Clinical trial NCT06037408
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Cellular Sciences, inc.
Start date: 2023-08-15; Completion date: 2024-05-20
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this clinical trial is to administer a sodium pyruvate nasal spray that eliminates nasal oxidative stresses, caused by oxygen radicals, and demonstrate the efficacy of sodium pyruvate to reduce coughing and increase lung functions in patients with idiopathic pulmonary fibrosis. This will be a 21-day double-blinded randomized placebo-controlled trial designed to determine if patients with idiopathic pulmonary fibrosis treated with 20mM sodium pyruvate in 0.9% sodium chloride nasal spray solution will have reduced chronic coughing, as well as increased lung function (FEV1, FVC endpoints of 12% or more within the first week) and improved FEV1/FVC ratios.

Detailed description:
Idiopathic pulmonary fibrosis (IPF) belongs to a group of conditions called interstitial lung diseases (also known as ILD), which describes lung diseases that involve inflammation or scarring in the lung. IPF is a chronic progressive lung disorder associated with excessive tissue remodeling, scarring, and fibrosis, which makes the lungs unable to effectively transport oxygen into the bloodstream resulting in decreased lung function and increased nasal inflammation with increased mucus and coughing and poor quality of life. IPF usually affects people between the ages of 30 and 70. The most common signs and symptoms of IPF are shortness of breath and persistent dry, hacking cough. Many affected individuals also experience a loss of appetite and gradual weight loss. Most affected individuals survive 3 to 5 years after their diagnosis. However, the course of the disease is highly variable; some affected people become seriously ill within a few months, while others may live with the disease for a decade or longer. In most cases, IPF is sporadic and results from environmental damage to the lungs and not genetic factors. However, a small percentage of people have genetic risk factors resulting in familial pulmonary fibrosis.

Sodium pyruvate is a natural antioxidant of the human body and as an antioxidant it has been shown to significantly reduce inflammatory agents throughout the human body, including the lungs and nasal passages, allowing nasal nitric oxide to reach the lungs to increase bronchodilation. In addition to 8 human clinical studies conducted on the effect of inhaled sodium pyruvate on the lungs, 7 human nasal inhalation clinical studies were conducted using a sodium pyruvate nasal spray which showed decreased nasal inflammation, a reduction in inflammatory cytokines, and when measured, demonstrated an increase in lung functions, a decrease in coughing, including in patients with pulmonary fibrosis and IPF. Cellular Sciences received Orphan Drug designations for Cystic Fibrosis and Interstitial lung Disease.

A previous open label phase 2, 21-day, sub-chronic clinical trial was conducted that included 15 patients with pulmonary fibrosis (9 with pulmonary fibrosis and chronic obstructive pulmonary disease (COPD) and 6 with idiopathic pulmonary fibrosis without COPD) that remained on their normal medications but were also administered a 20 mM (2.2 mg/mL) sodium pyruvate nasal spray 3 times per day for 22 days. The data from this study showed that coughing episodes per 24 hours, and especially at night, were significantly reduced in all 15 patients on day 8 by 30% (p = 0.007) and continued to decrease on day 14 by 55% (p = 0.0001) and on the 22 day of the trial, coughing decreased by 59% (p = 0.0001). This correlated with a significant (p = 0.010) improvement in nasal irritation/erythema with most patients being free of irritation by day 22 (p \< 0.001); and a significant (p = 0.010) increase in the group average expelled NO by day 8. A significant (p = 0.010) improvement in lung function (breathing) was observed in all patients with IPF without COPD (n=6) by day 1, increasing to p = 0.0005 by day 22 compared to their baseline therapies, determined by changes in FVC, FEV1, PEF, and FEV1/FVC ratios. The improved FEV1/FVC ratio from 52% to 86% was clinically significant and indicated that current therapies in use are inadequate to treat patient with IPF.

The current study will expand on these findings by conducting a phase 3, double-blind placebo-controlled clinical trial to determine the effectiveness of 20mM sodium pyruvate nasal spray to decrease coughing in idiopathic pulmonary fibrosis patients. Individuals with a clinical diagnosis of idiopathic pulmonary fibrosis (as defined by the WHO and the Thoracic Society) will be solicited for participation in this phase 3 trial. Patients will have their degree of nasal inflammation and erythema, nasal cellular morphology, SaO2, and FEV1, FVC levels and blood workup recorded (baseline). Women of child-bearing age will provide a urine sample. The subjects will fill out a quality-of-life questionnaire (chronic respiratory disease questionnaire (CRDQ), and they will be given a data logbook in which they will record the number of coughs they experience each 24 hour period, for 7 days. The coughing data will be entered into the patients' logbooks and will be separated into "total coughs per 24 hours," and "night-time coughs." These data will be used to establish a baseline for coughing. After 7 days, patients will return to the clinic to begin the 21 day study where they will be given drug or placebo in a double-blinded fashion and will record their coughs daily in a logbook. Patients will return to the clinic on days 8, 15 and 22 for further evaluation.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: 20mM sodium pyruvate nasal spray intervention 2: Saline Placebo control nasal spray
Intervention descriptions: intervention 1: The product is a 20 mM (0.2%, 2.2 mg/mL) sodium pyruvate nasal spray in 0.9% sodium chloride with benzalkonium chloride preservative, pH 7.2 (N115). Subjects will self-administer 3 squirts per nostril of the nasal spray, 3 times daily; upon wakening, noon/midday, and before bedtime. intervention 2: The placebo is 0.9% sodium chloride with benzalkonium chloride preservative, pH 7.2. Subjects will self-administer 3 squirts per nostril of the nasal spray, 3 times daily; upon wakening, noon/midday, and before bedtime.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
The Effect of Sodium Pyruvate Nasal Spray on Coughing in Patients 
with Idiopathic Pulmonary Fibrosis 
A double-blinded randomized placebo-controlled phase 3 clinical trial 
 
 
Research Facility 
Florida Advanced Medical Research, Inc. 
 
 
 
 
 
 
 
 
Sponsor 
Cellular Sciences, Inc. 
84 Park Avenue, Suite E-102, Flemington, NJ 08822 
Phone (908) 237-1561; Fax (908) 782-3819; E-Mail Al.martin.HQ@emphycorp.com 
 
 
08,25,2023 
Current Version: CSI-017 IPF 
IND: 50089 
 
 
 
 
 
 
 


Sodium Pyruvate and Pulmonary Fibrosis Patients 
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A. Signature Page 
 
Principal Investigator 
Name: _ Manuel Michael Lam, MD_______ 
Signature: ___________________________ 
Date: _______________________________ 
 
Co-investigator 
Name: ______________________________ 
Signature: ___________________________ 
Date: _______________________________ 
 
Sub-investigator(s) 
Name: ______________________________ 
Signature: ___________________________ 
Date: _______________________________ 
 
Clinical Coordinator 
Name: ___Christopher Lupfer, Ph.D.______ 
Signature: ___________________________ 
Date: _______________________________ 
 
Clinical Monitor 
Name: __Ronald J. Amen, Ph.D._________ 
Signature: ___________________________ 
Date: _______________________________ 
 
Sponsor 
Name: __Alain Martin, Ph.D.____________ 
Signature: ___________________________ 
Date: _______________________________ 


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B. TABLE OF CONTENTS 
 
1. 
A Statement of the Objectives and Purpose of the Study .................................................... 5 
1.1. 
Introduction ...................................................................................................................... 5 
1.1.1. 
Idiopathic Pulmonary Fibrosis Background ............................................................. 5 
1.1.2. 
Sodium Pyruvate ....................................................................................................... 5 
1.1.3. 
Pre-clinical Studies (NOAEL) .................................................................................. 6 
1.1.4. 
Safety, Dosing and Efficacy of Sodium Pyruvate Inhalation Therapy ................... 10 
1.1.5. 
The Nasal Mechanism of Action of Nitric Oxide in Patients with IPF .................. 10 
1.1.6. 
Prior Sodium Pyruvate Treatment in Pulmonary Fibrosis and IPF Studies............ 10 
1.1.7. 
Clinical Experience and Real-world Use ................................................................ 14 
1.1.8. 
Previous Studies ...................................................................................................... 14 
2. 
Purpose and Objectives of the Studies ............................................................................... 15 
2.1. 
Primary Objective .......................................................................................................... 15 
2.2. 
Secondary Objective ...................................................................................................... 15 
3. 
Product Description ........................................................................................................... 15 
4. 
Qualifications of the Principal Investigator ....................................................................... 15 
4.1. 
Research Facilities.......................................................................................................... 16 
4.2. 
Pulmonary Testing Center and Clinical Laboratory ...................................................... 16 
5. 
Study Design Overview ..................................................................................................... 16 
5.1. 
Pre-study......................................................................................................................... 16 
5.2. 
Study Days ..................................................................................................................... 16 
6. 
Criteria for Patient Selection, Exclusion of Patients, and Number of Patients .................. 17 
6.1. 
Subject Selection and Number of Patients to be Studied ............................................... 17 
6.2. 
Inclusion Criteria ............................................................................................................ 17 
6.3. 
Exclusion Criteria ........................................................................................................... 17 
6.4. 
Inclusion of Women and Minorities............................................................................... 18 
7. 
Study Design ...................................................................................................................... 18 
8. 
Randomization ................................................................................................................... 18 
9. 
Telephone Communication ................................................................................................ 18 
10. 
Products Description (How Administered) ........................................................................ 19 
11. 
Concomitant Therapy......................................................................................................... 19 
12. 
The Planned Maximum Dosage, and the Duration of Individual Patient Exposure to the 
Drug ............................................................................................................................................ 19 
13. 
A Description of the Observations and Measurements to be Made to Fulfill the Objectives 
of the Study ................................................................................................................................... 19 
13.1. 
Testing Schedule......................................................................................................... 20 
13.2. 
Safety Testing ............................................................................................................. 20 
14. 
Premature Withdrawal ....................................................................................................... 21 
15. 
A Description of Clinical Procedures, Laboratory Tests, or Other Measures to be Taken to 
Monitor the Effects of the Drug in Human Subjects and to Minimize Risk ................................. 21 
16. 
Safety Precautions Included in this Study ......................................................................... 22 
17. 
Product Evaluation Questionnaire ..................................................................................... 22 
18. 
Daily Data Logbook ........................................................................................................... 22 
19. 
Urinalysis ........................................................................................................................... 22 
20. 
Study Management ............................................................................................................ 23 


