Controlled Trial With Deep Brain Stimulation in Patients With Early Parkinson's Disease (EARLYSTIM)

The Effect of Deep Brain Stimulation of the Subthalamic Nucleus (STN-DBS) on Quality of Life in Comparison to Best Medical Treatment in Patients With Complicated Parkinson's Disease and Preserved Psychosocial Competence (EARLYSTIM-study)

Earlystim Study: Patients are randomized either to medical treatment or subthalamic stimulation. The observation period was 2 years. The primary outcome criterium: PDQ-39.

Post study Follow up studies: After the 24 months observation period also BMT patients could be operated and all patients will be observed for 10 years or longer to elucidate whether earlier stimulation has advantages (or drawbacks) compared to later stimulation.

Study Overview

• Status: Unknown
• Conditions: Parkinson Disease
• Intervention / Treatment: Device: Kinetra and Soletra (neurostimulator, Medtronic); Drug: Best Medical Treatment

Detailed Description

Parkinsons' disease is one of the most disabling chronic neurological diseases. It can be treated sufficiently until motor complications with fluctuations of mobility and dyskinesias develop. The quality of life and the social and occupational functioning is relentlessly deteriorating with longer disease duration once the complications of conservative therapy develop. High-frequency stimulation of the subthalamic nucleus especially improves the motor complications of Parkinson's disease and preliminary data suggest that also the quality of life and psychosocial handicap are improved. So far this therapy is only used for patients which have already undergone personal, professional and social degradation due to motor complications of the disease. The aim of this study is to assess the use of this therapy in earlier stages of the disease, when motor complications have just developed and before patients are significantly affected in their social and occupational functioning.

The main study (Earlystim) was finished in March 2012 and published in February 2013 (Schuepbach WM, Rau J, Knudsen K, et al. Neurostimulation for Parkinson's disease with early motor complications. N Engl J Med. Feb 14 2013;368(7):610-622.) Patients, who were treated with BMT only in the Earlystim Study were privileged to be operated after the 24 months and a follow up phase of 5 years was planned to elucidate whether earlier stimulation has advantages (or drawbacks) compared to later stimulation.

As operated patients fare better in terms of quality of life and other outcomes (see publication), it will be important to know if patients who are operated earlier keep an advantage in all thoses parameters over those who were operated later or if those operated later will catch up after surgery. Also the pattern of adverse events among earlier and later operated patients may differ. These issues can be addressed with the post-study follow-up (PSFU) studies of the patients of the Earlystim trial. The results of these investigations elucidate longterm issues of DBS in PD and may affect the recommendations of surgery for patients.

• Study Type: Interventional
• Enrollment (Actual): 251
• Phase: Phase 4

Contacts and Locations

Study Locations

• France
  • Grenoble Cedex, France, 38043
    • Michallon Hospital, CHU Grenoble, Service de Neurologie, BP217
  • Lyon, France, 69677
    • Service de Neurologie C, Hôpital Neurologique et neurochirurgical Pierre Wertheimer , 59 Bd Pinel 69677 BRON Cedex
  • Marseille, France, 13005
    • Centre hospitalier La Timone, Service de neurologie et pathologie du mouvement,Boulevard Jean Moulin
  • Nantes, France, 44093
    • "Hôpital Nord Laënnec Boulevard Jacques-Monod - Saint-Herblain
  • Paris Cedex 13, France, 75651
    • CIC, CHU Pitié-Salpêtrière, 47-83 Bd de l'Hôpital
  • Poitiers, France, 86021
    • Hôpital La Milétrie, Tour Jean Bernard, 350 Av Jacques Cœur, BP 577
  • Rouen, France, 76031
    • Centre Hospitalo-Universitaire de Rouen, Charles Nicolle, bat. DV, 1 rue de Germont
  • Toulouse, France, 31059
    • Centre d'investigation Clinique, Pavillon Riser, Hôpital Purpan,Place du Dr Baylac TSA 40031
• Germany
  • Berlin, Germany
    • Klinik und Poliklinik für Neurologie, Charite
  • Duesseldorf, Germany, 40225
    • Neurologische Klinik der Universität, Moorenstr. 5
  • Freiburg, Germany, 79106
    • Neurologische Universitätsklinik Freiburg, Breisacher Str. 64
  • Kassel, Germany, 34128
    • Paracelsus-Elena-Klinik, Kassel, Klinikstrasse 16
  • Kiel, Germany, 24105
    • Klinik für Neurologie, Universitätsklinikum Schleswig-Holstein, Schittenhelmstr. 10
  • Köln, Germany, 50924
    • Klinik und Poliklinik fur Neurologie
  • München, Germany, 81377
    • Klinikum der Universität München Neurologische Klinik und Poliklinik - Großhadern, Marchioninistr. 15
  • Tübingen, Germany, 72076
    • Universitätsklinikum Tübingen, Klinik für Neurochirurgie, Hoppe-Seyler-Str.3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Idiopathic Parkinson's Disease
• Hoehn and Yahr stage ≤ 2.5 in the best "on"med condition
• Disease duration > 4 years
• Presence of fluctuations and/or dyskinesias for no more than 3 years
• One of the two following forms of impairment:
• Impairment in activities of daily living (UPDRS II > 6) due to PD-symptoms despite medical treatment in the "worst" condition or
• Impairment of social and occupational functioning (measured with a modified SOFAS) due to PD-symptoms despite medical treatment (51-80%)
• PDQ-39 completed
• Written informed consent
• For the patients in France a social security number is required

