Trial Outcomes & Findings for Efficacy and Safety of Hydrocodone Bitartrate Extended-Release Tablets for Moderate to Severe Chronic Low Back Pain (NCT NCT01789970)

Last Updated: 2017-06-05

Results Overview

The WPI was recorded daily by participants in an electronic diary using an 11-point numerical rating scale (NRS-11), a Likert-type scale in which 0=no pain and 10=the worst pain imaginable. Participants selected the number that best described their worst pain intensity over the last 24 hours. Weekly WPI scores averaged daily scores collected over the previous 7 days for each analysis visit. Negative change from baseline scores indicate improvement in pain control. The analysis included WPI data observed before discontinuation of study drug and was based on the multiple imputations (MI) method to handle missing scores at week 12. Consistent with the recommendations of the National Academy of Sciences (NAS) report (Panel on Handling Missing Data in Clinical Trials 2010), the MI method includes an assumption of missing at random (MAR) and takes into account a potential bias toward the active-drug treatment group for patients who discontinued study drug because of adverse events.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

625 participants

Primary outcome timeframe

Days -6 to 0 of Treatment Period (baseline), Week 12 of Treatment Period

Results posted on

2017-06-05

Participant Flow

A total of 845 patients with moderate to severe chronic low back pain were screened at 78 centers in the U.S.

Of the 625 patients enrolled, 2 patients withdrew consent before taking any study drug. Of 623 patients who were enrolled and received study drug, 371 patients achieved a successful dose of hydrocodone extended-release (ER) tablets and were randomly assigned to receive hydrocodone ER or placebo during the double-blind treatment period

Participant milestones

Participant milestones
Measure	Hydrocodone ER (Open-Label Titration Period) All participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours to identify a dosage deemed successful for managing their pain.	Placebo (Double-blind Treatment Period) Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Open-label Titration Period STARTED	625	0	0
Open-label Titration Period Safety Analysis Set	623	0	0
Open-label Titration Period COMPLETED	371	0	0
Open-label Titration Period NOT COMPLETED	254	0	0
Double-blind Treatment Period (12 Weeks) STARTED	0	180	191
Double-blind Treatment Period (12 Weeks) Full Analysis Set and Safety Set	0	179	191
Double-blind Treatment Period (12 Weeks) COMPLETED	0	130	147
Double-blind Treatment Period (12 Weeks) NOT COMPLETED	0	50	44

Reasons for withdrawal

Reasons for withdrawal
Measure	Hydrocodone ER (Open-Label Titration Period) All participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours to identify a dosage deemed successful for managing their pain.	Placebo (Double-blind Treatment Period) Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Open-label Titration Period Adverse Event	68	0	0
Open-label Titration Period Lack of Efficacy	31	0	0
Open-label Titration Period Withdrawal by Subject	31	0	0
Open-label Titration Period Protocol Violation	18	0	0
Open-label Titration Period Lost to Follow-up	5	0	0
Open-label Titration Period Noncompliance to study drug admin	11	0	0
Open-label Titration Period Noncompliance with study rescue meds	2	0	0
Open-label Titration Period Noncompliance with study procedures	8	0	0
Open-label Titration Period Pregnancy	2	0	0
Open-label Titration Period Other	76	0	0
Open-label Titration Period Dropped out prior to dosing	2	0	0
Double-blind Treatment Period (12 Weeks) Adverse Event	0	9	15
Double-blind Treatment Period (12 Weeks) Lack of Efficacy	0	17	5
Double-blind Treatment Period (12 Weeks) Withdrawal by Subject	0	7	9
Double-blind Treatment Period (12 Weeks) Protocol Violation	0	9	7
Double-blind Treatment Period (12 Weeks) Noncompliance to study drug admin	0	2	2
Double-blind Treatment Period (12 Weeks) Noncompliance with study procedures	0	2	1
Double-blind Treatment Period (12 Weeks) Lost to Follow-up	0	1	2
Double-blind Treatment Period (12 Weeks) Pregnancy	0	1	0
Double-blind Treatment Period (12 Weeks) Other	0	1	3
Double-blind Treatment Period (12 Weeks) Dropped out prior to dosing	0	1	0

Baseline Characteristics

Efficacy and Safety of Hydrocodone Bitartrate Extended-Release Tablets for Moderate to Severe Chronic Low Back Pain

