Treatment of Chronic Idiopathic Cough (CIC) and Chronic Cough in patients with Idiopathic Pulmonary Fibrosis (IPF) with PA101.

Cough is the most common complaint for which patients seek medical attention
and is the second most common reason for a general medical examination. Upper
respiratory tract infection (URTI) or the common cold is by far the most common
cause of cough, but post-infectious cough, unexplained chronic cough, and cough
due to pulmonary disorders such as asthma, chronic obstructive pulmonary
disease (COPD), idiopathic pulmonary fibrosis, and lung cancer are also common.
Cough that lasts more than 4 weeks in children younger than
14 years of age or more than 8 weeks in adolescents and adults 14 years of age
and older is considered to be chronic by the American College of Chest
Physicians (ACCP).
Cough results from activation of myelinated cough receptors and unmyelinated
C-fibers, whose cell bodies are in the jugular and nodose ganglia. Extensive
C-fiber endings are found under the airway epithelium while cough receptors
endings terminate in the mucosa between the epithelium and smooth muscle.
Mast cells play an important role in cough. Degranulated mast cells release
mediators that activate C-fibers, causing release of Substance P, histamine,
serotonin, and proteases. Substance P release results in inflammation,
vasodilatation, and sensitization of nerves. In patients diagnosed with chronic
nonproductive cough, bronchoalveolar lavage (BAL) showed increased numbers of
inflammatory cells and airway inflammation when compared to controls. Elevated
levels of mast cells were found in BAL samples in patients with chronic cough.
Identifying the underlying etiology is the most important step in the
successful management of chronic cough. If, however, no cause can be
identified, or if treatment of the underlying etiology fails to resolve the
cough, then the cough may be treated symptomatically. In the majority of cases,
symptomatic treatment consists of antitussive therapy to decrease cough
frequency and severity. Antitussive treatments vary in mechanism of action.
Nonspecific antitussives such as dextromethorphan and codeine appear to act in
the brain stem to reduce the cough reflex. Other nonspecific antitussives, such
as benzonatate, act to anesthetize respiratory passages and thus reduce the
stimulus to cough. Other agents aim to decrease the volume of respiratory tract
secretions and thus the need to cough. These latter antitussive agents are also
used to treat certain common underlying etiologies and include antihistamines,
corticosteroids, antibiotics, decongestants, and mast cell stabilizers.
Cromolyn sodium with its well-established safety profile is expected to play a
therapeutic role in the treatment of chronic cough through its pleiotropic
activity including direct inhibitory effect on sensory C fibers and indirect
effects on mast cells mediated activity. Cromolyn sodium decreases the response
to antigen challenge with a reduction in mast cell degranulation; inhibits the
release of mediators such as histamine and leukotrienes (SRS-A) from the mast
cells; inhibits the early and late phase airway reactions after allergen
challenge; inhibits leukotriene D4-induced bronchoconstriction response;
inhibits tachykinine release; attenuates human neutrophils, eosinophils and
monocytes; and calcium antagonist effect. Studies also demonstrated that
cromolyn sodium blocks the activation and subsequent mediator release from
other inflammatory cells, including eosinophils, neutrophils, monocytes,
macrophages, and lymphocytes.
Patara Pharma is developing a new inhalation formulation of cromolyn sodium
(PA101) delivered via the eFlow® high efficiency nebulizer system. PA101 is a
novel inhalation solution formulation of cromolyn sodium having osmolality and
pH adjusted to a physiologically well tolerable range. PA101 is
preservative-free, room temperature-stable formulation optimized for improved
tolerability via oral inhalation and long-term chemical stability. The eFlow
nebulizer is a portable, handheld, silent, high- efficiency nebulizer with
rapid delivery that can deliver a dose in less than 3 minutes. Delivering PA101
with the eFlow nebulizer system achieves higher lung deposition and systemic
levels of cromolyn sodium relative to currently marketed formulations of
cromolyn sodium.
PA101 via eFlow® is being investigated as a first-line maintenance therapy for
the treatment of chronic cough related to chronic idiopathic cough, idiopathic
pulmonary fibrosis, and lung cancer recalcitrant to currently available
therapies.

