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

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02547428
• Collaborator: (none)
• Enrollment: 85
• Locations: 4
• Arms: 2
• Actual Duration (Months): 10.1
• Patients Per Site: 21.3
• Patients Per Site Per Month: 2.1

Study Details

Study Description

Brief Summary

This was a Phase 2b, randomized, double-blind, multicenter, 2-period, 2-treatment, crossover study to evaluate safety and efficacy of CTN SR compared with placebo in adults with ADHD. Efficacy was also evaluated in the subgroup of adults with ADHD treated with a target CTN SR dose of 400 mg/day.

Condition or Disease	Intervention/Treatment	Phase
Attention Deficit Disorder With Hyperactivity	Drug: CTN SR; Drug: Matching placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 85 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 2b, Randomized, Double-Blind, Multicenter, Placebo-Controlled, Crossover, Safety and Efficacy Study of Centanafadine Sustained-Release (CTN SR) in Adults With Attention-Deficit Hyperactivity Disorder (ADHD)
• Actual Study Start Date: Aug 3, 2015
• Actual Primary Completion Date: Jun 4, 2016
• Actual Study Completion Date: Jun 4, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: CTN SR; CTN SR tablets, daily, Orally.; Other Names: Centanafadine Sustained-Release ; Drug: Matching placebo; Matching-placebo tablets daily, orally.
Experimental: 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.	Drug: CTN SR; CTN SR tablets, daily, Orally.; Other Names: Centanafadine Sustained-Release ; Drug: Matching placebo; Matching-placebo tablets daily, orally.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Total Attention-Deficit Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV) Score [Baseline and Week 3]

   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.

2. Change From Baseline in ADHD-RS-IV Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day [Baseline and Week 3]

   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.

Secondary Outcome Measures

1. Change From Baseline in ADHD-RS-IV Score Total Score After 1 and 2 Weeks of Double-blind Treatment [Baseline, Weeks 1, and 2]

   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.

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 [Baseline, Weeks 1, and 2]

   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.

3. Change From Baseline in ADHD-RS-IV Inattention Subscale Score of Double-blind Treatment [Baseline, Weeks 1, 2 and 3]

   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.

4. 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 [Baseline, Weeks 1, 2 and 3]

   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.

5. Change From Baseline in ADHD-RS-IV Hyperactivity/Impulsivity Subscale Score of Double-blind Treatment [Baseline, Weeks 1, 2 and 3]

   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.

6. 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 [Baseline, Weeks 1, 2 and 3]

   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.

7. Permanent Product Measure of Performance (PERMP) Score [Predose -0.5 hour and post-dose 1, 3, 5, 7, 9, 11 and 13 hours at Weeks 4 and 8]

   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.

8. PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day [Predose -0.5 hour and post-dose 1, 3, 5, 7, 9, 11 and 13 hours at Weeks 4 and 8]

   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.

9. Number of Participants With Clinical Global Impressions of Severity (CGI-S) Score [Baseline]

   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.

10. Number of Participants With Clinical Global Impressions of Improvement (CGI-I) Score [Weeks 1, 2, and 3]

    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.

11. Number of Participants With CGI-I Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day [Weeks 1, 2, and 3]

    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.

12. Number of Participants With at Least One Treatment-Emergent Adverse Events (TEAEs) [From signing of informed consent up to approximately Week 9]

    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).

13. Number of Participants With at Least One TEAEs for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day [From signing of informed consent up to approximately Week 9]

    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).

14. Cmax: Maximum Concentration [Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8]

15. Tmax: Time to Maximum Concentration [Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8]

16. AUC0-t: Area Under the Concentration-Time Curve During the Steady-State 24-hour Dosing Interval [Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8]

17. t½: Elimination Phase Half-Life [Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8]

18. Clast: Last Measurable Concentration [Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8]

19. Tlast: Time Point of the Last Measurable Concentration [Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8]

20. ke: Elimination Phase Rate Constant [Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Participant was 18 to 60 years of age, inclusive, at the time of consent.

2. Participant meets Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for a primary diagnosis of ADHD, defined as, established by a comprehensive psychiatric evaluation based on DSM-5 criteria with at least 5 of the 9 subtype criteria met, as determined by the Conners' Adult ADHD Diagnostic Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-4). Note: DSM-5 was used for screening / diagnosis and DSM-4 was used for evaluation throughout the study.

3. Participant had a Baseline score of greater than or equal to 28 using the Attention-Deficit Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV).

4. Participant had a minimum score of 4 on the Clinical Global Impression of Severity at Baseline.

5. Participant was functioning at an age-appropriate level intellectually, as judged by the Investigator.

Exclusion Criteria:

1. Participant had a current comorbid psychiatric disorder that was either controlled with medications prohibited in this study or was uncontrolled and associated with significant symptoms. Exclusionary conditions included any severe comorbid Axis II disorder or severe Axis I disorder (such as post-traumatic stress disorder, psychosis, bipolar illness, severe obsessive compulsive disorder, severe depressive or severe anxiety disorder) or other symptomatic manifestations that, in the opinion of the examining physician, would have contraindicated CTN SR treatment or confound efficacy or safety assessments. Specifically, participants with mild to moderate forms of Axis I disorders (for example, social phobia and dysthymia) may have been included, whereas participants with a lifetime history of psychosis or bipolar disorder were excluded. Comorbid psychiatric diagnosis was established by a Semi-Structured Clinical Interview for DSM-5 Axis I Disorders (the Mini lnternational Neuropsychiatric lnterview, Version 6.0 [M.I.N.I. 6.0]).

