Trial Outcomes & Findings for A Study of Nalbuphine (Extended Release) ER in Idiopathic Pulmonary Fibrosis (IPF) for Treatment of Cough (NCT NCT04030026)
NCT ID: NCT04030026
Last Updated: 2025-05-29
Results Overview
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.
COMPLETED
PHASE2
42 participants
Up to Day 72
2025-05-29
Participant Flow
Participants were enrolled at 11 sites in the United Kingdom from 29 October 2019 to 27 May 2022.
A total of 56 participants were screened from whom 42 participants were enrolled and randomized to receive treatment in this study.
Participant milestones
| Measure |
First NAL ER Then Placebo
Participants received NAL ER in treatment period 1 at dose 27 mg once daily (QD) to 54 mg twice daily (BID) over a 5-day period and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week then to 162 mg BID for 6 days, followed by placebo for 3 weeks in treatment period 2. Both the treatment periods were separated by 2 weeks of washout period.
|
First Placebo Then NAL ER
Participants received placebo for 3 weeks in treatment period 1 followed by NAL ER in treatment period 2 at dose 27 mg QD to 54 mg BID over a 5-day period and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week then to 162 mg BID for 6 days. Both the treatment periods were separated by 2 weeks of washout period.
|
|---|---|---|
|
Treatment Period 1 (22 Days)
STARTED
|
21
|
21
|
|
Treatment Period 1 (22 Days)
Safety Analysis Set
|
20
|
21
|
|
Treatment Period 1 (22 Days)
COMPLETED
|
19
|
19
|
|
Treatment Period 1 (22 Days)
NOT COMPLETED
|
2
|
2
|
|
Treatment Period 2 (22 Days)
STARTED
|
19
|
19
|
|
Treatment Period 2 (22 Days)
COMPLETED
|
18
|
10
|
|
Treatment Period 2 (22 Days)
NOT COMPLETED
|
1
|
9
|
Reasons for withdrawal
| Measure |
First NAL ER Then Placebo
Participants received NAL ER in treatment period 1 at dose 27 mg once daily (QD) to 54 mg twice daily (BID) over a 5-day period and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week then to 162 mg BID for 6 days, followed by placebo for 3 weeks in treatment period 2. Both the treatment periods were separated by 2 weeks of washout period.
|
First Placebo Then NAL ER
Participants received placebo for 3 weeks in treatment period 1 followed by NAL ER in treatment period 2 at dose 27 mg QD to 54 mg BID over a 5-day period and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week then to 162 mg BID for 6 days. Both the treatment periods were separated by 2 weeks of washout period.
|
|---|---|---|
|
Treatment Period 1 (22 Days)
COVID-19 pandemic restrictions
|
0
|
1
|
|
Treatment Period 1 (22 Days)
Withdrawal by Participant
|
1
|
0
|
|
Treatment Period 1 (22 Days)
Protocol Deviation
|
0
|
1
|
|
Treatment Period 1 (22 Days)
Physician Decision
|
1
|
0
|
|
Treatment Period 2 (22 Days)
Adverse Event
|
0
|
6
|
|
Treatment Period 2 (22 Days)
COVID-19 pandemic restrictions
|
1
|
1
|
|
Treatment Period 2 (22 Days)
Withdrawal by Participant
|
0
|
2
|
Baseline Characteristics
A Study of Nalbuphine (Extended Release) ER in Idiopathic Pulmonary Fibrosis (IPF) for Treatment of Cough
Baseline characteristics by cohort
| Measure |
First NAL ER Then Placebo
n=21 Participants
Participants received NAL ER in treatment period 1 at dose 27 mg QD to 54 mg BID over a 5-day period and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week then to 162 mg BID for 6 days, followed by placebo for 3 weeks in treatment period 2. Both the treatment periods were separated by 2 weeks of washout period.
|
First Placebo Then NAL ER
n=21 Participants
Participants received placebo for 3 weeks in treatment period 1 followed by NAL ER in treatment period 2 at dose 27 mg QD to 54 mg BID over a 5-day period and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week then to 162 mg BID for 6 days. Both the treatment periods were separated by 2 weeks of washout period.
|
Total
n=42 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Customized
18-64 years
|
3 years
n=5 Participants
|
1 years
n=7 Participants
|
4 years
n=5 Participants
|
|
Age, Customized
65-85 years
|
18 years
n=5 Participants
|
19 years
n=7 Participants
|
37 years
n=5 Participants
|
|
Age, Customized
85 years and above
|
0 years
n=5 Participants
|
1 years
n=7 Participants
|
1 years
n=5 Participants
|
|
Sex: Female, Male
Female
|
2 Participants
n=5 Participants
|
4 Participants
n=7 Participants
|
6 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
19 Participants
n=5 Participants
|
17 Participants
n=7 Participants
|
36 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Asian
|
1 Participants
n=5 Participants
|
3 Participants
n=7 Participants
|
4 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
White
|
20 Participants
n=5 Participants
|
18 Participants
n=7 Participants
|
38 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Not Hispanic or Latino
|
20 Participants
n=5 Participants
|
20 Participants
n=7 Participants
|
40 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Not Reported
|
1 Participants
n=5 Participants
|
1 Participants
n=7 Participants
|
2 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: Up to Day 72Population: 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).
