Trial Outcomes & Findings for Safety and Efficacy Study of Centanafadine Sustained-Release (CTN SR) in Adults With Attention-Deficit Hyperactivity Disorder (ADHD) (NCT NCT02547428)

NCT ID: NCT02547428

Last Updated: 2021-11-11

Results Overview

The ADHD-RS-IV consists of 18 items and is designed to reflect the participant's current ADHD symptomatology; the severity, frequency, and impairment are measured for each of the items. The 18 items are grouped into 2 subscales of 9 symptoms each: Hyperactivity/Impulsivity (even numbered items 2-18) and Inattentiveness (odd numbered items 1-17). Each item is scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms), with the total score for the rating scale ranging from 0 to 54. Higher scores indicate more severe disease. A negative change from Baseline indicates improvement.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 85 participants
• Primary outcome timeframe: Baseline and Week 3
• Results posted on: 2021-11-11

Participant Flow

This study was conducted at 4 sites in United States from 03 Aug 2015 to 4 Jun 2016.

A total of 85 participants were enrolled in this study. Participants were randomly assigned to 1 of 2 treatment sequences to receive Centanafadine sustained-release (CTN SR) or placebo in sequence 1, followed by washout, followed by crossover treatment with placebo or CTN SR in sequence 2, with each treatment sequence lasting 3 weeks.

Participant milestones

Measure	CTN SR First, Then Placebo Participants received CTN SR tablets starting at a dose of 100 or 200 milligrams (mg) on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks in Period 1. The dose was decreased based on safety and tolerability based on Investigator's discretion, followed by a washout Period of 1 week followed by matching-placebo for up to 3 weeks in Period 2. The most common total daily dose (TDD) was 400 mg/day.	Placebo First, Then CTN SR Participants received matching-placebo for up to 3 weeks in Period 1, followed by a washout Period of 1 week, followed by CTN SR tablets starting at a dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks in Period 2. The dose was decreased based on safety and tolerability based on Investigator's discretion. The most common TDD was 400 mg/day.
Period 1- Treatment Sequence 1 (3 Weeks) STARTED	42	43
Period 1- Treatment Sequence 1 (3 Weeks) Received at Least 1 Dose of Study Drug	42	43
Period 1- Treatment Sequence 1 (3 Weeks) COMPLETED	31	37
Period 1- Treatment Sequence 1 (3 Weeks) NOT COMPLETED	11	6
Period 2- Treatment Sequence 2 (3 Weeks) STARTED	31	37
Period 2- Treatment Sequence 2 (3 Weeks) COMPLETED	30	30
Period 2- Treatment Sequence 2 (3 Weeks) NOT COMPLETED	1	7

Reasons for withdrawal

Measure	CTN SR First, Then Placebo Participants received CTN SR tablets starting at a dose of 100 or 200 milligrams (mg) on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks in Period 1. The dose was decreased based on safety and tolerability based on Investigator's discretion, followed by a washout Period of 1 week followed by matching-placebo for up to 3 weeks in Period 2. The most common total daily dose (TDD) was 400 mg/day.	Placebo First, Then CTN SR Participants received matching-placebo for up to 3 weeks in Period 1, followed by a washout Period of 1 week, followed by CTN SR tablets starting at a dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks in Period 2. The dose was decreased based on safety and tolerability based on Investigator's discretion. The most common TDD was 400 mg/day.
Period 1- Treatment Sequence 1 (3 Weeks) Adverse Event	8	1
Period 1- Treatment Sequence 1 (3 Weeks) Lost to Follow-up	1	1
Period 1- Treatment Sequence 1 (3 Weeks) Withdrawal by Subject	1	1
Period 1- Treatment Sequence 1 (3 Weeks) Dosing Suspension	1	3
Period 2- Treatment Sequence 2 (3 Weeks) Adverse Event	0	3
Period 2- Treatment Sequence 2 (3 Weeks) Lost to Follow-up	0	3
Period 2- Treatment Sequence 2 (3 Weeks) Withdrawal by Subject	0	1
Period 2- Treatment Sequence 2 (3 Weeks) Investigator Discretion	1	0

Baseline Characteristics

Safety and Efficacy Study of Centanafadine Sustained-Release (CTN SR) in Adults With Attention-Deficit Hyperactivity Disorder (ADHD)

Baseline characteristics by cohort

Measure	CTN SR First, Then Placebo n=42 Participants Participants received CTN SR tablets starting at a dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks in Period 1. The dose was decreased based on safety and tolerability based on Investigator's discretion, followed by a washout Period of 1 week followed by matching-placebo for up to 3 weeks in Period 2. The most common TDD was 400 mg/day.	Placebo First, Then CTN SR n=43 Participants Participants received matching-placebo for up to 3 weeks in Period 1, followed by a washout Period of 1 week, followed by CTN SR tablets starting at a dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks in Period 2. The dose was decreased based on safety and tolerability based on Investigator's discretion. The most common TDD was 400 mg/day.	Total n=85 Participants Total of all reporting groups
Age, Continuous	34.2 years STANDARD_DEVIATION 11.7 • n=5 Participants	36.5 years STANDARD_DEVIATION 11.9 • n=7 Participants	35.4 years STANDARD_DEVIATION 11.8 • n=5 Participants
Sex: Female, Male Female	18 Participants n=5 Participants	19 Participants n=7 Participants	37 Participants n=5 Participants
Sex: Female, Male Male	24 Participants n=5 Participants	24 Participants n=7 Participants	48 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	15 Participants n=5 Participants	11 Participants n=7 Participants	26 Participants n=5 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	27 Participants n=5 Participants	32 Participants n=7 Participants	59 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	9 Participants n=5 Participants	8 Participants n=7 Participants	17 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized White	28 Participants n=5 Participants	31 Participants n=7 Participants	59 Participants n=5 Participants
Race/Ethnicity, Customized Multiple	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Race/Ethnicity, Customized Other	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and Week 3

Population: FAS Full Analysis Set (FAS) included all participants who were randomized and had at least one post-dose efficacy assessment. Number analyzed is the number of participants with data available for analyses at the given time-point.

The ADHD-RS-IV consists of 18 items and is designed to reflect the participant's current ADHD symptomatology; the severity, frequency, and impairment are measured for each of the items. The 18 items are grouped into 2 subscales of 9 symptoms each: Hyperactivity/Impulsivity (even numbered items 2-18) and Inattentiveness (odd numbered items 1-17). Each item is scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms), with the total score for the rating scale ranging from 0 to 54. Higher scores indicate more severe disease. A negative change from Baseline indicates improvement.

