 
(6). The pathophysiology of ARDS involves injury to the alveolar-capillary barrier, atelectasis, 
intrapulmonary shunting of blood flow and surfactant dysfunction. Despite advances in medical 
management in intensive care units, mortality from ARDS can be as high as 40%, and current 
therapy remains entirely supportive with no therapies having been demonstrated safe and 
efficacious and receive regulatory approval (7,8,9,10,11,12,13). 
The primary goal of ARDS treatment is to identify and correct the underlying etiology. For 
coronavirus this is supportive care until the virus is cleared by the immune system. Prevention of 
potential adverse effects of mechanical ventilation such as barotrauma and volutrauma is also 
critical. Using mechanical ventilatory support as safely as possible and improving lung compliance 
can contribute to avoiding these complications.   
There is an unmet medical need for a therapy that will improve the patients’ respiratory status and 
potentially reduce the time on mechanical ventilators. 
1.1.2 
Lucinactant  
Since the initial report of ARDS by Ashbaugh et al. (14), abnormalities of the surfactant system 
have been recognized. In subsequent studies, Petty and colleagues reported both qualitative and 
quantitative alterations in surfactant obtained from patients with ARDS (15,16). It is now widely 
accepted that surfactant abnormalities play a major role in the pathophysiology of ARDS, favoring 
alveolar collapse, ventilation/perfusion mismatch, and increased pulmonary shunt fraction 
(17,18,19,20). Not only have these chemical and functional changes been described in patients 
with established ARDS, but similar alterations have been described in patients at-risk to develop 
ARDS (20,21).  


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Degradation of native surfactant by inflammatory mediators and reactive oxygen species, and 
inhibition of surfactant functional activity plasma proteins have been implicated in impairment of 
alveolar surfactant. One of the hallmarks of ARDS is damaged alveoli and airways that are filled 
with fluid containing inflammatory cells, protein, inflammatory mediators and other debris. In 
addition, damage to the epithelial type II cells may result in decreased production and/or release 
of altered surfactant.  
The biophysical change in the surfactant system that occurs with ARDS is an increase in minimum 
surface tension (20), while the biochemical changes in the surfactant system that occur with ARDS 
include: 
1) a decrease in the total phospholipid content (20),  
2) an alteration in the phospholipid profile as demonstrated by a decrease in the percentage 
of phosphotidylcholine (PC), dipalmitoyl phosphotidylcholine (DPPC), and 
phosphatidylglyerol (PG) (17,18,19,20),  
3) an alteration in the fatty acid composition of the phospholipids (17,22), 
4) a reduction in large surfactant aggregates (23,24), and 
5) a decrease in the surfactant associated proteins SP-A, SP-B, and SP-D (20,21,23). 
Since many of the major pulmonary consequences of ARDS may be directly influenced by 
surfactant dysfunction, replacement treatment with exogenous surfactant is potentially efficacious 
in this disorder. In addition, damaged alveoli and airways are filled with fluid containing 
inflammatory cells, protein, inflammatory mediators and other debris. 
In a series of in vitro studies, liquid lucinactant for intratracheal instillation (SURFAXIN®) has 
been shown to be more resistant than natural lung surfactant and exogenous, commercially 
available animal-derived surfactant to the inhibitory effects of plasma proteins (including 
fibrinogen (25,26)), and inactivation by hypochlorous acid and reactive oxygen species (27). This 
is especially relevant in the milieu of the inflamed lung that leads to natural surfactant inactivation 
and degradation. 
Additionally, lucinactant has been shown to modulate the inflammatory response in various 
models of lung injury. In addition to studies in a murine H1N1 influenza model, we have also 
generated data showing that lucinactant administration significantly attenuates protein leak and 
neutrophil migration into the alveolar space in a hyperoxic and LPS lung injury model in mice 
(28), decreases cytokine levels (including IL-6 and IL-8) in a preterm mechanically ventilated 
lamb model of RDS (as well in airway cell culture systems) (29), and ameliorates lung injury in a 
hydrochloric acid ALI model in spontaneously breathing pigs when delivered both as an 
intratracheal liquid instillate or as an aerosol (30,31).  


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1.2 
Objectives 
This study is designed to investigate the safety and efficacy of lyophilized lucinactant in adults 18-
75 (inclusive). Efficacy and safety will be based on clinical evaluations. The primary objective is 
to evaluate the safety and feasibility of lucinactant SRT in treating COVID-19, as assessed by 
oxygenation index (OI) through 12 hours post initiation of dosing and other physiological and 
outcome measurements through 24 hours or through Day 30.  
In addition, this study will assess other measures of efficacy to ensure consistency of results across 
multiple endpoints. The efficacy estimate will be used to calculate the sample size for future 
studies. The study also ensures that administration of lucinactant does not lead to safety concerns. 
1.2.1 
Efficacy Objective 
The primary estimand for this study is the change from baseline in OI through 12 hours post 
initiation of dosing in the modified intent-to-treat (mITT) population (all randomized subjects that 
received study medication). In addition, this study will assess other physiological and outcome 
measurements through 24 hours or through Day 30. All efficacy and safety parameters will be 
evaluated using summary statistics. Details on the implementation of the different strategies are 
provided in Section 4. 
1.2.2 
Primary Endpoints 
The primary endpoints for this study are safety and tolerability of reconstituted lyophilized 
lucinactant given as a bolus to patients with COVID-19 and change from baseline in OI at 12 hours 
post initiation of dosing. OI is defined as Paw×FiO2×100/PaO2. Improvements in oxygenation 
should be an indicator of surfactant physiological activity on gas exchange and compliance that 
should underly improvement in clinical parameters. 
Subject will continue to be followed for all efficacy evaluations until the time the subject completes 
the study or withdraws. 
1.2.3 
Secondary Endpoints 
The secondary endpoints of this study include the evaluation of the following: 
• Change from baseline through 24 hours post dosing initiation: 
o FiO2; 
o PaO2; 