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.
Outcome measures
| Measure |
NAL ER
n=38 Participants
Participants received NAL ER 27 mg QD to 54 mg BID over a 5-day period, and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week followed by 162 mg, BID for 6 days in treatment period 1 or 2 of the study.
|
Placebo
n=40 Participants
Participants received placebo for 3 weeks through treatment period 1 or 2 of the study.
|
|---|---|---|
|
Number of Participants Who Experienced at Least One Treatment Emergent Adverse Events (TEAEs)
|
35 Participants
|
26 Participants
|
PRIMARY outcome
Timeframe: Up to Day 72Population: 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.
Outcome measures
| Measure |
NAL ER
n=38 Participants
Participants received NAL ER 27 mg QD to 54 mg BID over a 5-day period, and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week followed by 162 mg, BID for 6 days in treatment period 1 or 2 of the study.
|
Placebo
n=40 Participants
Participants received placebo for 3 weeks through treatment period 1 or 2 of the study.
|
|---|---|---|
|
Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters
Urinalysis
|
0 Participants
|
0 Participants
|
|
Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters
Hematology
|
1 Participants
|
0 Participants
|
|
Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters
Serum Chemistry
|
1 Participants
|
1 Participants
|
|
Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters
Coagulation
|
0 Participants
|
1 Participants
|
|
Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters
Liver Function Parameters
|
0 Participants
|
0 Participants
|
PRIMARY outcome
Timeframe: Up to Day 72Population: 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.
Outcome measures
| Measure |
NAL ER
n=38 Participants
Participants received NAL ER 27 mg QD to 54 mg BID over a 5-day period, and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week followed by 162 mg, BID for 6 days in treatment period 1 or 2 of the study.
|
Placebo
n=40 Participants
Participants received placebo for 3 weeks through treatment period 1 or 2 of the study.
|
|---|---|---|
|
Number of Participants With Clinically Significant Changes in Vital Sign Parameters
|
0 Participants
|
0 Participants
|
PRIMARY outcome
Timeframe: Up to Day 72Population: 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.
Outcome measures
| Measure |
NAL ER
n=38 Participants
Participants received NAL ER 27 mg QD to 54 mg BID over a 5-day period, and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week followed by 162 mg, BID for 6 days in treatment period 1 or 2 of the study.
|
Placebo
n=40 Participants
Participants received placebo for 3 weeks through treatment period 1 or 2 of the study.
|
|---|---|---|
|
Number of Participants With Clinically Significant Changes in Physical Examination Parameters
|
0 Participants
|
0 Participants
|
PRIMARY outcome
Timeframe: Up to Day 72Population: 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.
Outcome measures
| Measure |
NAL ER
n=38 Participants
Participants received NAL ER 27 mg QD to 54 mg BID over a 5-day period, and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week followed by 162 mg, BID for 6 days in treatment period 1 or 2 of the study.
|
Placebo
n=40 Participants
Participants received placebo for 3 weeks through treatment period 1 or 2 of the study.
|
|---|---|---|
|
Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECG)
|
1 Participants
|
1 Participants
|
PRIMARY outcome
Timeframe: Baseline, Day 21Population: 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.
Spirometry was used to assess FVC. It was used to assess pulmonary breathing mechanics.
Outcome measures
| Measure |
NAL ER
n=28 Participants
Participants received NAL ER 27 mg QD to 54 mg BID over a 5-day period, and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week followed by 162 mg, BID for 6 days in treatment period 1 or 2 of the study.
|
Placebo
n=35 Participants
Participants received placebo for 3 weeks through treatment period 1 or 2 of the study.
|
|---|---|---|
|
Change From Baseline in Forced Vital Capacity (FVC) at Day 21
|
-2.3 litre(s)
Standard Deviation 5.58
|
-1.0 litre(s)
Standard Deviation 5.56
|
PRIMARY outcome
Timeframe: Up to Day 72Population: 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.
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.