Exclusion Criteria

• Major depression with suicidal thoughts (Beck Depression Inventory > 25)
• Dementia (Mattis Score ≤ 130)
• Acute psychosis
• Need for nursing care
• Any medical or psychological problems which may interfere with a smooth conduction of the study protocol (e.g. cancer with a limited life expectancy)
• Drug or alcohol addiction
• Surgical contraindications
• Fertile women not using adequate contraceptive methods
• Women who are pregnant or breast feeding
• Illiteracy or insufficient language skills (German or French) to complete the questionnaires
• Simultaneous participation in another clinical trial except that other trial does not affect the Earlystim study as approved and documented by the steering committee

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: DBS treatment; Patients in this arm are treated with Deep Brain Stimulation (DBS) of the Nucleus subthalamicus with the device Kinetra and Soletra (neurostimulator, Medtronic) and addtionally get best medical treatment	Device: Kinetra and Soletra (neurostimulator, Medtronic); Patients in this arm were implanted with a neurostimulator (Kinetra and Soletra from Medtronic) are stimulated. Additionally the get best medical treatment.
Active Comparator: BMT treatment; Patients in this arm get best medical treatment only.	Drug: Best Medical Treatment; Patients in this arm get best medical treatment only

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PDQ-39	Difference in the PDQ-39 summary index at 24 months compared to the baseline assessment.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
UPDRS part III	Change in the Unified Parkinson's disease Rating Scale (UPDRS) part III	24 months
UPDRS II scale	Change in the UPDRS II scale	24 months
Safety	Frequency, type and severity of therapy related adverse events of medication or DBS, Change in medication (L-DOPA equivalents)	24 months
UPDRS VI scale	Change in the UPDRS VI scale	24 months
SCOPA-PS	Change in the SCOPA-PS scale	24 months
BDI scale	Change in the BDI scale	24 months
MADRS scale	Change in the MADRS scale	24 months
BPRS scale	Change in the BPRS scale	24 months
Mattis Dementia Scale	Change in the Mattis Dementia Scale	24 months
Ardouin Behaviour Scale	Change in the Ardouin Behaviour Scale	24 months
Starkstein-Apathy Scale	Change in the Starkstein-Apathy Scale	24 months
professional Fitness scale	Change in the professional Fitness scale	24 months
SF-36 scale	Change in the SF-36 scale	24 months
pain (VAS) scale,	Change in the pain (VAS) scale	24 months
clinical global impression (CGI-GI) scale	change in the clinical global impression (CGI-GI) scale	24 months
"best"-state	Change in the number of hours per day in the "best"-state	24 months
"best" state dyskinesias	Frequency and severity of "best" state dyskinesias	24 months
Sleeping-hours per day	Sleeping-hours per day	24 months
Gait	Changes in gait	24 months
Speech	Changes in speech	24 months

Collaborators and Investigators

• Sponsor: German Parkinson Study Group (GPS)
• Collaborators: Assistance Publique - Hôpitaux de Paris; University Hospital Schleswig-Holstein; KKS Netzwerk
• Investigators: Principal Investigator: Guenther Deuschl, Prof., Department of Neurology, Christian-Albrechts-University Kiel, Schittenhelmstr. 10, D 24105 Kiel; Principal Investigator: Marie Vidailhet, Prof., Groupe Hospitalier Pitié- Salpêtrière, Fédération des Maladies du Système Nerveux, 47-83 Boulevard de l´Hôpital, F- 75651 Paris Cedex 13