2. Participants who were currently considered a suicide risk, any participant who had previously made a suicide attempt, or those who were currently demonstrating active suicidal ideation as measured by the Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening, or if in the opinion of the investigator the participant was considered a suicide risk. Participants who developed suicidal ideation or behavior during the study as measured by the C-SSRS were discontinued and followed appropriately.

3. The participant had a body mass index of less than 18.5 or greater than or equal to 40 at Baseline.

4. Participant had a concurrent chronic or acute illness (such as severe allergic rhinitis or an infectious process requiring antibiotics), disability, or other condition that might have confounded the results of safety assessments administered in the study or that might have increased risk to the participant.

5. Participant had a history of seizures (other than infantile febrile seizures), any tic disorder (except transient tic disorder and participant had no episodes greater than or equal to 1 year), or a current diagnosis and/or a known family history of Tourette's Disorder (that is, first degree relatives).

6. Participant had a known history of symptomatic cardiovascular disease, advanced arteriosclerosis, structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, transient ischemic attack or stroke or other serious cardiac problems that may have placed them at increased vulnerability to potential sympathomimetic effects.

7. Participant had a known family history of sudden cardiac death or ventricular arrhythmia.

8. Participant had a history of significant bleeding or coagulation disorder and/or low platelet levels (less than 130 x 10^9/liter) or increased international normalized ratio (greater than 1.3) at Screening.

9. Participant had a history of cancer (other than noncomplicated basal or squamous cell cancer).

10. Participant had any clinically significant 12-lead electrocardiogram or clinically significant laboratory abnormality at Screening and/or Baseline.

11. Participant had current abnormal thyroid function, as defined as abnormal Screening thyroid stimulating hormone (less than 0.34 or greater than 5.6 micro-International Units/milliliter). Treatment with a stable dose of thyroid medication for at least 3 months was permitted.

12. Participant had a resting sitting systolic blood pressure (SBP) greater than or equal to 140 millimeters of mercury (mm Hg) or diastolic blood pressure (DBP) greater than or equal to 90 mm Hg. No more than 1 repeat measurement was permitted.

13. Participant had a history of hyponatremia.

14. Participant was on an antihypertensive medication of any kind.

15. Participant has a known history of orthostatic hypotension or has an orthostatic blood pressure drop of greater than or equal to 20 mm Hg (based on the drop between sitting and standing [3 minutes] SBP) at Screening or Baseline.

16. Participant had a known history of hypertension.

17. Participant exhibited lifestyle that may have been confounding to safety or efficacy assessments per the judgment of the investigator (for example, exercises, diets or travels extensively).

18. Participant had a known history of glaucoma.

19. Participant had failed to respond to 1 or more adequate courses (for example, adequate dose and duration with poor response as judged by the Investigator) of stimulant therapy.

20. Participant had a recent history (within the past 6 months) of suspected substance abuse or dependence disorder (excluding nicotine) in accordance with DSM-5 criteria.

21. Participant was taking other medications that have central nervous system effects or affected performance, such as sedating antihistamines and decongestant sympathomimetic, or was recently on monoamine oxidase inhibitors (during or within 14 days of investigational product administration). Stable use of bronchodilator inhalers was not exclusionary. This also included use of any psychoactive prescription medication 30 days prior to Screening or psychoactive over-the-counter ) medication or herbal products that required more than a 7-day washout. Participants currently treated with methylphenidate or amphetamine products were permitted and underwent a 7-day washout period. Participants who had taken atomoxetine were required to undergo a 30-day washout.

22. Participant required the frequent or regular use of aspirin, ibuprofen, and naproxen sodium, or is on any anticoagulant, such as warfarin.

23. Participant was taking known potent inhibitors or inducers of common cytochrome P450 enzymes, including herbal products.

24. Participant had a positive urine drug screen (UDS) result at Screening or Baseline. Note: The UDS must be negative at Screening (with the exception of the participant's current ADHD psychostimulant, if applicable) or Baseline, if applicable, for the participant to potentially have been eligible for study participation. The Investigator, in conjunction with the Medical Monitor, evaluated the potential impact of a positive UDS regarding the continued participation of the participant.

25. Participant had taken an investigational product or taken part in a clinical study within 30 days prior to Screening.

26. Investigational site personnel were not permitted to participate in the study.

27. Participant had participated previously in a CTN investigational study.

28. The female participant was pregnant or lactating.

29. Participant had a documented allergy, hypersensitivity, or intolerance to CTN or to any excipients in the reference product.

30. Participant had a history of allergy or hypersensitivity to medications (for example., monoamine reuptake inhibitors or antibiotics).