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20.1. 
Case Report Forms ..................................................................................................... 23 
20.2. 
Data Collection, Management, and Statistical Analysis ............................................. 23 
20.3. 
Study Monitoring ........................................................................................................ 24 
20.4. 
Data from Patients who Withdraw from the Study .................................................... 24 
21. 
Product Packaging ............................................................................................................. 24 
22. 
Product Storage Requirements ........................................................................................... 24 
23. 
Record Retention ............................................................................................................... 25 
24. 
Reports on Adverse Events ................................................................................................ 25 
24.1. 
Definition of an Adverse Event .................................................................................. 25 
24.2. 
Examples of Adverse Events ...................................................................................... 26 
24.3. 
Recording and Documentation of Adverse Events ..................................................... 26 
24.4. 
Attribution .................................................................................................................. 29 
24.5. 
Post-study Adverse Events ......................................................................................... 30 
25. 
References .......................................................................................................................... 30 
 


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The Effect of Sodium Pyruvate Nasal Spray on Coughing in Patients 
with Idiopathic Pulmonary Fibrosis 
 
1. A Statement of the Objectives and Purpose of the Study 
1.1. Introduction 
1.1.1. Idiopathic Pulmonary Fibrosis Background 
Idiopathic pulmonary fibrosis (IPF) belongs to a group of conditions called interstitial lung 
diseases (also known as ILD), which describes lung diseases that involve inflammation or 
scarring in the lung. IPF is a chronic progressive lung disorder associated with excessive tissue 
remodeling, scarring, and fibrosis, which makes the lungs unable to effectively transport oxygen 
into the bloodstream resulting in decreased forced expiratory volume in the first second (FEV1) 
and forced vital capacity (FVC) values, decreased SaO2, a decrease in nitric oxide associated 
with nasal inflammation that causes congestion and coughing (31-39). 
Inflammatory pathways are upregulated in the nasal epithelium in 80% of patients with IPF 
which is part of the etiology of the disease that effects all lung functions (28). Nasal 
inflammation induces oxidative stress, decreases lung functions including FEV1 and FVC values, 
increases mucus and coughing (54, 55). A decrease in total lung functions and capacity results in 
hypoxemia, dyspnea, and poor quality of life, especially sleep disorders (31-39). 
IPF usually affects people between the ages of 30 and 70. The most common signs and 
symptoms of IPF are shortness of breath and persistent dry, hacking cough. Many affected 
individuals also experience a loss of appetite and gradual weight loss. Most affected individuals 
survive 3 to 5 years after their diagnosis. However, the course of the disease is highly variable; 
some affected people become seriously ill within a few months, while others may live with the 
disease for a decade or longer. In most cases, IPF is sporadic and results from environmental 
damage to the lungs and not genetic factors. However, a small percentage of people have genetic 
risk factors resulting in familial pulmonary fibrosis. 
1.1.2. Sodium Pyruvate 
Sodium pyruvate is a natural antioxidant of the human body and as an antioxidant it has been 
shown to significantly reduce inflammatory agents throughout the human body, including the 
lungs and nasal passages, allowing nasal nitric oxide to reach the lungs to increase 
bronchodilation (11-27). In addition to 8 human clinical studies conducted on the effect of 
inhaled sodium pyruvate on the lungs, 7 human nasal inhalation clinical studies were conducted 
using a sodium pyruvate nasal spray which showed decreased nasal inflammation, a reduction in 
inflammatory cytokines, and when measured, demonstrated an increase in lung functions, a 
decrease in coughing, including in patients with pulmonary fibrosis and IPF (21-27). Cellular 
Sciences received Orphan Drug designations for Cystic Fibrosis and Interstitial lung Disease. 
Globally over 3.5 million patients have been treated in over 200 hospitals, demonstrating the 
ability of sodium pyruvate nasal spray to reduce nasal inflammation, erythema, and edema, and 
allow an increased level of nasal nitric oxide to reach the lungs and increase lung functions 
(21-27). Additionally, in these studies, subjects reported a high degree of satisfaction with the 
product, which did as well as, or better than, nasal sprays containing steroids. 


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1.1.3. Pre-clinical Studies (NOAEL) 
As part of Cellular Science’s Investigational New Drug (IND) submissions, 5 animal 
studies were conducted with solutions of differing concentrations of sodium pyruvate. These 
included a "Maximum Tolerated Nose Dose" study in rabbits (2000× the therapeutic human dose). 
The human therapeutic dose of a 20 mM solution that contains 0.2% of sodium pyruvate in 
0.9% saline with 0.02% benzalkonium chloride (2.1 mg/mL sodium pyruvate). For humans, 
12 squirts per day equals 2.5 mg/day or 0.21 mg/squirt. In all animal studies, no adverse events 
were reported. Gross necropsy included terminal body weight, and gross observations of external 
surfaces (especially nares, eyes and mouth); all orifices; and thoracic, abdominal and pelvic 
cavities were examined with no abnormal findings. Tissues from the respiratory tree (defined as 
larynx, trachea and lungs), plus nasal passage tissue, were analyzed for any histopathology. There 
were no significant differences in the nasal passages and respiratory tree between rabbits and no 
tissue or histopathological abnormalities were found after histological examination. 
1.1.3.1. 
Rat Study: 180-Day 
Sodium Pyruvate: A 90- and 180-Day Nose-Only Inhalation Study in Rats (Study 2). 
In the second 180-day nose only inhalation study, the rats received a dosage of 5.76 mg 
sodium pyruvate/m3, 85 minutes in which rats were exposed to 25 times the sodium pyruvate 
level expected to be administered to humans based on body weights. No product-related adverse 
reactions were observed or reported in any animal study, and the drug regimens were judged to 
be safe as determined by the investigators report. In the 180-day rat study, the rats were given 
more than 2.5× the 20 mM (5.76 mg) dosages used in human inhalation studies. If you include 
the difference in body weights of humans vs rats the concentrations tested were 250× the 
0.2% sodium pyruvate concentration. After 180 days, the remaining rats from each group were 
sacrificed and gross morphological observations on lung, sinus cavities, liver, kidney, heart, and 
body weights were recorded. Histopathological evaluations were performed on lung, trachea, 
larynx, nose, liver, heart, and kidneys. No tissue or histopathological abnormalities were found. 
The study report concluded: “…inhalation of target concentrations of 5.76 mg sodium 
pyruvate/m3, 85 minutes/day, 7 days/week for 180 days resulted in no clinical signs of toxicity 
attributable to administration of the test article, minimal effects on body weight in females, and 
no compound-related microscopic lesions.” 
1.1.3.2. 
Rat Study: Lung Injury 
Effect of Multiple Intratracheal Administrations of Sodium Pyruvate on Lung Injury 
Caused by Bleomycin 
Bleomycin administered to rats to cause lung injury is the standard model used to test drugs 
for idiopathic pulmonary fibrosis. Sodium pyruvate in 0.9% sodium chloride solution or 0.9% 
sodium chloride (normal saline vehicle) was then administered to bleomycin treated rats by 
intratracheal injection to see if the drug regimen had any effect on the progression of the lung 
injury. The rats were sacrificed 24 hours, 72 hours, 1 week, and 2 weeks post injury (8 rats per 
group). The rats sacrificed at 2 weeks were administered the drug on the third and seventh-day 
post-bleomycin insult, while the other rats received only a single administration of sodium 
pyruvate. Significant improvement was only observed in the rats administered the sodium 
pyruvate and sacrificed 2 weeks after bleomycin insult, compared to the sodium chloride control. 
There was a significant (p<0.01) reduction in total cells found in the bronchoalveolar lavage, 
indicating a reduction in airway inflammation. It was concluded that sodium pyruvate was 


