Clinical Trial Results:
A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Two-Treatment, Two-Period Crossover Efficacy and Safety Study in Idiopathic Pulmonary Fibrosis With Nalbuphine ER Tablets for the Treatment of Cough
|
Summary
|
|
EudraCT number |
2018-004744-31 |
Trial protocol |
GB |
Global end of trial date |
27 May 2022
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
29 May 2025
|
First version publication date |
29 May 2025
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
TR12
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT04030026 | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
Trevi Therapeutics
|
||
Sponsor organisation address |
195 Church St, 14th Floor, New Haven, United States, 06510
|
||
Public contact |
VP Clinical Operations, Trevi Therapeutics, Inc., +1 203 304 2499,
|
||
Scientific contact |
VP Clinical Operations, Trevi Therapeutics, Inc., +1 203 304 2499,
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
27 May 2022
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
27 May 2022
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
27 May 2022
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
To evaluate the safety and tolerability of nalbuphine ER tablets in the study population and to evaluate the effect of NAL ER tablets on the mean daytime cough frequency (coughs per hour) at Day 22 (dose 162 mg BID) as compared to placebo tablets.
|
||
Protection of trial subjects |
Subjects were included with a level of respiratory and general health, per the inclusion/exclusion criteria.
Drugs with potential interactions with the study drug were restricted, per the inclusion/exclusion criteria.
Subjects were allowed to continue the anti-fibrotic treatment for IPF on a stable dose throughout the study, per the inclusion/exclusion criteria.
An independent Data Safety Monitoring Board (DSMB) periodically reviewed safety data.
Subjects were closely monitored for safety. AEs were continuously evaluated throughout the study. Vital signs, locally reviewed and central cardiac core laboratory-read ECGs, physical examinations, spirometry and clinical laboratory testing were conducted.
|
||
Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
29 Oct 2019
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
Yes
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
United Kingdom: 42
|
||
Worldwide total number of subjects |
42
|
||
EEA total number of subjects |
0
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
4
|
||
From 65 to 84 years |
37
|
||
85 years and over |
1
|
||
|
||||||||||||||||||||||||||||
|
Recruitment
|
||||||||||||||||||||||||||||
Recruitment details |
Subjects were enrolled at 11 sites in the United Kingdom from 29 October 2019 to 27 May 2022. | |||||||||||||||||||||||||||
|
Pre-assignment
|
||||||||||||||||||||||||||||
Screening details |
A total of 56 subjects were screened from whom 42 subjects were enrolled and randomized to receive treatment in this study. | |||||||||||||||||||||||||||
|
Period 1
|
||||||||||||||||||||||||||||
Period 1 title |
Treatment Period 1 (22 Days)
|
|||||||||||||||||||||||||||
Is this the baseline period? |
Yes | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
|
|||||||||||||||||||||||||||
Blinding used |
Double blind | |||||||||||||||||||||||||||
Roles blinded |
Investigator, Carer, Subject, Assessor | |||||||||||||||||||||||||||
Blinding implementation details |
This study utilized a cross-over design with all subjects planned to receive both placebo and active study treatment during the study. The treatments the subjects received, and the order of those treatments were double-blinded (blinding performed via Interactive Web Response System). Under normal circumstances, the blind was not broken. In the event of a medical emergency, when management of a subject’s condition required knowledge of the treatment assignment, the blind could have been broken.
|
|||||||||||||||||||||||||||
|
Arms
|
||||||||||||||||||||||||||||
Are arms mutually exclusive |
Yes
|
|||||||||||||||||||||||||||
|
Arm title
|
First NAL ER then Placebo | |||||||||||||||||||||||||||
Arm description |
Subjects 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. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Nalbuphine
|
|||||||||||||||||||||||||||
Investigational medicinal product code |
NAL ER
|
|||||||||||||||||||||||||||
Other name |
||||||||||||||||||||||||||||
Pharmaceutical forms |
Tablet
|
|||||||||||||||||||||||||||
Routes of administration |
Oral use
|
|||||||||||||||||||||||||||
Dosage and administration details |
Subjects received NAL ER 27 mg QD, 27 mg BID, 54 mg BID, 108 mg BID, and 162 mg BID for 3 weeks in treatment period 1.