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o SpO2; 
o OI; 
o PaCO2; 
o ETCO2; 
o P/F and or S/F ratios, defined as PaO2 or SpO2 divided by FiO2; 
o Plateau pressure and peak inspiratory pressure (PIP) measured on the ventilator; 
o Ventilation Index (VI). VI is defined as [RR×(PIP − PEEP)× PaCO2]/1000; 
o Lung compliance; 
o Pressure-volume loops if ventilator technology permits. 
• Through 30 days: 
o Daily lung compliance (static) on ventilator; 
o Ventilator free days; 
o Days in the intensive care unit (ICU); 
o Days in the hospital; 
o Incidence of all-cause mortality; 
o Organ failure free days. 
1.2.4 
Safety Evaluations 
The following safety measures are to be documented in the electronic case report form (eCRF) in 
accordance with timings outlined: 
1. All-cause mortality; 
2. Peri-dosing events (desaturation, bradycardia, ET reflux, hypotension) 
3. AEs and serious AEs (SAEs). SAEs that are ongoing at Day 30 will be followed for an 
additional 30 days; 
4. Air leaks as AEs of special interest; 
5. Assessments of vital signs. 
1.3 
Hypotheses 
As this is an open-label study with no comparison group, no hypotheses will be used for this study. 


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2 
INVESTIGATIONAL PLAN 
2.1 
Study Population 
This study population will be comprised of adults 18-75 (inclusive) who are positive for SARS-
CoV-2, are exhibiting symptoms of severe COVID-19 infection, who are intubated and are 
receiving mechanical ventilation in a critical care environment. 
The objective of the pilot safety study is to evaluate the safety and feasibility of lucinactant 
administration in COVID-19 patients. A small number of patients should be sufficient to provide 
evidence that liquid lucinactant can be safely delivered as an intratracheal bolus. A total of up to 
20 study subjects will be enrolled. Approximately 20 subjects will be enrolled at approximately 
10 study sites in the US, and it is anticipated that approximately 60 subjects will be screened to 
meet the enrollment goal (3:1 ratio of screened to enrolled). 
2.1.1 
Inclusion criteria 
Each subject must meet all of the following inclusion criteria to be enrolled in this study: 
1. 
Signed and dated ICF by the subject or legally authorized representative; 
2. 
Age 18-75 (inclusive); 
3. 
Assay positive for SARS-CoV-2 virus, preferably by polymerase chain reaction (PCR); 
4. 
Endotracheal intubation and MV, within 7 days of initial intubation; 
5. 
In-dwelling arterial line; 
6. 
P/F ratio < 300; 
7. 
Mean blood pressure ≥ 65 mmHg, with or without vasopressor support, immediately 
before enrollment; 
8. 
Bilateral infiltrates seen on frontal chest radiograph. 
2.1.2 
Exclusion Criteria  
Subjects meeting any of the following exclusion criteria may not be enrolled in this study: 
1. 
Life expectancy < 48 hours or do not resuscitate orders; 
2. 
Severe lung disease (home O2, FEV1 < 2 liters) not likely to respond to therapy  or profound 
hypoxemia (ie, OI ≥ 25 or P/F < 100); 
3. 
Severe renal impairment (creatinine clearance < 30 mL/min); 
4. 
Within the last 6 months has received, or is currently receiving, immunosuppression 
therapy (azothiaprine, cyclophosphamide or methotrexate) or any transplant recipient; 


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5. 
Clinically significant cardiac disease that adversely effects cardiopulmonary function: 
a. 
Acute coronary syndromes or active ischemic heart disease (as assessed by the PI 
using troponin and ECG); 
b. 
Cardiac ejection fraction < 40% (if known); 
c. 
Need for multiple-dose vasopressors to support blood pressure (single dose 
vasopressors, such as Levophed™ ≤ 0.1 mcg/kg/min are allowed); 
d. 
Cardiogenic pulmonary edema as the etiology of the current respiratory distress; 
e. 
Evidence of myocarditis or pericarditis; 
6. 
Neuromuscular disease; 
7. 
Neutropenia (ANC < 1000);  
8. 
Active malignancy that impacts treatment decisions or life expectancy related to this trial; 
9. 
Suspected concomitant bacterial or other viral lung infection. Bacterial infection defined 
as WBC > 15k and positive blood/urine/sputum culture results within 72 hours. 
2.2 
Study Design and Randomization 
This is a multicenter, single-treatment study in adults with COVID-19, who are being cared for in 
a critical care environment. Preliminary data from animal and adult human studies indicate that 
lucinactant could benefit those with ARDS in the context of COVID-19 infection, improving 
oxygenation and lessening lung damage. Furthermore, lucinactant, given early in the course of the 
disease, could potentially decrease the need for endotracheal intubation and mechanical 
ventilation. 
Subjects will be enrolled into the lucinactant treatment group if they meet all the screening criteria. 
Treatment initiation is to begin within 6 hours of randomization. Enrolled subjects will receive 
reconstituted lyophilized lucinactant (30 mg total TPL/mL) as a liquid at 160 ml (~80 mg TPL/kg 
lean body weight [~2.7 ml/kg lean body weight]). Sites from the US will participate in this study. 
For this study, the study drug (lyophilized lucinactant) is being delivered in an open-label manner. 
No procedures to minimize bias relative to randomization or blinding will be employed. 
2.2.1 
Treatment Groups 
Up to 20 enrolled subjects will be administered an investigational drug product, lyophilized 
lucinactant. Reconstituted lyophilized lucinactant (reconstituted with sterile water for injection) 
will be delivered as a liquid into the trachea in quarter doses. 
There is only one treatment group called “Lucinactant.” In this treatment group, the subject will 
receive Lyophilized lucinactant 160 ml (~80 mg TPL/kg lean body weight of 30 mg/ml 


