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

• ClinicalTrials.gov Identifier: NCT00354133
• Recruitment Status: Active, not recruiting
• First Posted: July 20, 2006
• Last Update Posted: June 26, 2018
• Sponsor: German Parkinson Study Group (GPS)
• Collaborators: University of Schleswig-Holstein; Assistance Publique - Hôpitaux de Paris; KKS Netzwerk
• Information provided by (Responsible Party): German Parkinson Study Group (GPS)

Tracking Information

• First Submitted Date: July 19, 2006
• First Posted Date: July 20, 2006
• Last Update Posted Date: June 26, 2018
• Study Start Date: July 2006
• Estimated Primary Completion Date: March 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 22, 2018)

PDQ-39 [ Time Frame: 24 months ]

Difference in the PDQ-39 summary index at 24 months compared to the baseline assessment.

• Original Primary Outcome Measures (submitted: July 19, 2006): Difference in the PDQ-39 summary index at 24 months compared to the baseline assessment.
• Change History: Complete list of historical versions of study NCT00354133 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: June 22, 2018)

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

Original Secondary Outcome Measures (submitted: July 19, 2006)

• UPDRS part III(medication-off and on-state), hours per day in the "best ON", Frequency and severity of ON-dyskinesia, Sleeping hours, Gait and speech
• UPDRS II, SCOPA-PS, BDI, MADRS, BPRS, Mattis Dementia Scale, Starkstein-Apathy Scale, professional fitness, SF-36,pain (VAS), clinical global impression (CGI-GI)
• Frequency, type and severity of therapy related adverse events of medication or DBS

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Controlled Trial With Deep Brain Stimulation in Patients With Early Parkinson's Disease
• Official Title: 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)

Brief Summary

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.

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
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Parkinson Disease

Intervention

• 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.
• Drug: Best Medical Treatment
  Patients in this arm get best medical treatment only

Study Arms

• 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
  Intervention: Device: Kinetra and Soletra (neurostimulator, Medtronic)
• Active Comparator: BMT treatment
  Patients in this arm get best medical treatment only.
  Intervention: Drug: Best Medical Treatment

Publications *

• Schuepbach WM, Rau J, Knudsen K, Volkmann J, Krack P, Timmermann L, Hälbig 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, Maltête D, Damier P, Raoul S, Sixel-Doering F, Hellwig D, Gharabaghi A, Krüger R, Pinsker MO, Amtage F, Régis 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.
• 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.
• Lhommée E, Wojtecki L, Czernecki V, Witt K, Maier F, Tonder L, Timmermann L, Hälbig TD, Pineau F, Durif F, Witjas T, Pinsker M, Mehdorn M, Sixel-Döring F, Kupsch A, Krüger R, Elben S, Chabardès S, Thobois S, Brefel-Courbon C, Ory-Magne F, Regis JM, Maltête D, Sauvaget A, Rau J, Schnitzler A, Schüpbach 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.
• Schüpbach 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. Review.
• Deuschl G, Schüpbach 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, Hälbig TD, Pineau F, Falk A, Paschen L, Paschen S, Volkmann J, Dafsari HS, Barbe MT, Fink GR, Kühn 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, Maltête D, Damier P, Derkinderen P, Sixel-Döring F, Trenkwalder C, Gharabaghi A, Wächter 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: July 16, 2010): 251
• Original Enrollment (submitted: July 19, 2006): 246
• Estimated Study Completion Date: March 2022
• Estimated Primary Completion Date: March 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France, Germany

Administrative Information

• NCT Number: NCT00354133
• Other Study ID Numbers: A 121/06
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

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

• Responsible Party: German Parkinson Study Group (GPS)
• Study Sponsor: German Parkinson Study Group (GPS)

Collaborators

• University of Schleswig-Holstein
• Assistance Publique - Hôpitaux de Paris
• 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

• PRS Account: German Parkinson Study Group (GPS)
• Verification Date: June 2018