Trial Outcomes & Findings for Phase 3 Study of Hydrocodone Bitartrate Controlled-release Capsules in Subjects With Chronic Low Back Pain (NCT NCT01081912)

NCT ID: NCT01081912

Last Updated: 2022-12-08

Results Overview

Change in average pain intensity as measured daily by Numeric Rating Scale (NRS) for Pain (0-10; where 0 = no pain, 10 = worst pain imaginable) comparing HC-ER with Placebo. Lower number equals better outcome.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

510 participants

Primary outcome timeframe

Baseline to Day 85 (Treatment Phase)

Results posted on

2022-12-08

Participant Flow

Out of 510 subjects treated with Hydrocodone Bitartrate Extended Release (HC-ER) capsules in the Conversion/Titration Phase, 208 subjects discontinued early and 151 subjects were randomized into each of the two treatment groups (Maintenance HC-ER Treatment and Placebo Treatment).

Participant milestones

Participant milestones
Measure	Conversion/Titration Phase - Open-Label Conversion/Titration Phase: Hydrocodone Bitartrate Extended Release capsules twice daily for up to 6 weeks (Open-Label Period)	Double-Blind Treatment Phase Treatment Phase: Hydrocodone Bitartrate Controlled-Release Capsules twice daily up to 12 weeks (Double-Blind Period) Hydrocodone bitartrate: dosage form: capsule Strengths 10mg, 20mg, 30mg, 40mg, 50mg	Double-Blind Treatment Phase: Placebo Comparator Placebo: Capsules, no active substance, shells identical to active comparator capsules. Placebo capsules twice daily for up to 12 weeks (Double-Blind Period)
Conversion/Titration STARTED	510	0	0
Conversion/Titration COMPLETED	302	0	0
Conversion/Titration NOT COMPLETED	208	0	0
Maintenance Treatment STARTED	0	151	151
Maintenance Treatment COMPLETED	0	124	59
Maintenance Treatment NOT COMPLETED	0	27	92

Reasons for withdrawal

Reasons for withdrawal
Measure	Conversion/Titration Phase - Open-Label Conversion/Titration Phase: Hydrocodone Bitartrate Extended Release capsules twice daily for up to 6 weeks (Open-Label Period)	Double-Blind Treatment Phase Treatment Phase: Hydrocodone Bitartrate Controlled-Release Capsules twice daily up to 12 weeks (Double-Blind Period) Hydrocodone bitartrate: dosage form: capsule Strengths 10mg, 20mg, 30mg, 40mg, 50mg	Double-Blind Treatment Phase: Placebo Comparator Placebo: Capsules, no active substance, shells identical to active comparator capsules. Placebo capsules twice daily for up to 12 weeks (Double-Blind Period)
Conversion/Titration Adverse Event	47	0	0
Conversion/Titration Lack of Efficacy	17	0	0
Conversion/Titration Lost to Follow-up	5	0	0
Conversion/Titration Physician Decision	2	0	0
Conversion/Titration Protocol Violation	67	0	0
Conversion/Titration Withdrawal by Subject	23	0	0
Conversion/Titration Non-Compliance	47	0	0
Maintenance Treatment Adverse Event	0	2	12
Maintenance Treatment Lack of Efficacy	0	14	64
Maintenance Treatment Lost to Follow-up	0	1	0
Maintenance Treatment Physician Decision	0	0	1
Maintenance Treatment Protocol Violation	0	1	2
Maintenance Treatment Withdrawal by Subject	0	5	5
Maintenance Treatment Non-Compliance	0	4	7
Maintenance Treatment Withdrawal by Medical Monitor	0	0	1

Baseline Characteristics

Phase 3 Study of Hydrocodone Bitartrate Controlled-release Capsules in Subjects With Chronic Low Back Pain

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Open-label Conversion/Titration Phase n=510 Participants Hydrocodone Bitartrate Extended Release capsules twice daily for up to 6 weeks (Open-Label)
Age, Categorical <=18 years	0 Participants n=93 Participants
Age, Categorical Between 18 and 65 years	462 Participants n=93 Participants
Age, Categorical >=65 years	48 Participants n=93 Participants
Sex: Female, Male Female	273 Participants n=93 Participants
Sex: Female, Male Male	237 Participants n=93 Participants
Region of Enrollment United States	510 participants n=93 Participants

PRIMARY outcome

Timeframe: Baseline to Day 85 (Treatment Phase)

Population: The primary efficacy analysis used the Intent to treat (ITT) population which included all 302 randomized subjects.