31. Participant did not agree to or was unable to abstain from consuming alcohol during the study.

Reproductive Potential Requirements

1. All female participants were required to have a negative serum beta human chorionic gonadotropin pregnancy test at Screening, a negative urine pregnancy test at Baseline, and be either postmenopausal (12 consecutive months of spontaneous amenorrhea and greater than or equal to 51 years of age), surgically sterile and at least 6 weeks post-sterilization or, for females of childbearing potential, had a negative pregnancy test prior to entering the study and agreed to use acceptable methods of contraception.

Contraceptive Requirements

1. Condoms were to be used with all forms of contraception (that is., double-barrier method). Acceptable contraceptives included the following:

2. Intrauterine devices

3. Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring)

4. Diaphragms with spermicidal gel or foam

5. Females of childbearing potential were advised to use acceptable contraceptives from the date of informed consent throughout the study period and for the defined follow-up period.

6. If hormonal contraceptives were used, they were to be administered according to the package insert.

7. Females of childbearing potential who were not currently sexually active agreed to use acceptable contraception, as defined above, if they became sexually active during their study participation and for the defined follow-up time period.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Newport Beach	California	United States	92660
2		Bradenton	Florida	United States	34201
3		Maitland	Florida	United States	32751
4		Las Vegas	Nevada	United States	89128

Sponsors and Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT02547428
• Other Study ID Numbers: NVI-EB-1020-202
• First Posted: Sep 11, 2015
• Last Update Posted: Nov 11, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.: centanafadine sustained-release; Attention-Deficit Hyperactivity Disorder
• Additional relevant MeSH terms: Hyperkinesis; Disease; Attention Deficit Disorder with Hyperactivity

Study Results

Participant Flow

Recruitment Details	This study was conducted at 4 sites in United States from 03 Aug 2015 to 4 Jun 2016.
Pre-assignment Detail	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.

Arm/Group Title	CTN SR First, Then Placebo	Placebo First, Then CTN SR
Arm/Group Description	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.	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 Title: Period 1- Treatment Sequence 1 (3 Weeks)
STARTED	42	43
Received at Least 1 Dose of Study Drug	42	43
COMPLETED	31	37
NOT COMPLETED	11	6
Period Title: Period 1- Treatment Sequence 1 (3 Weeks)
STARTED	31	37
COMPLETED	30	30
NOT COMPLETED	1	7

Baseline Characteristics

Arm/Group Title	CTN SR First, Then Placebo	Placebo First, Then CTN SR	Total
Arm/Group Description	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.	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 of all reporting groups
Overall Participants	42	43	85
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	34.2 (11.7)	36.5 (11.9)	35.4 (11.8)
Sex: Female, Male (Count of Participants)
Female	18 42.9%	19 44.2%	37 43.5%
Male	24 57.1%	24 55.8%	48 56.5%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	15 35.7%	11 25.6%	26 30.6%
Not Hispanic or Latino	27 64.3%	32 74.4%	59 69.4%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	1 2.3%	1 1.2%
Black or African American	9 21.4%	8 18.6%	17 20%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
White	28 66.7%	31 72.1%	59 69.4%
Multiple	3 7.1%	1 2.3%	4 4.7%
Other	2 4.8%	2 4.7%	4 4.7%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Total Attention-Deficit Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV) Score
Description	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.
Time Frame	Baseline and Week 3

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	CTN SR	Placebo
Arm/Group Description	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.	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.
Measure Participants	85	85
Mean (Standard Deviation) [score on a scale]	-16.2 (11.1)	-7.9 (7.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CTN SR, Placebo
	Comments	Null hypothesis was that there was no difference in ADHD-RS-IV total score change from Baseline between CTN SR and placebo. The analysis of covariance (ANCOVA) model included terms for period, sequence, and treatment as fixed effects, and Baseline score as a covariate, and a participate-within-sequence term as a random effect.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-8.1
	Confidence Interval	(2-Sided) 95%; -11.0 to -5.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.48
	Estimation Comments	Sample size of 60 participants (30 per treatment sequence) was needed to provide minimum 85% power to detect 5 point difference between treatments at a 2-sided significance level of 5% using a paired t-test.

2. Primary Outcome

Title	Change From Baseline in ADHD-RS-IV Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day
Description	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.
Time Frame	Baseline and Week 3

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	CTN SR 400 mg	Placebo
Arm/Group Description	Participants received CTN SR 400 mg tablets daily for 3 weeks in treatment Periods 1 and 2.	Participants received matching-placebo daily for 3 weeks in treatment Periods 1 and 2.
Measure Participants	47	47
Mean (Standard Deviation) [score on a scale]	-16.3 (11.1)	-8.4 (8.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CTN SR, Placebo
	Comments	Null hypothesis was that there was no difference in ADHD-RS-IV total score change from Baseline between CTN SR 400 mg/day and placebo.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-7.1
	Confidence Interval	(2-Sided) 95%; -10.7 to -3.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.74
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in ADHD-RS-IV Score Total Score After 1 and 2 Weeks of Double-blind Treatment
Description	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.
Time Frame	Baseline, Weeks 1, and 2

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	CTN SR	Placebo
Arm/Group Description	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.	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.
Measure Participants	85	85
Change from Baseline at Week 1	-12.0 (10.3)	-6.6 (7.7)
Change from Baseline at Week 2	-15.4 (10.6)	-7.6 (7.9)

4. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline, Weeks 1, and 2

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	CTN SR 400 mg	Placebo
Arm/Group Description	Participants received CTN SR 400 mg tablets daily for 3 weeks in treatment Periods 1 and 2.	Participants received matching-placebo daily for 3 weeks in treatment Periods 1 and 2.
Measure Participants	47	47
Change from Baseline at Week 1	-12.0 (10.1)	-7.7 (8.5)
Change from Baseline at Week 2	-15.0 (10.4)	-8.3 (8.2)

5. Secondary Outcome

Title	Change From Baseline in ADHD-RS-IV Inattention Subscale Score of Double-blind Treatment
Description	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.
Time Frame	Baseline, Weeks 1, 2 and 3

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	CTN SR	Placebo
Arm/Group Description	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.	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.
Measure Participants	85	85
Change from Baseline at Week 1	-7.0 (6.2)	-3.6 (4.6)
Change from Baseline at Week 2	-9.2 (6.7)	-4.2 (5.0)
Change from Baseline at Week 3	-9.3 (6.8)	-4.3 (5.2)

6. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline, Weeks 1, 2 and 3

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	CTN SR 400 mg	Placebo
Arm/Group Description	Participants received CTN SR 400 mg tablets daily for 3 weeks in treatment Periods 1 and 2.	Participants received matching-placebo daily for 3 weeks in treatment Periods 1 and 2.
Measure Participants	47	47
Change from Baseline at Week 1	-6.6 (6.2)	-4.5 (5.1)
Change from Baseline at Week 2	-9.4 (6.7)	-4.8 (5.0)
Change from Baseline at Week 3	-9.7 (6.7)	-4.8 (5.2)

7. Secondary Outcome

Title	Change From Baseline in ADHD-RS-IV Hyperactivity/Impulsivity Subscale Score of Double-blind Treatment
Description	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.
Time Frame	Baseline, Weeks 1, 2 and 3

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	CTN SR	Placebo
Arm/Group Description	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.	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.
Measure Participants	85	85
Change from Baseline at Week 1	-5.0 (5.8)	-2.9 (4.5)
Change from Baseline at Week 2	-6.2 (5.7)	-3.4 (4.6)
Change from Baseline at Week 3	-6.9 (6.0)	-3.6 (4.7)

8. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline, Weeks 1, 2 and 3

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	CTN SR 400 mg	Placebo
Arm/Group Description	Participants received CTN SR 400 mg tablets daily for 3 weeks in treatment Periods 1 and 2.	Participants received matching-placebo daily for 3 weeks in treatment Periods 1 and 2.
Measure Participants	47	47
Change from Baseline at Week 1	-5.3 (6.1)	-3.2 (5.0)
Change from Baseline at Week 2	-5.6 (5.5)	-3.5 (5.0)
Change from Baseline at Week 3	-6.6 (6.1)	-3.6 (5.2)

9. Secondary Outcome

Title	Permanent Product Measure of Performance (PERMP) Score
Description	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.
Time Frame	Predose -0.5 hour and post-dose 1, 3, 5, 7, 9, 11 and 13 hours at Weeks 4 and 8

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	CTN SR	Placebo
Arm/Group Description	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.	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.
Measure Participants	58	58
Total Score- 0.5 Hour Before Dosing	226.7 (87.1)	232.7 (90.9)
Total Score- 1 Hour After Dosing	238.7 (90.4)	246.2 (94.4)
Total Score- 3 Hour After Dosing	246.2 (96.3)	242.6 (94.4)
Total Score- 5 Hour After Dosing	244.5 (92.2)	246.0 (95.3)
Total Score- 7 Hour After Dosing	244.6 (95.3)	245.8 (100.1)
Total Score- 9 Hour After Dosing	246.6 (91.1)	245.4 (99.5)
Total Score- 11 Hour After Dosing	250.9 (91.5)	244.9 (104.5)
Total Score- 13 Hour After Dosing	250.7 (93.5)	244.0 (101.4)
Number of Math Problems Attempted- 0.5 Hour Before Dosing	115.3 (43.5)	119.0 (45.6)
Number of Math Problems Attempted- 1 Hour After Dosing	121.3 (45.3)	126.1 (47.6)
Number of Math Problems Attempted- 3 Hour After Dosing	124.9 (48.3)	123.8 (47.8)
Number of Math Problems Attempted- 5 Hour After Dosing	124.2 (46.4)	125.7 (47.9)
Number of Math Problems Attempted- 7 Hour After Dosing	124.2 (47.9)	125.4 (50.4)
Number of Math Problems Attempted- 9 Hour After Dosing	125.0 (45.6)	125.2 (50.1)
Number of Math Problems Attempted- 11 Hour After Dosing	127.2 (45.7)	124.2 (52.5)
Number of Math Problems Attempted- 13 Hour After Dosing	127.1 (46.8)	124.0 (51.0)
Number of Math Problems Answered Correctly- 0.5 Hour Before Dosing	111.4 (43.7)	113.7 (45.8)
Number of Math Problems Answered Correctly- 1 Hour After Dosing	117.3 (45.2)	120.1 (47.5)
Number of Math Problems Answered Correctly- 3 Hour After Dosing	121.3 (48.1)	118.8 (47.2)
Number of Math Problems Answered Correctly- 5 Hour After Dosing	120.3 (45.9)	120.3 (48.0)
Number of Math Problems Answered Correctly- 7 Hour After Dosing	120.4 (47.5)	120.4 (50.2)
Number of Math Problems Answered Correctly- 9 Hour After Dosing	121.6 (45.6)	120.2 (49.9)
Number of Math Problems Answered Correctly- 11 Hour After Dosing	123.7 (45.8)	120.6 (52.1)
Number of Math Problems Answered Correctly- 13 Hour After Dosing	123.6 (46.8)	120.0 (50.5)

