One Pass thalamIc aNd subthalamIc stimulatiON

Parkinson's Disease Clinical Trial

— OPINION  

Official title:

One Pass thalamIc aNd subthalamIc stimulatiON

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02288468
• Other study ID #: P000568
• Secondary ID: DRKS00007526
• Status: Completed
• Phase: N/A
• Start date: July 2015
• Est. completion date: November 18, 2020

Study information

• Verified date: July 2021
• Source: University Hospital Freiburg
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Main part of the study:

Randomised, active controlled, double blinded (patient and observer blinded), monocentric trial with three treatments, three periods and six treatment sequences allocated according to a Williams design

Open Label Extension:

After study treatment as described above, patients will be treated unblinded in their preferred stimulation mode until 36 months after implantation.

Description:

Tremor is the most salient symptom of Parkinson's disease (IPS=idiopathic Parkinson syndrome). Other symptoms are bradykinesia, rigidity and postural instability. As much as 75% of patients with IPS show resting tremor. Initially, tremor is typically unilateral and only visible in stress situation. In the later stage of the disease it becomes bilateral. The OPINION trial aims at the investigation of a combined approach to thalamic/subthalamic deep brain stimulation (DBS) for the treatment of patients with tremor dominant IPS or patients with equivalent type IPS who perceive tremor to be their dominant symptom. The planned approach will for the first time allow for the direct comparison of each condition in a homogeneous patient population and will furthermore allow an intra-individual comparison of the different stimulation conditions (Ventral intermediate nucleus (Vim/DRT) - Subthalamic nucleus (STN) - Vim/DRT+STN) with the outcome parameter "quality of life".

Patients will be registered to the trial and will undergo screening procedures (for eligibility criteria please see Inclusion and Exclusion criteria). If the patient is eligible the Investigational Medical Device (IMD) will be implanted (which is the Vercise™ Deep Brain Stimulation System manufactured by Boston Scientific). After implantation the IMD will remain OFF for a period of 1 month.

1 month after implantation treatment will be started. Patients will be randomized to one of the following 3 treatment groups: Subthalamic nucleus (STN) or Ventral intermediate nucleus (Vim/DRT) or combined stimulation (Vim/DRT+STN). Patients will undergo all three treatment groups each lasting 3 months. The patient is blinded meaning that study patients will not know what kind of treatment (e.g. mode/region of stimulation) they receive.

10 months after implantation the final visit of the randomized study will be performed. After that, patients will be asked to take part in an open label extension phase of the study where they will be treated unblinded according to established guidelines and according to their own preferred stimulation mode, just as they would be in a clinical routine setting. The extension phase is concluded by an end of study visit at 36 months after implantation.

After the end of the trial, further treatment will be performed at the Department of Stereotactic and Functional Neurosurgery in Freiburg (Germany) according to established guidelines. Devices will be monitored 3-6 monthly Patient's medications will be adjusted as to the level of best treatment adjunct to stimulation.

Study endpoints (e.g. quality of life) will be evaluated by a blinded rater. In addition, an external video rating will be performed.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: November 18, 2020
• Est. primary completion date: May 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 35 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Male or female patients aged = 35 and = 75 years with a life expectancy of at least 5 years

2. Patients with Parkinson's disease according to the criteria of the British Brain Bank as diagnosed by an in movement disorder specialized neurologist

3. Parkinson patients are included with a medical treatment resistant and disabling resting and/or postural tremor as their major complaint and with a less prominent or absent hypokinetic-rigid component of their disease.

4. Absence of postural instability (which would be aggravated under STN DBS)

5. Hoehn & Yahr stage 1-3. After stadium 3 patients will show increased incidence of falling that can be aggravated by (typical) STN DBS

6. Disease duration for at least 2 years and routine DAT-scan shows clear indication for Parkinsonism and atypical Parkinson syndromes are ruled out by routine glucose (FDG) PET

7. PDQ-39 to be completed within 42 days prior surgery

8. Written informed consent

Exclusion Criteria:

1. Major Depression with suicidal thoughts

2. Dementia (Mattis Dementia Rating Score = 130)

3. Patients with lifetime primary psychotic disorder, schizophrenia, or schizoaffective disorder

4. Patients with acute psychosis as diagnosed by a psychiatrist

5. Nursing care at home

6. Unable to give written informed consent

7. Surgical contraindications like deformed or displaced or not discernable target region, scarring after brain disease (infarction), need for continuous anticoagulation that cannot be bridged in order to obtain normal coagulation