|
|||||||||||||||||||||||||||
|
Arm title
|
First Placebo then NAL ER | |||||||||||||||||||||||||||
Arm description |
Subjects 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. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
|
|||||||||||||||||||||||||||
Investigational medicinal product code |
||||||||||||||||||||||||||||
Other name |
||||||||||||||||||||||||||||
Pharmaceutical forms |
Tablet
|
|||||||||||||||||||||||||||
Routes of administration |
Oral use
|
|||||||||||||||||||||||||||
Dosage and administration details |
Subjects received placebo for 3 weeks, in treatment period 1.
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
|
Period 2
|
||||||||||||||||||||||||||||
Period 2 title |
Treatment Period 2 (22 Days)
|
|||||||||||||||||||||||||||
Is this the baseline period? |
No | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
|
|||||||||||||||||||||||||||
Blinding used |
Double blind | |||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Carer, Assessor | |||||||||||||||||||||||||||
Blinding implementation details |
This study utilized a cross-over design with all subjects planned to receive both placebo and active study treatment during the study. The treatments the subjects received, and the order of those treatments were double-blinded (blinding performed via Interactive Web Response System). Under normal circumstances, the blind was not broken. In the event of a medical emergency, when management of a subject’s condition required knowledge of the treatment assignment, the blind could have been broken.
|
|||||||||||||||||||||||||||
|
Arms
|
||||||||||||||||||||||||||||
Are arms mutually exclusive |
Yes
|
|||||||||||||||||||||||||||
|
Arm title
|
First NAL ER then Placebo | |||||||||||||||||||||||||||
Arm description |
Subjects 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. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
|
|||||||||||||||||||||||||||
Investigational medicinal product code |
||||||||||||||||||||||||||||
Other name |
||||||||||||||||||||||||||||
Pharmaceutical forms |
Tablet
|
|||||||||||||||||||||||||||
Routes of administration |
Oral use
|
|||||||||||||||||||||||||||
Dosage and administration details |
Subjects received placebo for 3 weeks in treatment period 2.
|
|||||||||||||||||||||||||||
|
Arm title
|
First Placebo then NAL ER | |||||||||||||||||||||||||||
Arm description |
Subjects received placebo for 3 weeks in treatment period 2 followed by 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. Both the treatment periods were separated by 2 weeks of washout period. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Nalbuphine
|
|||||||||||||||||||||||||||
Investigational medicinal product code |
NAL ER
|
|||||||||||||||||||||||||||
Other name |
||||||||||||||||||||||||||||
Pharmaceutical forms |
Tablet
|
|||||||||||||||||||||||||||
Routes of administration |
Oral use
|
|||||||||||||||||||||||||||
Dosage and administration details |
Subjects received NAL ER 27 mg QD, 27 mg BID, 54 mg BID, 108 mg BID, 162 mg BID for 3 weeks in treatment period 2.
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
First NAL ER then Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
First Placebo then NAL ER
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Subject analysis sets
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set title |
NAL ER
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Subjects 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 by162 mg, BID for 6 days in treatment period 1 or 2 of the study.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set title |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Subjects received placebo for 3 weeks through treatment period 1 or 2 of the study.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
First NAL ER then Placebo
|
||
Reporting group description |
Subjects 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. | ||
Reporting group title |
First Placebo then NAL ER
|
||
Reporting group description |
Subjects 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. | ||
Reporting group title |
First NAL ER then Placebo
|
||
Reporting group description |
Subjects 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. | ||
Reporting group title |
First Placebo then NAL ER
|
||
Reporting group description |
Subjects received placebo for 3 weeks in treatment period 2 followed by 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. Both the treatment periods were separated by 2 weeks of washout period. | ||
Subject analysis set title |
NAL ER
|
||
Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Subjects 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 by162 mg, BID for 6 days in treatment period 1 or 2 of the study.