Outcome measures

Measure	CTN SR n=85 Participants Participants received CTN SR tablets starting at a dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks. The dose was decreased based on safety and tolerability based on Investigator's discretion. The most common total daily dose TDD was 400 mg/day.	Placebo n=85 Participants Participants received matching-placebo for up to 3 weeks. Placebo was titrated in the same manner to protect the blind. The most common TDD was 400 mg/day.	CTN SR 600 mg Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
Change From Baseline in Total Attention-Deficit Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV) Score	-16.2 score on a scale Standard Deviation 11.1	-7.9 score on a scale Standard Deviation 7.9	—

PRIMARY outcome

Timeframe: Baseline and Week 3

Population: FAS included all participants who were randomized and had at least one post-dose efficacy assessment. Overall number analyzed is the number of participants available for analyses. Number analyzed is the number of participants with data available for analyses at the given time-point.

The ADHD-RS-IV consists of 18 items and is designed to reflect the participant's current ADHD symptomatology; the severity, frequency, and impairment are measured for each of the items. The 18 items are grouped into 2 subscales of 9 symptoms each: Hyperactivity/Impulsivity (even numbered items 2-18) and Inattentiveness (odd numbered items 1-17). Each item is scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms), with the total score for the rating scale ranging from 0 to 54. Higher scores indicate more severe disease. A negative change from Baseline indicates improvement.

Outcome measures

Measure	CTN SR n=47 Participants Participants received CTN SR tablets starting at a dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks. The dose was decreased based on safety and tolerability based on Investigator's discretion. The most common total daily dose TDD was 400 mg/day.	Placebo n=47 Participants Participants received matching-placebo for up to 3 weeks. Placebo was titrated in the same manner to protect the blind. The most common TDD was 400 mg/day.	CTN SR 600 mg Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
Change From Baseline in ADHD-RS-IV Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day	-16.3 score on a scale Standard Deviation 11.1	-8.4 score on a scale Standard Deviation 8.1	—

SECONDARY outcome

Timeframe: Baseline, Weeks 1, and 2

Population: FAS included all participants who were randomized and had at least one post-dose efficacy assessment. Number analyzed is the number of participants with data available for analyses at the given time-point.

The ADHD-RS-IV consists of 18 items and is designed to reflect the participant's current ADHD symptomatology; the severity, frequency, and impairment are measured for each of the items. The 18 items are grouped into 2 subscales of 9 symptoms each: Hyperactivity/Impulsivity (even numbered items 2-18) and Inattentiveness (odd numbered items 1-17). Each item is scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms), with the total score for the rating scale ranging from 0 to 54. Higher scores indicate more severe disease. A negative change from Baseline indicates improvement.

Outcome measures

Measure	CTN SR n=85 Participants Participants received CTN SR tablets starting at a dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks. The dose was decreased based on safety and tolerability based on Investigator's discretion. The most common total daily dose TDD was 400 mg/day.	Placebo n=85 Participants Participants received matching-placebo for up to 3 weeks. Placebo was titrated in the same manner to protect the blind. The most common TDD was 400 mg/day.	CTN SR 600 mg Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
Change From Baseline in ADHD-RS-IV Score Total Score After 1 and 2 Weeks of Double-blind Treatment Change from Baseline at Week 1	-12.0 score on a scale Standard Deviation 10.3	-6.6 score on a scale Standard Deviation 7.7	—
Change From Baseline in ADHD-RS-IV Score Total Score After 1 and 2 Weeks of Double-blind Treatment Change from Baseline at Week 2	-15.4 score on a scale Standard Deviation 10.6	-7.6 score on a scale Standard Deviation 7.9	—

SECONDARY outcome

Timeframe: Baseline, Weeks 1, and 2

Population: FAS included all participants who were randomized and had at least one post-dose efficacy assessment. Overall number analyzed is the number of participants available for analyses. Number analyzed is the number of participants with data available for analyses at the given time-point.

The ADHD-RS-IV consists of 18 items and is designed to reflect the participant's current ADHD symptomatology; the severity, frequency, and impairment are measured for each of the items. The 18 items are grouped into 2 subscales of 9 symptoms each: Hyperactivity/Impulsivity (even numbered items 2-18) and Inattentiveness (odd numbered items 1-17). Each item is scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms), with the total score for the rating scale ranging from 0 to 54. Higher scores indicate more severe disease. A negative change from Baseline indicates improvement.

Outcome measures

Measure	CTN SR n=47 Participants Participants received CTN SR tablets starting at a dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks. The dose was decreased based on safety and tolerability based on Investigator's discretion. The most common total daily dose TDD was 400 mg/day.	Placebo n=47 Participants Participants received matching-placebo for up to 3 weeks. Placebo was titrated in the same manner to protect the blind. The most common TDD was 400 mg/day.	CTN SR 600 mg Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
Change From Baseline in ADHD-RS-IV Score Total Score After 1 and 2 Weeks of Double-blind Treatment for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Change from Baseline at Week 1	-12.0 score on a scale Standard Deviation 10.1	-7.7 score on a scale Standard Deviation 8.5	—
Change From Baseline in ADHD-RS-IV Score Total Score After 1 and 2 Weeks of Double-blind Treatment for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Change from Baseline at Week 2	-15.0 score on a scale Standard Deviation 10.4	-8.3 score on a scale Standard Deviation 8.2	—

SECONDARY outcome

Timeframe: Baseline, Weeks 1, 2 and 3

Population: FAS included all participants who were randomized and had at least one post-dose efficacy assessment. Number analyzed is the number of participants with data available for analyses at the given time-point.

The ADHD-RS-IV consists of 18 items and is designed to reflect the participant's current ADHD symptomatology; the severity, frequency, and impairment are measured for each of the items. The 18 items are grouped into 2 subscales of 9 symptoms each: Hyperactivity/Impulsivity (even numbered items 2-18) and Inattentiveness (odd numbered items 1-17). Each item is scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms), with the total score for the rating scale ranging from 0 to 54. The possible sub-scale score range is from 0 to 27. Higher scores indicate more severe disease. A negative change from Baseline indicates improvement.