8. Patients with advanced stage cardiovascular disease

9. Patients under immunosuppressive or chemotherapy because of malignant disease

10. Patients who had previous intracranial surgery

11. Patients who are already under DBS therapy

12. Patients with aneurysm clips

13. Patients with cochlear implants

14. Simultaneous participation or previous participation within 30 days prior to start of screening in a clinical trial involving investigational medicinal product(s) or investigational medical device(s)

15. Medications that are likely to cause interactions in the opinion of the investigator

16. Known or persistent abuse of medication, drugs or alcohol

17. Persons who are in a relationship of dependence/employment with the sponsor or the investigator

18. Fertile women not using adequate contraceptive methods: female condoms, diaphragm or coil, each used in combination with spermicides; intra-uterine device; hormonal contraception in combination with a mechanical method of contraception;

19. Current or planned pregnancy, nursing period

20. Contraindications according to device instructions or Investigator's Brochure:

• Diathermy: Shortwave, microwave, and/or therapeutic ultrasound diathermy. The energy generated by diathermy can be transferred to the Vercise™ DBS System, causing tissue damage at the contact site resulting in severe patient injury or death.

• Magnetic Resonance Imaging (MRI): Patients implanted with the Vercise™ DBS System should not be subjected to MRI.

• Patient incapability: Patients who are unable to properly operate the Remote Control and Charging System should not be implanted with the Vercise™ DBS System.

• Poor surgical risks: The Vercise™ DBS System is not recommended for patients who
• because of their primary disease or additional co-morbidities - are not likely to benefit from the DBS system implantation.

Related Conditions & MeSH terms

• Parkinson Disease
• Parkinson's Disease

Intervention

Device:
• Vercise™ Deep Brain Stimulation System
The Vercise™ DBS System includes a Stimulator with DBS Leads for unilateral or bilateral stimulation. There are also DBS Extensions that allow the DBS Leads mounted in the skull to be extended to reach the Stimulator implanted near the clavicle. The rechargeable Vercise DBS System utilizes current steering across eight contacts per DBS Lead to provide precise positioning of stimulation. The Stimulator is controlled by a handheld Remote Control, and can be interfaced with a Clinician's Programmer using the Bionic Navigator™ Software. Periodically, the Stimulator battery must be replenished with an RF (radiofrequency) charging device provided in the Patient DBS Charging Kit.

Locations

Country	Name	City	State
Germany	University of Freiburg - Medical Center - Dept. of Stereotactic and Functional Neurosurgery	Freiburg

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital Freiburg	Boston Scientific Corporation

Country where clinical trial is conducted

Germany, 

References & Publications (17)

Coenen VA, Allert N, Mädler B. A role of diffusion tensor imaging fiber tracking in deep brain stimulation surgery: DBS of the dentato-rubro-thalamic tract (drt) for the treatment of therapy-refractory tremor. Acta Neurochir (Wien). 2011 Aug;153(8):1579-85; discussion 1585. doi: 10.1007/s00701-011-1036-z. Epub 2011 May 8. — View Citation

Coenen VA, Allert N, Paus S, Kronenbürger M, Urbach H, Mädler B. Modulation of the cerebello-thalamo-cortical network in thalamic deep brain stimulation for tremor: a diffusion tensor imaging study. Neurosurgery. 2014 Dec;75(6):657-69; discussion 669-70. doi: 10.1227/NEU.0000000000000540. — View Citation

Coenen VA, Mädler B, Schiffbauer H, Urbach H, Allert N. Individual fiber anatomy of the subthalamic region revealed with diffusion tensor imaging: a concept to identify the deep brain stimulation target for tremor suppression. Neurosurgery. 2011 Apr;68(4):1069-75; discussion 1075-6. doi: 10.1227/NEU.0b013e31820a1a20. Erratum in: Neurosurgery. 2011 Jun;68(6):E1780-1. — View Citation

Coenen VA, Prescher A, Schmidt T, Picozzi P, Gielen FL. What is dorso-lateral in the subthalamic Nucleus (STN)?--a topographic and anatomical consideration on the ambiguous description of today's primary target for deep brain stimulation (DBS) surgery. Acta Neurochir (Wien). 2008 Nov;150(11):1163-5; discussion 1165. doi: 10.1007/s00701-008-0136-x. Epub 2008 Oct 29. — View Citation

