Factors Determining the Efficacy of Botulinum Toxin for Arm Tremor in Dystonia

Dystonia Clinical Trial

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Official title:

Factors Determining the Efficacy of Botulinum Toxin for Arm Tremor in Dystonia: An Exploratory Study

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06411028
• Other study ID #: 115083
• Secondary ID: NL86546.091.24
• Status: Not yet recruiting
• Start date: July 1, 2024
• Est. completion date: May 30, 2027

Study information

• Verified date: April 2024
• Source: Radboud University Medical Center
• Contact: Iris Visser, MSc
• Phone: +31 024 361 66 00
• Email: iris.visser[@]radboudumc.nl
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Tremor occurs in up to 55% of dystonia patients, which is known as dystonic tremor syndrome (DTS). Tremor can be present in the body part affected by dystonia (dystonic tremor, DT), or an unaffected body part (tremor associated with dystonia, TAWD). DTS can be treated with botulinum neurotoxin (BoNT) injections, but BoNT is effective in only about 60-70% of patients. It is unknown which patients benefit most from BoNT treatment. We aim to explore the associations between clinical and pathophysiological tremor characteristics and BoNT efficacy. To do so, we will measure clinical, electrophysiological, ultrasonographic and (functional) magnetic resonance imaging ((f)MRI) characteristics before the start of BoNT treatment and measure BoNT efficacy after three three-monthly BoNT sessions.

Description:

Rationale: Tremor occurs in up to 55% of dystonia patients, which is known as dystonic tremor syndrome (DTS). Tremor can be present in the body part affected by dystonia (dystonic tremor, DT), or an unaffected body part (tremor associated with dystonia, TAWD). DTS can be treated with botulinum neurotoxin (BoNT) injections, but BoNT is effective in only about 60-70% of patients. It is unknown which patients benefit from BoNT treatment. This highlights the need for personalized treatment.

Objective: The primary objective is to explore the differences in BoNT efficacy between DT and TAWD of the upper extremity. Secondary objectives are to: explore the electrophysiological and cerebral differences between DT and TAWD of the upper extremity, explore the associations between clinical, electrophysiological, ultrasonographic and (functional) magnetic resonance imaging ((f)MRI) tremor characteristics and BoNT efficacy in DTS of the upper extremity, and explore the agreement between a clinical assessment, polymyography (PMG) and muscle ultrasound (MUS) on muscle selection in DTS of the upper extremity.

Study design: Explorative prospective multi-centre cohort study Study population: 60 adults with DTS (± 30 DT/ 30 TAWD) of the upper extremity who start 12-weekly BoNT treatment as part of standard care.

Main study parameters/endpoints: The primary outcome measure is clinical tremor severity quantified by the TRG Essential Tremor Rating Assessment Scale (TETRAS) at 28 weeks. We will also collect clinical, electrophysiological, ultrasonographic and (f)MRI measures and patient-reported outcomes.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Subjects do not benefit from participation. The risk of the extra study procedures is negligible. The study procedures are harmless, but may be tiring. The time burden consists of five extra hours spent at the hospital divided across three visits and filling in questionnaires (one hour). The baseline visit for MRI scanning and the visit at 28 weeks are extra compared to standard care.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 60
• Est. completion date: May 30, 2027
• Est. primary completion date: May 30, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Clinical diagnosis of DT or TAWD according to the 2018 consensus statement on the classification of tremors

• Tremor of one or both upper extremities

• Age = 18 years

Exclusion Criteria:

• Contraindications for BoNT treatment

• Previous BoNT treatment of upper extremity

• Unstable dose medications for dystonia and tremor = 1 month before study enrolment

• Deep brain stimulation implantation = 6 months before study enrolment

• Unstable deep brain stimulation variables = 1 month before study enrolment

• Comorbidity interfering with study participation

• Pregnancy or breastfeeding

• Insufficient knowledge of the Dutch language

Exclusion criteria for MRI scanning:

• Contraindications for MRI (e.g. previous brain surgery, claustrophobia, active implant, epilepsy, metal objects in the upper body that are incompatible with MRI)

• Moderate to severe head tremor while lying supine (to avoid artefacts caused by extensive head motion during scanning).

• Inability to provoke postural tremor while lying supine.