Sodium Pyruvate and Pulmonary Fibrosis Patients 
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effective in reducing inflammation and lung damage in this chronic fibrotic stage of lung injury. 
(It should be noted that this type of injury, with subsequent fibrotic infiltration, is typical of the 
fibrosing group of interstitial diseases in humans including IPF.) 
1.1.3.3. 
Dog Study 
Effects on Cardiovascular and Respiratory Parameters in the Telemetered Dog (GLP) (30) 
NIH Independent Studies Safety Study: RCC Study 855869 (GE Study Number B101019) 
Four beagle dogs were dosed intravenously by slow bolus injection (5-10 mL/min). All 
treatments were given at a dose of 2.9 mL/kg. The period between each treatment was at least 
3 days. The dogs were treated with control item (0.9% saline), TRIS/EDTA vehicle control 
solution, and test item containing 44.6 mg/mL [1-13C] pyruvate and 0.85 mg/mL AH111501 and 
filtered test item. Animals were trained several times to accustom them to dosing procedures, as 
well as respiratory parameters measurements. Tracheal airflow was measured using a sealed 
mask (covering the animal's snout) attached to a pneumotachograph and a pulmonary monitoring 
system. Respiratory rate and tidal volume were monitored in the sling-restrained animals. Values 
were recorded for approximately 4 to 5 min before administration and at 15, 32, 62, and 122 min 
after the end of dosing. Mean values over 3 min were reported. 
The various treatments had no marked effects on absolute and percent change values of 
respiratory parameters (respiratory rate, tidal volume, and minute volume) when measured at 
approximately 15, 32, 62, and 122 min after treatment. There were no significant differences 
between the treatment groups. 
In conclusion, slow intravenous administration of test item containing [1-13C]pyruvate and 
AH111501 at a dose of 2.9 mL/kg had no significant effects on the respiratory parameters 
monitored in dogs. When dose levels were expressed as human equivalent doses based on body 
surface area, they correspond to 72 mg/kg of [1-13C]pyruvate and 1.4 mg/kg of AH111501. 
1.1.3.4. 
NIH Pharmacokinetics 
National Cancer Institute Nonclinical Studies: Safety and Efficacy Studies in Animals 
and Humans demonstrating the Pharmacodynamic, Pharmacokinetics and 
Noncarcinogenic Effect of Pyruvate (30) 
A range of nonclinical studies have been undertaken as part of the development program 
which was designed to support early clinical studies. These studies used non-13C enriched 
pyruvate and impurities, [1-13C] pyruvate , hyperpolarized [1-13C] pyruvate, and 
[1-14C] pyruvate, as appropriate. [13C] pyruvate and pyruvate have the same chemical 
characteristics and will therefore have the same safety profile, pharmacodynamics and 
pharmacokinetics as regular pyruvate. The program comprised: 
A pharmacodynamic study in the healthy dog using hyperpolarized [1-13C]pyruvate. 
Two biodistribution studies in rats using [1-13C]pyruvate test articles spiked with 
[1-14C]pyruvate. 


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Safety pharmacology studies assessing effects on 
 1) The hERG channel, 
 2) The cardiovascular system in the conscious and anesthetized dog, 
3) Central nervous system (CNS) in the conscious rat and dog, and 
4) Respiratory system in conscious dog. In these studies, 2 [1-13C]pyruvate test articles and 
various pyruvate test articles were used. 
Toxicology studies including 1) expanded acute toxicity in the rat and dog, 2) studies of 
genetic toxicology (in vitro and in vivo) using [1-13C]pyruvate test articles, and 3) a study of 
local tolerance using a pyruvate test article. 
In 1 of the pharmacokinetic studies and in all GLP safety pharmacology and toxicology 
studies the pyruvate or [1-13C]-pyruvate test articles contained AH111501. The injection dose 
was 0.43 mL/kg of drug product test article having a pyruvate concentration between 220 and 
280 mM, no more than 3.0 μM residual AH 111501 and in a TRIS/EDTA buffer of pH 6.7 to 
8.0. The recommended clinical injection rate was 5 mL/s. No adverse events or histological 
changes were noted. 
1.1.3.5. 
Pharmacodynamic 
Effects of Sodium Pyruvate and Mechanism of Action. NIH published clinical studies. 
Sodium pyruvate is biochemically classified as an alpha-ketoacid and is part of the body’s 
natural endogenous anti-oxidant defense system. It is found in every cell of the human body and 
is part of the Krebs citric acid cycle. It is transported into mitochondria and the breakdown 
products are acetate, CO2 and H2O. It is also converted to lactate and amino acids. The 
breakdown products and metabolism are well defined in biochemistry books and in the literature 
and this testing confirmed that hyperpolarized [13C]pyruvate is taken up by all organs including 
the respiratory system and metabolized to acetate and CO2 and H2O and is also converted to 
lactate or alanine in a well-defined biochemical pathway (13,14,16,19,21-28,30). When high 
doses of pyruvate are injected, the half-life was determined to be 15 minutes. Every organ of the 
body took up pyruvate via the pyruvate/lactate transporter and it was metabolized (30). It is also 
secreted by cells, readily enters cells, and can directly react with toxic compounds such as H2O2 
and peroxynitrites to “detoxify them” (13,14,16,19,21-28,30). Normal plasma levels of sodium 
pyruvate are approximately 0.1 mM (0.011 mg/mL) and normal intracellular levels can reach 
0.5 mM (0.055 mg/mL). Sodium pyruvate has been shown to have protective anti-oxidant 
activity both in vitro (36-48) and in vivo (49-66). There are 3 major chemical pathways by which 
sodium pyruvate can either directly or indirectly generate or augment an anti-oxidant or 
anti-inflammatory effect to increase lung functions including FEV1, FVC and reduce coughing: 
Hydrogen Peroxide 
H2O2 is directly toxic to cells and also is a precursor to other reactive oxygen species. 
Inhibition of H2O2 has broad anti-oxidant and anti-inflammatory effects. Sodium pyruvate 
directly interacts non-enzymatically with H2O2 to generate the non-toxic compounds acetate, 
CO2, and H2O (13-17). This effect is especially relevant to the nasal and respiratory pathway and 
is essential to increase lung function (21-27). 


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NADPH2 
An essential component in the reductive activity of thiol compounds like GSH is the 
generation of NADPH2, which aids in driving the reaction to the reduced state (i.e. GSH), thus 
replenishing anti-oxidant activity. Sodium pyruvate has been shown to play an important role in 
the generation of intracellular NADPH2 and therefore helps in maintaining optimal levels of thiol 
compounds, such as GSH (19). 
Reduction of Inflammatory Cytokines 
Sodium pyruvate has been shown to reduce several inflammatory cytokines (27, 30). 
1.1.3.6. 
Pharmacokinetics: Movement of Sodium Pyruvate in the Body 
(NIH Research Data) (30) 
Intravenous or inhalation of hyperpolarized [13C]pyruvate enables real-time detection of 
metabolism by magnetic resonance spectroscopic imaging (MRSI). The signal from a given 
tissue depends on the dose administered, the perfusion of the tissue and the rate of formation of 
the metabolites, and the relative levels of the metabolites depend on the energy needs of the 
specific tissue. The breakdown products and metabolism is well defined in biochemistry books 
and in the literature and this testing confirmed that hyperpolarized [13C]pyruvate is taken up by 
all organs including the respiratory system and metabolized to acetate and CO2 and H2O and is 
also converted to lactate or alanine in a well-defined biochemical pathway (28-30). When high 
doses of pyruvate are injected into the blood stream, the no observed adverse effect 
level (NOAEL) for pyruvate injection is 1.4 mL/kg (or 100 mL for a 70-kg subject) of a 250 mM 
formulation (equal to 31 mg/kg of a solution of [13C]pyruvate which is 2.1 g/70 kg), the half-life 
was determined to be 15 minutes. Every organ of the body took up pyruvate via the 
pyruvate/lactate transport and it was metabolized (28-30). In Bleomycin injured rats, injecting 
10 mL of a 32 mM [13C]-pyruvate demonstrated the uptake by lung cells and the nearly 100% 
conversion of pyruvate to lactate (30). Based on the data provide by National Institutes of 
Health (NIH), delivering 1 mL of a 20 mM sodium pyruvate saline solution (2 mg/mL for a 
70-kg subject) in the nasal cavity is 1000× less then delivered by injection. Pyruvate is 
completely metabolized in the nasal cavity and cannot enter the circulatory system and effect 
other organs. When high concentrations of oxygen radicals are present, sodium pyruvate directly 
interacts non-enzymatically with H2O2 to generate the non-toxic compounds acetate, CO2 and 
H2O (1-17). This effect is especially relevant to the nasal and respiratory pathway and is essential 
to increase lung function (21-27). 
1.1.3.7. 
NIH Carcinogenesis, Mutagenesis, Genotoxicity Tests 
The pyruvate test article has also been evaluated in 2 in vitro genetic toxicology systems, 
comprising the bacterial reverse mutation test (Ames test) and the chromosomal aberration assay 
with mouse lymphoma cells (MLA test), as well as in 2 separate mammalian in vivo assays in 
rats, comprising the test for induction of micronuclei in the polychromatic erythrocyte of the 
bone marrow, and detection of DNA damage in the blood using the Comet assay. In the tests, 
pyruvate has never been found to mutate DNA, is not genotoxic, mutagenic or carcinogenic (30). 


