Efficacy, Safety, and Tolerability of TC-5619 in Adults With Attention Deficit/Hyperactivity Disorder (ADHD)

Study Overview
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Brief Summary
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ADHD has been associated with persistent deficits in the efficient allocation of attention and supports the notion that regulation of the cholinergic system may improve these cognitive deficits in ADHD. It has been suggested that the effects of nicotine are most pronounced on tasks that demand effortful processing (Rusted and Warburton 1994). In addition, a recent theory proposes that the cholinergic system allocates additional attentional resources during tasks that are demanding (i.e. sustained attention, set shifting, etc; Sarter and Bruno 1997). Thus it may be that in ADHD, cholinergic systems are under-responsive or under-developed and thus stimulation of nicotinic receptors via nicotinic agents may result in improved cognitive performance particularly on tests requiring effortful processing.

Detailed Description
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A randomized, parallel, forced-titration design is being used to assess effects of TC-5619 versus placebo on efficacy. A parallel group design allows the effects of TC-5619 to be clearly established, and the randomized nature of the design allows minimization of observer and subject bias. Because a forced dose up-titration design will be used, effects of individual doses will be preliminary, because the design confounds dose with time. The doses chosen (1mg, 5mg, and 25mg) reflect an appropriate range around the anticipated efficacious dose (3-10 mg), based upon preclinical extrapolations to the human, and upon the pro-cognitive effects of TC-5619 identified by CDR in the MRD study (Targacept Study TC-5619-238-CLP-002). All subjects will be tobacco non-users. It is possible that tobacco (nicotine) interferes with α7 NNR-mediated effects.

Official Title
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A Double-blind, Randomized, Placebo-controlled, Multicenter, Fixed Dose Titration Study to Assess Efficacy, Safety, and Tolerability of TC-5619 in Adults With Attention Deficit/Hyperactivity Disorder (ADHD)

Conditions
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ADHD

Intervention / Treatment
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* Drug: TC-5619-238
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of ADHD per DSM-IV TR criteria Score > 2 on at least 6 of 9 items in at least 1 subscale of the CAARS-INV Score > 4 (at least moderate) on the Clinical Global Impression-Severity (CGI-S) index Age 18 - 65, male or female Tobacco non-users as indicated by lack of tobacco use within the last year prior to Screening, and by negative urinary cotinine level of < 50ng/mL after quantification Able to understand and sign informed consent Exclusion Criteria: Current DSM-IV Axis I psychiatric disorder other than ADHD; use of MINI to exclude other major DSM-IV TR psychiatric diagnoses Known or suspected drug abuse within the last 12 months prior to Screening Urine drug screen positive for illegal or non-prescribed drugs at Screening Patients at imminent risk of suicide or of danger to themselves or others Use of drugs affecting cognitive function within 3 weeks prior to Day 1, including use of any medications for treatment of ADHD. Any medication wash-outs must be completed during the 3 weeks between Screening and Day 1. Any other restricted or prohibited drugs. Other concomitant medications that have been changed within 4 weeks prior to Screening Unable to comply with study procedures in opinion of investigator, including CogState ADHD test battery History of significant other major or unstable neurological, metabolic, hepatic, renal, hematological, pulmonary, CV, GI, or urological disorder; or diagnosis of major depressive disorder Myocardial infarction within past year Seizure disorder within past year Type 1 diabetes mellitus (DM); type 2 DM that requires medication (diet-controlled allowed) HbA1C > 7.4 at Screening BMI < 15 or > 35; male weight < 100 lbs; female weight < 80 lbs. Current TB or known systemic infection (HBV, HCV, HIV) Clinically significant finding on physical exam Clinically significant lab or ECG abnormality that could be a safety issue in the study, including QTcF > 450 (males) or QTcF > 480msec (females), and excluding LFTs > 1.5 times upper limits of normal Women of child-bearing potential and men unwilling or unable to use accepted methods of birth control Women with a positive pregnancy test, or who are lactating Participation in another clinical trial in last 3 months prior to Screening

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo will be provided as white, opaque gelatin capsules in sham strengths of 1mg, 5mg, and 25mg | Drug: Placebo<br>* Placebo will be provided as white, opaque gelatin capsules in sham strengths of 1mg, 5mg, and 25mg<br>|
| Active Comparator: TC-5619<br>TC-5619-238 will be provided as white, opaque gelatin capsules in strengths of 1mg, 5mg, and 25mg (as free base). Subjects will take 1mg TC-5619, 5mg TC-5619, 25mg TC-5619, one capsule once daily p.o. | Drug: TC-5619-238<br>* TC-5619-238 will be provided as white, opaque gelatin capsules in strengths of 1mg, 5mg, and 25mg (as free base). Subjects will take 1mg TC-5619, 5mg TC-5619, 25mg TC-5619, or matching placebo - one capsule once daily p.o.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CAARS-INV ADHD-rating scale | •Clinician-administered ADHD-rating scale (CAARS-INV) and is the total of 3 subscales: Inattention, Hyperactivity-Impulsivity, and ADHD Index [ Time Frame: Week -3, Day 1, Week 1, Week 4 (evaluation of 1mg dose); Week 8 (evaluation of 5mg Dose); and Week 12 (evaluation of 25mg dose)] | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CAARS-INV subscales | CAARS-INV subscales: Inattention, Hyperactivity-Impulsivity, and ADHD Index, obtained [Time frame: Week -3, Day 1, Week 1, Week 4, Week 8, Week 12,Early Withdrawal (EW)] | Week 12 | 
| CogState ADHD Battery | CogState ADHD test battery [Time frame: Week -3, Day 1, Week 1, Week 4, Week 8, Week 12,Early Withdrawal (EW)] | Week 12 | 
| CogState Stop-Signal Task scores | CogState Stop-Signal Task scores [Time frame: Week -3, Day 1, Week 1, Week 4, Week 8, Week 12,Early Withdrawal (EW)] | Week 12 | 
| CAARS-Self Rating (CAARS-S) total score | CAARS-S total score [Time frame: Week -3, Day 1, Week 1, Week 4, Week 8, Week 12,Early Withdrawal (EW)] | Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ADHD, Attention Deficit Hyperactive Disorder