Dystonia Treatment With Injections Supplemented By Transcranial Magnetic Stimulation

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04916444

Acronym

D-TWIST

Enrollment

Registered

2021-06-07

Start date

2022-02-07

Completion date

2024-01-07

Last updated

2024-10-08

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Cervical Dystonia

Keywords

rTMS, cervical dystonia, botulinum toxin

Brief summary

We applied 16 sessions of rTMS over 4 consecutive days for adult patients suffering from cervical dystonia who received botulinum toxin (BoNT) injections on a regular basis. The TMS protocol took place 9 weeks following their last BoNT injection. The primary outcome measure was improvement in cervical dystonia as measured by the TWSTRS scale. The secondary outcome measures included mood, cognition, and gait measures.

Detailed description

This was a crossover study design in which patients were randomized to active or sham stimulation during session 1 (S1) and then crossed over to the condition they were not randomized to at first during session 2 (S1). Patients who were receiving BoNT injections for cervical dystonia on a regular basis but only noted benefit from BoNT for 9 weeks or less were eligible to participate. The total study protocol took place over 24 weeks. During week 1, patients had their regularly scheduled botox injections. During week 9, patients underwent either active or sham rTMS, as detailed below. They had outcome measures obtained at week 9 (S1:T0; baseline/pre-TMS), week 10 (S1:T1; post-TMS), and week 12 (S1:T2; 2 weeks post-TMS). At week 12, they underwent their regularly scheduled BoNT injections. During week 21, patients underwent either active or sham rTMS, whichever condition they were not randomized into during the first session. They then had outcome measures obtained at week 21 (S2:T0; baseline/pre-TMS), week 22 (S2:T1; post-TMS), and week 24 (S2:T2; 2 weeks post-TMS). The neurostimulation protocol was as follows: The dPMC target was defined as 1 cm medial and 2 cm anterior to the site of RMT acquisition. The rTMS protocol was as follows: each session consisted of 1-Hz rTMS over the dPMC for 30 minutes (1800 pulses) at 90% of the RMT. Patients received 4 sessions per day for 4 consecutive days with a 10-minute break between each session. The daily duration of the rTMS protocol, including breaks, lasted approximately 160 minutes.

Interventions

DEVICErTMS

repetitive transcranial magnetic stimulation is a painless, noninvasive form of neurostimulation. This study uses an accelerated protocol in which the neurostimulation pulses are delivered in 4 sessions per day over 4 consecutive days (16 total sessions). Active or sham rTMS will be provided at 9 weeks following botox injections.

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Outcomes Assessor)

Masking description

A sham coil was used for sham rTMS. Both conditions underwent the exact same study procedures except the sham coil did not deliver pulses; it did still deliver a sound and tapping sensation meant to mimic the real rTMS coil, but no real stimulation was provided in this condition. Patients and outcomes assessors were not made aware of the condition that the participant was partaking in.

Intervention model description

Patients were randomized to one of two conditions during session 1: active or sham rTMS. During session 2, patients underwent whichever condition they did not undergo in session 1.

Eligibility

Sex/Gender

ALL

Age

18 Years to 85 Years

Healthy volunteers

Inclusion criteria

* patients 18-85 years of age who receive regular botulinum toxin (BoNT) scheduled every 12 weeks, on stable optimized doses but with reported benefits lasting ≤ 9 weeks for 2 consecutive cycles. Patents followed at our center routinely fill out a self-reported form to document the duration of benefits perceived with BoNT therapy. Participants will be allowed to continue oral medications that they are taking for dystonia concurrently but will not be allowed to change their concurrent medication regimen throughout the duration of the study.

Exclusion criteria

* Presence of metallic objects or neurostimulators in the brain * Pregnancy * History of active seizures or epilepsy * Patients with severe scoliosis or other gait impairment that will preclude them from participating in gait evaluation.

Design outcomes

Primary

Measure	Time frame	Description
Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)	Before rTMS (Session 1: Week 9, Session 2: Week 21), Immediately after rTMS (Session 1: Week 10, Session 2: Week 22), 2 weeks after rTMS (Session 1: Week 12, Session 2: Week 24)	This is an objective scale evaluating patients on a variety of features including maximal excursion, duration, effects of sensory trick, shoulder elevation, range of motion, and time. Scores range from 0 to 85 where a higher score indicates more severity.