Sodium Pyruvate and Pulmonary Fibrosis Patients 
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1.1.4. Safety, Dosing and Efficacy of Sodium Pyruvate Inhalation Therapy 
Six different nasal spray formula combinations were tested for safety and efficacy in a series 
of studies with subjects who normally use nasal sprays. The sodium pyruvate concentrations 
were 5 mM (0.55 mg/mL, 10 mM (1.1 mg/mL), 20 mM (2.2 mg/mL) and 40 mM (4.4 mg/mL). 
The sodium pyruvate was delivered in sterile sodium chloride solutions of 0.9%. All 
formulations reduced inflammation in the nasal cavities and improved the nasal cellular 
morphology, and increased lung functions including FEV1, FVC, peak expiratory flow (PEF), 
and SaO2 values when measured. There were not any adverse events observed. In testing 
39 patients with 4 different formulations, 5 mM, 10 mM, 20 mM and 40 mM, the most 
efficacious was the 20 mM (0.2%, 2.2 mg/mL) sodium pyruvate nasal spray. Also in a cilia 
mobility test, again the formulation that produced the most effective cilia movement to remove 
mucus, and post nasal drip was the 20 mM (0.2%, 2.2mg/ml) sodium pyruvate formula against 
saline. The best formulas for cilia movement as reported in the literature were close to isotonic 
formulas (57,58)   The 5 mM and 10 mM formulations (hypotonic) were not as effective. The 40 
mM or the 50 mM formulation, when tested  later,  produced a hypertonic salt effect that 
decreases cilia movements and were irritating to the patients nasal cavities. The 20 mM (0.2%. 
2.2mg/ml) sodium pyruvate nasal spray,  which is slightly hypertonic but closer to isotonic  
produced excellent results in all the lung and sinus diseases tested, and in cilia movement,  
including patients with hypoxemia, where FEV1 and SaO2 values increased significantly (21-27). 
Human Mucociliary clearance time  MCT is a general measure of Sino nasal health. The MCT 
measures a composite of ciliary beat frequency (CBF), ciliary coordination and mucus rheology. 
Times longer than 20-25 minutes are generally considered abnormally delayed. Faster MCT is 
clinically beneficial to counteract stagnation of sinonasal secretions. Several studies have shown 
the effect of nasal saline on MCT.  PharmaMax investigators have found isotonic saline sped 
clearance time by 2%, while the 20mM sodium pyruvate formula sped clearance by 17% 10-20 
minutes after treatment in 32 adults. All other formulations of sodium pyruvate had clearance times 
of 4% or less.  
 
1.1.5. The Nasal Mechanism of Action of Nitric Oxide in Patients with IPF 
The upper and lower airways form 1 contiguous and functionally related organ that is critical 
to normal lung functions. The nasal cavity produces 900-1100 parts per billion of nitric oxide, 
which is used to kill invading bacteria, fungi, and viruses compared to the lungs which produce 
4-48 parts per billion nitric oxide. Nasal nitric oxide also produces clinically useful 
bronchodilation and has been shown to reduce pulmonary fibrosis (43-53). Blockage of nasal 
nitric oxide by inflammation reduces the amount of nitric oxide reaching the lungs, which 
reduces critical lung functions, leading to increased lung and nasal infections, a reduced SaO2 
level, reduced FEV1 and FVC levels also leading to mouth breathing and coughing. Nasal 
steroids and other over-the-counter (OTC) nasal treatments shut down the synthesis of nasal 
nitric oxide, which then leads to decreased lung functions and a 34% increase in infections 
(21-27). 
1.1.6. Prior Sodium Pyruvate Treatment in Pulmonary Fibrosis and IPF Studies 
A phase 2 study was designed to demonstrate safety, efficacy, and determine which medical 
endpoints produced clinically and statistically significant results. Inflammatory pathways are 
upregulated in the nasal epithelium in 80% of patients with IPF, which is part of the etiology of 


Sodium Pyruvate and Pulmonary Fibrosis Patients 
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the disease that effects all lung functions (28). Inflammation induced oxidative stress decreases 
lung functions including FEV1 and FVC values and increases mucus and coughing. Nasal 
steroids and OTC products have been ineffective in treating these conditions in IPF patients, 
especially when these patients experience exacerbation do to stress or allergies. 
Coughing frequency is high in patients with advanced IPF, with median (range) 24-h cough 
counts varying from 226 (36–946) to 520 (117–1493) depending on the population studied 
(34-41). In mild to moderate cases in IPF patients, cough counts vary from 4-57 per 24-h. 
Strikingly, IPF patients experience more cough symptoms during the daytime (median hourly 
cough rate 14.6 during the day versus 1.9 during the night) (34-41). Chronic cough in IPF is not 
related to age or gender and is more common in advanced disease and in “never-smokers” 
(34-41). There is no clear explanation why IPF patients without a history of smoking cough 
more. 


Sodium Pyruvate and Pulmonary Fibrosis Patients 
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An initial 21-day sub-chronic clinical trial was conducted that included 15 patients with 
pulmonary fibrosis (9 with pulmonary fibrosis and chronic obstructive pulmonary 
disease (COPD) and 6 with idiopathic pulmonary fibrosis without COPD) that remained on their 
normal medications, but were also administered the 20 mM (2.2 mg/mL) sodium pyruvate nasal 
spray. If the patients were using other nasal sprays as part of their normal therapy, the other nasal 
spray was eliminated. In all 15 patients, the test results were compared to their previous 3-week 
screening and baseline data (their current therapies) as the positive control for each variable 
including all their lung functions, FEV1, FVC, PEF, FEV1/FVC ratios, SaO2, nitric oxide, 
coughing rates and nasal inflammation (23). 
Results 
Coughing 
Nine patients with pulmonary fibrosis with COPD and 6 patients with idiopathic pulmonary 
fibrosis without COPD that remained on their normal medications, were administered the 20 mM 
(2.2 mg/mL) sodium pyruvate nasal spray 3 times per day for 22 days. The data from this study 
showed that coughing episodes per day was significantly reduced in all 15 patients on day 8 by 
30% (p = 0.007) and continued to decrease on day 14 by 55% (p = 0.0001) and on the 22 day of 
the trial, coughing decreased by 59% (p = 0.0001). This correlated with a significant (p = 0.010) 
improvement in nasal irritation/erythema with most patients being free of irritation by day 22 
(p < 0.001); and a significant (p = 0.010) increase in the group average expelled NO by day 8 
(23). 
A significant (p = 0.010) improvement in lung function (breathing) was observed in all 
patients with IPF without COPD (n6) by day 1, increasing to p = 0.0005 by day 22 compared to 
their baseline therapies, determined by changes in FVC, FEV1, PEF, and FEV1/FVC ratios. The 
improved FEV1/FVC ratio from 52% to 86% was clinically significant and indicated that current 
therapies in use are inadequate to treat patient with IPF. 
The screening data indicate that the 6 IPF patients were not receiving much, if any, benefit 
from their current therapy. However, they all had significant improvements in breathing at all 
time periods for FVC, FEV1, and PEF despite the fact that they were all on concomitant standard 
lung function therapy. Patients #5 and #7 were taking albuterol, a β2-receptor antagonist, and 
Advair Diskus, a β2-receptor antagonist-steroid combination for rescue; Patient #6 was taking 
ipratropium-albuterol, a β2-receptor antagonist; and patient #8 was taking albuterol and 
budesonide/formoterol (Symbicort; a steroid). The sodium pyruvate treatment was able to 
significantly improve the breathing of these 6 patients, despite 5 of them being on steroid 
medications. 


Sodium Pyruvate and Pulmonary Fibrosis Patients 
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Importantly, the percentage increase in lung function during the study period for the 
6 subjects with IPF, compared to the baseline (their current therapies), was also significant, with 
increases that ranged from 19% to 73% with p = 0.002. The clinical data demonstrated the ability 
of the sodium pyruvate nasal spray to immediately increase FEV1 and FVC values on day 1, 
while the patients continuously used their other steroid inhaled medications. 
 
Day 1 
Day 8 
Day 15 
Day 22 
FVC 
27% 
26% 
24% 
19% 
FEV1 
45% 
56% 
53% 
51% 
PEF 
53% 
68% 
73% 
63% 
 
The ratio was calculated from the data obtained. Note that a ratio of 80% or higher is 
considered normal. Group average ratios indicate that at baseline and then again at 1-hour 
post-pyruvate treatment, the ratios were 52% and 66% respectively. However, during sodium 
pyruvate administration during the trial, the ratios increased to 87%, 87%, and 86% for the 8, 15, 
and 22 test days. 
 
Baseline 
Day 1 
Day 8 
Day 15 
Day 22 
FEV1 Average 
0.80 
1.40 
1.81 
1.78 
1.64 
FVC Average 
1.55 
2.12 
2.08 
2.05 
1.92 
FEV1/FVC 
52% 
66% 
87% 
87% 
86% 
 
Following this, 5 new patients with pulmonary fibrosis and COPD had their medications 
removed and were administered a saline placebo control for 3 weeks. At the end of 3 weeks they 
were administered only the sodium pyruvate nasal spray solution for 3 days in order to assess its 
effect. The data from the 3-day trial, indicated a statistically and clinically significant immediate 
average improvement in lung function (breathing), compared to the saline placebo control 
baseline data, as determined by changes in FVC, FEV1, PEF, and FEV1/FVC, ratios which 
persisted throughout the 3-day trial. A significant immediate average improvement was also seen 
in SaO2 levels, compared to the placebo control, such that all subjects had SaO2 levels of ≥ 97, 
which persisted throughout the trial. 
Comparison to Nintedanib 
Nintedanib slows the rate of decline for FVC by 52.3% in 24 weeks compared to the 
non-treatment group of a 66.7% decline in FVC. It is a pill and has many side effects especially 
on the liver. Nintedanib also demonstrated no efficacy in reducing coughing, increasing SaO2, 
decreasing nasal inflammation, increasing the synthesis of nasal nitric oxide needed for bronchial 
dilation or sleeping. The sodium pyruvate nasal spray demonstrated in over 1,869 patients with 
various lung and sinus diseases that the effect occurs in minutes and lasts for 4-6 hours allowing 
the patient improved breathing and sleeping. Quality of life is important. 