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo (Double-blind Treatment Period) n=180 Participants Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) n=191 Participants Participants were administered extended-release hydrocodone tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.	Total n=371 Participants Total of all reporting groups
Age, Continuous	51.8 years STANDARD_DEVIATION 12.51 • n=93 Participants	51.7 years STANDARD_DEVIATION 13.48 • n=4 Participants	51.8 years STANDARD_DEVIATION 13.00 • n=27 Participants
Age, Customized <= 65 years	154 Participants n=93 Participants	156 Participants n=4 Participants	310 Participants n=27 Participants
Age, Customized > 65 years	26 Participants n=93 Participants	35 Participants n=4 Participants	61 Participants n=27 Participants
Sex: Female, Male Female	92 Participants n=93 Participants	97 Participants n=4 Participants	189 Participants n=27 Participants
Sex: Female, Male Male	88 Participants n=93 Participants	94 Participants n=4 Participants	182 Participants n=27 Participants
Race White	129 Participants n=93 Participants	133 Participants n=4 Participants	262 Participants n=27 Participants
Race Black	41 Participants n=93 Participants	39 Participants n=4 Participants	80 Participants n=27 Participants
Race Asian	8 Participants n=93 Participants	13 Participants n=4 Participants	21 Participants n=27 Participants
Race American Indian or Alaska Native	2 Participants n=93 Participants	2 Participants n=4 Participants	4 Participants n=27 Participants
Race Native Hawaiian or other Pacific Islander	0 Participants n=93 Participants	1 Participants n=4 Participants	1 Participants n=27 Participants
Race Other	0 Participants n=93 Participants	3 Participants n=4 Participants	3 Participants n=27 Participants
Ethnicity Hispanic or Latino	23 Participants n=93 Participants	24 Participants n=4 Participants	47 Participants n=27 Participants
Ethnicity Non-Hispanic and non-Latino	156 Participants n=93 Participants	167 Participants n=4 Participants	323 Participants n=27 Participants
Ethnicity Unknown	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants
Body Mass Index	31.5 kg/m^2 STANDARD_DEVIATION 8.22 • n=93 Participants	31.3 kg/m^2 STANDARD_DEVIATION 7.37 • n=4 Participants	31.4 kg/m^2 STANDARD_DEVIATION 7.78 • n=27 Participants
Participant Opioid Status Opioid-naive	105 Participants n=93 Participants	110 Participants n=4 Participants	215 Participants n=27 Participants
Participant Opioid Status Opioid-experienced	75 Participants n=93 Participants	81 Participants n=4 Participants	156 Participants n=27 Participants
Duration Since Diagnosis of Chronic Low Back Pain	11.5 years STANDARD_DEVIATION 10.35 • n=93 Participants	11.3 years STANDARD_DEVIATION 10.29 • n=4 Participants	11.4 years STANDARD_DEVIATION 10.31 • n=27 Participants
Duration of Opioid Therapy	2.9 years STANDARD_DEVIATION 3.76 • n=93 Participants	3.5 years STANDARD_DEVIATION 4.85 • n=4 Participants	3.2 years STANDARD_DEVIATION 4.37 • n=27 Participants
Average Daily Hydrocodone Equivalent Dose	18.2 mg STANDARD_DEVIATION 28.55 • n=93 Participants	22.1 mg STANDARD_DEVIATION 30.18 • n=4 Participants	20.2 mg STANDARD_DEVIATION 29.43 • n=27 Participants

PRIMARY outcome

Timeframe: Days -6 to 0 of Treatment Period (baseline), Week 12 of Treatment Period

Population: The full analysis set, which includes all randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline efficacy observation.

Outcome measures

Outcome measures
Measure	Placebo (Double-blind Treatment Period) n=179 Participants Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) n=191 Participants Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.	Placebo (Double-blind Treatment Period) Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Change From Baseline to Week 12 of the Treatment Period in Weekly Average of Daily Worst Pain Intensity (WPI)	0.71 units on a scale Standard Error 0.145	0.07 units on a scale Standard Error 0.134	—	—

SECONDARY outcome

Timeframe: Days -6 to 0 of Treatment Period (baseline), Week 12

Population: The full analysis set, which includes all randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline efficacy observation.