10. Secondary Outcome

Title	PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day
Description	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.
Time Frame	Predose -0.5 hour and post-dose 1, 3, 5, 7, 9, 11 and 13 hours at Weeks 4 and 8

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	CTN SR 400 mg	Placebo
Arm/Group Description	Participants received CTN SR 400 mg tablets daily for 3 weeks in treatment Periods 1 and 2.	Participants received matching-placebo daily for 3 weeks in treatment Periods 1 and 2.
Measure Participants	47	47
Total Score- 0.5 Hour Before Dosing	226.8 (81.4)	229.1 (88.4)
Total Score- 1 Hour After Dosing	241.5 (82.1)	242.6 (89.1)
Total Score- 3 Hour After Dosing	249.8 (90.0)	240.4 (94.4)
Total Score- 5 Hour After Dosing	248.8 (88.0)	241.0 (95.3)
Total Score- 7 Hour After Dosing	249.7 (96.2)	245.6 (96.6)
Total Score- 9 Hour After Dosing	249.5 (88.7)	246.2 (98.9)
Total Score- 11 Hour After Dosing	253.5 (91.8)	246.1 (102.4)
Total Score- 13 Hour After Dosing	257.5 (96.9)	248.6 (96.5)
Number of Math Problems Attempted- 0.5 Hour Before Dosing	115.4 (40.6)	116.6 (44.2)
Number of Math Problems Attempted- 1 Hour After Dosing	122.9 (40.9)	123.4 (44.8)
Number of Math Problems Attempted- 3 Hour After Dosing	127.0 (45.0)	122.2 (47.8)
Number of Math Problems Attempted- 5 Hour After Dosing	126.4 (44.2)	122.5 (47.6)
Number of Math Problems Attempted- 7 Hour After Dosing	126.9 (48.2)	124.6 (48.5)
Number of Math Problems Attempted- 9 Hour After Dosing	126.6 (44.3)	125.0 (49.4)
Number of Math Problems Attempted- 11 Hour After Dosing	128.6 (45.8)	124.6 (51.2)
Number of Math Problems Attempted- 13 Hour After Dosing	130.4 (48.5)	126.1 (48.4)
Number of Math Problems Answered Correctly- 0.5 Hour Before Dosing	111.4 (41.0)	112.6 (44.3)
Number of Math Problems Answered Correctly- 1 Hour After Dosing	118.6 (41.3)	119.2 (44.4)
Number of Math Problems Answered Correctly- 3 Hour After Dosing	122.9 (45.1)	118.3 (46.7)
Number of Math Problems Answered Correctly- 5 Hour After Dosing	122.4 (43.9)	118.6 (47.8)
Number of Math Problems Answered Correctly- 7 Hour After Dosing	122.9 (48.0)	121.0 (48.2)
Number of Math Problems Answered Correctly- 9 Hour After Dosing	122.9 (44.5)	121.2 (49.6)
Number of Math Problems Answered Correctly- 11 Hour After Dosing	124.9 (46.1)	121.5 (51.3)
Number of Math Problems Answered Correctly- 13 Hour After Dosing	127.1 (48.5)	122.5 (48.1)

11. Secondary Outcome

Title	Number of Participants With Clinical Global Impressions of Severity (CGI-S) Score
Description	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.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	CTN SR First, Then Placebo	Placebo First, Then CTN SR
Arm/Group Description	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.	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.
Measure Participants	42	43
Moderately ill	22 52.4%	18 41.9%
Markedly ill	15 35.7%	22 51.2%
Severely ill	5 11.9%	3 7%

12. Secondary Outcome

Title	Number of Participants With Clinical Global Impressions of Improvement (CGI-I) Score
Description	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.
Time Frame	Weeks 1, 2, and 3

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	CTN SR	Placebo
Arm/Group Description	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.	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.
Measure Participants	85	85
Score 1	4 9.5%	0 0%
Score 2	19 45.2%	8 18.6%
Score 3	22 52.4%	19 44.2%
Score 4	22 52.4%	41 95.3%
Score 5	1 2.4%	0 0%
Score 6	0 0%	0 0%
Score 7	0 0%	0 0%
Score 1	16 38.1%	2 4.7%
Score 2	17 40.5%	9 20.9%
Score 3	19 45.2%	17 39.5%
Score 4	16 38.1%	39 90.7%
Score 5	0 0%	1 2.3%
Score 6	0 0%	0 0%
Score 7	0 0%	0 0%
Score 1	16 38.1%	2 4.7%
Score 2	18 42.9%	8 18.6%
Score 3	19 45.2%	21 48.8%
Score 4	15 35.7%	37 86%
Score 5	0 0%	0 0%
Score 6	0 0%	0 0%
Score 7	0 0%	0 0%