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1.1.7. Clinical Experience and Real-world Use 
In China, over 3 million sodium pyruvate-based nasal spray units have been used to treat 
patients, which include 150,000 patients with COPD and 1,800 pulmonary fibrosis patients, in 
over 200 hospitals. To date, the hospitals have reported that the 0.2% pyruvate nasal spray has 
demonstrated both efficacy and safety, with no adverse events reported. The nasal inhalation of 
sodium pyruvate in clinical studies reduced the nasal inflammation while increasing lung 
functions, with a significant reduction in the use of steroids and over the counter medications. 
1.1.8. Previous Studies 
The safety and efficacy of the 0.2% sodium pyruvate nasal spray in patients with allergic 
rhinitis, nonallergic rhinitis, COPD, cystic fibrosis, sinusitis, and pulmonary fibrosis, including 
IPF, were collected from 1,869 patients over 22 years from the 23 phase 1/2 clinical trials listed 
in the 2022 investigator’s brochure. No adverse events in clinical trials have been reported. 
Seven of those studies were saline placebo-controlled clinicals, 3 were randomized placebo 
controlled clinicals, 5 were blinded randomized placebo controlled clinicals and 8 used a positive 
control. The 8 positive controlled studies were a direct comparison of the sodium pyruvate nasal 
spray (N115) to current Rx and OTC nasal sprays. The trials were from 8 hours to 12 weeks or 
more. N115 produced clinically and statistically significant results in reducing lung and sinus 
inflammation caused by oxygen radicals, reduced coughing, and increased SaO2 levels 
(decreased hypoxemia) that improved sleeping, so that the patient’s quality of life increased. 
We examined the effect in patients with long COVID in a phase 2 clinical trial (n22). During 
the first 7 days, when there was no treatment, patient data demonstrated little to no change in 
symptoms including body ache, headache, coughing/sneezing, and trouble breathing. However, 
after the inhalation of the 0.2% sodium pyruvate nasal spray for the next 7 days, patient data 
demonstrated clinically and statistically significant improvements in headaches (p = 0.0373), 
improvements in coughing/sneezing (p = 0.0091) by 60%, and improvements in trouble 
breathing (p < 0.0001) 61%. Fatigue, anxiety, loss of taste/smell, congestion and body aches also 
showed some improvement (23). 
Clinical studies with 75 COPD patients, demonstrated that nebulized inhalation of sodium 
pyruvate decreased expired hydrogen peroxide by 30% after 4 hours compared to patients 
administered a saline control. Inhaled nebulized sodium pyruvate (N115) increases FEV1 values 
and increased total lung capacity in COPD (n130) patients. N115 has been administered in single 
doses to subjects or up to 3 times per day for 6 weeks to subjects with chronic obstructive 
pulmonary disease (23-27). These patients experienced increased pulmonary function as 
determined by FEV1 (12.8%) and PEF (34.5%) measurements after 4 hours (referenced in 
Cellular Sciences IND 50089. 
Clinically, sodium pyruvate has been given to patients for a variety of disorders ranging from 
Friedreich's ataxia (20) to open heart operations. It has been administered via several routes 
including intravenous (10-20 times our inhaled therapeutic dose) (21-27,30), topical 
administration for hyperkeratotic disorders, and in dietary supplementation. Sodium pyruvate has 
been shown to protect neurons, lungs, hearts, muscles, cerebral metabolism, embryos, eyes, 
kidneys, cellular DNA and membranes from oxygen radical damage (13-18, 20-27). The levels 
of pyruvate in these studies were 2-32 mM. In human and animal studies, pyruvate was shown to 
facilitate wound healing, decrease inflammation, and decrease production of oxygen radicals 
(20-27). It is being sold as an OTC product and is a constituent in a therapeutic solution used in 


Sodium Pyruvate and Pulmonary Fibrosis Patients 
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open heart surgery, kidney surgery, eye surgery, for hyperkeratotic disorders, to treat 
mitochondrial diseases, in organ transplant media that is being used to preserve human lungs, 
hearts, and other organs for human transplants. These transplant media contain sodium pyruvate 
ranging from 10 mM to 32 mM to keep the organs safe and functional for longer periods of time. 
There were no safety concerns for this compound. 
Based on results from clinical research, it seems reasonable to treat patients with IPF with a 
sodium pyruvate nasal spray, which is shown to reduce inflammation, increase FEV1 and FVC 
and values, and decrease coughing and other nasal symptoms. 
2. Purpose and Objectives of the Studies 
The purpose of this clinical trial is to administer a sodium pyruvate nasal spray that 
eliminates nasal oxidative stresses, caused by oxygen radicals, and demonstrate the efficacy of 
sodium pyruvate to reduce coughing and increase lung functions. 
This will be a 21-day double-blinded randomized placebo-controlled trial designed to 
determine if patients with idiopathic pulmonary fibrosis treated with 0.2% sodium pyruvate 
(2.1 mg/mL) in 0.9% sodium chloride nasal spray solution will: 
2.1. Primary Objective 
Reduce coughing episodes in IPF patients by 25%. (An episode is defined as 5 or more 
coughs per hour.) 
2.2. Secondary Objective 
Increase lung function (FEV1, FVC endpoints of 12% or more) and Improve FEV1/FVC 
ratios. 
3. Product Description 
The product is a 20 mM (0.2%, 2.2 mg/mL) sodium pyruvate nasal spray in 0.9% sodium 
chloride with 0.02% benzalkonium chloride preservative, pH 7.2 (N115). The placebo control is 
0.9% saline and 0.02% benzalkonium chloride preservative, pH 7.2. Both N115 and saline 
controls are delivered by a Mistette Mark II (MeadWestvaco, Richmond, VA, USA) nasal spray 
pump, or similar device, that delivers a 0.1 mL metered dose from a 30 mL polypropylene bottle. 
The product is sealed in tamper evident plastic and labeled with “Caution: New Drug—Limited 
by Federal (or United States) law to investigational use.” 2 bottles are packaged in a white 
paperboard box with the expiration date of the product printed on the box. The N115 and placebo 
are packaged in identical packaging and are indistinguishable from each other to ensure blinding. 
Good clinical practice (GCP) rules will be followed and the trial will be conducted, 
monitored, audited, recorded and the data reported to the Food and Drug Administration (FDA) 
and on clinicaltrials.gov. 
4. Qualifications of the Principal Investigator 
Dr. Manuel Michael Lam MD, the principal investigator for this study, is a board-certified 
physician who specializes in internal medicine. His research team has clinical interests in 
idiopathic pulmonary fibrosis, asthma and COPD. The references list shows the clinical studies 
in lung diseases in which Dr. Lam and his team have performed clinical research. 


Sodium Pyruvate and Pulmonary Fibrosis Patients 
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4.1. Research Facilities 
Manuel Lam, M 
Family First Medical Research Center 
10550 NW 77 Ct Suite 403 
Hialeah Gardens, FL 33016 
     IRB#: 120180213 
4.2. Pulmonary Testing Center and Clinical Laboratory 
South Florida Pulmonary and Critical Care Associates 
Dr. Jorge Sanchez-Masiqués 
3181 Coral Way 
Miami, FL 33145 
Phone: (305) 567-1999 
New England IRB 
5. Study Design Overview 
5.1. Pre-study 
Individuals with a clinical diagnosis of idiopathic pulmonary fibrosis (as defined by the 
WHO and the Thoracic Society) will be solicited for participation in this phase 3 trial. After 
signing the informed consent, participants will be randomly assigned to either the placebo or 
drug groups in a double-blinded randomized fashion. On pre-study day 1 (Screening Visit), and, 
after signing the informed consent, they will have their degree of nasal inflammation and 
erythema, nasal cellular morphology, SaO2, and FEV1, and FVC levels recorded (baseline). All 
subjects will have a blood sample taken, and women of child-bearing age will provide a urine 
sample. The subjects will fill out a quality of life questionnaire (chronic respiratory disease 
questionnaire (CRDQ), and they will be given a data logbook in which they will record the 
number of coughs they experience each day for 7 days until they return to the clinic to begin the 
study (baseline). Any subject who is not compliant ≥ 80% will not be entered into the trial. 
Blood will be analyzed for CBCs, and for standard clinical variables, including urea nitrogen, 
serum creatinine, total protein, serum albumin, total globulin, albumin/globulin ratio, total 
bilirubin, alkaline phosphatase, aspartate aminotransferase (AST or SGOT), Alanine 
Aminotransferase (ALT or SGPT), Lactate Dehydrogenase (LDH), Gamma-glutamyl 
Transferase (GGT), Serum Sodium, Potassium, Chloride Serum, Carbon Dioxide, C-reactive 
protein, and Total Cholesterol:HDL Ratio to determine organ health. Subjects may not enter the 
study until the blood and urine samples are analyzed and evaluated to confirm that subjects do 
not have a metabolic abnormality that would prevent entry, and that women are not pregnant. 
5.2. Study Days 
Following the 7-day pre-study period, which includes time for analysis of the blood and 
urine, eligible IPF patients will return to the clinic and be admitted to the 21-day study. On the 
first day of the study, these patients will have a physical exam and their vital signs will be 
recorded. Then, their degree of nasal inflammation and erythema will be evaluated and recorded 
as before, as will their SaO2, FEV1 and FVC levels and frequency of coughing. Patients will be 
instructed on how to self-administer their first dose of the nasal spray drug (0.2% sodium 
pyruvate in 0.9% sodium chloride solution) by first forcefully expelling air from their lungs, and 