Outcome measures

Outcome measures
Measure	Hydrocodone Bitartrate Capsules n=151 Participants Hydrocodone Bitartrate Controlled-Release Capsules Hydrocodone bitartrate: dosage form: capsule Strengths 10mg, 20mg, 30mg, 40mg, 50mg	Placebo Comparator n=151 Participants Placebo: Capsules, no active substance, shells identical to active comparator capsules
Mean Change in 24-hour Pain Intensity Ratings Scale (NRS).	0.48 units on a scale Standard Deviation 1.563	0.96 units on a scale Standard Deviation 1.550

SECONDARY outcome

Timeframe: Baseline to Day 85 visit

The change in pain intensity as measured in the clinic by a 0-10 Numeric Rating Scale (NRS)

Outcome measures

Outcome data not reported

Adverse Events

Open-Label Conversion/Titration Phase

Serious events: 6 serious events

Other events: 253 other events

Deaths: 0 deaths

Double Blind Treatment Phase: Hydrocodone Bitartrate Capsules

Serious events: 10 serious events

Other events: 60 other events

Deaths: 0 deaths

Double Blind Treatment Phase: Placebo Comparator

Serious events: 0 serious events

Other events: 46 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Kevin Romanko

Zogenix

Phone: (510) 550-8323

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Measure	Open-Label Conversion/Titration Phase n=510 participants at risk Hydrocodone Bitartrate Extended Release capsules twice daily for up to 6 weeks (Open-Label Period)	Double Blind Treatment Phase: Hydrocodone Bitartrate Capsules n=151 participants at risk Hydrocodone Bitartrate Controlled-Release Capsules twice daily up to 12 weeks (Double-Blind Period) Hydrocodone bitartrate: dosage form: capsule Strengths 10mg, 20mg, 30mg, 40mg, 50mg	Double Blind Treatment Phase: Placebo Comparator n=151 participants at risk Placebo: Capsules, no active substance, shells identical to active comparator capsules. Placebo capsules twice daily for up to 12 weeks (Double-Blind Period)
Cardiac disorders Angina pectoris	0.20% 1/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Gastrointestinal disorders Haematemesis	0.20% 1/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
General disorders Non-cardiac chest pain	0.20% 1/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.66% 1/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Musculoskeletal and connective tissue disorders Joint instability	0.20% 1/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Psychiatric disorders Anxiety	0.20% 1/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.20% 1/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Blood and lymphatic system disorders Anaemia	0.00% 0/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.66% 1/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Gastrointestinal disorders Abdominal distension	0.00% 0/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.66% 1/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Gastrointestinal disorders Diarrhoea	0.00% 0/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.66% 1/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Gastrointestinal disorders Nausea	0.00% 0/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.66% 1/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Infections and infestations Ovarian abscess	0.00% 0/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.66% 1/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Metabolism and nutrition disorders Hypokalemia	0.00% 0/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.66% 1/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Musculoskeletal and connective tissue disorders Intervertebral disc disorder	0.00% 0/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.66% 1/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Psychiatric disorders Depression	0.00% 0/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.66% 1/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Psychiatric disorders Homicidal ideation	0.00% 0/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.66% 1/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.

Measure	Open-Label Conversion/Titration Phase n=510 participants at risk Hydrocodone Bitartrate Extended Release capsules twice daily for up to 6 weeks (Open-Label Period)	Double Blind Treatment Phase: Hydrocodone Bitartrate Capsules n=151 participants at risk Hydrocodone Bitartrate Controlled-Release Capsules twice daily up to 12 weeks (Double-Blind Period) Hydrocodone bitartrate: dosage form: capsule Strengths 10mg, 20mg, 30mg, 40mg, 50mg	Double Blind Treatment Phase: Placebo Comparator n=151 participants at risk Placebo: Capsules, no active substance, shells identical to active comparator capsules. Placebo capsules twice daily for up to 12 weeks (Double-Blind Period)
Gastrointestinal disorders Constipation	11.0% 56/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	7.9% 12/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Gastrointestinal disorders Nausea	9.8% 50/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	7.3% 11/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	3.3% 5/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Nervous system disorders Somnolence	4.7% 24/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.66% 1/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
General disorders Fatigue	4.1% 21/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.66% 1/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	1.3% 2/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Nervous system disorders Headache	3.7% 19/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	1.3% 2/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Nervous system disorders Dizziness	3.3% 17/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	2.0% 3/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.66% 1/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Gastrointestinal disorders Dry mouth	3.1% 16/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Gastrointestinal disorders Vomiting	2.7% 14/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	4.6% 7/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.66% 1/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Skin and subcutaneous tissue disorders Pruritis	2.5% 13/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.00% 0/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Infections and infestations Urinary Tract Infection	0.78% 4/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	5.3% 8/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	2.0% 3/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Musculoskeletal and connective tissue disorders Back Pain	0.78% 4/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	4.0% 6/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	3.3% 5/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Psychiatric disorders Insomnia	2.4% 12/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	2.0% 3/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	4.6% 7/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Gastrointestinal disorders Diarrhoea	2.2% 11/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	2.6% 4/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	5.3% 8/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Psychiatric disorders Withdrawal syndrome	0.59% 3/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	0.66% 1/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	6.0% 9/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Ear and labyrinth disorders Hypoacusis	0.59% 3/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	3.3% 5/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	2.6% 4/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.
Infections and infestations Sinusitis	0.39% 2/510 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	2.0% 3/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.	2.6% 4/151 • Adverse events (AEs) were recorded up to 19 weeks, beginning at the Conversion and Titration Phase through 14 days after the last treatment administration (Treatment Phase). Subjects received a follow-up phone call 14 days after the end of study (day 85 or early termination) to collect information regarding ongoing AEs or new serious AEs that occurred during this time.