The API over the last 24 hours was recorded daily by patients in an electronic diary using an 11-point numerical rating scale (NRS-11), a Likert-type scale in which 0=no pain and 10=the worst pain imaginable. Participants selected the number that best described the average pain intensity over the last 24 hours. Weekly API scores averaged daily scores collected over the previous 7 days for each analysis visit. Negative change from baseline scores indicate improvement in pain control. The analysis included API data observed before discontinuation of study drug and was based on the MI method to handle missing scores at week 12. Consistent with the recommendations of the National Academy of Sciences (NAS) report (Panel on Handling Missing Data in Clinical Trials 2010), the MI method includes an assumption of missing at random (MAR) and takes into account a potential bias toward the active-drug treatment group for patients who discontinued study drug because of adverse events.

Outcome measures

Outcome measures
Measure	Placebo (Double-blind Treatment Period) n=179 Participants Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) n=191 Participants Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.	Placebo (Double-blind Treatment Period) Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Change From Baseline to Week 12 of the Treatment Period in Weekly Average Pain Intensity (API)	0.57 units on a scale Standard Error 0.126	0.02 units on a scale Standard Error 0.116	—	—

SECONDARY outcome

Timeframe: Day 1 to Week 12 of Treatment Period

Population: The full analysis set, which includes all randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline efficacy observation.

Time to loss of efficacy was defined as discontinuation of study drug for lack of efficacy or the start of excessive rescue medication while taking study drug. Excessive rescue medication usage was defined as 10 or more days of rescue medication usage in any 14 consecutive days at a total of 15 mg (hydrocodone-equivalent) or higher each day during the post 2-week tapering period of the double-blind treatment period.

Outcome measures

Outcome measures
Measure	Placebo (Double-blind Treatment Period) n=179 Participants Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) n=191 Participants Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.	Placebo (Double-blind Treatment Period) Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Kaplan-Meier Estimates for Time to Loss of Efficacy	NA days Insufficient number of participants with loss of efficacy	NA days Insufficient number of participants with loss of efficacy	—	—

SECONDARY outcome

Timeframe: Days -6 to 0 of Treatment Period (baseline), Week 12

Population: Full analysis set, including participants with observed weekly average API for week 12

The API over the last 24 hours was recorded daily by participants in an electronic diary using an 11-point numerical rating scale (NRS-11), a Likert-type scale in which 0=no pain and 10=the worst pain imaginable. Participants selected the number that best described the average pain intensity over the last 24 hours. Weekly API scores averaged daily scores collected over the previous 7 days for each analysis visit.

Outcome measures

Outcome measures
Measure	Placebo (Double-blind Treatment Period) n=133 Participants Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) n=152 Participants Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.	Placebo (Double-blind Treatment Period) Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Percentage of Participants With a 30% or Greater Increase in Weekly Average Pain Intensity (API) From Baseline to Week 12 Visit, and an Average API Score of 5 or Higher at Week 12 API >=5	24.1 percentage of participants	16.4 percentage of participants	—	—
Percentage of Participants With a 30% or Greater Increase in Weekly Average Pain Intensity (API) From Baseline to Week 12 Visit, and an Average API Score of 5 or Higher at Week 12 API increase >=30% and API >=5	18.8 percentage of participants	12.5 percentage of participants	—	—
Percentage of Participants With a 30% or Greater Increase in Weekly Average Pain Intensity (API) From Baseline to Week 12 Visit, and an Average API Score of 5 or Higher at Week 12 API increase >=30%	36.1 percentage of participants	21.1 percentage of participants	—	—

SECONDARY outcome

Timeframe: Days 7-14 of Titration Period (baseline), Week 12 or end of study visit during the Treatment Period

Population: Full analysis set, including participants with RMDQ score for the final on-treatment visit.

The RMDQ is a patient-rated, 24-question evaluation used to assess acute disability associated with low back pain. Each question is answered with a YES or NO response, and each YES response is given 1 point. Scores on the RMDQ range from 0 to 24, with higher scores indicating greater disability. Negative change from baseline scores indicate improvement in level of disability.

Outcome measures

Outcome measures
Measure	Placebo (Double-blind Treatment Period) n=171 Participants Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) n=178 Participants Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.	Placebo (Double-blind Treatment Period) Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Change From Baseline to Final On-Treatment Visit in Roland Morris Disability Questionnaire (RMDQ) Score	-1.9 units on a scale Standard Deviation 4.47	-1.5 units on a scale Standard Deviation 4.70	—	—

SECONDARY outcome

Timeframe: Day 1 of Titration Period up to Week 12 of Treatment Period (maximum treatment duration was 127 days)

Population: Safety analysis set (Titration Period) and Full analysis set (Treatment Period)

An adverse event (AE) was defined in the protocol as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an inability to carry out usual activities. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.