The objectives of the study are as follows:
*
1. To assess the effectiveness of inhaled PA101 delivered via eFlow high
efficiency nebulizer for treating chronic cough. Improvements in chronic cough
will be assessed by measuring the change from baseline in average daytime cough
count as measured by Leicester Cough Monitor (LCM). Other assessments will
include changes in the quality of life score as measured by the Leicester Cough
Questionnaire (LCQ) and King*s Brief Interstitial Lung Disease Questionnaire
(K-BILD), changes in cough severity as measured by Visual Analog Scale (VAS),
changes in pulmonary function tests (PFTs), and fractional exhaled nitric oxide
(FeNO) as measured by Niox Vero.
*
2. To evaluate the safety and tolerability of PA101 in patients with chronic
cough.

This is a randomized, double-blind, placebo-controlled, 2-period crossover,
2-cohort, multi- center, Phase 2 study in 48 patients with chronic cough: 24
patients with idiopathic pulmonary fibrosis (IPF, Cohort 1) and 24 patients
with chronic idiopathic cough (CIC, Cohort 2).

The study will consist of two treatment periods of 14 days each separated by a
Washout Period of 14 days (±2 days) between Period 1 and Period 2. A Screening
Visit will be conducted within 14 days before the Baseline Visit of Period 1.
The two periods will be identical except that in Period 2, patients will
crossover to the alternate treatment from that received in Period 1, according
to a 1:1 randomization scheme.

Each treatment period will comprise of a Baseline Visit (Visit 1: Day -1)
followed by 14 days of treatment. During the 14 days of treatment, patients
will return to the clinic 4 times (Visit 2: Day 1, Visit 3: Day 7, Visit 4: Day
14 and Visit 5: Day 15) for completion of study assessments. Visits 3, 4 and 5
have a visit window of +/- 1 day. A member of the research team may be able to
conduct Baseline visit (Visit 1, Day -1) and Day 14 (Visit 4) at the patient*s
home; this option will be dependent on the Hospital*s policy, staff resource
and at the discretion of the investigator. Assessments performed at each visit
are listed below:

SCREENING VISIT (SV)
Patients will attend a SV where they will discuss the study with a member of
the research team. Patients will be required to provide written informed
consent if they wish to participate in the study. Patients who provide informed
consent will then undergo screening procedures to determine their eligibility
for participation in the study.

Screening procedures will include: medical history, physical examination
(including BMI calculation), blood and urine sample for clinical safety
laboratory testing, urine pregnancy test (for females), alcohol and drugs of
abuse screening, vital signs (blood pressure and heart rate), ECG, cough
severity by Visual Acuity Scale (VAS), cough recording and concomitant
medication review. A lung function test will also be carried out at the
Screening Visit if one has not been done within the last month.

Eligible patients will participate in two treatment periods separated by a
washout period of 14 days. The two treatment periods will be identical except
that in Period 2 patients will crossover to the alternate treatment from that
received in Period 1, according to the randomization scheme.
Each treatment period will comprise of a Baseline Visit (Visit 1: Day -1)
followed by 14 days of treatment. During the 14 days of treatment, patients
will return to the clinic 4 times (Visit 2: Day 1, Visit 3: Day 7, Visit 4: Day
14 and Visit 5: Day 15) for completion of study assessments. Visits 3, 4 and 5
have a visit window of +/- 1 day. Assessments performed at each visit are
listed below:

