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

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.

Study Overview

• Status: Completed
• Conditions: Attention Deficit and Disruptive Behavior Disorders; Hyperkinesis; Attention Deficit Disorder With Hyperactivity Disease
• Intervention / Treatment: Drug: Placebo; Drug: Tipepidine Hibenzate

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Japan
  • Chuo-ku
    • Chiba, Chuo-ku, Japan, 260-8670
      • Department of Psychiatry, Chiba University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 15 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

[Inclusion Criteria]

1. Diagnosis of attention deficit hyperactivity disorder besed on DSM-5 criteria.
2. Scores of 20 or higher in ADHD-RS (physician evaluation) total score.
3. currently is an outpatient at Chiba University Hospital Department of Psychiatry or Child Psychiatry.
4. currently receiving no medications for ADHD (atomoxetine, methylphenidate) treatment for the previous 4 weeks prior to enrollment in this study.
5. currently receiving no medications of antidepressants, mood stabilizers and the antipsychotics treatment for the previous 4 weeks prior to enrollment in this study.
6. currently receiving no medications of GIRK channel antagonist (tipepidine, cloperastine, caramiphen) treatment for the previous 4 weeks prior to enrollment in this study.
7. Ages 6 - 17, male or female
8. Provision of written informed consent by patients and parents or guardian.
9. must be able to swallow capsuled medicine.

[Exclusion Criteria]

1. History of allergic reaction or hypersensitivity to tipepidine hibenzate.
2. Patients who have not been informed of having the disease at the time of informed consent.
3. 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.
4. currently receiving medications for ADHD (atomoxetine, methylphenidate) treatment for the previous 4 weeks prior to enrollment in this study.
5. currently receiving medications of antidepressants, mood stabilizers and the antipsychotics treatment for the previous 4 weeks prior to enrollment in this study.
6. currently receiving medications of GIRK channel antagonist (tipepidine, cloperastine, caramiphen) treatment for the previous 4 weeks prior to enrollment in this study.
7. Somatic disorder which requires severe body management or severe meal management.
8. participating in another clinical trial within 3 months prior to enrollment into this study. (except for observation study without intervention).
9. planning change of treatment because of unstable neurological manifestations or somatic symptoms.
10. History of suicidal ideation within the past year.
11. pregnant or nursing, or intending to become pregnant or to start breastfeeding during the study.
12. Other clinically significant reasons for exclusion by investigators.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Tipepidine Hibenzate; 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
Placebo Comparator: Placebo; Placebo is taken orally after breakfast, after supper, and before for 4 weeks.	Drug: Placebo

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Chiba University

Study record dates

Study Major Dates

• Study Start (Actual): June 11, 2015
• Primary Completion (Actual): March 1, 2019
• Study Completion (Actual): March 1, 2019

Study Registration Dates

• First Submitted: November 27, 2014
• First Submitted That Met QC Criteria: December 1, 2014
• First Posted (Estimate): December 2, 2014

Study Record Updates

• Last Update Posted (Actual): March 19, 2019
• Last Update Submitted That Met QC Criteria: March 17, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: Tipepidine, GIRK
• Additional Relevant MeSH Terms: Behavioral Symptoms; Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Dyskinesias; Neurodevelopmental Disorders; Disease; Problem Behavior; Mental Disorders; Attention Deficit Disorder with Hyperactivity; Hyperkinesis; Attention Deficit and Disruptive Behavior Disorders
• Other Study ID Numbers: G26023; UMIN000015748 (Other Identifier: UMIN Clinical Trials Registry (UMIN-CTR))