Outcome measures
| Measure |
NAL ER
n=36 Participants
Participants received NAL ER 27 mg QD to 54 mg BID over a 5-day period, and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week followed by 162 mg, BID for 6 days in treatment period 1 or 2 of the study.
|
Placebo
n=38 Participants
Participants received placebo for 3 weeks through treatment period 1 or 2 of the study.
|
|---|---|---|
|
Subjective Opiate Withdrawal (SOWS) Total Raw Score
|
4.7055 score on a scale
Standard Deviation 5.0019
|
2.4082 score on a scale
Standard Deviation 3.5561
|
PRIMARY outcome
Timeframe: At BaselinePopulation: 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.
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.
Outcome measures
| Measure |
NAL ER
n=38 Participants
Participants received NAL ER 27 mg QD to 54 mg BID over a 5-day period, and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week followed by 162 mg, BID for 6 days in treatment period 1 or 2 of the study.
|
Placebo
n=38 Participants
Participants received placebo for 3 weeks through treatment period 1 or 2 of the study.
|
|---|---|---|
|
Daytime Cough Frequency at Baseline
|
27.99 coughs per hour
Standard Deviation 23.704
|
27.99 coughs per hour
Standard Deviation 23.704
|
PRIMARY outcome
Timeframe: Baseline, Day 22Population: 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.
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.
Outcome measures
| Measure |
NAL ER
n=29 Participants
Participants received NAL ER 27 mg QD to 54 mg BID over a 5-day period, and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week followed by 162 mg, BID for 6 days in treatment period 1 or 2 of the study.
|
Placebo
n=37 Participants
Participants received placebo for 3 weeks through treatment period 1 or 2 of the study.
|
|---|---|---|
|
Percent Change From Baseline in Daytime Cough Frequency at Day 22
|
-75.11 percent change
Interval -82.655 to -67.567
|
-22.62 percent change
Interval -42.531 to 2.715
|
SECONDARY outcome
Timeframe: Baseline, Day 22Population: 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.
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.
Outcome measures
| Measure |
NAL ER
n=29 Participants
Participants received NAL ER 27 mg QD to 54 mg BID over a 5-day period, and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week followed by 162 mg, BID for 6 days in treatment period 1 or 2 of the study.
|
Placebo
n=37 Participants
Participants received placebo for 3 weeks through treatment period 1 or 2 of the study.
|
|---|---|---|
|
Change From Baseline in Daytime Cough Frequency at Day 22
|
-19.386 coughs per hour
Standard Deviation 19.5688
|
-6.264 coughs per hour
Standard Deviation 12.4006
|
SECONDARY outcome
Timeframe: Baseline, Day 22Population: 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.
Outcome measures
| Measure |
NAL ER
n=29 Participants
Participants received NAL ER 27 mg QD to 54 mg BID over a 5-day period, and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week followed by 162 mg, BID for 6 days in treatment period 1 or 2 of the study.
|
Placebo
n=37 Participants
Participants received placebo for 3 weeks through treatment period 1 or 2 of the study.
|
|---|---|---|
|
Percent Change From Baseline in 24-Hour Cough Frequency at Day 22
|
-76.10 percent change
Interval -83.133 to -69.075
|
-25.29 percent change
Interval -43.894 to -6.69
|
SECONDARY outcome
Timeframe: Baseline, Day 22Population: 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.
Outcome measures
| Measure |
NAL ER
n=29 Participants
Participants received NAL ER 27 mg QD to 54 mg BID over a 5-day period, and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week followed by 162 mg, BID for 6 days in treatment period 1 or 2 of the study.
|
Placebo
n=37 Participants
Participants received placebo for 3 weeks through treatment period 1 or 2 of the study.
|
|---|---|---|
|
Percent Change From Baseline in Nighttime Cough Frequency at Day 22
|
-62.27 percent change
Interval -79.588 to -44.957
|
-20.30 percent change
Interval -51.391 to 10.783
|
SECONDARY outcome
Timeframe: Baseline, Days 9, 16, and 22Population: 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.