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suspension), and up to 3 repeat study treatments of the same dose volume may be given if criteria 
are met. 
Enrollment should occur as soon as possible once it has been confirmed that the subject has met 
all inclusion criteria and has not met any exclusion criteria, within 7 days of initial intubation. 
Treatment initiation is to begin within 6 hours of randomization. If the subject does not tolerate 
one of the 40 ml quarter doses, the dosing for that dose may be terminated at that time. It is 
recommended that the other quarter doses remain 40 ml; however, a lower dose may be 
administered for the remaining aliquots at the Investigator’s discretion. 
2.2.2 
Repeat Dosing 
Up to 3 retreatment doses are allowed no sooner than 6 hours apart (from completion of previous 
dose). Subjects are eligible for retreatments if they remain on MV, there is no evidence of 
pneumothorax, the P/F ratio is under 300 (or S/F ratio is under 315, if no arterial line is present), 
and there are no safety concerns that would prevent retreatment (in the opinion of the investigator). 
Retreatments are given at the discretion of the investigator. 
Retreatment should be performed in the same manner as the initial treatment. 
If, in the opinion of the PI, repeat dosing would compromise the safety of the subject, repeat dosing 
will not occur. If a subject qualifies for repeat dosing but does not receive repeat dosing, the reason 
for this will be documented. 
2.2.3 
Sample Size Justification 
The objective of this safety pilot study is to determine if lyophilized lucinactant administration is 
safe and tolerable, and to assess the impact on oxygenation for those patients suffering with 
COVID-19. As a result, no formal sample size calculation was performed. A total of 20 subjects 
should be sufficient to provide evidence that liquid lucinactant can be safely delivered as an 
intratracheal bolus. 
Thus, 20 subjects (out of approximately 60 screened) will be enrolled.  


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2.2.4 
Study Schedule 
 
 
Primary Phase Through Day 30 
Measurement/Procedure 
Screening 
Treatment 
Period 
(Day 1) 
Post-Treatment 
Period  
(Days 2-5) 
Final Period 
(Days 6 to 30) 
Informed consent 
X 
 
 
 
Inclusion/exclusion Criteria 
X 
 
 
 
Demographics 
X 
 
 
 
Medical history 
X 
 
 
 
Physical examination 
X 
 
 
 
Enrollment 
 
X 
 
 
Study treatment administration 
 
X 
 
 
Vital signs 
X 
X 
X2 
X 
ABG (PaO2, PaCO2, pH) 
 
X1 
X 
X 
FiO2, SpO2, Paw, EtCO2 
 
X1 
X 
X 
Ventilator parameters (rate, peak and 
plateau pressure, lung compliance) 
 
X2 
X2 
 
Respiratory support parameters 
X 
X 
X 
X 
Pressure volume loops 
 
X3 
 
 
AEs/SAEs 
 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
Final Visit/Discharge 
 
 
 
X4 
Note: Day 1 for all subjects is the day of enrollment. 
1 Time 0 (study treatment), 1, 2, 4, 8, 12, 18, 24 hours after treatment  
2 Recorded every 12 hours at 08:00 and 20:00 through Day 5. 
3 Recorded every 2 hours through 24 hours. 
4 Occurs at Day 30, withdrawal from the study, or death (whichever occurs first). 


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3 
STUDY SUBJECT CHARACTERISTICS 
3.1 
Subject Disposition 
Subject disposition will be summarized by treatment group using frequency and percent. The 
number of subjects screened, randomized and received study medication (modified intent-to-treat 
[mITT] population), received study medication regardless of randomization (safety population), 
and without protocol violations (per-protocol population) will be described. If more than 5% of 
subjects experience a treatment interruption, a population of subjects without interruptions will 
also be defined. 
The number of subjects who completed the study or died will be summarized using frequency and 
percent by treatment group and overall. Reasons for early discontinuation from the study include 
withdrawal of consent and lost-to-follow up. A subject may withdraw consent (through their 
legally authorized guardian) at any time without prejudice to further care. 
The number of subjects who discontinued treatment early will be summarized using frequency and 
percent by treatment group and overall. Reasons for early discontinuation of treatment include 
device failure or malfunction, AE or ADE during dosing, PI’s best medical judgment, and 
respiratory deterioration during dosing. 
3.2 
Demographics and Baseline Characteristics 
3.2.1 
Demographics 
Demographic parameters will be summarized by treatment group and assessed qualitatively for 
homogeneity of treatment groups. Continuous variables (eg, age, weight) will be summarized 
using mean, standard deviation (SD), median, minimum, and maximum. Categorical variables (eg, 
sex, race, ethnicity) will be summarized by treatment group using frequency and percent. 
Race categories with small numbers (frequencies of percentages of < 10%) will be combined as 
‘Other’ for summary displays. 
3.2.2 
Medical History 
Medical history findings will be documented during screening. And incidence of medical history 
findings will be summarized by treatment group using frequency and percent. 


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3.3 
Study and Concomitant Medication 
3.3.1 
Compliance 
Study treatments will be administered in an in-patient setting (ie, ICU) by the PI or a person 
approved for dosing by Windtree. Completion of drug delivery for each treatment and re-treatment 
will be monitored; no other compliance measurements will be employed. 
Percent compliance for this study is not applicable as all subjects will be administered at least one 
dose by study staff in the NICU. The number of subjects who experienced treatment interruptions 
for the initial or repeat doses will be summarized by treatment group. 
Lung compliance should be recorded during screening and lung compliance will be summarized 
as change from baseline at each time point measured using mean, SD, median, minimum, and 
maximum. 
3.3.2 
Number of Doses 
The number of doses (initial and repeat study treatments) received by subjects and the number of 
times a subject qualified for a repeat dose will be summarized by treatment group. 
3.3.3 
Concomitant Medication 
Concomitant medications and therapies required for the general care of the subject are permitted, 
including remdesivir and off-label drugs. Other investigational agents or investigational medical 
devices should be avoided. Concomitant medications will be documented until the time the subject 
completes the Day 30, is discharged from the hospital, dies, or is transferred to another hospital. 
Dose, route, unit, frequency of administration, indication for administration, and dates of 
medication will be captured on the CRF. 
Concomitant medications will be classified according to the World Health Organization (WHO) 
drug dictionary (March 2020 or later). Applicable concomitant medications (sedatives, paralytics, 
vasopressors, anti-coagulants, COVID-directed antiviral and anti-inflammatory therapy) will be 
recorded from enrollment until the final subject assessment. Medications will be summarized using 
frequency and percentages for each treatment group by drug category and generic name. 
 


