A Study of Nalbuphine (Extended Release) ER in Idiopathic Pulmonary Fibrosis (IPF) for Treatment of Cough

Spirometry was used to assess FVC. It was used to assess pulmonary breathing mechanics.

Time frame: Baseline, Day 21

Population: Participants in SAS were analyzed.3 participants did not receive at least 1 dose of NAL ER but received placebo and 1 participant did not receive at least 1 dose of placebo but received NAL ER treatment. Data was summarized under actual treatment received (NAL ER or placebo) independently whether in Treatment Period 1 or 2 (participants who received both treatments are counted in both NAL ER and placebo columns).Overall number of participants analyzed'=participants who were evaluable for the OM.

Daytime cough was defined as cough that occurs between the time that the participant is a wake in the 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 available assessment prior to the first Treatment Period 1 IP intake.

Time frame: At Baseline

Population: Full Analysis Set (FAS) included all randomized participants who had received at least single dose of the study medication and provided study baseline and at least one post -baseline primary efficacy variable assessment during the treatment Period.

An 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.

Time frame: Up to Day 72

Population: SAS included all randomized participants who had received at least 1 dose of the IP. 3 participants did not receive at least one dose of NAL ER but received placebo and 1 participant did not receive at least one dose of placebo but received NAL ER treatment. Data was summarized under actual treatment received (NAL ER or placebo) independently whether this was received in Treatment Period 1 or 2 (participants who received both treatments are counted in both NAL ER and placebo columns).

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.

Time frame: Up to Day 72

Population: SAS included all randomized participants who had received at least 1 dose of the IP. 3 participants did not receive at least one dose of NAL ER but received placebo and 1 participant did not receive at least one dose of placebo but received NAL ER treatment. Data was summarized under actual treatment received (NAL ER or placebo) independently whether this was received in Treatment Period 1 or 2 (participants who received both treatments are counted in both NAL ER and placebo columns).

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

Time frame: Up to Day 72

Population: SAS included all randomized participants who had received at least 1 dose of the IP. 3 participants did not receive at least one dose of NAL ER but received placebo and 1 participant did not receive at least one dose of placebo but received NAL ER treatment. Data was summarized under actual treatment received (NAL ER or placebo) independently whether this was received in Treatment Period 1 or 2 (participants who received both treatments are counted in both NAL ER and placebo columns).

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.

Time frame: Up to Day 72

Population: SAS included all randomized participants who had received at least 1 dose of the IP. 3 participants did not receive at least one dose of NAL ER but received placebo and 1 participant did not receive at least one dose of placebo but received NAL ER treatment. Data was summarized under actual treatment received (NAL ER or placebo) independently whether this was received in Treatment Period 1 or 2 (participants who received both treatments are counted in both NAL ER and placebo columns).

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

Time frame: Up to Day 72

Population: SAS included all randomized participants who had received at least 1 dose of the IP. 3 participants did not receive at least one dose of NAL ER but received placebo and 1 participant did not receive at least one dose of placebo but received NAL ER treatment. Data was summarized under actual treatment received (NAL ER or placebo) independently whether this was received in Treatment Period 1 or 2 (participants who received both treatments are counted in both NAL ER and placebo columns).

Daytime cough was defined as cough that occurs between the time that the participant is a wake in the 24 hours after the digital cough monitor was applied for use. Assessment was done using objective digital cough monitoring. Percent change in daytime cough frequency (coughs per hour) from baseline was assessed. Baseline was defined as the last available assessment prior to the first Treatment Period 1 IP intake.

Time frame: Baseline, Day 22

Population: FAS included all randomized participants who had received at least single dose of the study medication and provided study baseline and at least one post -baseline primary efficacy variable assessment during the treatment Period. 'Overall number of participants analyzed' included those participants who were evaluable for this outcome measure.

The SOWS is a self-administered scale for grading opioid withdrawal symptoms and was collected via the study issued e-diary. It consisted of 16 symptoms related to how the participant felt. Each symptom was scored between 0 to 4. The total score ranges between 0 to 64, higher score indicates more severe symptoms.

Time frame: Up to Day 72

Population: Participants in SAS were analyzed.3 participants did not receive at least 1 dose of NAL ER but received placebo and 1 participant did not receive at least 1 dose of placebo but received NAL ER treatment. Data was summarized under actual treatment received (NAL ER or placebo) independently whether in Treatment Period 1 or 2 (participants who received both treatments are counted in both NAL ER and placebo columns).Overall number of participants analyzed'=participants who were evaluable for the OM.

Daytime cough was defined as cough that occurs between the time that the participant wakes up and the time that the participant goes to bed. Assessment was done using objective digital cough monitoring. The change in daytime cough frequency (coughs per hour) from baseline was assessed. Baseline was defined as the last available assessment prior to the first Treatment Period 1 IP intake.

Time frame: Baseline, Day 22

Population: FAS included all randomized participants who had received at least single dose of the study medication and provided study baseline and at least one post -baseline primary efficacy variable assessment during the treatment Period. 'Overall number of participants analyzed' included those participants who were evaluable for this outcome measure.

The CGI-C is a one-item measure evaluating change from the initiation of treatment on a 7-point scale. It provides an overall clinician-determined summary measure that takes into account all available information, including knowledge of the patient's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the patient's ability to function. The total score ranges between 0 (very much improved) to 7 (very much worse). The lower scores indicate an improvement in respiratory symptoms.

