One Pass Thalamic and Subthalamic Stimulation for Patients with Tremor-Dominant Idiopathic Parkinson Syndrome (OPINION): Protocol for a Randomized, Active-Controlled, Double-Blinded Pilot Trial

Background Besides fluctuations, therapy refractory tremor is one of the main indications of deep brain stimulation (DBS) in patients with idiopathic Parkinson syndrome (IPS). Although thalamic DBS (ventral intermediate nucleus [Vim] of thalamus) has been shown to reduce tremor in 85-95% of patients, bradykinesia and rigidity often are not well controlled. The dentato-rubro-thalamic tract (DRT) that can directly be targeted with special diffusion tensor magnetic resonance imaging sequences has been shown as an efficient target for thalamic DBS. The subthalamic nucleus (STN) is typically chosen in younger patients as the target for dopamine-responsive motor symptoms. This study investigates a one-path thalamic (Vim/DRT) and subthalamic implantation of DBS electrodes and possibly a combined stimulation strategy for both target regions. Objective This study investigates a one path thalamic (Vim/DRT) and subthalamic implantation of DBS electrodes and a possibly combined stimulation strategy for both target regions. Methods This is a randomized, 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. Eighteen patients will undergo one-path thalamic (Vim/DRT) and STN implantation of DBS electrodes. After one month, a double-blinded and randomly-assigned stimulation of the thalamic target (Vim/DRT), the STN and a combined stimulation of both target regions will be performed for a period of three months each. The primary objective is to assess the quality of life obtained by the Parkinson’s Disease Questionnaire (39 items) for each stimulation modality. Secondary objectives include tremor reduction (obtained by the Fahn-Tolosa-Marin tremor rating scale, video recordings, the Unified Parkinson’s disease rating scale, and by tremor analysis), psychiatric assessment of patients, and to assess the safety of intervention. Results At the moment, the recruitment is stopped and 12 patients have been randomized and treated. A futility analysis is being carried out by means of a conditional power analysis. Conclusions The approach of the OPINION trial planned to make, for the first time, a direct comparison of the different stimulation conditions (Vim/DRT, compared to STN, compared to Vim/DRT+STN) in a homogeneous patient population and, furthermore, will allow for intraindividual comparison of each condition with the “quality of life” outcome parameter. We hypothesize that the combined stimulation of the STN and the thalamic (Vim/DRT) target will be superior with respect to the patients’ quality of life as compared to the singular stimulation of the individual target regions. If this holds true, this work might change the standardized treatment described in the previous section. Trial Registration ClinicalTrials.gov: NCT02288468; https://clinicaltrials.gov/ct2/show/NCT02288468 (Archived by WebCite at http://www.webcitation.org/6wlKnt2pJ); and German Clinical Trials Register: DRKS00007526; https://www.drks.de/drks_ web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00007526 (Archived by WebCite at http://www.webcitation.org/6wlKyXZZL).

TITLE AND ABSTRACT 1a) TITLE: IdentiUcation as a randomized trial in the title 1a) Does your paper address CONSORT item 1a? * I.e does the title contain the phrase "Randomized Controlled Trial"?(if not, explain the reason under "other") yes Sonstiges:

1a-i) Identify the mode of delivery in the title
Identify the mode of delivery.Preferably use "web-based" and/or "mobile" and/or "electronic game" in the title.Avoid ambiguous terms like "online", "virtual", "interactive".Use "Internet-based" only if Intervention includes non-web-based Internet components (e.g.email), use "computer-based" or "electronic" only if ooine products are used.Use "virtual" only in the context of "virtual reality" (3-D worlds).Use "online" only in the context of "online support groups".Complement or substitute product names with broader terms for the class of products (such as "mobile" or "smart phone" instead of "iphone"), especially if the application runs on different platforms.1 2 3 4 5 subitem not at all important essential Does your paper address subitem 1a-i?* Copy and paste relevant sections from manuscript title (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study This is a study protocol of a clinical randomized, active-controlled, double blinded pilot trial.There are no "web-based" , "mobile" and/or "electronic game" features included.