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3.4 
Protocol Violations/Deviations 
A protocol violation occurs when the PI fails to adhere to any significant protocol requirement 
affecting the inclusion, exclusion, subject safety, and primary endpoint criteria. A protocol 
deviation is any deviation from the protocol that does not rise to the level of a protocol violation. 
All protocol violations/deviations will be summarized by treatment group and listed by subject. 
Subjects with protocol violations will not be included in the per-protocol population. 
 


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4 
EFFICACY ANALYSIS  
The efficacy objective is to evaluate the safety and feasibility of lucinactant SRT in treating 
COVID-19, as assessed by OI (defined as Paw×FiO2×100/PaO2) at 12 hours post dosing and other 
physiological and outcome measurements through 24 hours or through Day 30. In addition, the 
study will assess other measurements changing from the baseline and the ability to administer up 
to 3 lucinactant for inhalation repeat treatments. 
4.1 
Efficacy Populations 
For efficacy analyses, subjects will be summarized according to their randomized treatment.  
The statistical analysis of both the primary and secondary objectives will be based on all enrolled 
subjects. For the efficacy analysis, the primary analysis will be based on a modified intent-to-treat 
population (mITT). In addition, populations of all randomized subjects (ITT) and subjects with no 
major protocol deviations (per-protocol) will be evaluated based upon the treatment group to which 
they were randomized. If treatment interruptions are experienced by > 10% of subjects, a 
population of subjects without treatment interruptions will also be defined and analyzed. 
4.1.1 
Modified Intent-to-Treat Population 
The modified intent-to-treat (mITT) population is the primary efficacy analysis population and is 
defined as all enrolled subjects who received any treatment.   
4.1.2 
ITT Population 
The ITT population is defined as all subjects who were randomized in the study, regardless of 
receipt of study treatment. 
4.2 
Statistical Analysis 
All analyses will be performed for all subjects combined and by treatment group, by baseline value, 
as appropriate.  
All efficacy and safety parameters will be evaluated using summary statistics. For continuous 
(parametric) data, data will be summarized using number (n), mean, standard deviation (SD), 
median, 1st quartile, 3rd quartile, minimum, and maximum. For categorical (discrete) data (eg, sex, 
race), data will be summarized using frequency (n) and percent.  
See Section 7, Statistical Technical Issues, for details on statistical methods and calculations. 


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4.2.1 
Primary Efficacy Endpoint 
The primary endpoint is the change from baseline in OI through 12 hours post dosing. OI is define 
as (FiO2 × Paw × 100)/PaO2. OI will be summarized using mean, standard deviation (SD), median, 
minimum, and maximum. 
4.2.2 
Secondary Endpoints 
The secondary efficacy is to assess other physiological and outcome measurements through 24 
hours or through Day 30 to ensure consistency of results across multiple endpoints. 
Through 24 hours post treatment, OI, FiO2, PaO2, SpO2, PaCO2, P/F and S/F ratios, change in 
plateau pressure and PIP measured on the ventilator, VI, and lung compliance will be summarized 
as change from baseline at each time point measured using mean, SD, median, minimum, and 
maximum. 
Through 30 days post treatment, Daily lung compliance on ventilator, ventilator free days, days in 
the ICU, days in the hospital, organ failure free days, and all-cause mortality will be summarized 
as was done for the primary endpoint. 
All deaths will be summarized using frequency and percent, overall and by type of death 
(respiratory or not respiratory) and included as part of the assessment of safety. Time to death will 
also be summarized using mean, standard deviation (SD), median, minimum, and maximum. Also, 
the deaths will be listed by subject and narratives for each death will be included. In this study, the 
secondary endpoint of ventilator-free days (VFD) is a mortality adjusted assessment. This issue 
will be dealt with in more detail in preparation for the next study. 
4.3 
Missing Data 
Missing values represent a potential source of bias in a clinical trial. Hence, every effort will be 
undertaken to fulfill all the requirements of the protocol concerning the collection and management 
of data; however, some missing data is inevitable. No imputation, including last observation 
carried forward, will be done for the any parameters; only available data will be considered. Any 
missing data or data anomalies will be communicated to the site(s) for clarification/resolution. 
4.4 
Subgroup Analyses 
Not applicable. No sub-group analyses are planned in this study. 


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4.5 
Exploratory Analyses 
Exploratory analyses may be performed based upon subject responses to treatment. 


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5 
SAFETY ANALYSES 
5.1 
Safety Population 
Since this is an open-lable study with only one treatment group. The safety population is defined 
as all subjects who received any study medication. All safety assessments will be based on this 
population. 
Safety analyses will be summarized by all subjects combined. 
5.2 
Extent of Exposure 
This is a multicenter, single-treatment study. All subjects will be enrolled into the lucinactant 
treatment group if they meet all the screening criteria. Enrolled subjects will receive reconstituted 
lyophilized lucinactant (30 mg total TPL/mL) as a liquid at 160 ml (~80 mg TPL/kg lean body 
weight) in the first dose. The number of subjects who receive a repeat dose, the number of doses 
received, the amount of treatment received (based on number of treatment), and the number of 
subjects whose study treatment is terminated early will be summarized. 
5.3 
Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence associated with the use of 
an intervention, whether or not considered intervention-related. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of an investigational product [21 CFR 312.32(a), ICH E6(R2)]. 
All treatment-emergent AEs (TEAEs; AEs occurring at or after randomization) will be coded by 
preferred term and system organ class (SOC) from the Medical Dictionary for Regulatory 
Activities (MedDRA), version 22.0 or above, and will be reviewed by the medical monitor or 
designee. All TEAEs will be summarized as categorical variables (frequency and percent) by 
treatment group unless otherwise indicated. TEAEs will not be compared between treatment 
groups. 
5.3.1 
Peri-Dosing AEs 
The incidence of peri-dosing events (desaturation, bradycardia, ET reflux, hypotension, 
gagging/regurgitation/vomiting) will be summarized. 