Time frame: At Day 21

Population: FAS included all randomized participants who had received at least single dose of the study medication and provided study baseline and at least one post -baseline primary efficacy variable assessment during the treatment Period. 'Overall number of participants analyzed' included those participants who were evaluable for this outcome measure.

E-RS daily diary instrument has four separate respiratory symptom domain scales which is a valid, reliable and sensitive measure of four distinct respiratory symptoms. The four domain scales included breathlessness \[E-RS items 7 (were you breathless today), 8 (how breathless were you today), 9 (breathlessness doing personal care activities),10 (breathlessness doing indoor activities) & 11 (breathlessness doing outdoor activities); score =0: not at all) - 23: almost constantly\]. Other items were cough (0: not at all-4: severe), sputum (0: not at all-8: severe), and chest symptoms (0: not at all)-12: severe symptoms). The raw totals for the E-RS score and for subscales were converted to a scale of 0 to 100 (least to most symptoms). Higher score=more severe grade to the symptom. Negative score=improvement in symptom. The mean change from baseline was assessed. Baseline was defined as the last available assessment prior to the first Treatment Period 1 IP intake.

Time frame: Baseline, Days 9, 16, and 22

Population: FAS included all randomized participants who had received at least single dose of the study medication and provided study baseline and at least one post -baseline primary efficacy variable assessment during the treatment Period. 'Number analyzed' indicates the number of participants with data available for analysis at the specified timepoint.

The EXACT tool is a 14-item Daily Diary Tool Patient-reported outcome (PRO) instrument that was developed to quantify and measure exacerbations of chronic obstructive pulmonary disease (COPD). It provides a total score and subscale scores for breathlessness, cough and sputum, and chest symptoms. The 14 items have interval-level scale ranging between 0 to 100. The total score of each domain of breathlessness, cough and sputum, and chest symptoms ranges from 0 to 100. A higher score indicates a more severe condition. Negative score indicated improvement in the symptoms. Baseline was defined as the last available assessment prior to the first Treatment Period 1 IP intake.

Time frame: Baseline, Days 9, 16, and 22

Population: FAS included all randomized participants who had received at least single dose of the study medication and provided study baseline and at least one post -baseline primary efficacy variable assessment during the treatment Period. 'Number analyzed' indicates the number of participants with data available for analysis at the specified timepoint.

The Cough Severity NRS instrument is a single-dimension 11-point Likert scale ranging from 0 (no cough) to 10 (worst possible cough). Negative score indicates improvement in the symptoms. Participants completed the cough numerical severity rating via the study specific e-diary. The mean change from baseline in the Cough Severity Numerical Rating Scale was assessed. Baseline was defined as the last available assessment prior to the first Treatment Period 1 IP intake.

Time frame: Baseline, Days 8, 15, and 21

Population: FAS included all randomized participants who had received at least single dose of the study medication and provided study baseline and at least one post -baseline primary efficacy variable assessment during the treatment Period. 'Number analyzed' indicates the number of participants with data available for analysis at the specified timepoint.

E-RS daily diary instrument has four separate respiratory symptom domain scales which is a valid, reliable and sensitive measure of four distinct respiratory symptoms. The four domain scales that included cough \[E-RS item 2- How often did you cough today?;score range 0 (not at all)-4 (almost constantly)\], and other items such as breathlessness \[score 0(not at all)-23(severe symptoms)\], sputum \[0(not at all)-8(severe symptoms)\], and chest symptoms \[0(not at all)-12(severe symptoms)\]. The raw totals for the E-RS score and for each of the subscales were converted to a scale range of 0 to 100 (least symptomatic to most symptomatic). A higher score on the scale indicates a more severe grade to the symptom. Negative score indicates improvement in the symptom. The mean change from baseline in the E-RS diary cough scores was assessed. Baseline was defined as the last available assessment prior to the first Treatment Period 1 IP intake.

Time frame: Baseline, Days 9, 16, and 22

Population: FAS included all randomized participants who had received at least single dose of the study medication and provided study baseline and at least one post -baseline primary efficacy variable assessment during the treatment Period. 'Number analyzed' indicates the number of participants with data available for analysis at the specified timepoint.

The PROMIS Fatigue Short Form 7a is a self-administered Likert-type rating 5-point scale of 7 questions that assess tiredness, exhaustion, energy, fatigue limit, tiredness to think, tiredness impact on hygiene and impact on ability to exercise strenuously over the past 7 days. It consisted of 7 items with each item was scored between 1 to 5. The total score could range between 1 to 35, higher score indicates more severe symptoms. Baseline was defined as the last available assessment prior to the first Treatment Period 1 IP intake.

Time frame: Baseline, Day 21

Population: FAS included all randomized participants who had received at least single dose of the study medication and provided study baseline and at least one post -baseline primary efficacy variable assessment during the treatment Period. 'Overall number of participants analyzed' included those participants who were evaluable for this outcome measure.

Percent 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 available assessment prior to the first Treatment Period 1 IP intake.

Time frame: Baseline, Day 22

Population: FAS included all randomized participants who had received at least single dose of the study medication and provided study baseline and at least one post -baseline primary efficacy variable assessment during the treatment Period. 'Overall number of participants analyzed' included those participants who were evaluable for this outcome measure.

Nighttime 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 available assessment prior to the first Treatment Period 1 IP intake.

Time frame: Baseline, Day 22

Population: FAS included all randomized participants who had received at least single dose of the study medication and provided study baseline and at least one post -baseline primary efficacy variable assessment during the treatment Period. 'Overall number of participants analyzed' included those participants who were evaluable for this outcome measure.