Outcome measures

Outcome measures
Measure	Placebo (Double-blind Treatment Period) n=368 Participants Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) n=255 Participants Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.	Placebo (Double-blind Treatment Period) n=179 Participants Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) n=191 Participants Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Participants With Adverse Events During Open-Label Titration and Double-Blind Treatment Periods Severe adverse event	13 Participants	5 Participants	3 Participants	9 Participants
Participants With Adverse Events During Open-Label Titration and Double-Blind Treatment Periods Deaths	0 Participants	0 Participants	0 Participants	0 Participants
Participants With Adverse Events During Open-Label Titration and Double-Blind Treatment Periods Serious adverse event	6 Participants	4 Participants	3 Participants	3 Participants
Participants With Adverse Events During Open-Label Titration and Double-Blind Treatment Periods Discontinued study drug treatment due to AE	53 Participants	22 Participants	7 Participants	11 Participants
Participants With Adverse Events During Open-Label Titration and Double-Blind Treatment Periods Any adverse event	196 Participants	117 Participants	88 Participants	106 Participants
Participants With Adverse Events During Open-Label Titration and Double-Blind Treatment Periods Treatment-related adverse event	166 Participants	81 Participants	50 Participants	67 Participants

SECONDARY outcome

Timeframe: Days 7-14 of Titration Period (baseline), Day 0 of Treatment Period (last day of Titration Period), Week 12 or end of study visit during the Treatment Period

Population: Safety analysis set (entire study), Full analysis set (treatment period)

Pure tone audiometry was performed by a qualified audiologist and was not done at the study center. During the test, the patient wore headphones and was seated in a quiet room; trained personnel manipulated the audiometry equipment to test the patient's hearing. For serial audiograms, the criteria for a clinically significant (CS) hearing change were based on the guidance from the American Speech-Language Hearing Association (ASHA) 1994 (Konrad-Martin et al 2005). These criteria included the following: greater than 20 decibels (dB) pure tone threshold shift at 1 frequency; greater than 10 dB shift at 2 consecutive test frequencies; or threshold response shifting to "no response" at 3 consecutive test frequencies.

Outcome measures

Outcome measures
Measure	Placebo (Double-blind Treatment Period) n=623 Participants Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) n=179 Participants Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.	Placebo (Double-blind Treatment Period) n=191 Participants Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Participants With Clinically Significant Hearing Changes From Baseline to Final Assessment in Pure Tone Audiometry Test Results >= CS value during open-label titration period	13 Participants	5 Participants	2 Participants	—
Participants With Clinically Significant Hearing Changes From Baseline to Final Assessment in Pure Tone Audiometry Test Results >= 1 CS value during study	29 Participants	10 Participants	8 Participants	—
Participants With Clinically Significant Hearing Changes From Baseline to Final Assessment in Pure Tone Audiometry Test Results >= 1 CS during double-blind treatment period	NA Participants See values in Hydrocodone ER (Double-blind Treatment Period) column	8 Participants	6 Participants	—
Participants With Clinically Significant Hearing Changes From Baseline to Final Assessment in Pure Tone Audiometry Test Results >=CS value at endpoint	NA Participants See values in Hydrocodone ER (Double-blind Treatment Period) column	8 Participants	7 Participants	—

SECONDARY outcome

Timeframe: Weeks 1, 2, 4 and Endpoint of the Treatment Period

Population: Full analysis set. Participants contributing to each time point are listed in the time point label.

The results of the SOWS were collected in the e-diary daily during the first 4 weeks of the double blind treatment period and then during clinic visits at week 12 or early termination. The SOWS was a self-administered questionnaire used to measure a participant's signs and symptoms of withdrawal from opiates. The scale contained 16 symptoms (such as my nose is running; I feel restless), the participant rated the intensity on a scale of 0 (not at all) to 4 (extremely) for a total score of 0-64. The daily total score for the first 4 weeks was the largest score observed during the time period preceding that visit. For example, the week 1 score for each participant was the largest total score on any day between baseline and the night before the week 1 visit; the week 4 score for each participant was the largest score observed between the week 2 visit and the night before the week 4 visit.