13. Secondary Outcome

Title	Number of Participants With CGI-I Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day
Description	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.
Time Frame	Weeks 1, 2, and 3

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	CTN SR 400 mg	Placebo
Arm/Group Description	Participants received CTN SR 400 mg tablets daily for 3 weeks in treatment Periods 1 and 2.	Participants received matching-placebo daily for 3 weeks in treatment Periods 1 and 2.
Measure Participants	47	47
Score 1	2 4.8%	0 0%
Score 2	11 26.2%	6 14%
Score 3	16 38.1%	15 34.9%
Score 4	14 33.3%	23 53.5%
Score 5	1 2.4%	0 0%
Score 6	0 0%	0 0%
Score 7	0 0%	0 0%
Score 1	8 19%	1 2.3%
Score 2	13 31%	6 14%
Score 3	11 26.2%	11 25.6%
Score 4	12 28.6%	26 60.5%
Score 5	0 0%	0 0%
Score 6	0 0%	0 0%
Score 7	0 0%	0 0%
Score 1	8 19%	0 0%
Score 2	14 33.3%	6 14%
Score 3	14 33.3%	17 39.5%
Score 4	8 19%	21 48.8%
Score 5	0 0%	0 0%
Score 6	0 0%	0 0%
Score 7	0 0%	0 0%

14. Secondary Outcome

Title	Number of Participants With at Least One Treatment-Emergent Adverse Events (TEAEs)
Description	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).
Time Frame	From signing of informed consent up to approximately Week 9

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	CTN SR	Placebo
Arm/Group Description	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.	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.
Measure Participants	79	74
Count of Participants [Participants]	63 150%	50 116.3%

15. Secondary Outcome

Title	Number of Participants With at Least One TEAEs for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day
Description	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).
Time Frame	From signing of informed consent up to approximately Week 9

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	CTN SR 400 mg	Placebo
Arm/Group Description	Participants received CTN SR 400 mg tablets daily for 3 weeks in treatment Periods 1 and 2.	Participants received matching-placebo daily for 3 weeks in treatment Periods 1 and 2.
Measure Participants	45	46
Count of Participants [Participants]	32 76.2%	30 69.8%

16. Secondary Outcome

Title	Cmax: Maximum Concentration
Time Frame	Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	CTN SR 300 mg	CTN SR 400 mg	CTN SR 600 mg
Arm/Group Description	Participants received CTN SR 300 mg tablet for up to 3 weeks in treatment Periods 1 and 2.	Participants received CTN SR 400 mg tablet for up to 3 weeks in treatment Periods 1 and 2.	Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
Measure Participants	4	33	6
Mean (Standard Deviation) [nanograms per milliliter (ng/ml)]	1450 (461)	1460 (570)	3080 (2260)

17. Secondary Outcome

Title	Tmax: Time to Maximum Concentration
Time Frame	Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	CTN SR 300 mg	CTN SR 400 mg	CTN SR 600 mg
Arm/Group Description	Participants received CTN SR 300 mg tablet for up to 3 weeks in treatment Periods 1 and 2.	Participants received CTN SR 400 mg tablet for up to 3 weeks in treatment Periods 1 and 2.	Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
Measure Participants	4	33	6
Median (Full Range) [hour]	3.36	8.10	8.12

18. Secondary Outcome

Title	AUC0-t: Area Under the Concentration-Time Curve During the Steady-State 24-hour Dosing Interval
Time Frame	Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	CTN SR 300 mg	CTN SR 400 mg	CTN SR 600 mg
Arm/Group Description	Participants received CTN SR 300 mg tablet for up to 3 weeks in treatment Periods 1 and 2.	Participants received CTN SR 400 mg tablet for up to 3 weeks in treatment Periods 1 and 2.	Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
Measure Participants	4	33	6
Mean (Standard Deviation) [hours*ng/mL]	14700 (5180)	16900 (5970)	34300 (23600)

19. Secondary Outcome

Title	t½: Elimination Phase Half-Life
Time Frame	Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	CTN SR 300 mg	CTN SR 400 mg	CTN SR 600 mg
Arm/Group Description	Participants received CTN SR 300 mg tablet for up to 3 weeks in treatment Periods 1 and 2.	Participants received CTN SR 400 mg tablet for up to 3 weeks in treatment Periods 1 and 2.	Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
Measure Participants	4	15	5
Mean (Standard Deviation) [hour]	5.53 (3.30)	5.08 (2.88)	4.06 (1.89)

20. Secondary Outcome

Title	Clast: Last Measurable Concentration
Time Frame	Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	CTN SR 300 mg	CTN SR 400 mg	CTN SR 600 mg
Arm/Group Description	Participants received CTN SR 300 mg tablet for up to 3 weeks in treatment Periods 1 and 2.	Participants received CTN SR 400 mg tablet for up to 3 weeks in treatment Periods 1 and 2.	Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
Measure Participants	0	0	0

