Pharmacogenomic Contributions to Trihexyphenidyl Biotransformation and Response in Children With Dystonic Cerebral Palsy (TRIKE2)

Pharmacogenomic Contribution to the Biotransformation of Trihexyphenidyl and Development of a Precision Dosing Model for Children With Dystonia and Cerebral Palsy

This study looks at how a medicine called trihexyphenidyl works in children with dystonic cerebral palsy. The study aims to understand how trihexyphenidyl is broken down and used in the body of pediatric patients and whether this is impacted by a person's genetics. Information from this study will also be used to design future clinical trials.

Study Overview

• Status: Recruiting
• Conditions: Dystonia; Cerebral Palsy, Dyskinetic; Pediatric Disorder; Genetic Predisposition; Dystonia, Secondary; Pharmacogenomic Drug Interaction; Cerebral Palsy, Dystonic-Rigid; Trihexyphenidyl Adverse Reaction
• Intervention / Treatment: Drug: Trihexyphenidyl

Detailed Description

This is a 16-week single-arm nonrandomized pilot study of trihexyphenidyl in children with dystonic cerebral palsy (DCP) to 1) evaluate the pharmacokinetics (PK) of trihexyphenidyl (THP) and variation in PK parameters between CYP2D6 and CYP2C19 genotypes and 2) evaluate the feasibility of a future exposure-controlled clinical trial of THP.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Rose Gelineau-Morel, MD; Phone Number: 816-302-3331; Email: rngelineaumorel@cmh.edu
• Study Contact Backup: Name: Rachel Nass; Phone Number: 8166011354; Email: rnass@cmh.edu

Study Locations

• United States
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Recruiting
      • Children's Mercy Hospital Kansas City
      • Contact: Rachel Nass; Phone Number: 8166011354; Email: rnass@cmh.edu
      • Principal Investigator: Rose Gelineau-Morel, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Ages 5-17 years of age
• Diagnosis of cerebral palsy and dystonia causing interference
• Parent/legal guardian of a child with a diagnosis of cerebral palsy and dystonia
• Parent/legal guardian is willing and able to provide informed permission/assent for the study

Exclusion Criteria:

• Previously or currently taking trihexyphenidyl
• Patients turning 18 years of age within the study period (16 weeks from Study Day 1)
• A language barrier for the patient that precludes communication and/or the ability to complete study-related requirements