|
||
Subject analysis set title |
Placebo
|
||
Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Subjects received placebo for 3 weeks through treatment period 1 or 2 of the study.
|
||
|
||||||||||
End point title |
Number of Subjects Who Experienced at Least one Treatment Emergent Adverse Events (TEAEs) [1] | |||||||||
End point description |
AE was defined as untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with treatment.AE can be any unfavorable, unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to medicinal product. TEAE was defined as any AE that occurs after first dose of study drug. TEAEs included both serious and non-serious TEAEs. Safety analysis set (SAS) included all randomized subjects who had received at least 1 dose of IP. 3 subjects did not receive at least one dose of NAL ER but received placebo and 1 subject 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 (subjects who received both treatments are counted in both arms.
|
|||||||||
End point type |
Primary
|
|||||||||
End point timeframe |
Up to Day 72
|
|||||||||
| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned to be performed for this endpoint. |
||||||||||
|
||||||||||
| No statistical analyses for this end point | ||||||||||
|
|||||||||||||||||||||||||
End point title |
Number of Subjects With Clinically Significant Abnormalities in Laboratory Parameters [2] | ||||||||||||||||||||||||
End point description |
The clinical laboratory parameters included the urinalysis, hematology, serum chemistry, coagulation and liver function parameters. Clinical significance was determined by the investigator. SAS included all randomized subjects who had received at least 1 dose of IP. 3 subjects did not receive at least one dose of NAL ER but received placebo and 1 subject 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 (subjects who received both treatments are counted in both arms.
|
||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||
End point timeframe |
Up to Day 72
|
||||||||||||||||||||||||
| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned to be performed for this endpoint. |
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
||||||||||
End point title |
Number of Subjects With Clinically Significant Changes in Vital Sign Parameters [3] | |||||||||
End point description |
Vital signs measurements included blood pressure, heart rate, and respiration rate, body temperature, pulse oximetry, and weight. Clinical significance was determined by the investigator. SAS included all randomized subjects who had received at least 1 dose of IP. 3 subjects did not receive at least one dose of NAL ER but received placebo and 1 subject 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 (subjects who received both treatments are counted in both arms.
|
|||||||||
End point type |
Primary
|
|||||||||
End point timeframe |
Up to Day 72
|
|||||||||
| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned to be performed for this endpoint. |
||||||||||
|
||||||||||
| No statistical analyses for this end point | ||||||||||
|
||||||||||
End point title |
Number of Subjects With Clinically Significant Changes in Physical Examination Parameters [4] | |||||||||
End point description |
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. SAS included all randomized subjects who had received at least 1 dose of IP. 3 subjects did not receive at least one dose of NAL ER but received placebo and 1 subject 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 (subjects who received both treatments are counted in both arms.
|
|||||||||
End point type |
Primary
|
|||||||||
End point timeframe |
Up to Day 72
|
|||||||||
| Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned to be performed for this endpoint. |
||||||||||
|
||||||||||
| No statistical analyses for this end point | ||||||||||
|
||||||||||
End point title |
Number of Subjects With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECG) [5] | |||||||||
End point description |
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. SAS included all randomized subjects who had received at least 1 dose of IP. 3 subjects did not receive at least one dose of NAL ER but received placebo and 1 subject 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 (subjects who received both treatments are counted in both arms.