Sodium Pyruvate and Pulmonary Fibrosis Patients 
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then spraying 3 squirts of the drug into each nostril, and then forcefully inhaling the drug so that 
the drug is inhaled into the lungs. After 1 hour, the subjects will have their vital signs taken 
again. Efficacy and safety evaluations will occur at this 1-hour time period, too, and then again at 
2 and 3 hours. The subjects will fill out the product evaluation questionnaire, be given a daily 
data log form and be given enough drug to last for 21 days (3 bottles), and released from the 
clinic. 
For the next 21 days, subjects will self-administer 3 squirts per nostril of the nasal spray, as 
instructed, 3 times daily; upon wakening, noon/midday, and before bedtime, Additionally, they 
will fill out the Daily Data Log form each day to record the number of daily coughs. Patients will 
be contacted by phone every 2 days to review symptoms and protocol compliance. 
On days 8, 14 and 22, they will return to the clinic and have their blood analyzed, vital signs 
taken, and their degree of nasal inflammation, erythema and cellular morphology recorded. As 
before, they will be tested for FEV1, FVC and SaO2 levels. The number of coughs they 
experienced and other information will be discussed with the clinician. They will fill out the 
product evaluation questionnaire and the CRDQ, and they will then be released from the study 
on day 22. These data will then be evaluated. 
6. Criteria for Patient Selection, Exclusion of Patients, and Number of Patients 
6.1. Subject Selection and Number of Patients to be Studied 
The patient population is adult patients ≥40 years old with mild to moderate IPF with FVC 
and FEV1 values ≥50% of predicted values. IPF is defined in accordance with the most recent 
collaborative guidelines from the American Thoracic Society, the European Respiratory Society, 
the Japanese Respiratory Society, and the Latin American Thoracic Association (56) including 
HRCT scan and/or lung biopsy consistent with unusual interstitial pneumonia (UIP), especially 
honeycombing, without identifiable cause related to other ILD such as drug toxicity, 
occupational or environmental exposure or connective tissue disease.  
The study goal will be to enroll 25 patients with confirmed IPF into the trial in the sodium 
pyruvate (N115) treatment group and 25 with confirmed IPF to be enrolled in the trial in the 
placebo group. Efforts will be made to include women and minorities. The study will be a 
randomized, double-blinded placebo-controlled trial to subjects and study investigators. 
6.2. Inclusion Criteria 
• Individuals with a clinical diagnosis of idiopathic pulmonary fibrosis as determined by 
clinical evaluation and lung function tests (56), with a condition-related cough. 
• Mild to moderate FEV1 and FVC at 50% or greater of standard 
• Individuals who agree to abstain from sexual intercourse, or agree to use condoms or 
vaginal diaphragms or other devices designed to prevent contraception, during the entire 
course of the study. 
 
6.3. Exclusion Criteria 
• Pulmonary disease other than idiopathic pulmonary fibrosis. 
• Respiratory infections in the last 2 weeks. 


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• Clinically significant cardiac disease including uncontrolled congestive heart failure and 
unstable angina. 
• Pregnancy (urine pregnancy test will be performed prior to enrollment). 
• Females of childbearing potential age not on adequate contraception or lactating females. 
• Subjects less than 18 years of age. 
• Hospitalization within last 6 months due to acute exacerbation of airway disease. 
• Subjects with a clinically significant abnormal chest X-ray within past 12 months. 
• Medication changes within 1 month of study entry except for antiviral, antibiotic, or 
antimicrobial medications as well as corticosteroids, antihistamines, or anti-inflammatory 
medications. 
• Subjects who have participated in another drug treatment study within the last month. 
• Subjects with a current history of alcohol or recreational drug abuse. 
• Subjects who have taken dietary supplements containing pyruvate within 24 hours prior 
to the screening visit. 
• Subjects with metabolic diseases (diabetes, hypoglycemia, etc.). 
6.4. Inclusion of Women and Minorities 
Every attempt will be made to include all genders and minorities that present with pulmonary 
fibrosis and are not exempted due to exclusion criteria. 
7. Study Design 
Assignment of Subject Number and Randomization 
This is a randomized placebo-controlled double-blinded trial. Upon enrollment, each subject 
will be sequentially issued a unique subject number starting at 100. Once a number has been 
assigned to a subject, it cannot be re-assigned to another subject. Subjects will be encouraged to 
complete the study, although they may withdraw at any time without prejudice. Termination will 
be reported to the sponsor in a timely manner. Details of the reason(s) why a subject was 
dropped or withdrew from the study will be documented. Enrollment will continue until the 
number of subjects specified in the protocol has been attained. The data from all subjects that 
have been given a study compound will be retained for analysis. 
8. Randomization 
The subjects will be randomized to the placebo control or N115 drug study groups using a 
random number set. 
9. Telephone Communication 
Subjects will be instructed to call the clinic should they be experiencing any self-perceived 
adverse events, or if they have any study-related questions. All telephone information will be 
documented. 


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10. Products Description (How Administered) 
The product is an all-natural patented 0.2% sodium pyruvate in 0.9% sodium chloride nasal 
spray solution, pH 7.2, with 0.02% benzalkonium chloride as a preservative. The patient will be 
instructed on the use of the nasal spray prior to the start of the clinical trial. The plastic bottle 
contains 30 mL. It is non-steroidal. Patients will forcibly expel air from their lungs and then will 
administer 3 sprays per nostril while inhaling strongly so that the drug is transported through the 
nose and into the lungs. The drug is to be administered 3 times per day (morning, mid-day, and 
evening). The product comes with instructions for administration (3 sprays per nostril).  
11. Concomitant Therapy  
 The investigator is to record the use of all concomitant medications, both prescribed and 
over the counter (OTC) (including but not limited to natural food supplements), in the CRF.  
Subjects may continue to use their normal therapy as long as they list it as a current medication, 
and it is not prohibited by the exclusion criteria. Allowable concomitant therapy includes 
antiviral, antibiotic, antimicrobial, corticosteroids, antihistamines, or anti-inflammatory 
medications. The clinician may prescribe “rescue medication” should it be required by any of the 
patients. Patients may continue taking nutritional supplements as long as they do not contain 
pyruvate.  
Subjects may not use any of the following during the trial or for 1 week before enrollment in 
the trial: all intranasal medications or lavages. 
12. The Planned Maximum Dosage, and the Duration of Individual Patient Exposure to the 
Drug 
This is a constant dose study. The amount of delivered sodium pyruvate was determined in 
prior clinical trials to be 3 sprays of 0.2% (2.2 mg/mL) sodium pyruvate in 0.9% sodium chloride 
solution per nostril, 3 times per day. The dose was determined by evaluating the data from both 
animal and human studies (cited above). Patients will forcibly expel air from their lungs and then 
will administer 3 sprays per nostril while inhaling strongly so that the drug is transported through 
the nose and into the lungs. The drug is to be administered 3 times per day (morning, mid-day, 
and evening). The product comes with instructions for administration (3 sprays per nostril). 
13. A Description of the Observations and Measurements to be Made to Fulfill the 
Objectives of the Study 
Observations for safety will include a pregnancy test for women of child-bearing age, blood 
tests for organ function, and vital signs. Adverse events will be monitored. 
Observations for efficacy will include evaluation of lung function, as determined by FEV1, 
FVC, nasal inflammation and erythema, and number of daily coughs. 


Sodium Pyruvate and Pulmonary Fibrosis Patients 
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13.1. Testing Schedule 
Test 
Screening 
Day 1; 0,1,2,3 
Hours 
Day 8 
Day 14 
Day 22 
Clinic Visit 
+ 
+ 
+ 
+ 
+ 
Informed Consent 
+ 
 
 
 
 
Medical History 
+ 
 
 
 
 
Physical Exam/ 
+ 
+ 
 
+ 
+ 
Product Eval Q 
+ 
 
 
+ 
+ 
CDRQ 
+ 
 
+ 
+ 
+ 
Administer Drug 
 
+ 
+ 
+ 
+ 
Blood Sample 
+ 
 
 
+ 
+ 
Vital Signs 
+ 
+ 
+ 
+ 
+ 
Pregnancy Test for Females 
+ 
 
 
 
 
Concurrent Medications Taken 
+ 
+ 
+ 
+ 
+ 
SaO2 
+ 
+ 
+ 
+ 
+ 
Nasal Inflammation 
+ 
+ 
+ 
+ 
+ 
FEV1 
+ 
+ 
+ 
+ 
+ 
FVC 
+ 
+ 
+ 
+ 
+ 
Coughing Data Logbook* 
+ 
+ 
+ 
+ 
+ 
Adverse Events 
 
 
+ 
+ 
+ 
Phase Product Evaluation. 
+ 
+ 
+ 
+ 
+ 
*The coughing data logbook will be filled out by the patient every day, starting at the pre-study visit 
through day 14. 
13.2. Safety Testing 
• Physical Exam 
• Vital Signs 
• Weight 
• Blood pressure 
• Pulse 
• Temperature 
• Blood analysis 
• Complete blood count (CBC) 
• Clinical tests, including: 
o Urea nitrogen: serum creatinine: total protein: serum albumin: total globulin: 
albumin/globulin ratio: total bilirubin: alkaline phosphatase: aspartate 
aminotransferase (AST or SGOT): alanine aminotransferase (ALT or SGPT): 
LDH: GGT: serum sodium: potassium: chloride serum: carbon dioxide: total 
cholesterol:hdl ratio: 
• Urine test for women of child-bearing age 