Outcome measures

Measure	CTN SR n=85 Participants Participants received CTN SR tablets starting at a dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks. The dose was decreased based on safety and tolerability based on Investigator's discretion. The most common total daily dose TDD was 400 mg/day.	Placebo n=85 Participants Participants received matching-placebo for up to 3 weeks. Placebo was titrated in the same manner to protect the blind. The most common TDD was 400 mg/day.	CTN SR 600 mg Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
Change From Baseline in ADHD-RS-IV Inattention Subscale Score of Double-blind Treatment Change from Baseline at Week 1	-7.0 score on a scale Standard Deviation 6.2	-3.6 score on a scale Standard Deviation 4.6	—
Change From Baseline in ADHD-RS-IV Inattention Subscale Score of Double-blind Treatment Change from Baseline at Week 2	-9.2 score on a scale Standard Deviation 6.7	-4.2 score on a scale Standard Deviation 5.0	—
Change From Baseline in ADHD-RS-IV Inattention Subscale Score of Double-blind Treatment Change from Baseline at Week 3	-9.3 score on a scale Standard Deviation 6.8	-4.3 score on a scale Standard Deviation 5.2	—

SECONDARY outcome

Timeframe: Baseline, Weeks 1, 2 and 3

Population: FAS included all participants who were randomized and had at least one post-dose efficacy assessment. Overall number analyzed is the number of participants available for analyses. Number analyzed is the number of participants with data available for analyses at the given time-point.

The ADHD-RS-IV consists of 18 items and is designed to reflect the participant's current ADHD symptomatology; the severity, frequency, and impairment are measured for each of the items. The 18 items are grouped into 2 subscales of 9 symptoms each: Hyperactivity/Impulsivity (even numbered items 2-18) and Inattentiveness (odd numbered items 1-17). Each item is scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms), with the total score for the rating scale ranging from 0 to 54. The possible sub-scale score range is from 0 to 27. Higher scores indicate more severe disease. A negative change from Baseline indicates improvement.

Outcome measures

Measure	CTN SR n=47 Participants Participants received CTN SR tablets starting at a dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks. The dose was decreased based on safety and tolerability based on Investigator's discretion. The most common total daily dose TDD was 400 mg/day.	Placebo n=47 Participants Participants received matching-placebo for up to 3 weeks. Placebo was titrated in the same manner to protect the blind. The most common TDD was 400 mg/day.	CTN SR 600 mg Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
Change From Baseline in ADHD-RS-IV Inattention Subscale Score of Double-blind Treatment for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Change from Baseline at Week 1	-6.6 score on a scale Standard Deviation 6.2	-4.5 score on a scale Standard Deviation 5.1	—
Change From Baseline in ADHD-RS-IV Inattention Subscale Score of Double-blind Treatment for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Change from Baseline at Week 2	-9.4 score on a scale Standard Deviation 6.7	-4.8 score on a scale Standard Deviation 5.0	—
Change From Baseline in ADHD-RS-IV Inattention Subscale Score of Double-blind Treatment for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Change from Baseline at Week 3	-9.7 score on a scale Standard Deviation 6.7	-4.8 score on a scale Standard Deviation 5.2	—

SECONDARY outcome

Timeframe: Baseline, Weeks 1, 2 and 3

Population: FAS included all participants who were randomized and had at least one post-dose efficacy assessment. Number analyzed is the number of participants with data available for analyses at the given time-point.

The ADHD-RS-IV consists of 18 items and is designed to reflect the participant's current ADHD symptomatology; the severity, frequency, and impairment are measured for each of the items. The 18 items are grouped into 2 subscales of 9 symptoms each: Hyperactivity/Impulsivity (even numbered items 2-18) and Inattentiveness (odd numbered items 1-17). Each item is scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms), with the total score for the rating scale ranging from 0 to 54. The possible sub-scale score range is from 0 to 27. Higher scores indicate more severe disease. A negative change from Baseline indicates improvement.

Outcome measures

Measure	CTN SR n=85 Participants Participants received CTN SR tablets starting at a dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks. The dose was decreased based on safety and tolerability based on Investigator's discretion. The most common total daily dose TDD was 400 mg/day.	Placebo n=85 Participants Participants received matching-placebo for up to 3 weeks. Placebo was titrated in the same manner to protect the blind. The most common TDD was 400 mg/day.	CTN SR 600 mg Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
Change From Baseline in ADHD-RS-IV Hyperactivity/Impulsivity Subscale Score of Double-blind Treatment Change from Baseline at Week 1	-5.0 score on a scale Standard Deviation 5.8	-2.9 score on a scale Standard Deviation 4.5	—
Change From Baseline in ADHD-RS-IV Hyperactivity/Impulsivity Subscale Score of Double-blind Treatment Change from Baseline at Week 2	-6.2 score on a scale Standard Deviation 5.7	-3.4 score on a scale Standard Deviation 4.6	—
Change From Baseline in ADHD-RS-IV Hyperactivity/Impulsivity Subscale Score of Double-blind Treatment Change from Baseline at Week 3	-6.9 score on a scale Standard Deviation 6.0	-3.6 score on a scale Standard Deviation 4.7	—

SECONDARY outcome

Timeframe: Baseline, Weeks 1, 2 and 3

Population: FAS included all participants who were randomized and had at least one post-dose efficacy assessment. Overall number analyzed is the number of participants available for analyses. Number analyzed is the number of participants with data available for analyses at the given time-point.

The ADHD-RS-IV consists of 18 items and is designed to reflect the participant's current ADHD symptomatology; the severity, frequency, and impairment are measured for each of the items. The 18 items are grouped into 2 subscales of 9 symptoms each: Hyperactivity/Impulsivity (even numbered items 2-18) and Inattentiveness (odd numbered items 1-17). Each item is scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms), with the total score for the rating scale ranging from 0 to 54. The possible sub-scale score range is from 0 to 27. Higher scores indicate more severe disease. A negative change from Baseline indicates improvement.

Outcome measures

Measure	CTN SR n=47 Participants Participants received CTN SR tablets starting at a dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks. The dose was decreased based on safety and tolerability based on Investigator's discretion. The most common total daily dose TDD was 400 mg/day.	Placebo n=47 Participants Participants received matching-placebo for up to 3 weeks. Placebo was titrated in the same manner to protect the blind. The most common TDD was 400 mg/day.	CTN SR 600 mg Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
Change From Baseline in ADHD-RS-IV Hyperactivity/Impulsivity Subscale Score of Double-blind Treatment for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Change from Baseline at Week 1	-5.3 score on a scale Standard Deviation 6.1	-3.2 score on a scale Standard Deviation 5.0	—
Change From Baseline in ADHD-RS-IV Hyperactivity/Impulsivity Subscale Score of Double-blind Treatment for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Change from Baseline at Week 2	-5.6 score on a scale Standard Deviation 5.5	-3.5 score on a scale Standard Deviation 5.0	—
Change From Baseline in ADHD-RS-IV Hyperactivity/Impulsivity Subscale Score of Double-blind Treatment for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Change from Baseline at Week 3	-6.6 score on a scale Standard Deviation 6.1	-3.6 score on a scale Standard Deviation 5.2	—

SECONDARY outcome

Timeframe: Predose -0.5 hour and post-dose 1, 3, 5, 7, 9, 11 and 13 hours at Weeks 4 and 8

Population: FAS included all participants who were randomized and had at least one post-dose efficacy assessment. Overall number analyzed is the number of participants available for analyses. Number analyzed is the number of participants with data available for analyses at the given time-point.