|
|||||||||
End point type |
Primary
|
|||||||||
End point timeframe |
Up to Day 72
|
|||||||||
| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned to be performed for this endpoint. |
||||||||||
|
||||||||||
| No statistical analyses for this end point | ||||||||||
|
|||||||||||||
End point title |
Change From Baseline in Forced Vital Capacity (FVC) at Day 21 [6] | ||||||||||||
End point description |
Spirometry was used to assess FVC. It was used to assess pulmonary breathing mechanics. Subjects in SAS were analyzed. 3 subjects did not receive at least 1 dose of NAL ER but received placebo and 1 subject 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 (subjects who received both treatments are counted in both NAL ER and placebo columns). Overall number of subjects analyzed’=subjects who were evaluable for the OM.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Baseline, Day 21
|
||||||||||||
| Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned to be performed for this endpoint. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Subjective Opiate Withdrawal (SOWS) Total Raw Score [7] | ||||||||||||
End point description |
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 subject felt. Each symptom was scored between 0 to 4. The total score ranges between 0 to 64, higher score indicates more severe symptoms. Subjects in SAS were analyzed. 3 subjects did not receive at least 1 dose of NAL ER but received placebo and 1 subject 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 (subjects who received both treatments are counted in both NAL ER and placebo columns). Overall number of subjects analyzed’=subjects who were evaluable for the OM.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Up to Day 72
|
||||||||||||
| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned to be performed for this endpoint. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Percent Change From Baseline in Daytime Cough Frequency at Day 22 | ||||||||||||
End point description |
Daytime cough was defined as cough that occurs between the time that the subject 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 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. Full Analysis Set (FAS) included all randomized subjects 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 of subjects analysed' included those subjects who were evaluable for this endpoint.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Baseline, Day 22
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
NAL ER vs Placebo | ||||||||||||
Comparison groups |
NAL ER v Placebo
|
||||||||||||
Number of subjects included in analysis |
66
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [8] | ||||||||||||
Method |
Mixed-effects model | ||||||||||||
Parameter type |
Geometric Mean Ratio | ||||||||||||
Point estimate |
0.32
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.208 | ||||||||||||
upper limit |
0.431 | ||||||||||||
| Notes [8] - Mixed-effects model: unstructured, heterogeneous toeplitz and autoregressive covariance matrices. Dependent variable: change from baseline in log-transformed scale of Daytime Cough Frequency. Fixed effects: sequence (arm), period and treatment. |
|||||||||||||
|
|||||||||||||
End point title |
Change From Baseline in Daytime Cough Frequency at Day 22 | ||||||||||||
End point description |
Daytime cough was defined as cough that occurs between the time that the subject wakes up and the time that the subject 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. FAS included all randomized subjects 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 of subjects analysed' included those subjects who were evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Day 22
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Percent Change From Baseline in 24-Hour Cough Frequency at Day 22 | ||||||||||||
End point description |
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. FAS included all randomized subjects 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 of subjects analysed' included those subjects who were evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Day 22
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
NAL ER vs Placebo | ||||||||||||
Comparison groups |
NAL ER v Placebo
|
||||||||||||
Number of subjects included in analysis |
66
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [9] | ||||||||||||
Method |
Mixed-effects model | ||||||||||||
Parameter type |
Geometric Mean Ratio | ||||||||||||
Point estimate |
0.32
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.208 | ||||||||||||
upper limit |
0.431 | ||||||||||||
| Notes [9] - Mixed-effects model: unstructured, heterogeneous toeplitz and autoregressive covariance matrices. Dependent variable: change from baseline in log-transformed scale of Daytime Cough Frequency. Fixed effects: sequence (arm), period and treatment. |
|||||||||||||
|
|||||||||||||
End point title |
Percent Change From Baseline in Nighttime Cough Frequency at Day 22 | ||||||||||||
End point description |