Sodium Pyruvate and Pulmonary Fibrosis Patients 
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• Efficacy tests 
o Nasal examinations by a rhinoscope fitted with a camera 
o FEV1, FVC 
14. Withdrawal Criteria 
The patients can withdraw from the study at any time, and for any reason. All data collected 
from these patients will be analyzed. Reasons for withdrawal will be recorded to insure that it 
was not due to an adverse event. 
The subject has the right to withdraw from the study at any time. 
The subject will be withdrawn from the study if: 
• There is deterioration in the subject’s signs and symptoms and/or the subject develops a 
disease or condition that, in the opinion of the investigator, would compromise the 
subject’s safety by continuing in the study. 
• In the investigator’s judgment, it is in the best interest of the subject. 
• There is a violation of the protocol inclusion and/or exclusion criteria, as deemed relevant 
by the investigator and discussed with the medical monitor. 
• The subject begins to take any medication(s) that is(are) excluded by the protocol. 
• 
Any of the conditions for stopping rules are met. 
If a subject withdraws prematurely from the study due to the above criteria or any other 
reason, study staff should make every effort (at withdrawal) to complete the full set of 
evaluations listed for the early termination/end-of-study visit.  The reason for subject withdrawal 
must be documented in the case report form (CRF). 
If a subject withdraws from the study due to an adverse event (AE) (eg, clinical signs, 
symptoms, or clinically significant laboratory abnormality), the subject will be asked to return to 
the clinic, at a minimum, for the evaluations scheduled for the posttreatment follow-up period.  If 
the AE has still not resolved, additional follow-up will be performed, as appropriate, and 
documented in the subject’s medical records.  As a minimum requirement, AEs should be 
followed for 30 days after the subject’s last dose of study medication. 
In the case of a subject lost to follow-up, attempts to contact the subject must be made and 
documented in the subject’s medical records. 
Withdrawn subjects will not be replaced. 
15. A Description of Clinical Procedures, Laboratory Tests, or Other Measures to be Taken 
to Monitor the Effects of the Drug in Human Subjects and to Minimize Risk 
Tests and analyses will be conducted 3 times during the study. If any aberrant values occur, 
the principal investigator will determine if that patient should continue in the study or be 
removed. All aberrant values that occur during the study will be considered adverse events. A 
summary of possible risks will be provided to the patients. Previous risks of using the product 
are minimal, which included irritation to the nose cavity reported by 1 patient out of 1,869. 


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16. Safety Precautions Included in this Study 
The 0.2% nasal sodium pyruvate inhalation has been administered to both healthy humans 
and humans with lung diseases, without the occurrence of any SAE. 
• First administration of nasal spray on the premises of a hospital/clinic. 
• The initial nasal spray will be administered under the supervision of medical staff. 
• If a subject develops any adverse event during the follow-up period after study drug 
administration, the subject will be treated to a satisfactory resolution before being 
discharged from the clinic. 
• Subjects will remain at the test site for monitoring for 30 minutes after the initial 
inhalation of the nasal spray. 
• Follow up telephone communications, as needed. 
17. Product Evaluation Questionnaire 
This self-administered questionnaire measures the patients’ impressions of how the drug 
affected their nasal cavity, their coughing, and their breathing. It is designed to evaluate changes 
in a subject’s quality of life over time. It will be administered during all clinic visits. 
18. Daily Data Logbook 
Subjects will use this diary card to record the number of their coughs per day, any 
self-perceived adverse events, and any medication changes during the study. 
19. Urinalysis 
Samples will be taken and analyzed to determine if any child-bearing females are pregnant. 


Sodium Pyruvate and Pulmonary Fibrosis Patients 
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20. Study Management 
20.1. Case Report Forms 
Case Report Forms (CRF) will be supplied by Cellular Sciences. Data will be recorded in the 
CRFs according to the following: 
Instructions to data entry personnel and monitor: 
Explain all missing data and include reference to any original data that is not contained in the 
study file. If a space is blank because the item was not done, mark the item “N/D”. If the item is 
not applicable to the individual case, mark the item "N/A”. If an item is unknown, mark the 
space “UNK". Legibly write or print all entries in black ink. If an entry error has been made, 
draw a single straight line through the wrong entry and enter the correct data above it. Initial and 
date all such changes. Do not erase or opaque out errors. For clarification of illegible or uncertain 
entries, print the clarification above the item, then initial and date the clarification. 
20.2. Data Collection, Management, and Statistical Analysis 
The data management staff at the research clinic will collect and manage the data. Data will 
be obtained, maintained, and transmitted securely in accordance with HIPAA guidelines. 
Monitoring and auditing of the data will be conducted by a staff member of Cellular Sciences.  
Statistical analysis will be performed on deidentified data. The basic statistical analysis will 
be repeated measurements of Analysis of Variance using baseline measurements as a covariant 
(ANCOVA). Age, sex, time since initial diagnosis with IPF, concurrent medications and 
smoking status are considered potential covariates. Number of coughing episodes reported for a 
24-hour pre-study period, and other pre-study data information, will be compared to the data 
collected during the trial. The differences between baseline data and the data collected during the 
trial will be compared and analyzed (Within treatment). Additionally, the data of the patients on 
the experimental therapy will be compared to the data generated by the patients on placebo 
(Between treatments). P values of <0.5 will be considered significant. FEV1 and FVC will 
similarly be analyzed as secondary outcome measurements. Relative changes will be analyzed by 
JMP, Matillion, XLSTAT or R software by Dr. Masiqués or Dr. Lupfer, who will be responsible 
for the statistical analysis.  
Partial patient data will be included in the statistical analysis if patients withdraw from the 
study, but data from non-compliant patients will be excluded. Our previous research (REF) 
indicates that a sample size of 20 is sufficient to detect a statistically significant difference 
(p<0.05) between treatment groups. We have chosen to enroll 25 patients in each treatment 
group to ensure we achieve the necessary sample size, taking into account that some patients 
may not complete the study, and some data will be incomplete or excluded from the study. 


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Study Monitoring Sciences. The monitor will visit the clinical frequently  during the 
trial to assure that all data are being collected and that the Case Report Forms are 
completed and correctly filled out. The CRFs and related source documents will be 
reviewed in detail by the study monitor at each visit, in accordance with relevant SOPs and 
ICH GCP regulations. This includes results of tests performed as a requirement for 
participation in this study and any other medical records required to confirm information 
contained in the CRFs, such as past medical history and secondary diagnoses. The 
investigator and staff will be expected to cooperate with the study monitor and provide any 
missing or incomplete information whenever possible. 
 
20.3. Data from Patients who Withdraw from the Study 
If a subject withdraws from a study, the data collected on the subject to the point of 
withdrawal will remain part of the study database and will not be removed. 
The investigator may ask a subject who is withdrawing whether the subject wishes to provide 
continued follow-up and further data collection subsequent to their withdrawal from the 
interventional portion of the study. Under this circumstance, the discussion with the subject 
would distinguish between study-related interventions and continued follow-up of associated 
clinical outcome information, such as medical course or laboratory results obtained through 
non-invasive chart review and address the maintenance of privacy and confidentiality of the 
subject’s information. 
If a subject withdraws from the interventional portion of the study but agrees to continued 
follow-up of associated clinical outcome information as described in the previous paragraph, the 
investigator must obtain the subject’s informed consent for this limited participation in the study 
(assuming such a situation was not described in the original informed consent form). In 
accordance with FDA regulations, Institutional Review Board (IRB) approval of informed 
consent documents would be required (21 CFR 50.25, 56.109(b), 312.60, 312.66, 812.100). 
If a subject withdraws from the interventional portion of a study and does not consent to 
continued follow-up of associated clinical outcome information, the investigator must not access 
for purposes related to the study the subject’s medical record or other confidential records 
requiring the subject’s consent. However, an investigator may review study data related to the 
subject, collected prior to the subject’s withdrawal from the study, and may consult public 
records, such as those establishing survival status. 
21. Product Packaging 
The product packaging will comply with FDA regulations. The nasal spray will be contained 
in a sterile plastic vial that can be squeezed to administer the correct dosage. The vials necessary 
for each study period (i.e. 14 days) will be placed in a paperboard box in a plastic bag with the 
patient’s number. 
22. Product Storage Requirements 
At Research Center 
The products will be stored at room temperature, but not above 85oF. 


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In Home 
The products will be stored at room temperature, but not above 85oF. 
23. Record Retention 
All records will be kept by the clinic for a period of 3 years. After that they will be sent to 
Cellular Sciences. 
24. Reports on Adverse Events 
All Adverse Events, as defined below, will be recorded, evaluated and reported in accordance 
with 21 CFR 312.32. These Adverse Events may occur during the study or after the study has 
completed.  
24.1. Definition of an Adverse Event 
Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  
Life-threatening adverse event or life-threatening suspected adverse reaction. An adverse 
event or suspected adverse reaction is considered “life-threatening” if, in the view of either 
the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred 
in a more severe form, might have caused death.  
Serious adverse event or serious suspected adverse reaction. An adverse event or suspected 
adverse reaction is considered “serious” if, in the view of either the investigator or sponsor, it 
results in any of the following outcomes: 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 patient or subject 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, or the development of drug dependency or drug abuse.  
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal relationship between the 
drug and the adverse event. Suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction, which means any adverse event caused by a drug.  
Unexpected adverse event or unexpected suspected adverse reaction. An adverse event or 
suspected adverse reaction is considered “unexpected” if it is not listed in the investigator 
brochure or is not listed at the specificity or severity that has been observed; or, if an 
investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application, as 
amended. For example, under this definition, hepatic necrosis would be unexpected (by 
virtue of greater severity) if the investigator brochure referred only to elevated hepatic 


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enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be 
unexpected (by virtue of greater specificity) if the investigator brochure listed only cerebral 
vascular accidents. “Unexpected,” as used in this definition, also refers to adverse events or 
suspected adverse reactions that are mentioned in the investigator brochure as occurring with 
a class of drugs or as anticipated from the pharmacological properties of the drug, but are not 
specifically mentioned as occurring with the particular drug under investigation.  
 
