Refractory Chronic Cough Improvement Via NAL ER (RIVER)

An adverse event (AE) was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A TEAE was defined as any AE that occurs after the first dose of study drug. TEAEs included both serious and non-serious TEAEs.

The clinical laboratory parameters included urinalysis, hematology, serum chemistry and coagulation. Clinical significance was determined by the investigator.

Vital signs measurements included blood pressure, heart rate, respiration rate, body temperature, pulse oximetry, and weight. Clinical significance was determined by the investigator.

Changes in ECG data such as heart rate, rhythm, and other clinically significant abnormalities (left ventricular hypertrophy, pathological Q-waves) were measured. Clinical significance was determined by the investigator.

Physical examination included examination of the following body systems: general appearance, eyes, ears, nose, throat, head and neck, chest and lungs, cardiovascular, abdomen, musculoskeletal, lymphatic, dermatological, neurological, and extremities. Clinical significance was determined by the investigator.

Relative change in 24-hour (combined daytime and nighttime) cough frequency (coughs per hour) from baseline was assessed. Assessment was done using objective digital cough monitoring. Baseline was defined as the last non-missing assessment, prior to the first dose of study drug.

Responders were defined as those with ≥30%, ≥50%, or ≥75% reduction in 24-hour cough frequency from Baseline at Days 7, 14, or 21.

Awake cough was defined as cough that occurs between the time that the participant is awaken 24 hours after the digital cough monitor was applied for use. Assessment was done using objective digital cough monitoring. Baseline was defined as the last non-missing assessment, prior to the first dose of study drug.

Sleep cough frequency was intended as the average coughs per hour while the participant was flagged as being asleep. Assessment was done using objective digital cough monitoring. Percent change in cough frequency (coughs per hour) from baseline was assessed. Baseline was defined as the last non-missing assessment, prior to the first dose of study drug.

The CS-VAS is a brief, easily administered patient reported outcome (PRO) questionnaire that is used to assess cough severity in both acute and chronic cough. CS-VAS is a 1-item scale that rates the severity of participants' cough from 0 millimeter (mm) where 0 indicated "no cough" and 100 represented "worst cough ever". A negative change from baseline indicates improvement.

LCQ is a self-reporting quality of life measure of chronic cough. It consists of 19 items with a 7-point Likert response scale ranging from 1 to 7. The responses are as follows: 1 = all of the time, 2 = most of the time, 3 = a good bit of the time, 4 = some of the time, 5 = a little of the time, 6 = hardly any of the time, and 7 = none of the time. Each item is designed to assess cough symptoms and the impact of cough across three main domains, physical (8 items), psychological (7 items), and social (4 items). Domain scores are calculated as the total score from items in the domain divided by the number of items in the domain and range from 1 to 7. The LCQ total score is calculated by summing the individual domain scores and ranges from 3 to 21, with higher scores indicating better health status.

Patient-Reported Cough Frequency (PR-CF) is a daily, self-reported, 1 item scale, PRO that is used to assess cough frequency. Participants rate their cough frequency over the past 24 hours using a 5-point Likert scale (0- to 4: 0 = Not at all, 1 = Rarely, 2 = Occasionally, 3 = Frequently, 4 = Almost constantly). A higher score indicates more severe symptoms. A negative change from baseline indicates improvement.

PR-CF is a daily, self-reported, 1 item scale, PRO that is used to assess cough frequency. Participants rate their cough frequency over the past 24 hours using a 5-point Likert scale (0 to 4: 0 = Not at all, 1 = Rarely, 2 = Occasionally, 3 = Frequently, 4 = Almost constantly). A higher score indicates more severe symptoms. PR CF responders were defined as participants with at least a one category improvement at Days 7, 14, and 21.

The PGI-S Cough scale is a self-reported, single-item categorical scale that is increasingly used when assessing chronic cough. Participants rate the severity of their cough in the last week with a 4-point Likert scale ranging from 0 to 3 (0 = No Cough, 1 = Mild, 2 = Moderate, or 3 = Severe). A higher score indicates more severe symptoms. A negative change from baseline indicates improvement.

The PGI-C Cough scale is a self-reported, single-item categorical scale that is increasingly used when assessing chronic cough. Participants rate the severity of their cough in the last week with a 7-point Likert scale ranging from 0 to 7 (0 = No Cough, 1 = Much better, 2 = Moderately better, 3 = A little better, 4 = No change, 5 = A little worse, 6 = Moderately worse, or 7 = Much worse). A higher score indicates more severe symptoms. A negative change from baseline indicates improvement.

The CGI-S Cough scale is an investigator-reported, single-item categorical scale that is increasingly used when assessing the severity of the condition. Investigator rate the severity of their cough in the last week with a 4-point Likert scale ranging from 0 to 3 (0 = No Cough, 1 = Mild, 2 = Moderate, or 3 = Severe). A higher score indicates more severe symptoms. A negative change from baseline indicates improvement.

The PGI-C Cough scale is an investigator-reported, single-item categorical scale that is increasingly used when assessing the investigator's belief of the participant's overall improvement pre-treatment baseline. Investigator rate the change in improvement in the last week with a 7-point Likert scale ranging from 1 to 7 (1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6= Much worse, or 7= Very much worse). A higher score indicates more severe symptoms. A negative change from baseline indicates improvement.