Outcome measures
| Measure |
NAL ER
n=38 Participants
Participants received NAL ER 27 mg QD to 54 mg BID over a 5-day period, and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week followed by 162 mg, BID for 6 days in treatment period 1 or 2 of the study.
|
Placebo
n=38 Participants
Participants received placebo for 3 weeks through treatment period 1 or 2 of the study.
|
|---|---|---|
|
Mean Change From Baseline in the Evaluating Respiratory Symptoms (E-RS) Diary Cough Subscale at Days 9, 16, and 22
Change at Day 9
|
-0.7 score on a scale
Standard Deviation 0.77
|
-0.1 score on a scale
Standard Deviation 0.70
|
|
Mean Change From Baseline in the Evaluating Respiratory Symptoms (E-RS) Diary Cough Subscale at Days 9, 16, and 22
Change at Day 16
|
-0.9 score on a scale
Standard Deviation 0.82
|
-0.2 score on a scale
Standard Deviation 0.59
|
|
Mean Change From Baseline in the Evaluating Respiratory Symptoms (E-RS) Diary Cough Subscale at Days 9, 16, and 22
Change at Day 22
|
-1.0 score on a scale
Standard Deviation 0.94
|
-0.2 score on a scale
Standard Deviation 0.85
|
SECONDARY outcome
Timeframe: Baseline, Days 9, 16, and 22Population: 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 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.
Outcome measures
| Measure |
NAL ER
n=38 Participants
Participants received NAL ER 27 mg QD to 54 mg BID over a 5-day period, and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week followed by 162 mg, BID for 6 days in treatment period 1 or 2 of the study.
|
Placebo
n=38 Participants
Participants received placebo for 3 weeks through treatment period 1 or 2 of the study.
|
|---|---|---|
|
Mean Change From Baseline in E-RS Breathlessness Score at Days 9, 16, and 22
Change at Day 9
|
-0.5 score on a scale
Standard Deviation 2.68
|
1.1 score on a scale
Standard Deviation 2.74
|
|
Mean Change From Baseline in E-RS Breathlessness Score at Days 9, 16, and 22
Change at Day 16
|
0.0 score on a scale
Standard Deviation 2.30
|
1.2 score on a scale
Standard Deviation 2.26
|
|
Mean Change From Baseline in E-RS Breathlessness Score at Days 9, 16, and 22
Change at Day 22
|
0.1 score on a scale
Standard Deviation 2.45
|
0.8 score on a scale
Standard Deviation 2.43
|
SECONDARY outcome
Timeframe: Baseline, Days 8, 15, and 21Population: 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.
Outcome measures
| Measure |
NAL ER
n=38 Participants
Participants received NAL ER 27 mg QD to 54 mg BID over a 5-day period, and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week followed by 162 mg, BID for 6 days in treatment period 1 or 2 of the study.
|
Placebo
n=38 Participants
Participants received placebo for 3 weeks through treatment period 1 or 2 of the study.
|
|---|---|---|
|
Mean Change From Baseline in the Cough Severity Numerical Rating Scale (NRS) at Days 8, 15, and 21
Change at Day 8
|
-1.7 score on a scale
Standard Deviation 1.98
|
-0.4 score on a scale
Standard Deviation 1.54
|
|
Mean Change From Baseline in the Cough Severity Numerical Rating Scale (NRS) at Days 8, 15, and 21
Change at Day 15
|
-2.7 score on a scale
Standard Deviation 1.75
|
-0.6 score on a scale
Standard Deviation 1.74
|
|
Mean Change From Baseline in the Cough Severity Numerical Rating Scale (NRS) at Days 8, 15, and 21
Change at Day 21
|
-2.5 score on a scale
Standard Deviation 2.19
|
-0.3 score on a scale
Standard Deviation 1.85
|
SECONDARY outcome
Timeframe: Baseline, Days 9, 16, and 22Population: 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.
Outcome measures
| Measure |
NAL ER
n=38 Participants
Participants received NAL ER 27 mg QD to 54 mg BID over a 5-day period, and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week followed by 162 mg, BID for 6 days in treatment period 1 or 2 of the study.
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Placebo
n=38 Participants
Participants received placebo for 3 weeks through treatment period 1 or 2 of the study.
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|---|---|---|
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Mean Change From Baseline in the 14-item EXAcerbation of Chronic Pulmonary Disease Tool (EXACT) v1.1 e-Diary Tool Total Score at Days 9, 16, and 22
Change at Day 9
|
-2.0 score on a scale
Standard Deviation 5.63
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1.6 score on a scale
Standard Deviation 5.55
|
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Mean Change From Baseline in the 14-item EXAcerbation of Chronic Pulmonary Disease Tool (EXACT) v1.1 e-Diary Tool Total Score at Days 9, 16, and 22
Change at Day 16
|
-1.8 score on a scale
Standard Deviation 4.89
|
1.9 score on a scale
Standard Deviation 5.46
|
|
Mean Change From Baseline in the 14-item EXAcerbation of Chronic Pulmonary Disease Tool (EXACT) v1.1 e-Diary Tool Total Score at Days 9, 16, and 22
Change at Day 22
|
-1.6 score on a scale
Standard Deviation 5.92
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0.6 score on a scale
Standard Deviation 5.76
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SECONDARY outcome
Timeframe: Baseline, Day 21Population: 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 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.