Nighttime cough frequency was intended as the average coughs per hour while the subject 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. FAS included all randomized subjects 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 of subjects analysed' included those subjects who were evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Day 22
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
NAL ER vs Placebo | ||||||||||||
Comparison groups |
Placebo v NAL ER
|
||||||||||||
Number of subjects included in analysis |
66
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0087 [10] | ||||||||||||
Method |
Mixed-effects model | ||||||||||||
Parameter type |
Geometric Mean Ratio | ||||||||||||
Point estimate |
0.47
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.23 | ||||||||||||
upper limit |
0.717 | ||||||||||||
| Notes [10] - Mixed-effects model: unstructured, heterogeneous toeplitz and autoregressive covariance matrices. Dependent variable: change from baseline in log-transformed scale of Daytime Cough Frequency. Fixed effects: sequence (arm), period and treatment. |
|||||||||||||
|
||||||||||||||||||||||
End point title |
Mean Change From Baseline in the Evaluating Respiratory Symptoms (E-RS) Diary Cough Subscale at Days 9, 16, and 22 | |||||||||||||||||||||
End point description |
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, sputum, and chest symptoms. The raw totals for the E-RS for each subscales were converted to a scale range of 0 to 100 (least symptomatic to most symptomatic). Higher score =more severe grade to the symptom. Negative score=improvement in symptoms. Baseline was defined as the last available assessment prior to the first Treatment Period 1 IP intake. FAS =randomized subjects who received at least single dose of the study medication and provided study baseline and one post -baseline primary efficacy assessment. ‘Number analyzed’= data available for analysis at the specified timepoint.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Days 9, 16, and 22
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
NAL ER vs Placebo | |||||||||||||||||||||
Statistical analysis description |
Change from baseline at Day 9
|
|||||||||||||||||||||
Comparison groups |
Placebo v NAL ER
|
|||||||||||||||||||||
Number of subjects included in analysis |
76
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority | |||||||||||||||||||||
P-value |
= 0.0014 [11] | |||||||||||||||||||||
Method |
Student's T-test | |||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
| Notes [11] - Student's T-test was used to evaluate if the difference in mean change from baseline is different between planned treatments (NAL ER vs placebo). |
||||||||||||||||||||||
Statistical analysis title |
NAL ER vs Placebo | |||||||||||||||||||||
Statistical analysis description |
Change from baseline at Day 16
|
|||||||||||||||||||||
Comparison groups |
Placebo v NAL ER
|
|||||||||||||||||||||
Number of subjects included in analysis |
76
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority | |||||||||||||||||||||
P-value |
= 0.0001 [12] | |||||||||||||||||||||
Method |
Student's T-test | |||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
| Notes [12] - Student's T-test was used to evaluate if the difference in mean change from baseline is different between planned treatments (NAL ER vs placebo). |
||||||||||||||||||||||
Statistical analysis title |
NAL ER vs Placebo | |||||||||||||||||||||
Statistical analysis description |
Change from baseline at Day 22
|
|||||||||||||||||||||
Comparison groups |
NAL ER v Placebo
|
|||||||||||||||||||||
Number of subjects included in analysis |
76
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority | |||||||||||||||||||||
P-value |
= 0.001 [13] | |||||||||||||||||||||
Method |
Student's T-test | |||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
| Notes [13] - Student's T-test was used to evaluate if the difference in mean change from baseline is different between planned treatments (NAL ER vs placebo). |
||||||||||||||||||||||
|
||||||||||||||||||||||
End point title |
Mean Change from Baseline in E-RS Breathlessness Score at Days 9, 16, and 22 | |||||||||||||||||||||
End point description |
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.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].Raw totals for the E-RS 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 symptoms.Baseline=last available assessment prior to the first Treatment Period 1 investigational product intake.FAS=randomized subjects who received at least single dose of the study medication and provided study baseline and one post -baseline primary efficacy assessment. ‘Number analyzed’= data available for analysis at the specified timepoint.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Days 9, 16 and 22
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
NAL ER vs Placebo | |||||||||||||||||||||
Statistical analysis description |
Change from baseline at Day 9
|
|||||||||||||||||||||
Comparison groups |
NAL ER v Placebo
|
|||||||||||||||||||||
Number of subjects included in analysis |
76
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority | |||||||||||||||||||||
P-value |
= 0.0198 [14] | |||||||||||||||||||||
Method |
Student's T-test | |||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
