Dystonia Image-based Programming of Stimulation: A Prospective, Randomized, Double-blind Crossover Trial (DIPS)

The primary objective of this exploratory study is to prospectively evaluate the feasibility of image-guided programming of pallidal deep brain stimulation (DBS) for dystonia. The dystonias are a heterogeneous group of movement disorders that share the core clinical feature of abnormal involuntary muscle contractions in common. Pallidal DBS is an established therapy for severe cases with an average improvement in dystonia severity of 50-60%. However, outcomes are variable and difficult to predict, and clinical trials report up to 25% of Nonresponders. Variability in electrode placement and inappropriate stimulation settings may account for much of this variability in outcome. In addition, improvement in dystonia is delayed, often days to weeks after a change in DBS therapy, complicating programming.

Our group recently developed a computer model to predict optimal individualized stimulation settings in patients based on the outcome of a large cohort of of chronically treated patients. In-silico testing showed a 16.3% better mean group improvement with computer-assisted programming compared with physician-assisted programming and a dramatic reduction in non-responders (from 25% to 5%).

In this prospective study, the computer model will be compared in a randomized, controlled, and double blinded setting against best clinical DBS programming. The primary outcome will be a responder analysis in which dystonia severity will be compared between conventional clinical and model-based programming will be compared.

Study Overview

• Status: Recruiting
• Conditions: Dystonia; Deep Brain Stimulation
• Intervention / Treatment: Other: DBS programming

Detailed Description

Dystonia is a neurological syndrome characterized by involuntary, sustained, or repetitive muscle contractions of opposing muscle groups that cause twisting movements and abnormal postures. Dystonias meet the prevalence criterion of a rare disorder, with prevalence estimates ranging from 0.2-5/100,000 for infantile or juvenile forms to 3-732/100,000 for dystonias manifesting in adults. In addition to motor impairments and mobility limitations, patients - especially young patients - suffer from non-motor symptoms: depression (> 15%), anxiety (> 25%), decreased sleep quality (> 70%), and pain (> 75%). In addition, there is a high risk of economic impairment, including job loss (> 55%), and decreased productivity are serious social consequences (> 50%). However, disability is usually secondary to motor impairment, and adequate treatment of motor symptoms can lead to profound improvements in quality of life (Skogseid et al. 2007). Currently, there is no cure for dystonia, and pharmacological symptom treatment is limited. Deep brain stimulation (DBS) of the internal globus pallidus (GPi) is a recommended therapy for severe dystonia with Class I evidence for safety and efficacy (Vidailhet et al. 2005; Volkmann et al. 2012; Volkmann et al. 2014). However, clinical trials report up to 25% non-responders (<25% motor improvement) (Volkmann et al. 2012; Volkmann et al. 2014). Variability in electrode placement and inappropriate stimulation settings may explain much of this outcome variability (Reich et al. 2019). In addition, dystonia improves with a delay, often weeks after initiation or days after switching neurostimulation therapy, complicating clinical programming for DBS (Kupsch et al. 2011). Our group recently presented a novel approach based on empirical knowledge from a large cohort of chronically treated patients. We defined probabilistic maps of antidystonic effects using electrode position and volumes of tissue activation (VTA) from >100 patients. This method predicts a 16.3% better mean group improvement with computer-selected electrode choices compared with physician programming and a reduced proportion of non-responders from 25% to <5% (Reich et al. 2019). This potential advantage of computer-assisted programming capabilities will be tested in the study described here.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Martin Reich, Dr.; Phone Number: 0931-201-0; Email: Reich_M1@ukw.de
• Study Contact Backup: Name: Florian Lange, Dr.; Phone Number: 0931-201-0; Email: Lange_L@ukw.de

Study Locations

• Germany
  • Bavaria
    • Würzburg, Bavaria, Germany, 97080
      • Recruiting
      • Department of Neurology, University Hospital Würzburg
      • Contact: Martin Reich, Dr.; Phone Number: 0931 201-0; Email: Reich_M1@ukw.de
      • Contact: Florian Lange, Dr.; Phone Number: 0931 201-0; Email: Lange_L@ukw.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Chronic deep brain stimulation (> 1 year) in the internal globus pallidus in patients with isolated dystonia.
• Deep brain stimulation settings and dystonia medication stable for > 3 months.
• Understanding about and consent to the study and signed informed consent form.

Exclusion Criteria:

• Relevant comorbidities that might interfere with study endpoints (esp. palliative disease and severe neurologic or psychiatric comorbidities).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Computer; Programming based on computer-guided assessment	Other: DBS programming; DBS readjustment based on COMPUTER or CLINICAL program
Active Comparator: CLINICAL; Programming based on clinically-guided assessment	Other: DBS programming; DBS readjustment based on COMPUTER or CLINICAL program

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
successful treatment with model predicted settings	The primary efficacy endpoint is based on the blinded physician rating of dystonia severity reflected by Clinical Dystonia Rating Scales (BFMDRS or TWSTRS). The raters will be internationally recognized leading experts in the field of movement disorders that are not part of the study team or otherwise related to our center. For both interventions (best clinical settings and model predicted settings) we will calculate the symptom severity score after 4 weeks of continuous stimulation, expressed in percent of the pre-operative score. The primary endpoint is defined as "successful treatment with model predicted settings" (yes or no). The value is "yes" if the motor symptoms with model predicted settings are equal or better (tolerance 5%) to clinical settings.	8 week follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
quality of life SF-36 (Short Form-36)	SF-36 questionnaire (Short Form-36): 36 items [0-36 points, the higher the score, the worse the symptoms]	4 week and 8 week follow-up
quality of life CDQ24	CDQ24 questionnaire (Craniocervical dystonia questionnaire 24): 24 items [0-24 points, the higher the score, the worse the symptoms]	4 week and 8 week follow-up
calculated energy consumption	Energy consumption by the DBS pulse generators	Baseline visit
time for programming	Time necessary to program the optimal DBS settings	Baseline visit

Collaborators and Investigators

• Sponsor: Wuerzburg University Hospital
• Investigators: Principal Investigator: Martin Reich, Department of Neurology - University Hosiptal Würzburg

Publications and helpful links

General Publications

• Lange F, Roothans J, Wichmann T, Gelbrich G, Roser C, Volkmann J, Reich M. DIPS (Dystonia Image-based Programming of Stimulation: a prospective, randomized, double-blind crossover trial). Neurol Res Pract. 2021 Dec 20;3(1):65. doi: 10.1186/s42466-021-00165-6.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2021
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: October 1, 2021
• First Submitted That Met QC Criteria: October 14, 2021
• First Posted (Actual): October 27, 2021

Study Record Updates

• Last Update Posted (Actual): April 29, 2024
• Last Update Submitted That Met QC Criteria: April 26, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Movement Disorders; Dyskinesias; Dystonia; Dystonic Disorders
• Other Study ID Numbers: DIPS

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No