The Permanent Product Measure of Performance (PERMP) is a skill-adjusted math test consisting of 400 problems. The PERMP total score is the sum of the number of math problems attempted plus the number of math problems answered correctly in a 10-minute session. The score range of number of math problems attempted and number of math problems answered correctly is 0-400 and the total score range from 0-800. The higher scores indicate better performance. Higher scores mean higher performance and less severe ADHD symptoms.

Outcome measures

Measure	CTN SR n=58 Participants Participants received CTN SR tablets starting at a dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks. The dose was decreased based on safety and tolerability based on Investigator's discretion. The most common total daily dose TDD was 400 mg/day.	Placebo n=58 Participants Participants received matching-placebo for up to 3 weeks. Placebo was titrated in the same manner to protect the blind. The most common TDD was 400 mg/day.	CTN SR 600 mg Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
Permanent Product Measure of Performance (PERMP) Score Total Score- 0.5 Hour Before Dosing	226.7 score on a scale Standard Deviation 87.1	232.7 score on a scale Standard Deviation 90.9	—
Permanent Product Measure of Performance (PERMP) Score Total Score- 1 Hour After Dosing	238.7 score on a scale Standard Deviation 90.4	246.2 score on a scale Standard Deviation 94.4	—
Permanent Product Measure of Performance (PERMP) Score Total Score- 3 Hour After Dosing	246.2 score on a scale Standard Deviation 96.3	242.6 score on a scale Standard Deviation 94.4	—
Permanent Product Measure of Performance (PERMP) Score Total Score- 5 Hour After Dosing	244.5 score on a scale Standard Deviation 92.2	246.0 score on a scale Standard Deviation 95.3	—
Permanent Product Measure of Performance (PERMP) Score Total Score- 7 Hour After Dosing	244.6 score on a scale Standard Deviation 95.3	245.8 score on a scale Standard Deviation 100.1	—
Permanent Product Measure of Performance (PERMP) Score Total Score- 9 Hour After Dosing	246.6 score on a scale Standard Deviation 91.1	245.4 score on a scale Standard Deviation 99.5	—
Permanent Product Measure of Performance (PERMP) Score Total Score- 11 Hour After Dosing	250.9 score on a scale Standard Deviation 91.5	244.9 score on a scale Standard Deviation 104.5	—
Permanent Product Measure of Performance (PERMP) Score Total Score- 13 Hour After Dosing	250.7 score on a scale Standard Deviation 93.5	244.0 score on a scale Standard Deviation 101.4	—
Permanent Product Measure of Performance (PERMP) Score Number of Math Problems Attempted- 0.5 Hour Before Dosing	115.3 score on a scale Standard Deviation 43.5	119.0 score on a scale Standard Deviation 45.6	—
Permanent Product Measure of Performance (PERMP) Score Number of Math Problems Attempted- 1 Hour After Dosing	121.3 score on a scale Standard Deviation 45.3	126.1 score on a scale Standard Deviation 47.6	—
Permanent Product Measure of Performance (PERMP) Score Number of Math Problems Attempted- 3 Hour After Dosing	124.9 score on a scale Standard Deviation 48.3	123.8 score on a scale Standard Deviation 47.8	—
Permanent Product Measure of Performance (PERMP) Score Number of Math Problems Attempted- 5 Hour After Dosing	124.2 score on a scale Standard Deviation 46.4	125.7 score on a scale Standard Deviation 47.9	—
Permanent Product Measure of Performance (PERMP) Score Number of Math Problems Attempted- 7 Hour After Dosing	124.2 score on a scale Standard Deviation 47.9	125.4 score on a scale Standard Deviation 50.4	—
Permanent Product Measure of Performance (PERMP) Score Number of Math Problems Attempted- 9 Hour After Dosing	125.0 score on a scale Standard Deviation 45.6	125.2 score on a scale Standard Deviation 50.1	—
Permanent Product Measure of Performance (PERMP) Score Number of Math Problems Attempted- 11 Hour After Dosing	127.2 score on a scale Standard Deviation 45.7	124.2 score on a scale Standard Deviation 52.5	—
Permanent Product Measure of Performance (PERMP) Score Number of Math Problems Attempted- 13 Hour After Dosing	127.1 score on a scale Standard Deviation 46.8	124.0 score on a scale Standard Deviation 51.0	—
Permanent Product Measure of Performance (PERMP) Score Number of Math Problems Answered Correctly- 0.5 Hour Before Dosing	111.4 score on a scale Standard Deviation 43.7	113.7 score on a scale Standard Deviation 45.8	—
Permanent Product Measure of Performance (PERMP) Score Number of Math Problems Answered Correctly- 1 Hour After Dosing	117.3 score on a scale Standard Deviation 45.2	120.1 score on a scale Standard Deviation 47.5	—
Permanent Product Measure of Performance (PERMP) Score Number of Math Problems Answered Correctly- 3 Hour After Dosing	121.3 score on a scale Standard Deviation 48.1	118.8 score on a scale Standard Deviation 47.2	—
Permanent Product Measure of Performance (PERMP) Score Number of Math Problems Answered Correctly- 5 Hour After Dosing	120.3 score on a scale Standard Deviation 45.9	120.3 score on a scale Standard Deviation 48.0	—
Permanent Product Measure of Performance (PERMP) Score Number of Math Problems Answered Correctly- 7 Hour After Dosing	120.4 score on a scale Standard Deviation 47.5	120.4 score on a scale Standard Deviation 50.2	—
Permanent Product Measure of Performance (PERMP) Score Number of Math Problems Answered Correctly- 9 Hour After Dosing	121.6 score on a scale Standard Deviation 45.6	120.2 score on a scale Standard Deviation 49.9	—
Permanent Product Measure of Performance (PERMP) Score Number of Math Problems Answered Correctly- 11 Hour After Dosing	123.7 score on a scale Standard Deviation 45.8	120.6 score on a scale Standard Deviation 52.1	—
Permanent Product Measure of Performance (PERMP) Score Number of Math Problems Answered Correctly- 13 Hour After Dosing	123.6 score on a scale Standard Deviation 46.8	120.0 score on a scale Standard Deviation 50.5	—

SECONDARY outcome

Timeframe: Predose -0.5 hour and post-dose 1, 3, 5, 7, 9, 11 and 13 hours at Weeks 4 and 8

Population: FAS included all participants who were randomized and had at least one post-dose efficacy assessment. Overall number analyzed is the number of participants available for analyses. Number analyzed is the number of participants with data available for analyses at the given time-point.