Outcome measures

Outcome measures
Measure	Placebo (Double-blind Treatment Period) n=179 Participants Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) n=191 Participants Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.	Placebo (Double-blind Treatment Period) Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Subjective Opiate Withdrawal Scales (SOWS) Total Scores During the Double-Blind Treatment Period Week 1	6.9 units on a scale Standard Deviation 7.03	6.6 units on a scale Standard Deviation 7.36	—	—
Subjective Opiate Withdrawal Scales (SOWS) Total Scores During the Double-Blind Treatment Period Week 2	5.1 units on a scale Standard Deviation 6.10	5.1 units on a scale Standard Deviation 6.89	—	—
Subjective Opiate Withdrawal Scales (SOWS) Total Scores During the Double-Blind Treatment Period Week 4	5.0 units on a scale Standard Deviation 5.52	5.5 units on a scale Standard Deviation 6.58	—	—
Subjective Opiate Withdrawal Scales (SOWS) Total Scores During the Double-Blind Treatment Period Endpoint	5.7 units on a scale Standard Deviation 6.70	6.1 units on a scale Standard Deviation 7.63	—	—

SECONDARY outcome

Timeframe: Weeks 1, 2, 4 and Endpoint of the Treatment Period

Population: Full analysis set. Participants contributing to each time point are listed in the time point label.

COWS is a clinician-rated scale used to measure a participant's signs and symptoms of withdrawal from opiates, with ratings based only on apparent relationship to withdrawal. The COWS was performed at weeks 1, 2, 4, and 12 (double blind treatment period) or early termination. The scale contained 11 signs/symptoms whose intensity the clinician rated on a scale of 0 to 4 or 5. A total score was calculated as the sum of the responses to the 11 signs/symptoms for a total range of 0-48. Withdrawal severity was classified, based on the total score, as follows: * 0 to 4=normal * 5 to 12=mild * 13 to 24=moderate * 25 to 36=moderately severe * 36=severe

Outcome measures

Outcome measures
Measure	Placebo (Double-blind Treatment Period) n=179 Participants Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) n=191 Participants Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.	Placebo (Double-blind Treatment Period) Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Clinical Opiate Withdrawal Scales (COWS) Total Scores During the Double-Blind Treatment Period Week 2	0.8 units on a scale Standard Deviation 1.52	0.7 units on a scale Standard Deviation 1.13	—	—
Clinical Opiate Withdrawal Scales (COWS) Total Scores During the Double-Blind Treatment Period Week 4	0.8 units on a scale Standard Deviation 1.33	0.6 units on a scale Standard Deviation 1.03	—	—
Clinical Opiate Withdrawal Scales (COWS) Total Scores During the Double-Blind Treatment Period Week 1	0.9 units on a scale Standard Deviation 1.66	0.8 units on a scale Standard Deviation 1.33	—	—
Clinical Opiate Withdrawal Scales (COWS) Total Scores During the Double-Blind Treatment Period Endpoint	0.9 units on a scale Standard Deviation 1.49	0.7 units on a scale Standard Deviation 1.12	—	—

SECONDARY outcome

Timeframe: Day 1 up to Week 12 of the Treatment Period

Population: Full analysis set including participants with laboratory assessments. Participants with a postbaseline result for that test are counted in each laboratory tests' label.

Data represents participants with potentially clinically significant abnormal serum chemistry, hematology and urinalysis values. Significance criteria: * Blood urea nitrogen: \>=10.71 mmol/L * Creatinine: \>=177 μmol/L * Uric acid: M\>=625, F\>=506 μmol/L * Alanine aminotransferase (ALT): \>=3\* upper limit of normal (ULN) * Gamma-glutamyl transpeptidase (GGT): \>=3\* upper limit of normal (ULN) * Serum white blood cells: \<=3.0 \* 10\^9/L * Hemoglobin: M\<=115, F\<=95 g/dL * Hematocrit: M\<0.37, F\<0.32 L/L * Eosinophils: \>=10.0 % * Absolute neutrophils: \<=1.0 \* 10\^9/L * Urinalysis: Glucose: \>=2 unit increase from baseline

