Tipepidine in Children With Attention Deficit/Hyperactivity Disorder (AD/HD): a Double-blind, Placebo-controlled Trial

Study Overview
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Brief Summary
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Tipepidine (3-[di-2-thienylmethylene]-1-methylpiperidine) has been used solely as a nonnarcotic antitussive in Japan since 1959. The safety of tipepidine in children and adults has already been established. It is reported that tipepidine inhibits G-protein-coupled inwardly rectifying potassium (GIRK)-channel currents. The inhibition of GIRK channels by tipepidine is expected to modulate the level of monoamines in the brain. We put forward the hypothesis that tipepidine can improve attention deficit/hyperactivity disorder (ADHD) symptoms by modulating monoaminergic neurotransmission through the inhibition of GIRK channels. The purpose of this double-blind, placebo-controlled trial is to confirm whether treatment with tipepidine can improve symptoms in pediatric patients with ADHD.

Detailed Description
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Tipepidine (3-[di-2-thienylmethylene]-1-methylpiperidine) has been used solely as a nonnarcotic antitussive in Japan since 1959. The safety of tipepidine in children and adults has already been established. It is reported that tipepidine inhibits G-protein-coupled inwardly rectifying potassium (GIRK)-channel currents. The inhibition of GIRK channels by tipepidine is expected to modulate the level of monoamines in the brain. We put forward the hypothesis that tipepidine can improve attention deficit/hyperactivity disorder (ADHD) symptoms by modulating monoaminergic neurotransmission through the inhibition of GIRK channels. The purpose of this double-blind, placebo-controlled trial is to confirm whether treatment with tipepidine can improve symptoms in pediatric patients with ADHD. See our previous open trial, An Open Study of Tipepidine Hibenzate in Patients With Attention Deficit Hyperactivity Disorder (ADHD) http://clinicaltrials.gov/show/NCT01835093

Official Title
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Tipepidine in Children With Attention Deficit/Hyperactivity Disorder (AD/HD): a Double-blind, Placebo-controlled Trial

Conditions
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Attention Deficit Disorder With Hyperactivity Disease, Hyperkinesis, Attention Deficit and Disruptive Behavior Disorders

Intervention / Treatment
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* Drug: Tipepidine Hibenzate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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[Inclusion Criteria] Diagnosis of attention deficit hyperactivity disorder besed on DSM-5 criteria. Scores of 20 or higher in ADHD-RS (physician evaluation) total score. currently is an outpatient at Chiba University Hospital Department of Psychiatry or Child Psychiatry. currently receiving no medications for ADHD (atomoxetine, methylphenidate) treatment for the previous 4 weeks prior to enrollment in this study. currently receiving no medications of antidepressants, mood stabilizers and the antipsychotics treatment for the previous 4 weeks prior to enrollment in this study. currently receiving no medications of GIRK channel antagonist (tipepidine, cloperastine, caramiphen) treatment for the previous 4 weeks prior to enrollment in this study. Ages 6 - 17, male or female Provision of written informed consent by patients and parents or guardian. must be able to swallow capsuled medicine. [Exclusion Criteria] History of allergic reaction or hypersensitivity to tipepidine hibenzate. Patients who have not been informed of having the disease at the time of informed consent. Diagnosis of any of the following diseases based on the DSM-5 criteria. Autism Spectrum Disorder, Schizophrenia Spectrum and Other Psychotic Disorders, Neurocognitive Disorders, Substance Related and Addictive Disorders, Feeding and Eating Disorders, Personality Disorders, Paraphilic Disorders. currently receiving medications for ADHD (atomoxetine, methylphenidate) treatment for the previous 4 weeks prior to enrollment in this study. currently receiving medications of antidepressants, mood stabilizers and the antipsychotics treatment for the previous 4 weeks prior to enrollment in this study. currently receiving medications of GIRK channel antagonist (tipepidine, cloperastine, caramiphen) treatment for the previous 4 weeks prior to enrollment in this study. Somatic disorder which requires severe body management or severe meal management. participating in another clinical trial within 3 months prior to enrollment into this study. (except for observation study without intervention). planning change of treatment because of unstable neurological manifestations or somatic symptoms. History of suicidal ideation within the past year. pregnant or nursing, or intending to become pregnant or to start breastfeeding during the study. Other clinically significant reasons for exclusion by investigators.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tipepidine Hibenzate<br>Tipepidine is taken orally at 30 mg/day (10 mg after breakfast, 10 mg after supper, and 10 mg before bedtime), for 4 weeks. | Drug: Tipepidine Hibenzate<br> <br> |
| Placebo Comparator: Placebo<br>Placebo is taken orally after breakfast, after supper, and before for 4 weeks. | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The ADHD Rating Scale IV Japanese Version (ADHD-RS-IV-J) by physician. | The ADHD Rating Scale-IV obtains parent ratings regarding the frequency of each ADHD symptom based on DSM-IV criteria. The ADHD Rating Scale-IV is completed independently by the parent and scored by a clinician. The scale consists of 2 subscales: inattention (9 items) and hyperactivity-impulsivity (9 items). | Changes from baseline in ADHD-RS-IV-J at 4-weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subscores (Inattentive subscore, Hyperactive/impulsive subscore) of the ADHD-RS-IV-J by physician. |  | Changes from baseline in at 4-weeks | 
| Total scores and subscores (Inattentive subscore, Hyperactive/impulsive subscore) of the ADHD-RS-IV-J by parents. |  | Changes from baseline in at 4-weeks | 
| Total scores and subscores (planning subscore, attention subscore, simultaneous subscore, successive subscore) of DN-CAS (Das-Naglieri Cognitive Assessment System) Japanese Version. | The DN-CAS is an assessment battery designed to evaluate cognitive processing. It was developed to integrate theoretical and applied areas of psychological knowledge using cognitive processing theory and tests designed to measure-Planning, Attention, Simultaneous, and Successive Processing (PASS)-in individuals ages 5-17. This assessment facilitates mental health professionals in the identification of Attention-Deficit/Hyperactivity Disorder, Traumatic Brain Injury, learning disabilities, Mental Retardation, and giftedness. | Changes from baseline in at 4-weeks | 
| Scores of CGI-ADHD-S, CGI-ADHD-I |  | Changes from baseline in at 4-weeks | 
| Biologocal markers (Serum levels of Pro-BDNF, Mature-BDNF, Oxytocin) |  | Changes from baseline in at 4-weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tipepidine, GIRK