1a-ii) Non-web-based components or important co-interventions in title
Mention non-web-based components or important co-interventions in title, if any (e.g., "with telephone support").
1 2 3 4 5 subitem not at all important essential Does your paper address subitem 1a-ii?
Copy and paste relevant sections from manuscript title (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study This is a protocol for a purely clinical study.Copy and paste relevant sections from the manuscript abstract (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "This is a randomized, 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." 1b-ii) Level of human involvement in the METHODS section of the ABSTRACT Clarify the level of human involvement in the abstract, e.g., use phrases like "fully automated" vs. "therapist/nurse/care provider/physician-assisted" (mention number and expertise of providers involved, if any).(Note: Only report in the abstract what the main paper is reporting.If this information is missing from the main body of text, consider adding it) 1 2 3 4 5 subitem not at all important essential Does your paper address subitem 1b-ii?
Copy and paste relevant sections from the manuscript abstract (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study This is a protocol of a monocentric clinical trial and patients admitted to the hospital, ensuring human involvement of the nurses and physicians.

Does your paper address subitem 1b-iii?
Copy and paste relevant sections from the manuscript abstract (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "This is a randomized, active-controlled, double blinded (patient and observer blinded), monocentric trial " 1b-iv) RESULTS section in abstract must contain use data Report number of participants enrolled/assessed in each group, the use/uptake of the intervention (e.g., attrition/adherence metrics, use over time, number of logins etc.), in addition to primary/secondary outcomes.(Note: Only report in the abstract what the main paper is reporting.If this information is missing from the main body of text, consider adding it) 1 2 3 4 5 subitem not at all important essential Does your paper address subitem 1b-iv?
Copy and paste relevant sections from the manuscript abstract (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "Eighteen patients will undergo one path thalamic (Vim/DRT) and subthalamic implantation of DBS electrodes.After one month, a double blinded and randomly assigned stimulation of the thalamic target (Vim/DRT), the STN and a combined stimulation of both target regions will be perfomed for a period of three months, respectively." in addition to primary/secondary outcomes: "The primary objective is to assess the Quality of Life Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "A treatment arm or the entire clinical trial must be terminated prematurely if: • the benefit-risk ratio for the patient changes markedly and/or indications arise that the trial patients' safety is no longer guaranteed, defined as: after surgical treatment of the sixth patient two or more patients experienced severe intra-cranial hemorrhage or ischemia (as diagnosed with computed tomography) or infection and/or severe neurological deterioration (hemiparesis persisting over 24 hours.); in this case recruitment will be stopped and the DMC will discuss continuation of the trial.Bleeding rate is known to be between 1-3% and approx.0.78% of patients experience a clinically significant bleeding [18] (e.g.life changing complications because of persisting disabilities).Therefore, it seems appropriate to temporarily hold the trial if two or more patients out of the first six implanted subjects experience the aforementioned severe complications.
• following recommendation of the DMC (e.g. after futility analysis) the coordinating investigator considers that the termination of the trial is necessary, • the question(s) addressed in the trial can be clearly answered on the basis of an interim analysis, • the questions(s) addressed in the trial can be clearly answered on the basis of results of another trial on the same subject, • an insufficient recruitment rate makes a successful conclusion of the clinical trial appear impossible (e.g. less than 3 patients are recruited per year)."

3b-i) Bug Zxes, Downtimes, Content Changes
Bug Uxes, Downtimes, Content Changes: ehealth systems are often dynamic systems.A description of changes to methods therefore also includes important changes made on the intervention or comparator during the trial (e.g., major bug Uxes or changes in the functionality or content) (5-iii) and other "unexpected events" that may have inpuenced study design such as staff changes, system failures/downtimes, etc. [2]. 1 2 3 4 5 subitem not at all important essential Does your paper address subitem 3b-i?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study

4a-i) Computer / Internet literacy
Computer / Internet literacy is often an implicit "de facto" eligibility criterion -this should be explicitly clariUed.