The PERMP is a skill-adjusted math test consisting of 400 problems. The PERMP total score is the sum of the number of math problems attempted plus the number of math problems answered correctly in a 10-minute session. The score range of number of math problems attempted and number of math problems answered correctly is 0-400 and the total score range from 0-800. The higher scores indicate better performance. Higher scores mean higher performance and less severe ADHD symptoms.

Outcome measures

Measure	CTN SR n=47 Participants Participants received CTN SR tablets starting at a dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks. The dose was decreased based on safety and tolerability based on Investigator's discretion. The most common total daily dose TDD was 400 mg/day.	Placebo n=47 Participants Participants received matching-placebo for up to 3 weeks. Placebo was titrated in the same manner to protect the blind. The most common TDD was 400 mg/day.	CTN SR 600 mg Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Total Score- 0.5 Hour Before Dosing	226.8 score on a scale Standard Deviation 81.4	229.1 score on a scale Standard Deviation 88.4	—
PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Total Score- 1 Hour After Dosing	241.5 score on a scale Standard Deviation 82.1	242.6 score on a scale Standard Deviation 89.1	—
PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Total Score- 3 Hour After Dosing	249.8 score on a scale Standard Deviation 90.0	240.4 score on a scale Standard Deviation 94.4	—
PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Total Score- 5 Hour After Dosing	248.8 score on a scale Standard Deviation 88.0	241.0 score on a scale Standard Deviation 95.3	—
PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Total Score- 7 Hour After Dosing	249.7 score on a scale Standard Deviation 96.2	245.6 score on a scale Standard Deviation 96.6	—
PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Total Score- 9 Hour After Dosing	249.5 score on a scale Standard Deviation 88.7	246.2 score on a scale Standard Deviation 98.9	—
PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Total Score- 11 Hour After Dosing	253.5 score on a scale Standard Deviation 91.8	246.1 score on a scale Standard Deviation 102.4	—
PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Total Score- 13 Hour After Dosing	257.5 score on a scale Standard Deviation 96.9	248.6 score on a scale Standard Deviation 96.5	—
PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Number of Math Problems Attempted- 0.5 Hour Before Dosing	115.4 score on a scale Standard Deviation 40.6	116.6 score on a scale Standard Deviation 44.2	—
PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Number of Math Problems Attempted- 1 Hour After Dosing	122.9 score on a scale Standard Deviation 40.9	123.4 score on a scale Standard Deviation 44.8	—
PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Number of Math Problems Attempted- 3 Hour After Dosing	127.0 score on a scale Standard Deviation 45.0	122.2 score on a scale Standard Deviation 47.8	—
PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Number of Math Problems Attempted- 5 Hour After Dosing	126.4 score on a scale Standard Deviation 44.2	122.5 score on a scale Standard Deviation 47.6	—
PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Number of Math Problems Attempted- 7 Hour After Dosing	126.9 score on a scale Standard Deviation 48.2	124.6 score on a scale Standard Deviation 48.5	—
PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Number of Math Problems Attempted- 9 Hour After Dosing	126.6 score on a scale Standard Deviation 44.3	125.0 score on a scale Standard Deviation 49.4	—
PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Number of Math Problems Attempted- 11 Hour After Dosing	128.6 score on a scale Standard Deviation 45.8	124.6 score on a scale Standard Deviation 51.2	—
PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Number of Math Problems Answered Correctly- 1 Hour After Dosing	118.6 score on a scale Standard Deviation 41.3	119.2 score on a scale Standard Deviation 44.4	—
PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Number of Math Problems Answered Correctly- 3 Hour After Dosing	122.9 score on a scale Standard Deviation 45.1	118.3 score on a scale Standard Deviation 46.7	—
PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Number of Math Problems Answered Correctly- 5 Hour After Dosing	122.4 score on a scale Standard Deviation 43.9	118.6 score on a scale Standard Deviation 47.8	—
PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Number of Math Problems Answered Correctly- 7 Hour After Dosing	122.9 score on a scale Standard Deviation 48.0	121.0 score on a scale Standard Deviation 48.2	—
PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Number of Math Problems Attempted- 13 Hour After Dosing	130.4 score on a scale Standard Deviation 48.5	126.1 score on a scale Standard Deviation 48.4	—
PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Number of Math Problems Answered Correctly- 0.5 Hour Before Dosing	111.4 score on a scale Standard Deviation 41.0	112.6 score on a scale Standard Deviation 44.3	—
PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Number of Math Problems Answered Correctly- 9 Hour After Dosing	122.9 score on a scale Standard Deviation 44.5	121.2 score on a scale Standard Deviation 49.6	—
PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Number of Math Problems Answered Correctly- 11 Hour After Dosing	124.9 score on a scale Standard Deviation 46.1	121.5 score on a scale Standard Deviation 51.3	—
PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Number of Math Problems Answered Correctly- 13 Hour After Dosing	127.1 score on a scale Standard Deviation 48.5	122.5 score on a scale Standard Deviation 48.1	—

SECONDARY outcome

Timeframe: Baseline

Population: FAS included all participants who were randomized and had at least one post-dose efficacy assessment. The data is reported as per the crossover dose received.

The CGI-S is performed to rate the severity of a participant's condition on a 8- point scale ranging from 0 to 7 where 0=not assessed, 1=normal, not at all ill, 2=borderline mentally ill, 3=mildly ill, 4=moderately ill, 5=markedly ill, 6=severely ill, and 7 = among the most extremely ill participants.

Outcome measures

Measure	CTN SR n=42 Participants Participants received CTN SR tablets starting at a dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks. The dose was decreased based on safety and tolerability based on Investigator's discretion. The most common total daily dose TDD was 400 mg/day.	Placebo n=43 Participants Participants received matching-placebo for up to 3 weeks. Placebo was titrated in the same manner to protect the blind. The most common TDD was 400 mg/day.	CTN SR 600 mg Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
Number of Participants With Clinical Global Impressions of Severity (CGI-S) Score Severely ill	5 Participants	3 Participants	—
Number of Participants With Clinical Global Impressions of Severity (CGI-S) Score Moderately ill	22 Participants	18 Participants	—
Number of Participants With Clinical Global Impressions of Severity (CGI-S) Score Markedly ill	15 Participants	22 Participants	—

SECONDARY outcome

Timeframe: Weeks 1, 2, and 3

Population: FAS included all participants who were randomized and had at least one post-dose efficacy assessment. Number analyzed is the number of participants with data available for analyses at the given time-point.