Outcome measures
| Measure |
NAL ER
n=24 Participants
Participants received NAL ER 27 mg QD to 54 mg BID over a 5-day period, and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week followed by 162 mg, BID for 6 days in treatment period 1 or 2 of the study.
|
Placebo
n=30 Participants
Participants received placebo for 3 weeks through treatment period 1 or 2 of the study.
|
|---|---|---|
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Mean Change From Baseline in the Patient Reported Outcomes Measurement Information System (PROMIS) Item Bank v1.0 Fatigue Short Form 7a Scale Total Score at Day 21
|
0.9 score on a scale
Standard Deviation 3.98
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0.0 score on a scale
Standard Deviation 2.98
|
SECONDARY outcome
Timeframe: At Day 21Population: 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.
Outcome measures
| Measure |
NAL ER
n=29 Participants
Participants received NAL ER 27 mg QD to 54 mg BID over a 5-day period, and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week followed by 162 mg, BID for 6 days in treatment period 1 or 2 of the study.
|
Placebo
n=36 Participants
Participants received placebo for 3 weeks through treatment period 1 or 2 of the study.
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|---|---|---|
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Clinical Global Impression of Change (CGI-C) Over Time Measured at Day 21
|
3.0 score on a scale
Standard Deviation 1.50
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3.9 score on a scale
Standard Deviation 0.91
|
Adverse Events
NAL ER
Placebo
Serious adverse events
| Measure |
NAL ER
n=38 participants at risk
Participants received NAL ER 27 mg QD to 54 mg BID over a 5-day period, and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week followed by 162 mg, BID for 6 days in treatment period 1 or 2 of the study.
|
Placebo
n=40 participants at risk
Participants received placebo for 3 weeks through treatment period 1 or 2 of the study.
|
|---|---|---|
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Infections and infestations
Urosepsis
|
2.6%
1/38 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
0.00%
0/40 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
|
Infections and infestations
Pneumonia
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0.00%
0/38 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
2.5%
1/40 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
Other adverse events
| Measure |
NAL ER
n=38 participants at risk
Participants received NAL ER 27 mg QD to 54 mg BID over a 5-day period, and then maintained at 54 mg BID for 4 days. Dose was increased to 108 mg BID for 1 week followed by 162 mg, BID for 6 days in treatment period 1 or 2 of the study.
|
Placebo
n=40 participants at risk
Participants received placebo for 3 weeks through treatment period 1 or 2 of the study.
|
|---|---|---|
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Nervous system disorders
Dizziness
|
26.3%
10/38 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
0.00%
0/40 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
|
Nervous system disorders
Somnolence
|
23.7%
9/38 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
2.5%
1/40 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
|
Nervous system disorders
Headache
|
13.2%
5/38 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
12.5%
5/40 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
|
Nervous system disorders
Lethargy
|
7.9%
3/38 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
5.0%
2/40 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
|
General disorders
Fatigue
|
31.6%
12/38 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
7.5%
3/40 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
|
Gastrointestinal disorders
Nausea
|
42.1%
16/38 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
0.00%
0/40 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
|
Gastrointestinal disorders
Constipation
|
28.9%
11/38 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
5.0%
2/40 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
|
Gastrointestinal disorders
Vomiting
|
18.4%
7/38 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
12.5%
5/40 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
|
Gastrointestinal disorders
Dry Mouth
|
13.2%
5/38 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
2.5%
1/40 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
|
Gastrointestinal disorders
Diarrhoea
|
7.9%
3/38 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
15.0%
6/40 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
|
Respiratory, thoracic and mediastinal disorders
Dyspnea
|
15.8%
6/38 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
5.0%
2/40 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
|
Respiratory, thoracic and mediastinal disorders
Cough
|
7.9%
3/38 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
15.0%
6/40 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
|
Psychiatric disorders
Anxiety
|
13.2%
5/38 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
0.00%
0/40 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
|
Metabolism and nutrition disorders
Decreased appetite
|
10.5%
4/38 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
7.5%
3/40 • Up to Day 72
All-cause mortality:All randomized participants.Adverse events:SAS=all randomized participants who received at least 1 dose of IP.3 participants did not receive at least 1 dose of NAL ER but received placebo,1 participant did not receive at least 1 dose of placebo but received NAL ER treatment.Data was summarized under actual treatment received independently whether this was received in Treatment Period 1/2(participants who received both treatments are counted in both NAL ER,placebo columns).
|
Additional Information
Thomas Sciascia, MD, Chief Scientific Officer
Trevi Therapeutics, Inc.
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place