Does your paper address subitem 4a-i?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study 4a-ii) Open vs. closed, web-based vs. face-to-face assessments: Open vs. closed, web-based vs. face-to-face assessments: Mention how participants were recruited (online vs. ooine), e.g., from an open access website or from a clinic, and clarify if this was a purely web-based trial, or there were face-to-face components (as part of the intervention or for assessment), i.e., to what degree got the study team to know the participant.In online-only trials, clarify if participants were quasi-anonymous and whether having multiple identities was possible or whether technical or logistical measures (e.g., cookies, email conUrmation, phone calls) were used to detect/prevent these.
1 2 3 4 5 subitem not at all important essential Does your paper address subitem 4a-ii?* Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study Screening assessments will be performed within 28 days prior to implantation.The patient will be admitted to hospital for this visit and inclusion and exclusion criteria are checked and validated.The complete pre-therapeutic work-up includes a physical examination including a neurological examination and vital signs (incl.weight and height), medical history, demography, a pregnancy test in women of childbearing potential, Mattis Dementia Rating Scale, PDQ-39, UPDRS, FTMTRS with Video recording, , CGI-I, tremor analysis, psychiatric assessment, PD medication, concomitant medication, L-Dopa equivalent dose (LED) and a cMRI.

4a-iii) Information giving during recruitment
Information given during recruitment.Specify how participants were briefed for recruitment and in the informed consent procedures (e.g., publish the informed consent documentation as appendix, see also item X26), as this information may have an effect on user self-selection, user expectation and may also bias results.
1 2 3 4 5 subitem not at all important essential Does your paper address subitem 4a-iii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study The information discussed obtaining informed consent is described in detail in the manuscript.
4b) Settings and locations where the data were collected

Does your paper address CONSORT subitem 4b? *
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "This is a randomized, active controlled, double blinded (patient and observer blinded), monocentric trial" -all data is collected in the study center.

4b-i) Report if outcomes were (self-)assessed through online questionnaires
Clearly report if outcomes were (self-)assessed through online questionnaires (as common in webbased trials) or otherwise.
1 2 3 4 5 subitem not at all important essential Does your paper address subitem 4b-i?* Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study outcomes are not (self-)assessed through online questionnaires but under support of a nurse or physician.

4b-ii) Report how institutional a@liations are displayed
Report how institutional atliations are displayed to potential participants [on ehealth media], as atliations with prestigious hospitals or universities may affect volunteer rates, use, and reactions with regards to an intervention.(Nota required item -describe only if this may bias results) 1 2 3 4 5 subitem not at all important essential Does your paper address subitem 4b-ii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study This is a monocentric trial.The affiliations of the involved institutions listed in the manuscript .
5) The interventions for each group with sutcient details to allow replication, including how and when they were actually administered

5-i) Mention names, credential, a@liations of the developers, sponsors, and owners
Mention names, credential, atliations of the developers, sponsors, and owners [6] (if authors/evaluators are owners or developer of the software, this needs to be declared in a "Conpict of interest" section or mentioned elsewhere in the manuscript).

Does your paper address subitem 5-i?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study The procedure investigated in this trial has been previously described: "Recently we implanted bilateral octopolar DBS electrodes in the STN additionally traversing the DRT region via a parietal image-assisted approach in two patients allowing compassionate use of a combined stimulation of two tremor targets (STN and DRT) [12].Both patients showed immediate and sustained improvement of their tremor and the symptoms of the bradykinetic syndrom, bilaterally."

5-ii) Describe the history/development process
Describe the history/development process of the application and previous formative evaluations (e.g., focus groups, usability testing), as these will have an impact on adoption/use rates and help with interpreting results.