21. Secondary Outcome

Title	Tlast: Time Point of the Last Measurable Concentration
Time Frame	Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	CTN SR 300 mg	CTN SR 400 mg	CTN SR 600 mg
Arm/Group Description	Participants received CTN SR 300 mg tablet for up to 3 weeks in treatment Periods 1 and 2.	Participants received CTN SR 400 mg tablet for up to 3 weeks in treatment Periods 1 and 2.	Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
Measure Participants	0	0	0

22. Secondary Outcome

Title	ke: Elimination Phase Rate Constant
Time Frame	Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	CTN SR 300 mg	CTN SR 400 mg	CTN SR 600 mg
Arm/Group Description	Participants received CTN SR 300 mg tablet for up to 3 weeks in treatment Periods 1 and 2.	Participants received CTN SR 400 mg tablet for up to 3 weeks in treatment Periods 1 and 2.	Participants received CTN SR 600 mg tablet for up to 3 weeks in treatment Periods 1 and 2.
Measure Participants	0	0	0

Adverse Events

Time Frame	From signing of informed consent up to approximately Week 9
Adverse Event Reporting Description	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).
Arm/Group Title	CTN SR		Placebo
Arm/Group Description	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.		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.
All Cause Mortality
	CTN SR		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/79 (0%)		0/74 (0%)
Serious Adverse Events
	CTN SR		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/79 (0%)		0/74 (0%)
Other (Not Including Serious) Adverse Events
	CTN SR		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	63/79 (79.7%)		50/74 (67.6%)
Cardiac disorders
Tachycardia	9/79 (11.4%)		7/74 (9.5%)
Palpitations	2/79 (2.5%)		0/74 (0%)
Bradycardia	1/79 (1.3%)		1/74 (1.4%)
Supraventricular Extrasystoles	0/79 (0%)		1/74 (1.4%)
Ear and labyrinth disorders
Tinnitus	1/79 (1.3%)		0/74 (0%)
Eye disorders
Vision Blurred	3/79 (3.8%)		0/74 (0%)
Dry Eye	1/79 (1.3%)		0/74 (0%)
Gastrointestinal disorders
Nausea	16/79 (20.3%)		0/74 (0%)
Diarrohea	14/79 (17.7%)		2/74 (2.7%)
Abdominal Pain Upper	4/79 (5.1%)		1/74 (1.4%)
Dyspepsia	3/79 (3.8%)		0/74 (0%)
Toothache	2/79 (2.5%)		3/74 (4.1%)
Abdominal Discomfort	1/79 (1.3%)		0/74 (0%)
Abdominal Pain	1/79 (1.3%)		0/74 (0%)
Abdominal Pain Lower	1/79 (1.3%)		0/74 (0%)
Constipation	1/79 (1.3%)		1/74 (1.4%)
Hypoaesthesia Oral	1/79 (1.3%)		0/74 (0%)
Vomiting	1/79 (1.3%)		0/74 (0%)
Abdominal Distension	0/79 (0%)		1/74 (1.4%)
Aphthous Stomatitis	0/79 (0%)		1/74 (1.4%)
Food Poisoning	0/79 (0%)		1/74 (1.4%)
Dry Mouth	11/79 (13.9%)		0/74 (0%)
General disorders
Discomfort	1/79 (1.3%)		0/74 (0%)
Fatigue	11/79 (13.9%)		0/74 (0%)
Chest Discomfort	2/79 (2.5%)		1/74 (1.4%)
Energy Increased	1/79 (1.3%)		0/74 (0%)
Feeling Abnormal	1/79 (1.3%)		0/74 (0%)
Sluggishness	1/79 (1.3%)		0/74 (0%)
Thirst	1/79 (1.3%)		0/74 (0%)
Infusion Site Bruising	0/79 (0%)		1/74 (1.4%)
Vessel Puncture Site Haemorrhage	0/79 (0%)		1/74 (1.4%)
Vessel Puncture Site Pain	0/79 (0%)		1/74 (1.4%)
Infusion Site Pain	0/79 (0%)		1/74 (1.4%)
Hepatobiliary disorders
Choleithiasis	0/79 (0%)		1/74 (1.4%)
Infections and infestations
Upper Respiratory Tract Infection	8/79 (10.1%)		7/74 (9.5%)
Gastroenteritis Viral	1/79 (1.3%)		0/74 (0%)
Pharyngitis	1/79 (1.3%)		1/74 (1.4%)
Tooth Abscess	1/79 (1.3%)		0/74 (0%)
Conjunctivitis	0/79 (0%)		1/74 (1.4%)
Gastroenteritis	0/79 (0%)		1/74 (1.4%)