The CGI-I permits a global evaluation of the participant's improvement over time. The CGI-I is a 8-point scale ranging from 0 to 7 where 0=not assessed, 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse and 7=very much worse. The CGI-I is completed by the clinician and assesses the participant's improvement relative to the symptoms at Baseline.

Outcome measures

Measure	CTN SR n=85 Participants Participants received CTN SR tablets starting at a dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks. The dose was decreased based on safety and tolerability based on Investigator's discretion. The most common total daily dose TDD was 400 mg/day.	Placebo n=85 Participants Participants received matching-placebo for up to 3 weeks. Placebo was titrated in the same manner to protect the blind. The most common TDD was 400 mg/day.	CTN SR 600 mg Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
Number of Participants With Clinical Global Impressions of Improvement (CGI-I) Score Week 1 · Score 1	4 Participants	0 Participants	—
Number of Participants With Clinical Global Impressions of Improvement (CGI-I) Score Week 1 · Score 2	19 Participants	8 Participants	—
Number of Participants With Clinical Global Impressions of Improvement (CGI-I) Score Week 1 · Score 3	22 Participants	19 Participants	—
Number of Participants With Clinical Global Impressions of Improvement (CGI-I) Score Week 1 · Score 4	22 Participants	41 Participants	—
Number of Participants With Clinical Global Impressions of Improvement (CGI-I) Score Week 1 · Score 5	1 Participants	0 Participants	—
Number of Participants With Clinical Global Impressions of Improvement (CGI-I) Score Week 1 · Score 6	0 Participants	0 Participants	—
Number of Participants With Clinical Global Impressions of Improvement (CGI-I) Score Week 1 · Score 7	0 Participants	0 Participants	—
Number of Participants With Clinical Global Impressions of Improvement (CGI-I) Score Week 2 · Score 1	16 Participants	2 Participants	—
Number of Participants With Clinical Global Impressions of Improvement (CGI-I) Score Week 2 · Score 2	17 Participants	9 Participants	—
Number of Participants With Clinical Global Impressions of Improvement (CGI-I) Score Week 2 · Score 3	19 Participants	17 Participants	—
Number of Participants With Clinical Global Impressions of Improvement (CGI-I) Score Week 2 · Score 4	16 Participants	39 Participants	—
Number of Participants With Clinical Global Impressions of Improvement (CGI-I) Score Week 2 · Score 5	0 Participants	1 Participants	—
Number of Participants With Clinical Global Impressions of Improvement (CGI-I) Score Week 2 · Score 6	0 Participants	0 Participants	—
Number of Participants With Clinical Global Impressions of Improvement (CGI-I) Score Week 2 · Score 7	0 Participants	0 Participants	—
Number of Participants With Clinical Global Impressions of Improvement (CGI-I) Score Week 3 · Score 1	16 Participants	2 Participants	—
Number of Participants With Clinical Global Impressions of Improvement (CGI-I) Score Week 3 · Score 2	18 Participants	8 Participants	—
Number of Participants With Clinical Global Impressions of Improvement (CGI-I) Score Week 3 · Score 3	19 Participants	21 Participants	—
Number of Participants With Clinical Global Impressions of Improvement (CGI-I) Score Week 3 · Score 4	15 Participants	37 Participants	—
Number of Participants With Clinical Global Impressions of Improvement (CGI-I) Score Week 3 · Score 5	0 Participants	0 Participants	—
Number of Participants With Clinical Global Impressions of Improvement (CGI-I) Score Week 3 · Score 6	0 Participants	0 Participants	—
Number of Participants With Clinical Global Impressions of Improvement (CGI-I) Score Week 3 · Score 7	0 Participants	0 Participants	—

SECONDARY outcome

Timeframe: Weeks 1, 2, and 3

Population: FAS included all participants who were randomized and had at least one post-dose efficacy assessment. Overall number analyzed is the number of participants available for analyses. Number analyzed is the number of participants with data available for analyses at the given time-point.

The CGI-I permits a global evaluation of the participant's improvement over time. The CGI-I is a 8-point scale ranging from 0 to 7 where 0=not assessed, 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse and 7=very much worse. The CGI-I is completed by the clinician and assesses the participant's improvement relative to the symptoms at Baseline.

Outcome measures

Measure	CTN SR n=47 Participants Participants received CTN SR tablets starting at a dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks. The dose was decreased based on safety and tolerability based on Investigator's discretion. The most common total daily dose TDD was 400 mg/day.	Placebo n=47 Participants Participants received matching-placebo for up to 3 weeks. Placebo was titrated in the same manner to protect the blind. The most common TDD was 400 mg/day.	CTN SR 600 mg Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
Number of Participants With CGI-I Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Week 1 · Score 1	2 Participants	0 Participants	—
Number of Participants With CGI-I Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Week 1 · Score 2	11 Participants	6 Participants	—
Number of Participants With CGI-I Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Week 1 · Score 3	16 Participants	15 Participants	—
Number of Participants With CGI-I Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Week 1 · Score 4	14 Participants	23 Participants	—
Number of Participants With CGI-I Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Week 1 · Score 5	1 Participants	0 Participants	—
Number of Participants With CGI-I Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Week 1 · Score 6	0 Participants	0 Participants	—
Number of Participants With CGI-I Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Week 1 · Score 7	0 Participants	0 Participants	—
Number of Participants With CGI-I Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Week 2 · Score 1	8 Participants	1 Participants	—
Number of Participants With CGI-I Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Week 2 · Score 2	13 Participants	6 Participants	—
Number of Participants With CGI-I Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Week 2 · Score 3	11 Participants	11 Participants	—
Number of Participants With CGI-I Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Week 2 · Score 4	12 Participants	26 Participants	—
Number of Participants With CGI-I Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Week 2 · Score 5	0 Participants	0 Participants	—
Number of Participants With CGI-I Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Week 2 · Score 6	0 Participants	0 Participants	—
Number of Participants With CGI-I Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Week 2 · Score 7	0 Participants	0 Participants	—
Number of Participants With CGI-I Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Week 3 · Score 1	8 Participants	0 Participants	—
Number of Participants With CGI-I Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Week 3 · Score 2	14 Participants	6 Participants	—
Number of Participants With CGI-I Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Week 3 · Score 3	14 Participants	17 Participants	—
Number of Participants With CGI-I Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Week 3 · Score 4	8 Participants	21 Participants	—
Number of Participants With CGI-I Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Week 3 · Score 5	0 Participants	0 Participants	—
Number of Participants With CGI-I Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Week 3 · Score 6	0 Participants	0 Participants	—
Number of Participants With CGI-I Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day Week 3 · Score 7	0 Participants	0 Participants	—

SECONDARY outcome

Timeframe: From signing of informed consent up to approximately Week 9

Population: Safety population included all participants who were randomized and had taken any dose of investigational product (including placebo) in the Double-blind Crossover Phase.