Does your paper address subitem 5-ii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "First studies have shown that thalamic DBS, which targets the ventral intermediate nucleus of thalamus (Vim), can effectively (95%) reduce Parkinson's disease (PD) tremor.In larger cohorts, this number was reduced to 85% favorable outcome [5,6].It was also reported that the other symptoms of IPS are not favorably influenced with thalamic DBS and while tremor can be nicely controlled over years, bradykinesia and rigidity are not well controlled under stimulation [6].
We have recently provided evidence that a fiber structure (DRT=dentato-rubro-thalamic tract) that traverses the thalamic (Vim) region is a powerful target of thalamic (Vim) DBS.This structure can directly be targeted with the aid of Diffusion Tensor magnetic resonance imaging (DTI) sequences

5-iii) Revisions and updating
Revisions and updating.Clearly mention the date and/or version number of the application/intervention (and comparator, if applicable) evaluated, or describe whether the intervention underwent major changes during the evaluation process, or whether the development and/or content was "frozen" during the trial.Describe dynamic components such as news feeds or changing content which may have an impact on the replicability of the intervention (for unexpected events see item 3b).

Does your paper address subitem 5-iii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study does not apply

5-iv) Quality assurance methods
Provide information on quality assurance methods to ensure accuracy and quality of information provided [1], if applicable.
1 2 3 4 5 subitem not at all important essential Does your paper address subitem 5-iv?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "Safety Adverse Events (AEs) will be documented in the CRF and in the patient's medical chart (source documents).Serious Adverse Events (SAEs) will be reported according to the provisions set forth in the German Medical Devices Safety Plan Ordinance.Data monitoring committee (DMC) The Data Monitoring Committee (DMC) will consist of the coordinating investigator and the unblinded investigators.As stated above the trial will be stopped if the conditional power is below 30% in all three scenarios; the trial will continue if the conditional power of any of the 5-v) Ensure replicability by publishing the source code, and/or providing screenshots/screencapture video, and/or providing bowcharts of the algorithms used Ensure replicability by publishing the source code, and/or providing screenshots/screen-capture video, and/or providing powcharts of the algorithms used.Replicability (i.e., other researchers should in principle be able to replicate the study) is a hallmark of scientiUc reporting.
1 2 3 4 5 subitem not at all important essential Does your paper address subitem 5-v?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study does not apply for this study

5-vi) Digital preservation
Digital preservation: Provide the URL of the application, but as the intervention is likely to change or disappear over the course of the years; also make sure the intervention is archived (Internet Archive, webcitation.org,and/or publishing the source code or screenshots/videos alongside the article).As pages behind login screens cannot be archived, consider creating demo pages which are accessible without login.

Does your paper address subitem 5-vi?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study

URL of the application:
The intervention has been published and the publication is freely accessible at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791468/

5-vii) Access
Access: Describe how participants accessed the application, in what setting/context, if they had to pay (or were paid) or not, whether they had to be a member of speciUc group.If known, describe how participants obtained "access to the platform and Internet" [1].To ensure access for editors/reviewers/readers, consider to provide a "backdoor" login account or demo mode for reviewers/readers to explore the application (also important for archiving purposes, see vi).
subitem not at all important essential Does your paper address subitem 5-vii?* Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study Patient screening is described in the manuscript: "Screening Screening assessments will be performed within 28 days prior to implantation.The patient will be admitted to hospital for this visit and inclusion and exclusion criteria are checked and validated.The Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study The procedure is described in detail in the manuscript.

5-ix) Describe use parameters
Describe use parameters (e.g., intended "doses" and optimal timing for use).Clarify what instructions or recommendations were given to the user, e.g., regarding timing, frequency, heaviness of use, if any, or was the intervention used ad libitum.
1 2 3 4 5 subitem not at all important essential Does your paper address subitem 5-ix?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study Does not apply in this study.