| Notes [14] - Student's T-test was used to evaluate if the difference in mean change from baseline is different between planned treatments (NAL ER vs placebo). |
||||||||||||||||||||||
Statistical analysis title |
NAL ER vs Placebo | |||||||||||||||||||||
Statistical analysis description |
Change from baseline at Day 16
|
|||||||||||||||||||||
Comparison groups |
NAL ER v Placebo
|
|||||||||||||||||||||
Number of subjects included in analysis |
76
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority | |||||||||||||||||||||
P-value |
= 0.0374 [15] | |||||||||||||||||||||
Method |
Student's T-test | |||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
| Notes [15] - Student's T-test was used to evaluate if the difference in mean change from baseline is different between planned treatments (NAL ER vs placebo). |
||||||||||||||||||||||
Statistical analysis title |
NAL ER vs Placebo | |||||||||||||||||||||
Statistical analysis description |
Change from baseline at Day 22
|
|||||||||||||||||||||
Comparison groups |
Placebo v NAL ER
|
|||||||||||||||||||||
Number of subjects included in analysis |
76
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority | |||||||||||||||||||||
P-value |
= 0.2982 [16] | |||||||||||||||||||||
Method |
Student's T-test | |||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
| Notes [16] - Student's T-test was used to evaluate if the difference in mean change from baseline is different between planned treatments (NAL ER vs placebo). |
||||||||||||||||||||||
|
||||||||||||||||||||||
End point title |
Mean Change From Baseline in the Cough Severity Numerical Rating Scale at Days 8, 15, and 21 | |||||||||||||||||||||
End point description |
The Cough Severity NRS instrument is a single-dimension 11-point Likert scale ranging from 0 (no cough) to 10 (worst possible cough). Subjects 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. FAS included all randomized subjects 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. Here, 'n’ signifies number of subjects analysed for this endpoint.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Days 8, 15, and 21
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
NAL ER vs Placebo | |||||||||||||||||||||
Statistical analysis description |
Change from baseline at Day 8
|
|||||||||||||||||||||
Comparison groups |
NAL ER v Placebo
|
|||||||||||||||||||||
Number of subjects included in analysis |
76
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority | |||||||||||||||||||||
P-value |
= 0.0054 [17] | |||||||||||||||||||||
Method |
Student's T-test | |||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
| Notes [17] - Student's T-test was used to evaluate if the difference in mean change from baseline is different between planned treatments (NAL ER vs placebo) |
||||||||||||||||||||||
Statistical analysis title |
NAL ER vs Placebo | |||||||||||||||||||||
Statistical analysis description |
Change from baseline at Day 15
|
|||||||||||||||||||||
Comparison groups |
NAL ER v Placebo
|
|||||||||||||||||||||
Number of subjects included in analysis |
76
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority | |||||||||||||||||||||
P-value |
< 0.0001 [18] | |||||||||||||||||||||
Method |
Student's T-test | |||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
| Notes [18] - Student's T-test was used to evaluate if the difference in mean change from baseline is different between planned treatments (NAL ER vs placebo). |
||||||||||||||||||||||
Statistical analysis title |
NAL ER vs Placebo | |||||||||||||||||||||
Statistical analysis description |
Change from baseline at Day 21
|
|||||||||||||||||||||
Comparison groups |
NAL ER v Placebo
|
|||||||||||||||||||||
Number of subjects included in analysis |
76
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority | |||||||||||||||||||||
P-value |
= 0.0001 [19] | |||||||||||||||||||||
Method |
Student's T-test | |||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
| Notes [19] - Student's T-test was used to evaluate if the difference in mean change from baseline is different between planned treatments (NAL ER vs placebo). |
||||||||||||||||||||||
|
||||||||||||||||||||||
End point title |
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 | |||||||||||||||||||||
End point description |
EXACT tool is a 14-item Daily Diary Tool Patient-reported outcome (PRO) instrument developed to quantify and measure exacerbations of 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. Total score of each domain of breathlessness, cough and sputum, and chest symptoms ranges from 0 to 100. Higher score indicated a more severe condition. Negative score=improvement. Baseline was defined as the last available assessment prior to the first Treatment Period 1 IP intake.FAS included all randomized subjects 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.Here,'n’ signifies number of subjects analysed for this endpoint.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Days 9, 16, and 22
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
NAL ER vs Placebo | |||||||||||||||||||||
Statistical analysis description |
Change from baseline at Day 9
|
|||||||||||||||||||||
Comparison groups |
NAL ER v Placebo
|
|||||||||||||||||||||