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Trihexyphenidyl; Participants receive trihexyphenidyl following the dose escalation schedule below: Week 1: 0.05 mg/kg BID Week 2: 0.05 mg/kg TID Week 3: 0.1 mg/kg TID Week 4: 0.15 mg/kg TID Week 5: 0.20 mg/kg TID Week 6-15: 0.25 mg/kg TID	Drug: Trihexyphenidyl; 6-week dose escalation up to 0.25mg/kg TID, followed by a 9-week maintenance period at this dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in Cmax between CYP2D6 and CYP2C19 phenotype groups	Cmax will be measured in first-dose pharmacokinetic study on study day 1	Baseline
Difference in AUC0-n between CYP2D6 and CYP2C19 phenotype groups	AUC0-n will be measured in first-dose pharmacokinetic study on study day 1	Baseline
Difference in AUC0-∞ between CYP2D6 and CYP2C19 phenotype groups	AUC0-∞ will be measured in first-dose pharmacokinetic study on study day 1	Baseline
Recruitment percentage	Measure percent of participants who were approached for the study that enrolled in the study	Through study completion, an average of 2 years
Retention percentage	Measure percent of participants enrolled who completed the study	Through study completion, an average of 2 years
Dystonia Efficacy Measures Outcome Completion	Measure percent of participants enrolled who were able to complete each dystonia efficacy measure (see secondary outcome measures)	Through study completion, an average of 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with at least one adverse event as measured by the Safety Monitoring Uniform Report Form (SMURF)	Adverse events will only include those that are determined to be related to the study drug.	Through study completion, an average of 2 years
Change from baseline in dystonia duration as measured by the Dyskinesia Impairment Scale (exploratory)	Duration of dystonia using subscale DIS-D are measured in 12 body regions during activity and rest. Dystonia duration scores are measured on a 4-point scale from 0 to 4 with 0 being dystonia is absent and 4 being dystonia is always present (≥90%).	Baseline, 16 weeks
Change from baseline in dystonia amplitude as measured by the Dyskinesia Impairment Scale (exploratory)	Amplitude of dystonia using subscale DIS-D are measured in 12 body regions during activity and rest. Dystonia amplitude scores are measured on a 4-point scale from 0 to 4 with 0 being dystonia is absent and 4 being dystonia in maximal range of motion (≥90%).	Baseline, 16 weeks
Change from baseline in dystonia as measured by the Quality of Upper Extremity Skills Test (QUEST) (exploratory)	Upper extremity function in 1 domain; grasp. 13 activities with item-level scores and three items for the tester to rate: hand function, spasticity, and cooperativeness. All scores are summed, and formulas are used to calculate percentages for this domain. Domain percentage is summed with a minimum score less than 0, and the maximum score is 100.	Baseline, 16 weeks
Change in functional impact from baseline as measured by the Dyskinetic Cerebral Palsy Functional Impact Scale (D-FIS) (exploratory)	Functional impact scores are measured on a 5-point scale from 0 to 4 with 0 being dyskinesia may be present but has no impact on the named activity, and 4 being dyskinesia is present and prevents child from doing a named activity, even with help. An "NA" option indicates the activity is difficult but NOT due to dyskinesia.	Baseline, 16 weeks
Change in priority scores in functional impact from baseline as measured by the Dyskinetic Cerebral Palsy Functional Impact Scale (D-FIS) (exploratory)	Priority scores are measured on a 4-point scale from 1 to 4 with 1 being an activity is not a priority and 4 being an activity is highest priority.	Baseline, 16 weeks
Change in patient-driven performance from baseline as measured by the Canadian Occupational Performance Measure (exploratory)	Performance scores are measured on a 10-point scale with 1 being not able to do an activity at all and 10 being able to do an activity extremely well.	Baseline, 16 weeks
Change in patient-driven goal satisfaction from baseline as measured by the Canadian Occupational Performance Measure (exploratory)	Satisfaction scores are measured on a 10-point scale with 1 being not satisfied at all with the way they do an activity to 10 being extremely satisfied with the way they do an activity.	Baseline, 16 weeks
Change in caregiver's perspective about their child in 4 domains: health status, comfort, wellbeing, functional abilities, and ease of caregiving from baseline as measured by Caregiver Priorities and Child Health Index of Life with Disabilities	Scores for each domain and for the total survey are standardized and range from 0 to 100 with 0 being the worst and 100 being the best.	Baseline, 16 weeks
Measure the acceptability of outcome measures at 16 weeks as measured by the Acceptability of Intervention Measure	Scores are measured on a 5-point scale from Completely Disagree to Completely Agree for items 1) The outcome measure meets my approval. 2) The outcome measure is appealing to me. 3) I like the outcome measure. 4) I welcome the outcome measure	16 weeks

Collaborators and Investigators

• Sponsor: Children's Mercy Hospital Kansas City
• Collaborators: University of Kansas Medical Center
• Investigators: Principal Investigator: Rose Gelineau-Morel, MD, Children's Mercy Kansas City

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2024
• Primary Completion (Estimated): November 30, 2029
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: July 29, 2024
• First Submitted That Met QC Criteria: August 13, 2024
• First Posted (Actual): August 15, 2024

Study Record Updates

• Last Update Posted (Actual): July 18, 2025
• Last Update Submitted That Met QC Criteria: July 17, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Cerebral Palsy; Pediatric; Pharmacogenomics; Dystonia; Trihexyphenidyl
• Additional Relevant MeSH Terms: Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Disease Attributes; Movement Disorders; Brain Damage, Chronic; Dyskinesias; Disease Susceptibility; Cerebral Palsy; Paralysis; Genetic Predisposition to Disease; Dystonia; Dystonic Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Antiparkinson Agents; Anti-Dyskinesia Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Trihexyphenidyl
• Other Study ID Numbers: STUDY00003228

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Pharmacokinetic data, including genotypes and THP levels, will be in publications for analysis replication. This will include participant genotypes and corresponding levels of THP, R-THP, and S-THP. Raw data and technical duplicates are available on request for result transparency and clinical trial design. CYP2D6 and CYP2C19 data will also be published; raw sequences go to NICHD's Data Hub (https://dash.nichd.nih.gov/), new haplotypes to PharmVar (https://www.pharmvar.org/). Recruitment, retention, and scientific methods outcomes will be published to guide future THP trials, though the study isn't powered for efficacy endpoints.
• IPD Sharing Time Frame: The data will be made available at the time of the associated publication or at the end of the study period, whichever comes first. The datasets made available through publications in PubMed will be made available indefinitely. Sharing of raw data upon request will be accommodated for at least 10 years. Once genetic data are published or uploaded to DASH or PharmVar, they will be available indefinitely.
• IPD Sharing Access Criteria: Access to raw pharmacokinetic data/samples and genetic samples will be controlled because it will only be available upon request. For DASH, a request for study data can be submitted and managed within their system.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No