Outcome measures

Outcome measures
Measure	Placebo (Double-blind Treatment Period) n=171 Participants Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) n=178 Participants Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.	Placebo (Double-blind Treatment Period) Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Participants With Potentially Clinically Significant Abnormal Laboratory Values During the Double-Blind Treatment Period Creatinine	0 Participants	1 Participants	—	—
Participants With Potentially Clinically Significant Abnormal Laboratory Values During the Double-Blind Treatment Period ALT	1 Participants	2 Participants	—	—
Participants With Potentially Clinically Significant Abnormal Laboratory Values During the Double-Blind Treatment Period Eosinophils	1 Participants	2 Participants	—	—
Participants With Potentially Clinically Significant Abnormal Laboratory Values During the Double-Blind Treatment Period Blood urea nitrogen	3 Participants	1 Participants	—	—
Participants With Potentially Clinically Significant Abnormal Laboratory Values During the Double-Blind Treatment Period Uric acid	3 Participants	4 Participants	—	—
Participants With Potentially Clinically Significant Abnormal Laboratory Values During the Double-Blind Treatment Period GGT	6 Participants	5 Participants	—	—
Participants With Potentially Clinically Significant Abnormal Laboratory Values During the Double-Blind Treatment Period White blood cells	1 Participants	0 Participants	—	—
Participants With Potentially Clinically Significant Abnormal Laboratory Values During the Double-Blind Treatment Period Hemoglobin	1 Participants	2 Participants	—	—
Participants With Potentially Clinically Significant Abnormal Laboratory Values During the Double-Blind Treatment Period Hematocrit	6 Participants	3 Participants	—	—
Participants With Potentially Clinically Significant Abnormal Laboratory Values During the Double-Blind Treatment Period Absolute neutrophils	1 Participants	2 Participants	—	—
Participants With Potentially Clinically Significant Abnormal Laboratory Values During the Double-Blind Treatment Period Urine glucose	2 Participants	3 Participants	—	—

SECONDARY outcome

Timeframe: Day 1 to Week 12 of the Treatment Period

Population: Full analysis set

Data represents participants with potentially clinically significant (PCS) vital sign values. Significance criteria * Pulse - high: \>=120 and increase of \>= 15 beats/minute from baseline * Pulse - low: \<=50 and decrease of \>=15 beats/minute * Systolic blood pressure - high: \>=180 and increase \>=20 mmHg * Systolic blood pressure - low: \<=90 and decrease \>=20 mmHg * Diastolic blood pressure - high: \>=105 and increase of \>=15 mmHg * Diastolic blood pressure - low: \<=50 and decrease of \>=15 mmHg

Outcome measures

Outcome measures
Measure	Placebo (Double-blind Treatment Period) n=179 Participants Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) n=191 Participants Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.	Placebo (Double-blind Treatment Period) Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Participants With Potentially Clinically Significant Abnormal Vital Sign Values During the Double-Blind Treatment Period Pulse - high	2 Participants	1 Participants	—	—
Participants With Potentially Clinically Significant Abnormal Vital Sign Values During the Double-Blind Treatment Period Pulse - low	1 Participants	1 Participants	—	—
Participants With Potentially Clinically Significant Abnormal Vital Sign Values During the Double-Blind Treatment Period Systolic BP - high	1 Participants	2 Participants	—	—
Participants With Potentially Clinically Significant Abnormal Vital Sign Values During the Double-Blind Treatment Period Systolic BP - low	2 Participants	3 Participants	—	—
Participants With Potentially Clinically Significant Abnormal Vital Sign Values During the Double-Blind Treatment Period Diastolic BP - high	0 Participants	3 Participants	—	—
Participants With Potentially Clinically Significant Abnormal Vital Sign Values During the Double-Blind Treatment Period Diastolic BP - low	0 Participants	2 Participants	—	—

SECONDARY outcome

Timeframe: Final study visit (week 12 or end of treatment visit)

Population: Full analysis set

Data represents the number of participants with potentially clinically significant (PCS) electrocardiogram findings on the final study visit.