Deuschl G, Bain P, Brin M. Consensus statement of the Movement Disorder Society on Tremor. Ad Hoc Scientific Committee. Mov Disord. 1998;13 Suppl 3:2-23. Review. — View Citation

Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schäfer H, Bötzel K, Daniels C, Deutschländer A, Dillmann U, Eisner W, Gruber D, Hamel W, Herzog J, Hilker R, Klebe S, Kloss M, Koy J, Krause M, Kupsch A, Lorenz D, Lorenzl S, Mehdorn HM, Moringlane JR, Oertel W, Pinsker MO, Reichmann H, Reuss A, Schneider GH, Schnitzler A, Steude U, Sturm V, Timmermann L, Tronnier V, Trottenberg T, Wojtecki L, Wolf E, Poewe W, Voges J; German Parkinson Study Group, Neurostimulation Section. A randomized trial of deep-brain stimulation for Parkinson's disease. N Engl J Med. 2006 Aug 31;355(9):896-908. Erratum in: N Engl J Med. 2006 Sep 21;355(12):1289. — View Citation

Fraix V, Pollak P, Moro E, Chabardes S, Xie J, Ardouin C, Benabid AL. Subthalamic nucleus stimulation in tremor dominant parkinsonian patients with previous thalamic surgery. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):246-8. — View Citation

Hilker R, Benecke R, Deuschl G, Fogel W, Kupsch A, Schrader C, Sixel-Döring F, Timmermann L, Volkmann J, Lange M; German Deep Brain Stimulation Association. [Deep brain stimulation for Parkinson's disease. Consensus recommendations of the German Deep Brain Stimulation Association]. Nervenarzt. 2009 Jun;80(6):646-55. doi: 10.1007/s00115-009-2695-3. German. — View Citation

Krack P, Pollak P, Limousin P, Benazzouz A, Benabid AL. Stimulation of subthalamic nucleus alleviates tremor in Parkinson's disease. Lancet. 1997 Dec 6;350(9092):1675. — View Citation

LANCE JW, SCHWAB RS, PETERSON EA. Action tremor and the cogwheel phenomenon in Parkinson's disease. Brain. 1963 Mar;86:95-110. — View Citation

Limousin P, Speelman JD, Gielen F, Janssens M. Multicentre European study of thalamic stimulation in parkinsonian and essential tremor. J Neurol Neurosurg Psychiatry. 1999 Mar;66(3):289-96. — View Citation

Okun MS, Rodriguez RL, Foote KD, Sudhyadhom A, Bova F, Jacobson C, Bello B, Zeilman P, Fernandez HH. A case-based review of troubleshooting deep brain stimulator issues in movement and neuropsychiatric disorders. Parkinsonism Relat Disord. 2008 Nov;14(7):532-8. doi: 10.1016/j.parkreldis.2008.01.001. Epub 2008 Mar 5. Review. — View Citation

Patel DM, Walker HC, Brooks R, Omar N, Ditty B, Guthrie BL. Adverse events associated with deep brain stimulation for movement disorders: analysis of 510 consecutive cases. Neurosurgery. 2015 Mar;11 Suppl 2:190-9. doi: 10.1227/NEU.0000000000000659. — View Citation

Rehncrona S, Johnels B, Widner H, Törnqvist AL, Hariz M, Sydow O. Long-term efficacy of thalamic deep brain stimulation for tremor: double-blind assessments. Mov Disord. 2003 Feb;18(2):163-70. — View Citation

Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE. Systematic review of levodopa dose equivalency reporting in Parkinson's disease. Mov Disord. 2010 Nov 15;25(15):2649-53. doi: 10.1002/mds.23429. Review. — View Citation

Volkmann J, Daniels C, Witt K. Neuropsychiatric effects of subthalamic neurostimulation in Parkinson disease. Nat Rev Neurol. 2010 Sep;6(9):487-98. doi: 10.1038/nrneurol.2010.111. Epub 2010 Aug 3. Review. — View Citation