5-x) Clarify the level of human involvement
Clarify the level of human involvement (care providers or health professionals, also technical assistance) in the e-intervention or as co-intervention (detail number and expertise of professionals involved, if any, as well as "type of assistance offered, the timing and frequency of the support, how it is initiated, and the medium by which the assistance is delivered".It may be necessary to distinguish between the level of human involvement required for the trial, and the level of human involvement required for a routine application outside of a RCT setting (discuss under item 21 -generalizability).

Does your paper address subitem 5-x?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study This is a monocentric trial involving nurses, study nurses, physicians and statisticians of the University of Freiburg.

5-xi) Report any prompts/reminders used
Report any prompts/reminders used: Clarify if there were prompts (letters, emails, phone calls, SMS) to use the application, what triggered them, frequency etc.It may be necessary to distinguish between the level of prompts/reminders required for the trial, and the level of prompts/reminders for a routine application outside of a RCT setting (discuss under item 21 -generalizability).

Does your paper address subitem 5-xi? *
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study Does not apply, the study intervention is carried out in an inpatient hospital setting.Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "Before enrolment in the clinical trial, the patient will be informed that participation in the clinical trial is voluntary and that he/she may withdraw from the clinical trial at any time without having to give reasons and without penalty or loss of benefits to which the patient is otherwise entitled.

5-xii
The treating physician will provide the patient with information about the treatment methods to be compared and the possible risks involved.At the same time, the nature, significance, implications, expected benefits and potential risks of the clinical trial and alternative treatments will be explained to the patient.During the informed consent discussion, the patient will also be informed about the insurance cover that exists and the insured's obligations.The patient will be given ample time and opportunity to obtain answers to any open questions.All questions relating to the clinical trial should be answered to the satisfaction of the patient.In addition, the patient will be given a patient information sheet which contains all the important information in writing.The patient's written consent must be obtained before any trial-specific tests/treatments.For this purpose, the written consent form will be personally dated and signed by the trial patient and the investigator conducting the informed consent discussion.Safety Adverse Events (AEs) will be documented in the CRF and in the patient's medical chart (source documents).Serious Adverse Events (SAEs) will be reported according to the provisions set forth in the German Medical Devices Safety Plan Ordinance.Data monitoring committee (DMC) The Data Monitoring Committee (DMC) will consist of the coordinating investigator and the unblinded investigators.As stated above the trial will be stopped if the conditional power is below 30% in all three scenarios; the trial will continue if the conditional power of any of the three scenarios is above 50%.If the conditional power is between 30 -50% the DMC will decide on the continuance of the trial.For this purpose the DMC will receive unblinded trial data and will discuss whether or not continuation of the trial is ethically justified.
The DMC will also receive data on severe intra-cranial hemorrhages or ischemias or infections and/or severe neurological deteriorations.
In case of higher occurrence rates than expected the DMC will 6a) Completely deUned pre-speciUed primary and secondary outcome measures, including how and when they were assessed Does your paper address CONSORT subitem 6a? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "Stimulation procedure is conducted by an unblinded investigator, who is not involved in data acquisition.All stimulation contacts will first be checked for impedance as an indicator for cable break, short-circuit or other device-related complications prior to stimulation.Afterwards all eight contacts will be tested for clinical effect on both tremor and hypokinetic-rigid symptoms (rigidity, bradykinesia), thresholds for side effects and side effects will be evaluated.

Does your paper address subitem 6a-i?
Copy and paste relevant sections from manuscript text No online questionnaire is used.

6a-ii) Describe whether and how "use" (including intensity of use/dosage) was deZned/measured/monitored
Describe whether and how "use" (including intensity of use/dosage) was deUned/measured/monitored (logins, logUle analysis, etc.).Use/adoption metrics are important process outcomes that should be reported in any ehealth trial.

Does your paper address subitem 6a-ii?
Copy and paste relevant sections from manuscript text does not apply 6a-iii) Describe whether, how, and when qualitative feedback from participants was obtained Describe whether, how, and when qualitative feedback from participants was obtained (e.g., through emails, feedback forms, interviews, focus groups).