Outcome measures

Outcome measures
Measure	Placebo (Double-blind Treatment Period) n=179 Participants Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) n=191 Participants Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.	Placebo (Double-blind Treatment Period) Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Participants With Potentially Clinically Significant Abnormal Electrocardiogram Findings During the Double-Blind Treatment Period	2 Participants	2 Participants	—	—

Adverse Events

Hydrocodone ER (Open-Label Titration Period)

Serious events: 10 serious events

Other events: 211 other events

Deaths: 0 deaths

Placebo (Double-blind Treatment Period)

Serious events: 3 serious events

Other events: 41 other events

Deaths: 0 deaths

Hydrocodone ER (Double-blind Treatment Period)

Serious events: 3 serious events

Other events: 58 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Hydrocodone ER (Open-Label Titration Period) n=623 participants at risk All participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours to identify a dosage deemed successful for managing their pain.	Placebo (Double-blind Treatment Period) n=179 participants at risk Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) n=191 participants at risk Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Gastrointestinal disorders Constipation	15.6% 97/623 • Number of events 102 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	4.5% 8/179 • Number of events 8 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	14.1% 27/191 • Number of events 29 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period
Gastrointestinal disorders Nausea	15.7% 98/623 • Number of events 101 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	7.8% 14/179 • Number of events 16 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	10.5% 20/191 • Number of events 23 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period
Gastrointestinal disorders Vomiting	6.3% 39/623 • Number of events 39 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	3.4% 6/179 • Number of events 6 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	4.2% 8/191 • Number of events 8 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period
Infections and infestations Upper respiratory tract infection	0.48% 3/623 • Number of events 3 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	5.0% 9/179 • Number of events 9 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	4.2% 8/191 • Number of events 9 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period
Nervous system disorders Dizziness	5.3% 33/623 • Number of events 35 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	2.2% 4/179 • Number of events 4 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	1.0% 2/191 • Number of events 2 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period
Nervous system disorders Headache	6.7% 42/623 • Number of events 44 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	4.5% 8/179 • Number of events 8 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	5.8% 11/191 • Number of events 11 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period
Nervous system disorders Somnolence	5.8% 36/623 • Number of events 38 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	1.1% 2/179 • Number of events 2 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	3.1% 6/191 • Number of events 7 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period

Additional Information

Director, Clinical Research

Teva Branded Pharmaceutical Products, R&D Inc.

Phone: 215-591-3000

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor's review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor's designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.
Publication restrictions are in place

Restriction type: OTHER

Measure	Hydrocodone ER (Open-Label Titration Period) n=623 participants at risk All participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours to identify a dosage deemed successful for managing their pain.	Placebo (Double-blind Treatment Period) n=179 participants at risk Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Hydrocodone ER (Double-blind Treatment Period) n=191 participants at risk Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Cardiac disorders Acute coronary syndrome	0.16% 1/623 • Number of events 1 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/179 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/191 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period
Gastrointestinal disorders Pancreatitis	0.00% 0/623 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/179 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.52% 1/191 • Number of events 1 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period
General disorders Chest pain	0.16% 1/623 • Number of events 1 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/179 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/191 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period
Infections and infestations Cellulitis	0.16% 1/623 • Number of events 1 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/179 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.52% 1/191 • Number of events 1 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period
Infections and infestations Pneumonia	0.32% 2/623 • Number of events 2 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/179 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/191 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period
Injury, poisoning and procedural complications Accidental overdose	0.16% 1/623 • Number of events 1 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/179 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/191 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period
Injury, poisoning and procedural complications Laceration	0.16% 1/623 • Number of events 1 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/179 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/191 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period
Injury, poisoning and procedural complications Tracheal injury	0.16% 1/623 • Number of events 1 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/179 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/191 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period
Metabolism and nutrition disorders Hypernatraemia	0.00% 0/623 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.56% 1/179 • Number of events 1 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/191 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period
Musculoskeletal and connective tissue disorders Rhabdomyolysis	0.00% 0/623 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.56% 1/179 • Number of events 1 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/191 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Papillary thyroid cancer	0.00% 0/623 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.56% 1/179 • Number of events 1 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/191 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period
Pregnancy, puerperium and perinatal conditions Abortion spontaneous	0.16% 1/623 • Number of events 1 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/179 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/191 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period
Psychiatric disorders Bipolar disorder	0.00% 0/623 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.56% 1/179 • Number of events 1 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/191 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period
Psychiatric disorders Depression	0.16% 1/623 • Number of events 1 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/179 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/191 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period
Psychiatric disorders Panic attack	0.00% 0/623 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.56% 1/179 • Number of events 1 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.52% 1/191 • Number of events 1 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.16% 1/623 • Number of events 1 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/179 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/191 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.16% 1/623 • Number of events 1 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/179 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/191 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period
Respiratory, thoracic and mediastinal disorders Respiratory arrest	0.16% 1/623 • Number of events 1 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/179 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period	0.00% 0/191 • - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period