Publications and helpful links

General Publications

• Schuepbach WM, Rau J, Knudsen K, Volkmann J, Krack P, Timmermann L, Halbig TD, Hesekamp H, Navarro SM, Meier N, Falk D, Mehdorn M, Paschen S, Maarouf M, Barbe MT, Fink GR, Kupsch A, Gruber D, Schneider GH, Seigneuret E, Kistner A, Chaynes P, Ory-Magne F, Brefel Courbon C, Vesper J, Schnitzler A, Wojtecki L, Houeto JL, Bataille B, Maltete D, Damier P, Raoul S, Sixel-Doering F, Hellwig D, Gharabaghi A, Kruger R, Pinsker MO, Amtage F, Regis JM, Witjas T, Thobois S, Mertens P, Kloss M, Hartmann A, Oertel WH, Post B, Speelman H, Agid Y, Schade-Brittinger C, Deuschl G; EARLYSTIM Study Group. Neurostimulation for Parkinson's disease with early motor complications. N Engl J Med. 2013 Feb 14;368(7):610-22. doi: 10.1056/NEJMoa1205158.
• Deuschl G, Schade-Brittinger C, Agid Y; EARLYSTIM Study Group. Neurostimulation for Parkinson's disease with early motor complications. N Engl J Med. 2013 May 23;368(21):2038. doi: 10.1056/NEJMc1303485. No abstract available.
• Dams J, Balzer-Geldsetzer M, Siebert U, Deuschl G, Schuepbach WM, Krack P, Timmermann L, Schnitzler A, Reese JP, Dodel R; EARLYSTIM-investigators. Cost-effectiveness of neurostimulation in Parkinson's disease with early motor complications. Mov Disord. 2016 Aug;31(8):1183-91. doi: 10.1002/mds.26740.
• Lhommee E, Wojtecki L, Czernecki V, Witt K, Maier F, Tonder L, Timmermann L, Halbig TD, Pineau F, Durif F, Witjas T, Pinsker M, Mehdorn M, Sixel-Doring F, Kupsch A, Kruger R, Elben S, Chabardes S, Thobois S, Brefel-Courbon C, Ory-Magne F, Regis JM, Maltete D, Sauvaget A, Rau J, Schnitzler A, Schupbach M, Schade-Brittinger C, Deuschl G, Houeto JL, Krack P; EARLYSTIM study group. Behavioural outcomes of subthalamic stimulation and medical therapy versus medical therapy alone for Parkinson's disease with early motor complications (EARLYSTIM trial): secondary analysis of an open-label randomised trial. Lancet Neurol. 2018 Mar;17(3):223-231. doi: 10.1016/S1474-4422(18)30035-8.
• Schupbach WM, Rau J, Houeto JL, Krack P, Schnitzler A, Schade-Brittinger C, Timmermann L, Deuschl G. Myths and facts about the EARLYSTIM study. Mov Disord. 2014 Dec;29(14):1742-50. doi: 10.1002/mds.26080. Epub 2014 Nov 14.
• Deuschl G, Schupbach M, Knudsen K, Pinsker MO, Cornu P, Rau J, Agid Y, Schade-Brittinger C. Stimulation of the subthalamic nucleus at an earlier disease stage of Parkinson's disease: concept and standards of the EARLYSTIM-study. Parkinsonism Relat Disord. 2013 Jan;19(1):56-61. doi: 10.1016/j.parkreldis.2012.07.004. Epub 2012 Jul 28.
• Schuepbach WMM, Tonder L, Schnitzler A, Krack P, Rau J, Hartmann A, Halbig TD, Pineau F, Falk A, Paschen L, Paschen S, Volkmann J, Dafsari HS, Barbe MT, Fink GR, Kuhn A, Kupsch A, Schneider GH, Seigneuret E, Fraix V, Kistner A, Chaynes PP, Ory-Magne F, Brefel-Courbon C, Vesper J, Wojtecki L, Derrey S, Maltete D, Damier P, Derkinderen P, Sixel-Doring F, Trenkwalder C, Gharabaghi A, Wachter T, Weiss D, Pinsker MO, Regis JM, Witjas T, Thobois S, Mertens P, Knudsen K, Schade-Brittinger C, Houeto JL, Agid Y, Vidailhet M, Timmermann L, Deuschl G; EARLYSTIM study group. Quality of life predicts outcome of deep brain stimulation in early Parkinson disease. Neurology. 2019 Mar 5;92(10):e1109-e1120. doi: 10.1212/WNL.0000000000007037. Epub 2019 Feb 8. Erratum In: Neurology. 2019 Jun 11;92(24):1166.

Helpful Links

• (German Research Collaboration, funded by the German Ministry of Research)
• (Homepage Coordination Center for Clinical Studies to STN Study, Language: German)
• Schuepbach WM, Rau J, Knudsen K, et al. Neurostimulation for Parkinson's disease with early motor complications. N Engl J Med. Feb 14 2013;368(7):610-622.

Study record dates

Study Major Dates

• Study Start: July 1, 2006
• Primary Completion (Anticipated): March 1, 2022
• Study Completion (Anticipated): March 1, 2022

Study Registration Dates

• First Submitted: July 19, 2006
• First Submitted That Met QC Criteria: July 19, 2006
• First Posted (Estimate): July 20, 2006

Study Record Updates

• Last Update Posted (Actual): June 26, 2018
• Last Update Submitted That Met QC Criteria: June 22, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: Parkinson Disease; Deep Brain Stimulation; PDQ-39
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease
• Other Study ID Numbers: A 121/06

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures and appendices).
• IPD Sharing Time Frame: Beginning 9 months and ending 36 months following article publication.
• IPD Sharing Access Criteria: by inidividual contact with the Coordinatin Investigator Prof.Dr. Deuschl
• IPD Sharing Supporting Information Type: Study Protocol