24.2. Examples of Adverse Events 
• Inter-current illnesses 
• Injuries 
• New symptomatology (this does not include symptoms expected as a result of the 
subject’s condition unless it is beyond what is normally expected) 
• Significant laboratory abnormalities 
• New abnormal physical exam findings 
• Significant exacerbation of pre-existing conditions 
• Death 
• A life-threatening event 
• In-patient hospitalization (not required as part of the treatment) or prolongation of 
existing hospitalization 
• Disability or permanent damage 
• A congenital anomaly/birth defect 
• Cancer 
• Drug overdose 
 
24.3. Recording and Documentation of Adverse Events 
Any adverse event (i.e., a new adverse event or an exacerbation of a pre-existing condition) 
with an onset date after study enrollment should be recorded as an adverse event on the CRF. All 
adverse events must be recorded on the appropriate CRF regardless of the severity or relationship 
to study medication. An adverse event or laboratory abnormality with an onset date before study 
enrollment is considered to be pre-existing in nature. These pre-existing events will be noted in 
the CRFs. 
All SAEs occurring during this study, whether observed by the physician, nurse, or reported 
by the patient, will be recorded on the Florida Advanced Medical Research Adverse Events 
form. 
24.3.1 Investigator Report of a "Serious Adverse Event" to Cellular Sciences. 


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Cellular Sciences (Sponsor) must be notified regarding the occurrence of any SAE that 
occurs after enrollment in the study protocol, regardless of the causal assessment to study 
medication. The procedures for reporting SAEs are as follows: 
• Complete the “Serious Adverse Event Report.” 
• Email the SAE Report to Cellular Sciences (see below) within 24 hours of the 
investigator’s knowledge of the event. 
• These preliminary reports must be followed by detailed descriptions that include copies 
of hospital case reports, autopsy reports, and other documents when requested and 
applicable. Cellular Sciences may request additional information from the Investigator to 
ensure the timely completion of accurate safety reports. 
The contact information for reporting SAEs is as follows: 
Ronald J. Amen, Ph.D. 
 
 
 
 
 
Alain Martin, Ph.D. 
Director 
 
 
 
 
 
 
 
 
 
Director 
Cellular Sciences  
 
 
 
 
 
 
Cellular Sciences 
18101 Catherine Circle 
 
 
 
 
 
84 Park Ave 
Villa Park, CA 92861  
 
 
 
 
 
Flemington, NJ 08822 
ronald.amen@techenterprises.org 
 
 
al.martin.hq@emphycorp.com  
 
24.3.2 Sponsor Safety Reporting 
(1) IND safety reports. The sponsor must notify the FDA and all participating investigators 
(i.e., all investigators to whom the sponsor is providing drug under its INDs or under any 
investigator's IND) in an IND safety report of potential serious risks, from clinical trials or 
any other source, as soon as possible, but in no case later than 15 calendar days after the 
sponsor determines that the information qualifies for reporting under paragraph (c)(1)(i), 
(c)(1)(ii), (c)(1)(iii), or (c)(1)(iv) of 21 CFR 312.32. In each IND safety report, the sponsor 
must identify all IND safety reports previously submitted to FDA concerning a similar 
suspected adverse reaction and must analyze the significance of the suspected adverse 
reaction in light of previous, similar reports or any other relevant information.  
(i) Serious and unexpected suspected adverse reaction. The sponsor must report any 
suspected adverse reaction that is both serious and unexpected. The sponsor must report an 
adverse event as a suspected adverse reaction only if there is evidence to suggest a causal 
relationship between the drug and the adverse event, such as:  
(A) A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson 
Syndrome);  
(B) One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug (e.g., tendon 
rupture);  


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(C) An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events 
that commonly occur in the study population independent of drug therapy) that indicates 
those events occur more frequently in the drug treatment group than in a concurrent or 
historical control group.  
(ii) Findings from other studies. The sponsor must report any findings from 
epidemiological studies, pooled analysis of multiple studies, or clinical studies (other than 
those reported under paragraph (c)(1)(i) of 21 CFR 312.32), whether or not conducted 
under an IND, and whether or not conducted by the sponsor, that suggest a significant risk 
in humans exposed to the drug. Ordinarily, such a finding would result in a safety-related 
change in the protocol, informed consent, investigator brochure (excluding routine updates 
of these documents), or other aspects of the overall conduct of the clinical investigation.  
(iii) Findings from animal or in vitro testing. The sponsor must report any findings from 
animal or in vitro testing, whether or not conducted by the sponsor, that suggest a 
significant risk in humans exposed to the drug, such as reports of mutagenicity, 
teratogenicity, or carcinogenicity, or reports of significant organ toxicity at or near the 
expected human exposure. Ordinarily, any such findings would result in a safety-related 
change in the protocol, informed consent, investigator brochure (excluding routine updates 
of these documents), or other aspects of the overall conduct of the clinical investigation.  
(iv) Increased rate of occurrence of serious suspected adverse reactions. The sponsor 
must report any clinically important increase in the rate of a serious suspected adverse 
reaction over that listed in the protocol or investigator brochure.  
(v) Submission of IND safety reports. The sponsor must submit each IND safety report in 
a narrative format or on FDA Form 3500A or in an electronic format that FDA can process, 
review, and archive. FDA will periodically issue guidance on how to provide the electronic 
submission (e.g., method of transmission, media, file formats, preparation and organization 
of files). The sponsor may submit foreign suspected adverse reactions on a Council for 
International Organizations of Medical Sciences (CIOMS) I Form instead of a FDA Form 
3500A. Reports of overall findings or pooled analyses from published and unpublished in 
vitro, animal, epidemiological, or clinical studies must be submitted in a narrative format. 
Each notification to FDA must bear prominent identification of its contents, i.e., “IND 
Safety Report,” and must be transmitted to the review division in the Center for Drug 
Evaluation and Research or in the Center for Biologics Evaluation and Research that has 
responsibility for review of the IND. Upon request from FDA, the sponsor must submit to 
FDA any additional data or information that the agency deems necessary, as soon as 
possible, but in no case later than 15 calendar days after receiving the request.  
(2) Unexpected fatal or life-threatening suspected adverse reaction reports. The sponsor 
must also notify FDA of any unexpected fatal or life-threatening suspected adverse reaction 
as soon as possible but in no case later than 7 calendar days after the sponsor's initial receipt 
of the information.  


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(3) Reporting format or frequency. FDA may require a sponsor to submit IND safety reports 
in a format or at a frequency different than that required under this paragraph. The sponsor 
may also propose and adopt a different reporting format or frequency if the change is agreed 
to in advance by the director of the FDA review division that has responsibility for review of 
the IND.  
(4) Investigations of marketed drugs. A sponsor of a clinical study of a drug marketed or 
approved in the United States that is conducted under an IND is required to submit IND 
safety reports for suspected adverse reactions that are observed in the clinical study, at 
domestic or foreign study sites. The sponsor must also submit safety information from the 
clinical study as prescribed by the postmarketing safety reporting requirements. 
(5) Reporting study endpoints. Study endpoints (e.g., mortality or major morbidity) must be 
reported to FDA by the sponsor as described in the protocol and ordinarily would not be 
reported under paragraph (c) of this section. However, if a serious and unexpected adverse 
event occurs for which there is evidence suggesting a causal relationship between the drug 
and the event (e.g., death from anaphylaxis), the event must be reported under § 
312.32(c)(1)(i) as a serious and unexpected suspected adverse reaction even if it is a 
component of the study endpoint (e.g., all-cause mortality).  
(d) Followup.  
(1) The sponsor must promptly investigate all safety information it receives.  
(2) Relevant followup information to an IND safety report must be submitted as soon as the 
information is available and must be identified as such, i.e., “Followup IND Safety Report.”  
(3) If the results of a sponsor's investigation show that an adverse event not initially 
determined to be reportable is so reportable, the sponsor must report such suspected adverse 
reaction in an IND safety report as soon as possible, but in no case later than 15 calendar 
days after the determination is made.  
All AEs will be monitored by the PMT. Less than serious or non-serious expected adverse 
events will be reported only at the time of protocol continuation reports.  
24.4. Attribution 
For reporting purposes, attribution is the assessment of the likelihood that an AE is caused by 
the research agent or protocol intervention. The attribution is assigned by the treating 
physician/Principal Investigator after considering the clinical information, the medical history of 
the subject, and experience with the research agent/intervention. This is recorded using the 
Adverse Event Report (COH AER) form in 1 of 5 categories scored as the following: 5 = related, 
4 = probably related, 3 = possibly related, 2 = unlikely related, and 1 = unrelated. 
Disclaimer. A safety report or other information submitted by a sponsor under this part (and 
any release by FDA of that report or information) does not necessarily reflect a conclusion by 
the sponsor or FDA that the report or information constitutes an admission that the drug caused 
or contributed to an adverse event. A sponsor need not admit, and may deny, that the report or 
information submitted by the sponsor constitutes an admission that the drug caused or 
contributed to an adverse event.  


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24.5. Post-study Adverse Events 
The Investigator will notify Cellular Sciences of any serious adverse event he/she becomes 
aware of that occurs at any time after a subject has completed study participation, if in the 
Investigator’s judgment the event may be reasonably related to the medication used in the study. 
The Investigator will follow the subject until the adverse event resolves or becomes stable. 
 
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