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5.3.2 
AEs Related to Surfactant Administration (AEs of Special Interest) 
Individual air leaks (eg, pneumothorax, pulmonary interstitial emphysema, pneumo-mediastinum, 
pneumopericardium, and subcutaneous emphysema) will be identified by medical review of all 
AEs and summarized by treatment group.  
Occurrences of apnea, bradycardia, and desaturation after the peri-dosing period will be 
summarized by treatment group. 
5.3.3 
Other TEAEs 
TEAEs, other than those listed above, will be summarized by treatment group by the MedDRA 
preferred term and SOC for all TEAEs, regardless of relationship to study drug, and for TEAEs at 
least remotely related. If a TEAE occurs multiple times for the same subject within the same term 
or body system, only the most severe occurrence for that term or body system will be counted. 
In addition, all TEAEs will be summarized by severity (mild, moderate, severe), relationship to 
the study drug (unrelated, unlikely related, possibly related, related), whether or not the TEAE was 
device related, and, if sufficient number of subjects warrant, by gender, race, and ethnic origin. 
5.3.4 
Serious Adverse Events 
An AE 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: death, 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 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, blood dyscrasias or convulsions that do not result in inpatient hospitalization. 
All SAEs will be listed and summarized by treatment group using frequency counts and 
percentages. If the same SAE occurs multiple times for the same subject, the most severe 
occurrence will be counted. SAEs, including multiple occurrences, will also be listed, to include 
severity, relationship to the study drug, gender, race, and ethnic origin. 


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5.3.5 
Deaths 
All-cause mortality and deaths due to RDS during the study will be summarized by treatment 
group using frequency counts and percentages. Deaths by subject will also be listed and will 
include primary cause, date and time of death, gender, race, and ethnic origin. 
5.4 
Clinical Assessments of Safety 
5.4.1 
Vital Signs 
Vital signs, including body temperature, blood pressure, and heart rate, will be measured every 12 
(±1.0) hours until Day 5 and at Day 30. Systolic and diastolic blood pressure should be measured 
using either an arterial line or a manual sphygmomanometer with the patient in a supine or semi-
supine position. Weight will be measured at baseline and at Day 30.  
Clinically significant vital signs will also be recorded as AEs. 
5.4.2 
Physical Examination 
For each body system evaluated at screening and at the final physical examination, frequency 
counts and percentages of normal and abnormal results will be summarized by treatment group. In 
addition, a shift table to describe the changes in normal/abnormal results between screening and 
the final visit will be presented. Any new abnormal physical examination findings must be 
documented as AEs. 
5.4.3 
Respiratory Support and Supplemental Oxygen 
The respiratory support includs mechanical ventilation and extracorporeal membrane oxygenation 
(ECMO). Information on respiratory support parameters will be captured from screening through 
Day 30 or discharge, whichever occurs first. For each intubation and change in respiratory support, 
date and time, the type of respiratory support and mode, the reason for each intubation and change 
of respiratory support will be documented. 
Lung compliance should be recorded every 12 (±1.0) hours through Day 5. The plateau pressure 
and peak inspiratory pressure (PIP) will be measured every 12 (±1.0) hours through Day 5. The 
ventilation index will be calculated. 
The number of subjects requiring respiratory support in the delivery room, including sustained 
inflation, will be summarized using frequency and percent. 


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5.5 
Follow-Up 
The follow-up period is from Day 6 to Day 30. The assessments  conducted at the final visit 
(Day 30), including vital signs, ABG (PaO2, PaCO2, pH), FiO2, SpO2, Paw, EtCO2, Respiratory 
support parameters, AEs/SAEs, and Concomitant medications. 


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6 
INTERIM ANALYSES AND DATA MONITORING 
6.1 
Data Monitoring Committee 
The DMC, made up of at least 3 experts in the field of infectious diseases, will evaluate the degree 
of risk involved in study subject participation within each treatment group and to determine if 
study continuation in accordance with the current protocol holds the potential to institute any 
undue harm or threat to the safety and welfare of study subjects.  
During the treatment and post-dosing phases, the chair of the DMC will receive regular reports on 
SAEs and DMC members will be periodically updated on the program and trial status. An ad hoc 
meeting of the DMC will occur if the chair deems it necessary to address safety in the study. The 
DMC may recommend that study enrollment be suspended if safety concerns are identified or 
suspected. 
The DMC will meet after every 6 subjects have been enrolled and dosed. The DMC will continue 
to meet after every 6 enrollments and these reviews will continue until enrollment and dosing is 
complete. 
The DMC review may consist of the evaluation of (1) demographics and baseline, (2) all AEs, 
especially peri-dosing AEs and AEs of special interest, (3) case reviews of subjects with reported 
SAEs, (4) summary tables of all safety endpoints, and (5) any other available relevant data. 
Following a meeting, the DMC will provide timely recommendations to the Windtree study team. 
Recommendations may consist of, but not be limited to the following:  
• Continue the study as planned 
• Suspend study enrollment, pending additional information 
• Close study enrollment  
An independent statistician, not a member of the committee, will be responsible for the statistical 
analysis of the data. 
6.2 
Interim Analyses/DMC Meetings 
No interim analyses are planned, other than the safety assessments performed by the DMC. 


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6.3 
Data Monitoring  
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) will 
be entered into a 21 CFR Part 11-compliant data capture system. The data system includes 
password protection and internal quality checks, such as automatic range checks, to identify data 
that appear inconsistent, incomplete, or inaccurate.  
Members of Windtree’s Data Management department are responsible for data processing, in 
accordance with procedural documentation and a study specific Data Management Plan (DMP). 
Windtree’s Data Management will also provide eCRF Completion Guidelines; extra training will 
be provided to the study sites when necessary.  
Clinical data will be entered directly from the source documents. After data have been entered into 
the study database, a system of computerized data validation checks will be implemented and 
applied to the database on a regular basis. Corrections for an existing eCRF record will 
automatically be recorded by the eCRF system (audit trail capturing the time, date, and the 
identification of the user who entered or updated eCRF data). Recorded corrections by the eCRF 
will create an electronic audit trail of study documentation. 
Database lock will occur once all quality assurance procedures have been completed; this will 
include but not be limited to the following: (1) all site-based study data have been entered into the 
eCRF, (2) all entered data have been reconciled and reviewed by Windtree or designee, and (3) all 
data related queries have been rendered and resolved. 
All procedures for the handling and analysis of data will be conducted using good computing 
practices meeting FDA guidelines for the handling and analysis of data for clinical trials. 