An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. A TEAE was defined as any AE with onset post study drug treatment in the two crossover treatment periods. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).

Outcome measures

Measure	CTN SR n=79 Participants Participants received CTN SR tablets starting at a dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks. The dose was decreased based on safety and tolerability based on Investigator's discretion. The most common total daily dose TDD was 400 mg/day.	Placebo n=74 Participants Participants received matching-placebo for up to 3 weeks. Placebo was titrated in the same manner to protect the blind. The most common TDD was 400 mg/day.	CTN SR 600 mg Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
Number of Participants With at Least One Treatment-Emergent Adverse Events (TEAEs)	63 Participants	50 Participants	—

SECONDARY outcome

Timeframe: From signing of informed consent up to approximately Week 9

Population: Safety population included all participants who were randomized and had taken any dose of investigational product (including placebo) in the Double-blind Crossover Phase. Overall number analyzed is the number of participants available for analyses.

An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. A TEAE was defined as any AE with onset post study drug treatment in the two crossover treatment periods. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).

Outcome measures

Measure	CTN SR n=45 Participants Participants received CTN SR tablets starting at a dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks. The dose was decreased based on safety and tolerability based on Investigator's discretion. The most common total daily dose TDD was 400 mg/day.	Placebo n=46 Participants Participants received matching-placebo for up to 3 weeks. Placebo was titrated in the same manner to protect the blind. The most common TDD was 400 mg/day.	CTN SR 600 mg Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
Number of Participants With at Least One TEAEs for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day	32 Participants	30 Participants	—

SECONDARY outcome

Timeframe: Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8

Population: The Pharmacokinetic Analysis Set included all participants in the Safety Population who have post-dose drug concentration data available for analysis. Overall number analyzed is the number of participants available for analyses.

Outcome measures

Measure	CTN SR n=4 Participants Participants received CTN SR tablets starting at a dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks. The dose was decreased based on safety and tolerability based on Investigator's discretion. The most common total daily dose TDD was 400 mg/day.	Placebo n=33 Participants Participants received matching-placebo for up to 3 weeks. Placebo was titrated in the same manner to protect the blind. The most common TDD was 400 mg/day.	CTN SR 600 mg n=6 Participants Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
Cmax: Maximum Concentration	1450 nanograms per milliliter (ng/ml) Standard Deviation 461	1460 nanograms per milliliter (ng/ml) Standard Deviation 570	3080 nanograms per milliliter (ng/ml) Standard Deviation 2260

SECONDARY outcome

Timeframe: Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8

Population: The Pharmacokinetic Analysis Set included all participants in the Safety Population who have post-dose drug concentration data available for analysis. Overall number analyzed is the number of participants available for analyses.

Outcome measures

Measure	CTN SR n=4 Participants Participants received CTN SR tablets starting at a dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks. The dose was decreased based on safety and tolerability based on Investigator's discretion. The most common total daily dose TDD was 400 mg/day.	Placebo n=33 Participants Participants received matching-placebo for up to 3 weeks. Placebo was titrated in the same manner to protect the blind. The most common TDD was 400 mg/day.	CTN SR 600 mg n=6 Participants Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
Tmax: Time to Maximum Concentration	3.36 hour Interval 2.0 to 6.48	8.10 hour Interval 1.95 to 12.0	8.12 hour Interval 1.72 to 11.5

SECONDARY outcome

Timeframe: Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8

Population: The Pharmacokinetic Analysis Set included all participants in the Safety Population who have post-dose drug concentration data available for analysis. Overall number analyzed is the number of participants available for analyses.

Outcome measures

Measure	CTN SR n=4 Participants Participants received CTN SR tablets starting at a dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks. The dose was decreased based on safety and tolerability based on Investigator's discretion. The most common total daily dose TDD was 400 mg/day.	Placebo n=33 Participants Participants received matching-placebo for up to 3 weeks. Placebo was titrated in the same manner to protect the blind. The most common TDD was 400 mg/day.	CTN SR 600 mg n=6 Participants Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
AUC0-t: Area Under the Concentration-Time Curve During the Steady-State 24-hour Dosing Interval	14700 hours*ng/mL Standard Deviation 5180	16900 hours*ng/mL Standard Deviation 5970	34300 hours*ng/mL Standard Deviation 23600

SECONDARY outcome

Timeframe: Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8

Population: The Pharmacokinetic Analysis Set included all participants in the Safety Population who have post-dose drug concentration data available for analysis. Overall number analyzed is the number of participants available for analyses.

Outcome measures

Measure	CTN SR n=4 Participants Participants received CTN SR tablets starting at a dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks. The dose was decreased based on safety and tolerability based on Investigator's discretion. The most common total daily dose TDD was 400 mg/day.	Placebo n=15 Participants Participants received matching-placebo for up to 3 weeks. Placebo was titrated in the same manner to protect the blind. The most common TDD was 400 mg/day.	CTN SR 600 mg n=5 Participants Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
t½: Elimination Phase Half-Life	5.53 hour Standard Deviation 3.30	5.08 hour Standard Deviation 2.88	4.06 hour Standard Deviation 1.89

SECONDARY outcome

Timeframe: Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8

Population: All efforts have been exhausted to locate this data and it has since been destroyed, therefore no data is available to report for this outcome measure.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8

Population: All efforts have been exhausted to locate this data and it has since been destroyed, therefore no data is available to report for this outcome measure.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8

Population: All efforts have been exhausted to locate this data and it has since been destroyed, therefore no data is available to report for this outcome measure.