Secondary

Measure	Time frame	Description
Beck Depression Inventory (BDI)	Before rTMS (Session 1: Week 9, Session 2: Week 21), Immediately after rTMS (Session 1: Week 10, Session 2: Week 22), 2 weeks after rTMS (Session 1: Week 12, Session 2: Week 24)	This is a 21-question survey evaluating depression in patients on a 0 to 3 scale, with a minimum score of 0 and maximum score 63, and higher score indicating a higher level of depression.
Trail-Making Test: Part A	Before rTMS (Session 1: Week 9, Session 2: Week 21), Immediately after rTMS (Session 1: Week 10, Session 2: Week 22), 2 weeks after rTMS (Session 1: Week 12, Session 2: Week 24)	Patients are instructed to connect circles in ascending numerical order and are scored on how quickly they are able to complete the task. A longer amount of time indicates more severe cognitive impairment (in general, more than 78 seconds to complete Part A is considered impaired).
Trail-Making Test: Part B	Before rTMS (Session 1: Week 9, Session 2: Week 21), Immediately after rTMS (Session 1: Week 10, Session 2: Week 22), 2 weeks after rTMS (Session 1: Week 12, Session 2: Week 24)	Patients are instructed to connect circles in ascending numerical order and are scored on how quickly they are able to complete the task. A longer amount of time indicates more severe cognitive impairment (in general, more than 273 seconds to complete Part B is considered impaired).
Wisconsin Card Sorting Task (WCST) - %Total Errors	Before rTMS (Session 1: Week 9, Session 2: Week 21), Immediately after rTMS (Session 1: Week 10, Session 2: Week 22), 2 weeks after rTMS (Session 1: Week 12, Session 2: Week 24)	The Wisconsin Card Sorting Test is a test of rule-learning and conceptual flexibility. The participant is required to learn to sort a series of cards according to one of three principles (color, form or number) based on response feedback. This measure is computed by calculating the ration of total errors to trials administered and multiplied by 100.
Wisconsin Card Sorting Task (WCST) - %Perseverative Errors	Before rTMS (Session 1: Week 9, Session 2: Week 21), Immediately after rTMS (Session 1: Week 10, Session 2: Week 22), 2 weeks after rTMS (Session 1: Week 12, Session 2: Week 24)	The Wisconsin Card Sorting Test is a test of rule-learning and conceptual flexibility. The participant is required to learn to sort a series of cards according to one of three principles (color, form or number) based on response feedback. This measure reflects the density of perseverative errors in relation to the overall test performance. It is computed by calculating the ration of total errors to trials administered and multiplied by 100.

Countries

United States

Participant flow

Recruitment details

This was a prospective, randomized, double-blind, crossover study. Five participants were recruited at the University of Florida Norman Fixel Institute for Neurological Diseases. Recruitment occurred between January and February 2022.

Pre-assignment details

At 9 weeks after their regularly scheduled botulinum toxin injection visits, the participants were randomly assigned to receive either active rTMS first or sham first.

Participants by arm

Arm	Count
Active rTMS First The active repetitive transcranial magnetic stimulation (rTMS) was provided at 9 weeks following the botulinum toxin injection. First, a clinical therapeutic NeuroStar TMS coil (Neuronetics, Malvern, PA) was used to determine the resting motor threshold (RMT), defined as the lowest stimulation intensity required to evoke a muscle twitch in a target muscle (first dorsal interosseus) for 5/10 pulses. The dPMC target was defined as 1 cm medial and 2 cm anterior to the site of RMT acquisition, consistent with how this target has been defined in the literature previously. Then, the clinical therapeutic TMS coil was switched to the active NeuroStar TMS coil. The rTMS protocol was as follows: each session consisted of 1-Hz rTMS over the dPMC for 30 minutes (1800 pulses) at 90% of the RMT. This study used an accelerated protocol: patients received 4 sessions per day for 4 consecutive days with a 10-minute break between each session. The daily duration of the rTMS protocol, including breaks, lasted approximately 160 minutes.	3
Sham rTMS First The sham rTMS was provided at 9 weeks following the botulinum toxin injection. First, the participants underwent the same procedure for identifying the target location and RMT as was used in patients receiving active rTMS. Then, the simulated rTMS was administered using a NeuroStar sham coil, which looked the same as the active stimulation coil and produced discharge noise and vibration without stimulating the cerebral cortex. This technique has been suggested to provide the most effective blinding compared to other methods used in randomized, controlled rTMS studies. The physician who set up the active and sham coils played no role in outcome measure assessments in order to maintain blinding.	2
Total	5

Baseline characteristics

Characteristic	Active rTMS First	Sham rTMS First	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	2 Participants	2 Participants	4 Participants
Age, Categorical Between 18 and 65 years	1 Participants	0 Participants	1 Participants
Age, Continuous	63.3 years	76 years	68.4 years
Dosage IncobotulinumtoxinA	—	370 units	370 units
Dosage OnabotulinumtoxinA	323.3 units	—	323.3 units
Dosage RimabotulinumtoxinB	—	10000 units	10000 units
Duration since dystonia onset	11 years	6.5 years	9.2 years
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants	2 Participants	5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Family history No	3 Participants	2 Participants	5 Participants
Family history Yes	0 Participants	0 Participants	0 Participants
Neurotoxin IncobotulinumtoxinA	0 Participants	1 Participants	1 Participants
Neurotoxin OnabotulinumtoxinA	3 Participants	0 Participants	3 Participants
Neurotoxin RimabotulinumtoxinB	0 Participants	1 Participants	1 Participants
Other dystonic features No	2 Participants	2 Participants	4 Participants
Other dystonic features Yes	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	3 Participants	2 Participants	5 Participants
Region of Enrollment United States	3 Participants	2 Participants	5 Participants
Sensory trick No	1 Participants	2 Participants	3 Participants
Sensory trick Yes	2 Participants	0 Participants	2 Participants
Sex: Female, Male Female	2 Participants	2 Participants	4 Participants
Sex: Female, Male Male	1 Participants	0 Participants	1 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 5	0 / 5
other Total, other adverse events	2 / 5	2 / 5
serious Total, serious adverse events	0 / 5	0 / 5

Outcome results

Primary

Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)

This is an objective scale evaluating patients on a variety of features including maximal excursion, duration, effects of sensory trick, shoulder elevation, range of motion, and time. Scores range from 0 to 85 where a higher score indicates more severity.