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7 
STATISTICAL TECHNICAL ISSUES 
7.1 
Methods of Assigning Subjects to Treatment Groups 
Subjects will be enrolled into the lucinactant treatment group if they meet all the screening criteria. 
Enrolled subjects will receive reconstituted lyophilized lucinactant (30 mg total TPL/mL) as a 
liquid at 160 ml (~80 mg TPL/kg lean body weight [~2.7 ml/kg lean body weight]). Sites from the 
US will participate in this study. 
This is a single-treatment, open-label study, so there are no randomized procedures. 
7.2 
Blinding/Masking  
Not applicable as this is an open-lable study. No procedures to minimize bias relative to blinding 
will be employed. 
7.3 
Details on Statistical Methods 
There is no comparison in the study, since the study has only one treatment group. There is no 
model fitted by any statistical methodology in the study. 
The continuous efficacy endpoints will be summarized using mean, standard deviation (SD), 
median, minimum, and maximum. And the discrete efficacy endpoints will be summarized using 
frequency and percent. 
7.4 
Multiplicity 
Not applicable. There is no multiple comparison in the study. 


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8 
GENERAL ANALYSIS DEFINITIONS 
All summaries and statistical analyses will be generated using SAS® System for Windows, 
version 9.1 or higher. 
8.1 
Baseline Definition 
Baseline is defined as the measurements at the start of study drug administration for subjects 
enrolled in the treatment.  
8.2 
Windows for Visits 
Accurate clock times will be recorded for each timed event in military time (24-hour clock). Day 1 
is the day of enrollment; Day 2 begins at midnight following enrollment; Day 3 is the 2nd day 
following randomization; Day 30 will be the 29th day after the day of randomization. 
All assessments at pre-specified time points are to be conducted within the windows specified in 
the protocol. Summary tables will use the pre-specified time points, not the actual times, to 
summarize the data. 
8.3 
Site Pooling Methods 
As no statistical modeling will be performed, pooling of centers will not be done. 


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9 
REFERENCES 
1. Hoffmann M, Kleine-Weber H, Krüger N, Müller M, Drosten C, Pöhlmann S. bioRxiv. 
[Online].; 2020 [cited 2020 01 31. Available from: www.bioRxiv.org. 
2. Bernheim A, XM, Huang M, Yang Y, Fayad ZA, Zhang N, et al. Chest CT Findings in 
Coranavirus Disease-19 (COVID-19): Relationship to Duration of Infection. Radiology. 
2020 Feb 20. 
3. Hosseiny M, Kooraki S, Gholamrezanezhad A, Reddy S, Myers L. Radiology Perspective of 
Coronavirus Disease 2019 (COVID-19): Lessons From Severe Acute Respiratory Syndrome 
and Middle East Respiratory Syndrome. AJR Am J Roentgenol. 2020 Feb;: p. 1-5. 
4. Song F, Shi N, Shan F, Zhang Z, Shen J, Lu H, et al. Emerging 2019 Novel Coronavirus 
(2019-nCoV) Pneumonia. Radiology. 2020 Feb; 295: p. 210-217. 
5. Gregory TJ, Steinberg KP, Spragg R, Gadek JE, Hyers TM, Longmore WJ, et al. Bovine 
surfactant therapy for patients with acute respiratory distress syndrome. Am J Respir Crit 
Care Med. 1997 Apr; 155(4): p. 1309-1315. 
6. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, et al. The American-
European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, 
and clinical trial coordination. Am J Respir Crit Care Med. 1994 Mar; 49(3 Pt 1): p. 818-
824. 
7. Nicholas TE, Doyle IR, Bersten AD. Surfactant replacement therapy in ARDS. White 
knight or noise in the system? Thoax. 1997; 52: p. 195-197. 
8. Brandstetter RD, Sharma KC, DellaBadia M, Cabreros LJ, Kabinoff GS. Adult respiratory 
distress syndrome: A disorder in need of improved outcome. Heart & Lung. 1997; 26: p. 3-
14. 
9. Wiedemann HP, Tai DY. Adult respiratory distress syndrome (ARDS): Current 
management, future directions. Cleve Clin J Med. 1997; 64: p. 365-372. 
10. Fulkerson WJ, MacIntyre N, Stamler J, Crapo JD. Pathogenesis and treatment of the adult 
respiratory distress syndrome. Arch Intern Med. 1996; 156: p. 29-38. 
11. Schuster DP, Kollef MH. Acute respiratory distress syndrome. Dis Mon. 1996 May; 42(5): 
p. 270-326. 
12. Schuster DP, Kollef MH. The acute respiratory distress syndrome. New Engl J Med. 1995; 
332: p. 27-37. 
13. Sachdeva RC, Guntupalli KK. Acute respiratory distress syndrome. Crit Care Clin. 1997; 
13: p. 503-521. 
14. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. 
Lancet. 1967; 2: p. 319-323. 
15. Petty TL, Reiss OK, Paul GW, Silvers GW, Elkins ND. Characteristics of pulmonary 
surfactant in adult respiratory distress syndrome associated with trauma and shock. Am Rev 
Respir Dis. 1977 Mar; 115(3): p. 531-536. 