Zrinzo L, Holl EM, Petersen EA, Limousin P, Foltynie T, Hariz MI. Skewering the subthalamic nucleus via a parietal approach. Stereotact Funct Neurosurg. 2011;89(2):70-5. doi: 10.1159/000323371. Epub 2011 Feb 2. Review. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in PDQ-39 total score	Change in PDQ-39 total score from base value (i.e. mean value of screening and baseline visit) until end of each treatment (Vim/DRT-DBS, STN-DBS, combined STN+Vim/DRT-DBS) 3 months after start of each treatment up to 9 months	From baseline every 3 months up to 9 months
Secondary	Change in FTMTRS	Change in Fahn-Tolosa-Marin Tremor Rating Scale (FTMTRS) every three months after start of each treatment (Vim/DRT-DBS, STN-DBS, combined STN+Vim/DRT-DBS), and at 36 months, compared to base value (i.e. mean value of screening and baseline visit)recording at the tremor peak in tremor analysis	From baseline every 3 months up to 9 months, and at 36 months
Secondary	Change in UPDRS motor score (part III, except items 20 & 21)	Change in Unified Parkinson's Disease Rating Scale (UPDRS) motor score (part III, except items 20 & 21) every three months after start of each treatment (Vim/DRT-DBS, STN-DBS, combined STN+Vim/DRT-DBS), and at 36 months, compared to base value (i.e. mean value of screening and baseline visit)	From baseline every 3 months up to 9 months, and at 36 months
Secondary	Change in UPDRS (part III, tremor subscore (items 20 & 21)) or total power of accelerometry recording at the tremor peak in tremor analysis	Change in UPDRS (part III, tremor subscore (items 20 & 21)) or total power of accelerometry recording at the tremor peak in tremor analysis every three months after start of each treatment (Vim/DRT-DBS, STN-DBS, combined STN+Vim/DRT-DBS), and at 36 months, compared to base value (i.e. mean value of screening and baseline visit)	From baseline every 3 months up to 9 months, and at 36 months
Secondary	Clinical Global Impression Scale (CGI-I)	Assessment of Clinical Global Impression Scale (CGI-I) at screening, at baseline (month 1) and then every three months after start of each treatment (Vim/DRT-DBS, STN-DBS, combined STN+Vim/DRT-DBS) until month 10, and at 36 months	Screening, baseline, then every 3 months until month 10, and at 36 months
Secondary	Change in PDQ-39 total score at 36 months	Change in PDQ-39 total score from base value (i.e. mean value of screening and baseline visit) until 36 months after implantation	Baseline, month 36
Secondary	Psychiatric assessment: C-SSRS	Psychiatric assessment: Columbia Suicide Severity Rating Scale (C-SSRS) at screening, at baseline (month 1) and then every three months after start of each treatment (Vim/DRT-DBS, STN-DBS, combined STN+Vim/DRT-DBS) until month 10, and at 36 months	Screening, baseline, then every 3 months until month 10, and at 36 months
Secondary	Psychiatric assessment: YMRS	Psychiatric assessment: Young Mania Rating Scale (YMRS) at screening, at baseline (month 1) and then every three months after start of each treatment (Vim/DRT-DBS, STN-DBS, combined STN+Vim/DRT-DBS) until month 10, and at 36 months	Screening, baseline, then every 3 months until month 10, and at 36 months
Secondary	Psychiatric assessment: MADRS	Psychiatric assessment: Montgomery-Asberg Depression Scale (MADRS) at screening, at baseline (month 1) and then every three months after start of each treatment (Vim/DRT-DBS, STN-DBS, combined STN+Vim/DRT-DBS) until month 10, and at 36 months	Screening, baseline, then every 3 months until month 10, and at 36 months
Secondary	Psychiatric assessment: BIS-11	Psychiatric assessment: Barratt Impulsiveness Scale (BIS-11) at screening, at baseline (month 1) and then every three months after start of each treatment (Vim/DRT-DBS, STN-DBS, combined STN+Vim/DRT-DBS) until month 10, and at 36 months	Screening, baseline, then every 3 months until month 10, and at 36 months
Secondary	Assessment of (Serious) Adverse Events related to Investigational Medical Device, surgical procedures, stimulation settings and/or changes to medication	Assessment of Adverse Events (AEs) and Serious Adverse Events (SAEs) related to Investigational Medical Device (IMD), surgical procedures, stimulation settings and/or surgical procedures	Starting from implantation of device until last visit at month 36