Hordeolum	0/79 (0%)		1/74 (1.4%)
Sinusitis	0/79 (0%)		1/74 (1.4%)
Viral Infection	0/79 (0%)		1/74 (1.4%)
Injury, poisoning and procedural complications
Muscle Strain	2/79 (2.5%)		0/74 (0%)
Investigations
Orthostatic Heart Rate Response Increased	6/79 (7.6%)		0/74 (0%)
Blood Pressure Increased	2/79 (2.5%)		1/74 (1.4%)
Hepatic Enzyme Increased	2/79 (2.5%)		0/74 (0%)
Weight Decreased	2/79 (2.5%)		0/74 (0%)
Blood Pressure Diastolic Increased	1/79 (1.3%)		3/74 (4.1%)
Blood Pressure Orthostatic Decreased	1/79 (1.3%)		0/74 (0%)
Blood Thyroid Stimulating Hormone Increased	1/79 (1.3%)		1/74 (1.4%)
Heart Rate Increased	1/79 (1.3%)		0/74 (0%)
Liver Function Test Abnormal	1/79 (1.3%)		0/74 (0%)
Lymph Node Palpable	1/79 (1.3%)		0/74 (0%)
Aspartate Aminotransferase Increased	0/79 (0%)		1/74 (1.4%)
Blood Lactate Dehydrogenase Increased	0/79 (0%)		1/74 (1.4%)
Blood Pressure Systolic Increased	0/79 (0%)		1/74 (1.4%)
Weight Increased	0/79 (0%)		1/74 (1.4%)
Metabolism and nutrition disorders
Decreased Appetite	19/79 (24.1%)		0/74 (0%)
Increased Appetite	2/79 (2.5%)		0/74 (0%)
Polydipsia	1/79 (1.3%)		0/74 (0%)
Musculoskeletal and connective tissue disorders
Muscle Spasms	2/79 (2.5%)		0/74 (0%)
Arthralgia	1/79 (1.3%)		0/74 (0%)
Musculoskeletal Pain	1/79 (1.3%)		1/74 (1.4%)
Musculoskeletal Stiffness	1/79 (1.3%)		0/74 (0%)
Myalgia	1/79 (1.3%)		1/74 (1.4%)
Nervous system disorders
Headache	18/79 (22.8%)		6/74 (8.1%)
Dizziness	6/79 (7.6%)		1/74 (1.4%)
Dysgeusia	4/79 (5.1%)		0/74 (0%)
Poor Quality Sleep	2/79 (2.5%)		0/74 (0%)
Mental Impairment	1/79 (1.3%)		0/74 (0%)
Paraesthesia	1/79 (1.3%)		0/74 (0%)
Sedation	1/79 (1.3%)		1/74 (1.4%)
Somnolence	1/79 (1.3%)		1/74 (1.4%)
Tension Headache	1/79 (1.3%)		0/74 (0%)
Tremor	1/79 (1.3%)		0/74 (0%)
Lethargy	0/79 (0%)		2/74 (2.7%)
Migraine	0/79 (0%)		1/74 (1.4%)
Sinus Headache	0/79 (0%)		1/74 (1.4%)
Psychiatric disorders
Insomnia	9/79 (11.4%)		2/74 (2.7%)
Irritability	4/79 (5.1%)		3/74 (4.1%)
Agitation	3/79 (3.8%)		0/74 (0%)
Affect Lability	2/79 (2.5%)		0/74 (0%)
Bruxism	2/79 (2.5%)		0/74 (0%)
Derealisation	2/79 (2.5%)		0/74 (0%)
Dysphoria	2/79 (2.5%)		0/74 (0%)
Restlessness	2/79 (2.5%)		0/74 (0%)
Suicidal Ideation	2/79 (2.5%)		0/74 (0%)
Abnormal Dreams	1/79 (1.3%)		3/74 (4.1%)
Apathy	1/79 (1.3%)		0/74 (0%)
Emotional Disorder	1/79 (1.3%)		0/74 (0%)
Jealous Delusion	1/79 (1.3%)		0/74 (0%)
Libido Decreased	1/79 (1.3%)		0/74 (0%)
Paranoia	1/79 (1.3%)		0/74 (0%)
Pressure Of Speech	1/79 (1.3%)		0/74 (0%)
Initial Insomnia	0/79 (0%)		5/74 (6.8%)
Middle Insomnia	0/79 (0%)		4/74 (5.4%)
Terminal Insomnia	0/79 (0%)		1/74 (1.4%)
Renal and urinary disorders
Pollakiuria	1/79 (1.3%)		0/74 (0%)
Reproductive system and breast disorders
Dysmenorrhoea	1/79 (1.3%)		0/74 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	2/79 (2.5%)		1/74 (1.4%)
Oropharyngeal Pain	2/79 (2.5%)		2/74 (2.7%)
Nasal Congestion	1/79 (1.3%)		0/74 (0%)
Skin and subcutaneous tissue disorders
Rash	8/79 (10.1%)		0/74 (0%)
Acne	1/79 (1.3%)		0/74 (0%)
Hyperhidrosis	1/79 (1.3%)		1/74 (1.4%)
Pruritus	1/79 (1.3%)		0/74 (0%)
Dermatitis Contact	0/79 (0%)		1/74 (1.4%)
Dry Skin	0/79 (0%)		2/74 (2.7%)
Surgical and medical procedures
Sinus Operation	0/79 (0%)		1/74 (1.4%)
Vascular disorders
Flushing	2/79 (2.5%)		0/74 (0%)
Hot Flush	1/79 (1.3%)		0/74 (0%)
Orthostatic Hypotension	1/79 (1.3%)		0/74 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.