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16. Petty TL, Silvers GW, Paul GW, Stanford RE. Abnormalities in lung elastic properties and 
surfactant function in adult respiratory distress syndrome. Chest. 1979 May; 75(5): p. 571-
574. 
17. Hallman M, Spragg RG, Harrell JH, Moser KM, Gluck L. Evidence of lung surfactant 
abnormality in respiratory failure: Study of bronchoalveolar lavage phospholipids, surface 
activity, phospholilpase activity, and plasma myoinositol. J Clin Invest. 1982; 70: p. 673-
683. 
18. Pison U, Seeger W, Buchhorn R, Joka T, Brand M, Obertacke U, et al. Surfactant 
abnormalities in patients with respiratory failure after multiple trauma. Am Rev Respir Dis. 
1989 Oct; 140(4): p. 1033-1039. 
19. Pison U, Obertacke U, Brand M, Seeger W, Joka T, Bruch J, et al. Altered pulmonary 
surfactant in uncomplicated and septicemia-complicated courses of acute respiratory failure. 
J Trauma. 1990 Jan; 30(1): p. 19-26. 
20. Gregory TJ, Longmore WJ, Moxley MA, Whitsett JA, Reed CR, Fowler AA, et al. 
Surfactant chemical composition and biophysical activity in acute respiratory distress 
syndrome. J Clin Invest. 1991 Dec; 88(6): p. 1976-1981. 
21. Greene KE, Wright JR, Steinberg KP, Ruzinski JT, Caldwell E, Wong WB, et al. Serial 
changes in surfactant-associated proteins in lung and serum before and after onset of ARDS. 
Am J Respir Crit Care Med. 1999 Dec; 160(6): p. 1843-1850. 
22. Schmidt R, Meier U, Yabut-Perez M, Walmrath D, Grimminger F, Seeger W, et al. 
Alteration of fatty acid profile in different surfactant phospholipids in acute respiratory 
distress syndrome and severe pneumonia. Am J Respir Crit Care Med. 2001 Jan; 163(1): p. 
95-100. 
23. Günther A, Schmidt R, Feustel A, Meier U, Pucker C, Ermert M, et al. Surfactant subtype 
conversion is related to loss of surfactant apoprotein B and surface activity in large 
surfactant aggregates. Am J Respir Crit Care Med. 1999 Jan; 159(1): p. 244-251. 
24. Veldhuizen RA, McCaig LA, Akino T, Lewis JF. Pulmonary surfactant subfractions in 
patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 1995 Dec; 
152(6 Pt 1): p. 1867-1871. 
25. Amirkhanian JD. Inhibitory effects of oxyradicals on surfactant function utilizing in vitro 
Fenton reaction. Lun. 1998; 176: p. 63-72. 
26. Manalo E, Merritt TA, Kheiter A, Amirkhanian J, Cochrane C. Comparative Effects of 
Some Serum Components and Proteolytic Products of Fibrinogen on Surface Tension-
Lowering Abilities of Beractant and a Synthetic Peptide Containing Surfactant KL4. Pediatr 
Res. 1996; 39: p. 947-952. 
27. Merritt T, Amirkhanian J, Helbock H, Halliwell B, Cross C. Reduction of the surface-
tension-lowering ability of surfactant after exposure to hypochlorous acid. 1993; 295(Pt 1): 
p. 19-22. 


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28. Kinniry P, Pick JSS, Jain D, Solomides C, Niven R, Segal R, et al. KL4-surfactant prevents 
hyperoxic and LPS-induced lung injury in mice. Pediatr Pulmonol. 2006; 41(10): p. 916-
928. 
29. Wolfson MR, Wu J, Hubert TL, Gregory TJ, Mazela J, Shaffer TH. Lucinactant attenuates 
pulmonary inflammatory response, preserves lung structure, and improves physiologic 
outcomes in a preterm lamb model of RDS. Pediatr Res. 2012 Oct; 72(4): p. 375-383. 
30. Zimmermann AM, Roberts KD, Lampland AL, Meyers PA, Worwa CT, Plumm B, et al. 
Improved gas exchange and survival after KL-4 surfactant in newborn pigs with severe 
acute lung injury. Pediatr Pulmonol. 2010; 45(8): p. 782-788. 
31. Lampland AL, Wolfson MR, Mazela J, Henderson C, Gregory TJ, Meyers P, et al. 
Aerosolized KL4 surfactant improves short‐term survival and gas exchange in 
spontaneously breathing newborn pigs with hydrochloric acid‐induced acute lung injury. 
Pediatr Pulmonol. 2014; 49(5): p. 482-489. 


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10 
LIST OF SUMMARY TABLES, LISTINGS, AND FIGURES 
Table 
Title 
 
1.1 
Subject Disposition – Study Populations – All Subjects 
1.2 
Subject Disposition – Study Completion/Termination Status – All Subjects 
1.3 
Subject Disposition – Number of Subjects who Discontinued Early – All Subjects 
1.4 
Subject Disposition – Protocol Deviations/Violations – All Subjects 
2.1 
Subject Demographics – Intent-to-Treat Population 
2.2 
Medical Information – Medical History – Intent-to-Treat Population 
3.1 
Concomitant Medications – Safety Population 
3.2 
Number and Time of Treatments Received – Modified Intent-to-Treat Population 
4.1.1 
Efficacy Analysis – Change in Oxygenation Index (OI) at 12 Hours – Modified 
Intent-to-Treat Population 
4.1.2 
Efficacy Analysis – Change in Oxygenation Index (OI) at 12 Hours – Intent-to-Treat 
Population 
4.2.1 
Efficacy Analysis – Change in Oxygenation Index (OI) through 24 Hours – Modified 
Intent-to-Treat Population 
4.2.2 
Efficacy Analysis – Change in Oxygenation Index (OI) through 24 Hours – Intent-to-
Treat Population 
4.3.1 
Efficacy Analysis – Change in PaO2 through 24 Hours – Modified Intent-to-Treat 
Population 
4.3.2 
Efficacy Analysis – Change in PaO2 through 24 Hours – Intent-to-Treat Population 
4.4.1 
Efficacy Analysis – Change in SpO2 through 24 Hours – Modified Intent-to-Treat 
Population 
4.4.2 
Efficacy Analysis – Change in SpO2 through 24 Hours – Intent-to-Treat Population 
4.5.1 
Efficacy Analysis – Change in FiO2 through 24 Hours – Modified Intent-to-Treat 
Population 
4.5.2 
Efficacy Analysis – Change in FiO2 through 24 Hours – Intent-to-Treat Population 
4.6.1 
Efficacy Analysis – Change in PaCO2 through 24 Hours – Modified Intent-to-Treat 
Population  
4.6.2 
Efficacy Analysis – Change in PaCO2 through 24 Hours – Intent-to-Treat Population 
4.7.1 
Efficacy Analysis – Change in ETCO2 through 24 Hours – Modified Intent-to-Treat 
Population 
4.7.2 
Efficacy Analysis – Change in ETCO2 through 24 Hours – Intent-to-Treat Population 
4.8.1 
Efficacy Analysis – P/F (PaO2/ FiO2) and S/F (SpO2/ FiO2) Ratios through 24 Hours 
– Modified Intent-to-Treat Population 
4.8.2 
Efficacy Analysis – P/F (PaO2/ FiO2) and S/F (SpO2/ FiO2) Ratios through 24 Hours 
– Intent-to-Treat Population 