Number of subjects included in analysis |
76
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority | |||||||||||||||||||||
P-value |
= 0.0107 [20] | |||||||||||||||||||||
Method |
Student's T-test | |||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
| Notes [20] - Student's T-test was used to evaluate if the difference in mean change from baseline is different between planned treatments (NAL ER vs placebo). |
||||||||||||||||||||||
Statistical analysis title |
NAL ER vs Placebo | |||||||||||||||||||||
Statistical analysis description |
Change for baseline at Day 16
|
|||||||||||||||||||||
Comparison groups |
NAL ER v Placebo
|
|||||||||||||||||||||
Number of subjects included in analysis |
76
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority | |||||||||||||||||||||
P-value |
= 0.0051 [21] | |||||||||||||||||||||
Method |
Student's T-test | |||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
| Notes [21] - Student's T-test was used to evaluate if the difference in mean change from baseline is different between planned treatments (NAL ER vs placebo). |
||||||||||||||||||||||
Statistical analysis title |
NAL ER vs Placebo | |||||||||||||||||||||
Statistical analysis description |
Change from baseline at Day 22
|
|||||||||||||||||||||
Comparison groups |
NAL ER v Placebo
|
|||||||||||||||||||||
Number of subjects included in analysis |
76
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority | |||||||||||||||||||||
P-value |
= 0.1513 [22] | |||||||||||||||||||||
Method |
Student's T-test | |||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
| Notes [22] - Student's T-test was used to evaluate if the difference in mean change from baseline is different between planned treatments (NAL ER vs placebo). |
||||||||||||||||||||||
|
|||||||||||||
End point title |
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 | ||||||||||||
End point description |
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. FAS included all randomized subjects 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. Baseline was defined as the last available assessment prior to the first Treatment Period 1 IP intake. 'Number of subjects analysed' included those subjects who were evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Day 21
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
NAL ER vs Placebo | ||||||||||||
Comparison groups |
NAL ER v Placebo
|
||||||||||||
Number of subjects included in analysis |
54
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.3601 [23] | ||||||||||||
Method |
Student's T-test | ||||||||||||
Confidence interval |
|||||||||||||
| Notes [23] - Student's T-test was used to evaluate if the difference in mean change from baseline is different between planned treatments (NAL ER vs placebo). |
|||||||||||||
|
|||||||||||||
End point title |
Clinical Global Impression of Change (CGI-C) Over Time Measured at Day 21 | ||||||||||||
End point description |
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. FAS included all randomized subjects 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 of subjects analysed' included those subjects who were evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At Day 21
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Up to Day 72
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
All-cause mortality: All randomized subjects. AEs: SAS included all randomized subjects who received ≥1 dose of IP. 3 received only placebo, 1 only NAL ER. Data summarized by actual treatment received (NAL ER/placebo), regardless of period; subjects receiving both counted in both.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.1
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
NAL ER
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received placebo for 3 weeks through treatment period 1 or 2 of the study. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||
Substantial protocol amendments (globally) |
|||||||
| Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
||||||
08 Apr 2019 |
Incorporated MHRA feedback:
• Added exclusion for patients taking medications which may
induce serotonin syndrome.
• Added exclusion for patients taking benzodiazepines,
alcohol, and other CNS depressants.
• Deleted the following sentence from Section 9.3
(“Procedures for Breaking the Randomization Code”),
“Investigators contemplating unblinding a subject should
make every effort to contact the Medical Monitor prior to
unblinding.” Unblinding of treatment assignments is at the
discretion of the site medical personnel. |
||||||
13 Jun 2019 |
Incorporated suggestions in from the overall study
team/Investigators based on the experiences with practical
implementations of the protocol.
• Modified the primary objectives to update the definition of
‘daytime’ wherein the digital cough monitor was the tool
used to obtain cough frequency. The text related to the
primary efficacy endpoint was updated to be consistent
with the primary objective.
• Modified the secondary objective based on the discussions
with the scientific team and the cough monitor experts. The
text related to secondary endpoint was also updated to be
consistent with the secondary objective.