Outcome measures

Outcome data not reported

Adverse Events

CTN SR

Serious events: 0 serious events

Other events: 63 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 50 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	CTN SR n=79 participants at risk Participants received CTN SR tablets at a starting dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks. The dose was decreased based on safety and tolerability based on Investigator's discretion. The most common TDD was 400 mg/day.	Placebo n=74 participants at risk Participants received matching-placebo for up to 3 weeks. Placebo was titrated in the same manner to protect the blind. The most common TDD was 400 mg/day.
Cardiac disorders Tachycardia	11.4% 9/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	9.5% 7/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Cardiac disorders Palpitations	2.5% 2/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Cardiac disorders Bradycardia	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Cardiac disorders Supraventricular Extrasystoles	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Ear and labyrinth disorders Tinnitus	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Eye disorders Vision Blurred	3.8% 3/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Eye disorders Dry Eye	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Gastrointestinal disorders Nausea	20.3% 16/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Gastrointestinal disorders Diarrohea	17.7% 14/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	2.7% 2/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Gastrointestinal disorders Abdominal Pain Upper	5.1% 4/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Gastrointestinal disorders Dyspepsia	3.8% 3/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Gastrointestinal disorders Toothache	2.5% 2/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	4.1% 3/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Gastrointestinal disorders Abdominal Discomfort	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Gastrointestinal disorders Abdominal Pain	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Gastrointestinal disorders Abdominal Pain Lower	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Gastrointestinal disorders Constipation	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Gastrointestinal disorders Hypoaesthesia Oral	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Gastrointestinal disorders Vomiting	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
General disorders Discomfort	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Gastrointestinal disorders Abdominal Distension	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Gastrointestinal disorders Aphthous Stomatitis	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Gastrointestinal disorders Food Poisoning	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
General disorders Fatigue	13.9% 11/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
General disorders Chest Discomfort	2.5% 2/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
General disorders Energy Increased	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
General disorders Feeling Abnormal	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
General disorders Sluggishness	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
General disorders Thirst	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
General disorders Infusion Site Bruising	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
General disorders Vessel Puncture Site Haemorrhage	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
General disorders Vessel Puncture Site Pain	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Hepatobiliary disorders Choleithiasis	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Infections and infestations Upper Respiratory Tract Infection	10.1% 8/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	9.5% 7/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Infections and infestations Gastroenteritis Viral	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Infections and infestations Pharyngitis	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Infections and infestations Tooth Abscess	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Infections and infestations Conjunctivitis	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Infections and infestations Gastroenteritis	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Infections and infestations Hordeolum	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Infections and infestations Sinusitis	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Infections and infestations Viral Infection	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Injury, poisoning and procedural complications Muscle Strain	2.5% 2/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Investigations Orthostatic Heart Rate Response Increased	7.6% 6/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Investigations Blood Pressure Increased	2.5% 2/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Investigations Hepatic Enzyme Increased	2.5% 2/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Investigations Weight Decreased	2.5% 2/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Investigations Blood Pressure Diastolic Increased	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	4.1% 3/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Investigations Blood Pressure Orthostatic Decreased	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Investigations Blood Thyroid Stimulating Hormone Increased	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Investigations Heart Rate Increased	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Investigations Liver Function Test Abnormal	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Investigations Lymph Node Palpable	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Investigations Aspartate Aminotransferase Increased	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Investigations Blood Lactate Dehydrogenase Increased	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Investigations Blood Pressure Systolic Increased	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Investigations Weight Increased	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Metabolism and nutrition disorders Decreased Appetite	24.1% 19/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Metabolism and nutrition disorders Increased Appetite	2.5% 2/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Metabolism and nutrition disorders Polydipsia	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Musculoskeletal and connective tissue disorders Muscle Spasms	2.5% 2/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Musculoskeletal and connective tissue disorders Arthralgia	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Musculoskeletal and connective tissue disorders Musculoskeletal Pain	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Musculoskeletal and connective tissue disorders Musculoskeletal Stiffness	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Musculoskeletal and connective tissue disorders Myalgia	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Nervous system disorders Headache	22.8% 18/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	8.1% 6/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Nervous system disorders Dizziness	7.6% 6/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Nervous system disorders Dysgeusia	5.1% 4/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Nervous system disorders Poor Quality Sleep	2.5% 2/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Nervous system disorders Mental Impairment	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Nervous system disorders Paraesthesia	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Nervous system disorders Sedation	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Nervous system disorders Somnolence	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Nervous system disorders Tension Headache	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Nervous system disorders Tremor	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Nervous system disorders Lethargy	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	2.7% 2/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Nervous system disorders Migraine	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Nervous system disorders Sinus Headache	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Psychiatric disorders Insomnia	11.4% 9/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	2.7% 2/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Psychiatric disorders Irritability	5.1% 4/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	4.1% 3/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Psychiatric disorders Agitation	3.8% 3/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Psychiatric disorders Affect Lability	2.5% 2/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Psychiatric disorders Bruxism	2.5% 2/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Psychiatric disorders Derealisation	2.5% 2/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Psychiatric disorders Dysphoria	2.5% 2/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Psychiatric disorders Restlessness	2.5% 2/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Psychiatric disorders Suicidal Ideation	2.5% 2/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Psychiatric disorders Abnormal Dreams	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	4.1% 3/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Psychiatric disorders Apathy	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Psychiatric disorders Emotional Disorder	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Psychiatric disorders Jealous Delusion	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Psychiatric disorders Libido Decreased	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Psychiatric disorders Paranoia	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Psychiatric disorders Pressure Of Speech	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Psychiatric disorders Initial Insomnia	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	6.8% 5/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Psychiatric disorders Middle Insomnia	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	5.4% 4/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Psychiatric disorders Terminal Insomnia	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Renal and urinary disorders Pollakiuria	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Reproductive system and breast disorders Dysmenorrhoea	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Respiratory, thoracic and mediastinal disorders Cough	2.5% 2/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Respiratory, thoracic and mediastinal disorders Oropharyngeal Pain	2.5% 2/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	2.7% 2/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Respiratory, thoracic and mediastinal disorders Nasal Congestion	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Skin and subcutaneous tissue disorders Rash	10.1% 8/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Skin and subcutaneous tissue disorders Acne	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Skin and subcutaneous tissue disorders Hyperhidrosis	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Skin and subcutaneous tissue disorders Pruritus	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Skin and subcutaneous tissue disorders Dermatitis Contact	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Skin and subcutaneous tissue disorders Dry Skin	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	2.7% 2/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Surgical and medical procedures Sinus Operation	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Vascular disorders Flushing	2.5% 2/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Vascular disorders Hot Flush	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Vascular disorders Orthostatic Hypotension	1.3% 1/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Gastrointestinal disorders Dry Mouth	13.9% 11/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	0.00% 0/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
General disorders Infusion Site Pain	0.00% 0/79 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).	1.4% 1/74 • From signing of informed consent up to approximately Week 9 Safety Population consisted of all participants who were randomized and had taken any dose of investigational product in the Double-blind Crossover Phase. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).

Additional Information

Global Clinical Development

Otsuka Pharmaceutical Development & Commercialization, Inc.

Phone: +1-609-524-6788

Email: clinicaltransparency@otsuka-us.com

Results disclosure agreements

• Principal investigator is a sponsor employee Sponsor reserves the right to review results publications prior to public release and can delay such publications for a period greater than 60 days but no more than 120 days from the date that the publication is submitted to the Sponsor for review. Sponsor can require changes to the publication to protect Sponsor's intellectual property rights and/or confidential information and reserves the right to limit publication timing and scope of data published based on the number of study locations.
• Publication restrictions are in place

Restriction type: OTHER