BASELINE VISIT (VISIT 1: DAY -1)
The day after the SV or completion of the washout period, patients will have a
24 hour cough monitor fitted to provide a baseline measurement of coughing.
VISIT 2: Day 1
Removal of the 24 hour cough monitor, medical history and eligibility review,
concomitant medication review, adverse event review, vital signs, ECG,
nebuliser training, cough severity and quality of life assessments (VAS and,
Leicester Cough Questionnaire [LCQ])and assessment of fractional exhaled nitric
oxide (FeNO) using Niox Vero®.
Blood and urine samples for clinical safety laboratory tests will be collected
at this visit for treatment period 2 only.
Additionally, for patients in the IPF cohort, pulmonary function tests
(PFT)(spirometry) and the King's Brief Interstitial Lung Disease [K-BILD]
questionnaire will be carried out.
At this visit in the first treatment period, the patient will be randomised to
a treatment sequence. In both treatment periods the study drug will be
dispensed to the patient to be taken at home, three times daily.
Vital signs and ECG will be carried out pre-dose and 30 minutes after the
morning dose of the study medication is taken in the clinic. For IPF patients,
PFTs will be carried out pre-dose at this visit.
VISIT 3: Day 7
The following assessments will be carried out: vital signs, ECG, VAS, LCQ,
K-BILD (IPF cohort only), FeNO, concomitant and adverse event (AE) review and
the 24 hour cough monitor will be fitted.
Vital signs and ECG will be carried out pre-dose and 30 minutes after the
morning dose of the study medication is taken in the clinic.
VISIT 4: Day 14
24 hour cough monitor fitted and AEs reviewed. VISIT 5: Day 15
The following assessments will be carried out: blood and urine samples for
clinical safety laboratory tests (treatment period 2 only), vital signs, ECG,
VAS, LCQ, K-BILD (IPF cohort only), spirometry (IPF cohort only), FeNO, removal
of 24 cough monitor, concomitant medication and AE review.
Vital signs and ECG will be carried out 30 minutes after the morning dose of
the study medication is taken in the clinic. PFTs for patients in the IPF
cohort will be completed 60 minutes post dose.
SAFETY FOLLOW UP
The safety follow up call will be carried out 7 days (+/- 2 days) after the
last treatment. In this phone call, AEs will be reviewed.

There will be two treatment periods of 14 days each, separated by 14 days
without treatment. The two treatment periods will be the same, except that in
Treatment Period 2, patients will crossover to the alternative treatment from
that received in Treatment Period 1 (according to a 1:1 randomization schedule).

During each treatment period, patients will self administer the study drug (40
mg PA101 or placebo PA101 via an eFlow nebuliser), three times daily (i.e.,
8:00am +/- 1 hour, 2:00pm +/- 1 hour and 8:00pm +/- 1 hour) for 14 consecutive
days of each treatment period.

DISCOMFORT
Participants may be required to undergo procedures for this study which they
ordinarily would not be subjected to, some of which the participant may find
uncomfortable.
ADVERSE EVENTS
The main ethical issues posed by this study are the potential for adverse
events. The full adverse event profile of the study drug has been fully
explained in the Patient Information Sheet and participants will have the
opportunity to discuss these with the study doctor at any time. The dose of
study medication intended to be administered in this study are of a reasonable
level and as such the adverse event profile should be well managed.
Sites will take every precaution to ensure the safety of study participants.
Participants/carers will be provided with a contact telephone number for the
site to use both during normal hours and out of hours.
IDENTIFICATION OF PREVIOUSLY UNKNOWN HEALTH PROBLEMS
There is always the possibility that tests conducted as part of the trial will
identify an unknown health problem or possibility of a health problem in the
participants (for example, abnormal blood laboratory results). All participants
will be asked to consent to their GP being informed of their participation in
the study. If any test result conducted as part of the trial is abnormal and a
cause for concern, the participant and their GP will be informed. The
participant will be referred to their GP for further advice.
INCONVENIENCE
Participants will attend the clinic more frequently than is required for normal
routine care. The expectations and requirements of this trial are clearly
indicated in the Patient Information Sheet to allow participants/carers to
consider the commitment needed before they enter the trial. Should the
frequency of visits or assessments conducted become too much for the
participant, they are free to withdraw from the study at any time.
This study was designed according to ICH/GCP and with due thought given to
potential ethical dilemmas. It is not anticipated that any significant ethical
issues will now arise.