• Increased the number of sites from 10 sites to
approximately 15.
• Updated the study procedures related to:
- inclusion of triplicate ECG runs,
- use of e-diary,
- administration of certain scales in the study that will
use the e-diary,
- use and restrictions of opioid medication,
- corrections of previous SOWS document,
- administration of the Cough Severity Numerical Rating
Scale during the study,
- removal of cough monitor in relation to dosing and
procedure to return it.
• Corrected the administrative issues and other minor errors. |
||||||
15 Nov 2019 |
Incorporated suggestions from the overall investigative
sites; based on their experiences with practical
implementation of the protocol.
• Updated the exclusion criteria related to:
- ECG assessments where the ECG assessments had to
be performed in triplicate within the 3-5 minute period
and if any of the 3 tracings were out of range, the
subject had to be excluded,
- length of time and modality constituting the continuous
oxygen therapy,
- limitation of alcohol consumption instead of
prohibition during the study treatment due to potential
CNS effects
• Clarified the study procedures related to:
- the timeframe (29 days) for randomization with
relation to the Screening period
- clinical laboratory tests where subjects had to be in a
fasting state at the time of the laboratory assessments
unless contraindicated due to clinical reasons
- inclusion of rescreening at the discretion of the medical
monitor and written permission from the Sponsor
- spirometry
- swallow test
- safety monitoring and assessments regarding
clarification that ECGs had to be locally reviewed at
the site level (for safety) in addition to the central
cardiac laboratory-read.
• Corrected minor administrative errors for clarity and
consistency of suggested order of procedures. |
||||||
17 Jul 2020 |
Updated study procedures as part of the mitigation
strategies due to COVID-19 pandemic:
- extended the overall study timelines due to enrollment
challenges and to provide greater flexibility to sites for
scheduling subject visits
- added potential countries to the study
- reduced the number and frequency of the interpersonal
(face-to-face) contact between subject population and
the site personnel for the efficacy and safety
assessments to reduce exposure of this high-risk
subject population
- increased the enrollment of subjects to allow for the
possibility that COVID-19 related disruption could
result in the premature discontinuation of subjects
- allowed for utilization of the telemedicine in order to
decrease face-to-face contact and reduce exposure of
high risk subject population
- provided greater flexibility to sites for scheduling
subject visits and facilitate adherence to protocol
requirements
- provided administrative clarification throughout the
protocol including for rescreening subjects
- provided administrative changes throughout the
protocol for clarity.
• Clarified the statistical analysis methodology for data
analysis using continuous-based methods
• Clarified the wording and rationale for use of the e-diary
instrument to capture data from EXACT 14-item e-diary
Tool and E-RS Diary Cough and Breathlessness Scales |
||||||
11 Jun 2021 |
Clarified the QTcF values in exclusion criteria #30 and 31
to prevent exclusion of subjects who were presented with
Right Bundle Branch block.
• Modified the withdrawal criteria related to QTcF to
accurately reflect the electrophysiologically meaningful
change on ECG parameters that would be used as the basis
for excluding subjects from the study.
• Deleted text related to QTcF>500 ms was deleted in
sections related to ECG assessments as QTcF clarifications
and appropriate actions to be taken are provided in the
withdrawal criteria section.
• Modified text in sections related to ECG assessments to
clarify that local ECG read was for safety purposes and
central ECG read was related to subject
inclusion/withdrawal.
• Corrected minor administrative errors. |
||||||
14 Dec 2021 |
Modified text related to sample size and power to allow for
a potential statistical update when a minimum of 12
subjects had completed the study periods for the purposes
of determining whether POC could be established prior to
complete enrollment of the study.
• Updated the Sponsor contact information was updated.
• Other administrative updates were done as needed for
consistency with the above changes (additions to
abbreviations list, updated document date and version
number). |
||||||
Interruptions (globally) |
|||||||
| Were there any global interruptions to the trial? Yes | |||||||
|
|||||||
Limitations and caveats |
|||||||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| None reported | |||||||