Related Conditions & MeSH terms

• Dystonia
• Dystonic Disorders
• Tremor

Intervention

Diagnostic Test:
• Polymyography
We will measure muscle activity using surface electromyography and tremor using inertial measurement units while subjects perform rest, posturing and kinetic tasks.
• Muscle ultrasound
We will obtain B-mode images and videos of upper extremity muscles of the most affected upper extremity.
• (Functional) magnetic resonance imaging
Subjects will undergo (f)MRI scanning involving concurrent electromyography, accelerometry and functional magnetic resonance imaging.
• Clinical assessment
We will assess tremor and dystonia severity using clinical scales.
• Questionnaires
We will collect patient-reported outcomes.

Locations

Country	Name	City	State
n/a

Sponsors (3)

Lead Sponsor	Collaborator
Radboud University Medical Center	Canisius-Wilhelmina Hospital, Donders Centre for Cognitive Neuroimaging

References & Publications (2)

Nieuwhof F, Toni I, Dirkx MF, Gallea C, Vidailhet M, Buijink AWG, van Rootselaar AF, van de Warrenburg BPC, Helmich RC. Cerebello-thalamic activity drives an abnormal motor network into dystonic tremor. Neuroimage Clin. 2022;33:102919. doi: 10.1016/j.nicl.2021.102919. Epub 2021 Dec 16. — View Citation

Panyakaew P, Cho HJ, Lee SW, Wu T, Hallett M. The Pathophysiology of Dystonic Tremors and Comparison With Essential Tremor. J Neurosci. 2020 Nov 25;40(48):9317-9326. doi: 10.1523/JNEUROSCI.1181-20.2020. Epub 2020 Oct 23. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Tremor severity assessed by the TRG Essential Tremor Rating Assessment Scale (TETRAS)	Our primary outcome will be clinical tremor severity measured by the TRG Essential Tremor Rating Assessment Scale (TETRAS) (35) at 28 weeks. The scale ranges between 0 and 112 points, with higher scores indicating a more severe tremor. The TETRAS consists of two subcategories: a 12-item activities of daily living subscale and a 9-item performance scale. The daily living subscale is scored by interviewing the participant. The performance scale is rated by observing the participants while they are performing multiple tasks.	Baseline, 28 weeks
Secondary	Tremor severity assessed by the Fahn-Tolosa-Marin Tremor Rating Scale (FTM-TRS)	FTM-TRS [0-152]: higher scores indicate a more severe tremor.	Baseline, 28 weeks
Secondary	Dystonia severity assessed by the Burke-Fahn-Marsden Dystonia Rating Scale (BFM-DRS)	BFM-DRS [0-150]: higher scores indicate more severe dystonia.	Baseline, 28 weeks
Secondary	Additional neurological signs assessed by the Standardised Tremor Elements Assessment (STEA)	STEA [0-27]: higher scores make a diagnosis of dystonic tremor syndrome instead of essential tremor more likely.	Baseline
Secondary	Cognitive functioning assessed by Montreal Cognitive Assessment (MOCA)	MOCA [0-30]: score = 26 indicates normal cognitive functioning.	Baseline
Secondary	Quality of life assessed by the Quality of Life Essential Tremor Questionnaire (QUEST)	QUEST [0-120]: higher scores indicate greater dissatisfaction.	Baseline, 28 weeks
Secondary	Psychological stress assessed by the Perceived stress scale (PSS)	PSS [0-4]: higher scores indicate higher levels of perceived stress	Baseline, 28 weeks
Secondary	Pain assessed by the Numeric Pain Rating Scale (NPRS)	NPRS [0-10]: 0 indicates no pain and 10 the worst imaginable pain	Baseline, 28 weeks
Secondary	Patient-reported change in tremor severity assessed by the Patient Global Impression of Change (PGIC)	PGIC [-3: much worse, -2: moderately worse, -1: slightly worse, 0: no change, 1: slightly better, 2: moderately better, 3: much better]	28 weeks
Secondary	Electrophysiological characteristics	e.g. tremor power, dominant frequency, frequency-width at half-width power, intermuscular coherence, tremulous muscles	Baseline, 28 weeks
Secondary	Ultrasonographic characteristics	e.g. echogenicity, muscle thickness, tremulous muscles	Baseline, 28 weeks
Secondary	(f)MRI characteristics	e.g. grey matter volume, tremor related-activity in cerebello-thalamo-cortical circuit and basal ganglia	Baseline
Secondary	Botulinum toxin parameters	e.g. injection schemes, rationale for muscle selection, adherence	Baseline, 12 and 24 weeks