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4.9.1 
Efficacy Analysis – Plateau Pressure and Peak Inspiratory Pressure (PIP) through 24 
Hours – Modified Intent-to-Treat Population 
4.9.2 
Efficacy Analysis – Plateau Pressure and Peak Inspiratory Pressure (PIP) through 24 
Hours – Intent-to-Treat Population 
4.10.1 
Efficacy Analysis – Ventilation Index (VI) through 24 Hours – Modified Intent-to-
Treat Population 
4.10.2 
Efficacy Analysis – Ventilation Index (VI) through 24 Hours –Intent-to-Treat 
Population 
4.11.1 
Efficacy Analysis – Lung Compliance (Dynamic) through 24 Hours – Modified 
Intent-to-Treat Population 
4.11.2 
Efficacy Analysis – Lung Compliance (Dynamic) through 24 Hours – Intent-to-Treat 
Population 
4.12.1 
Efficacy Analysis – Daily Lung Compliance (Static) on Ventilator – Modified Intent-
to-Treat Population 
4.12.2 
Efficacy Analysis – Daily Lung Compliance (Static) on Ventilator – Intent-to-Treat 
Population 
4.13.1 
Efficacy Analysis – Ventilator Free Days – Modified Intent-to-Treat Population 
4.13.2 
Efficacy Analysis – Ventilator Free Days – Intent-to-Treat Population 
4.14.1 
Efficacy Analysis – Days in the Intensive Care Unit (ICU) – Modified Intent-to-Treat 
Population 
4.14.2 
Efficacy Analysis – Days in the Intensive Care Unit (ICU) – Intent-to-Treat 
Population 
4.15.1 
Efficacy Analysis – Days in the Hospital – Modified Intent-to-Treat Population 
4.15.2 
Efficacy Analysis – Days in the Hospital – Intent-to-Treat Population 
4.16.1 
Efficacy Analysis – Incidence of All-Cause Mortality – Modified Intent-to-Treat 
Population 
4.16.2 
Efficacy Analysis – Incidence of All-Cause Mortality – Intent-to-Treat Population 
4.17.1 
Efficacy Analysis – Organ Failure Free Days – Modified Intent-to-Treat Population 
4.17.2 
Efficacy Analysis – Organ Failure Free Days – Intent-to-Treat Population 
5.1.1 
Peri-Dosing Adverse Events – Initial Dose – Safety Population 
5.1.2 
Peri-Dosing Adverse Events – Repeat Doses – Safety Population 
5.2 
Air Leaks – Safety Population 
5.3.1 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term – 
Safety Population 
5.3.2 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term by 
Severity – Safety Population 
5.3.3 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term by 
Relationship to Study Treatment – Safety Population 
5.3.4 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term by 
Severity and Relationship to Study Treatment – Safety Population 


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5.3.5 
Treatment-Emergent Adverse Events in Descending Order of Frequency – Safety 
Population 
5.4.1 
Serious Adverse Events by System Organ Class and Preferred Term – Safety 
Population 
5.4.2 
Serious Adverse Events by System Organ Class and Preferred Term by Severity – 
Safety Population 
5.4.3 
Serious Adverse Events by System Organ Class and Preferred Term by Relationship 
to Study Treatment – Safety Population 
5.4.4 
Serious Adverse Events by Preferred Term in Descending Order of Frequency – 
Safety Population 
5.5 
All-Cause Mortality – Safety Population 
6.1.1 
Clinical Assessments – Vital Signs – Body Temperature – Observed Values and 
Change from Baseline – Safety Population 
6.1.2 
Clinical Assessments – Vital Signs – Blood Pressure – Observed Values and Change 
from Baseline – Safety Population 
6.1.3 
Clinical Assessments – Vital Signs – Heart Rate – Observed Values and Change from 
Baseline – Safety Population 
6.1.4 
Clinical Assessments – Vital Signs – Respiratory Rate – Observed Values and 
Change from Baseline – Safety Population 
6.2 
Clinical Assessments – Physical Examination – Safety Population 
6.3 
Clinical Assessments – Respiratory Support – Mechanical Ventilation – Safety 
Population 
6.4 
30-Day Follow-Up – General Health Assessments – Safety Population 
 
Listing 
Title 
 
1.1 
Protocol Violations/Deviations 
2.1 
All-Cause Mortality 
2.2 
Serious Adverse Events 
2.3 
Treatment-Emergent Adverse Events 
3.1 
Pre-Study/Concomitant Medications 
4.1 
Description of Early Termination of Treatment 
5.1 
Reporting of Pregnancy 
 
Figure 
Title 
 
1.1 
Change from Baseline in Oxygenation Index (OI) 
1.2 
Change from Baseline in FiO2 
1.3 
Change from Baseline in PaO2 
1.4 
Change from Baseline in SpO2 
1.5 
Change from Baseline in PaCO2 


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2.1             Change from Baseline in ETCO2 
2.6.1          Change from Baseline of P/F Ratios 
2.6.2       Change from Baseline of S/F Ratios 
2.7.1          Change from Baseline in Plateau Pressure  
2.7.2       Change from Baseline in PIP 
2.7.3       Change from Baseline in PEEP 
2.8             Change from baseline in Ventilation Index (VI)