Does your paper address subitem 6a-iii?
Copy and paste relevant sections from manuscript text Qualitative feedback is assessed postoperatively using different assessments described in detail above (6a).• the benefit-risk ratio for the patient changes markedly and/or indications arise that the trial patients' safety is no longer guaranteed, defined as: after surgical treatment of the sixth patient two or more patients experienced severe intra-cranial hemorrhage or ischemia (as diagnosed with computed tomography) or infection and/or severe neurological deterioration (hemiparesis persisting over 24 hours.); in this case recruitment will be stopped and the DMC will discuss continuation of the trial.Bleeding rate is known to be between 1-3% and approx.0.78% of patients experience a clinically significant bleeding [18] (e.g.life changing complications because of persisting disabilities).Therefore, it seems appropriate to temporarily hold the trial if two or more patients out of the first six implanted subjects experience the aforementioned severe complications.
• following recommendation of the DMC (e.g. after futility analysis) the coordinating investigator considers that the termination of the trial is necessary, • the question(s) addressed in the trial can be clearly answered on the basis of an interim analysis, • the questions(s) addressed in the trial can be clearly answered on the basis of results of another trial on the same subject, • an insufficient recruitment rate makes a successful conclusion of the clinical trial appear impossible (e.g. less than 3 patients are recruited per year).Premature discontinuation of DBS DBS therapy of a patient will be terminated prematurely in the following cases: • Adverse events (including intercurrent illnesses) which preclude further treatment with the IMD or make further participation in the clinical trial inadvisable because the informational value of the trial results is impaired.

•
Premature termination of the trial treatment is considered to be medically indicated, e.g. because it is subsequently found that inclusion/exclusion criteria were violated.• Continuation of the trial treatment is unacceptable when the risks outweigh the benefits.This is the case if stimulation treatment induces unstable gait and falls or unbearable side effects like severe dyskinesia.
7a) How sample size was determined NPT: When applicable, details of whether and how the clustering by care provides or centers was addressed

7a-i) Describe whether and how expected attrition was taken into account when calculating the sample size
Describe whether and how expected attrition was taken into account when calculating the sample size. 1 2 3 4 5 subitem not at all important essential

Does your paper address subitem 7a-i?
Copy and paste relevant sections from manuscript title (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "Description of the primary efficacy analysis and population: Analysis of the primary endpoint will be done by intention to treat in a linear mixed model with baseline score, treatment, period and sequence included as fixed effects [18], and within-patient correlation modelled by a compound symmetry covariance matrix to account for the random subject effect.The sequence effect will be dropped if nonsignificant at the 5%-level.In the final model, treatment comparisons will be based on contrasts estimated by least-squares means with two-sided 95% confidence intervals.For confirmatory analysis, a closed test procedure will be applied: First, the null-hypothesis of equal means in the three arms will be tested at a significance level of 5%.Only if it can be rejected will the three pairwise treatment comparisons be carried out in a confirmatory fashion.This multiple test procedure assures control of the multiple type I error rate of 5%.In addition, all fixed effects will be tested descriptively at the two-sided 5%-level.Recruitment will be stopped after 12 patients have been randomized and treated.Then, a futility analysis will be carried out by means of a conditional power analysis.The conditional probability to attain a significant result for STN+Vim/DRT-DBS versus STN-DBS and Vim/DRT-DBS, respectively, after recruitment of another 6 patients, given the results of the first 12 patients, will be estimated.Three scenarios will be considered: One in which the effect size for the 6 patients to follow will be estimated from the results of the first 12 patients, one in which the upper (optimistic) limits of the 95% confidence intervals for the treatment effects estimated from the first 12 patients will be used, and one in which the treatment effect for the 6 patients to follow will be assumed to be 10.2 points as anticipated in the sample size calculation.The optional possibility to stop the trial prematurely for futility after this interim analysis does not inflate the type one error rate.If the conditional power is below 30% in all three chosen scenarios the trial will be stopped.If the conditional power of any of the three scenarios is between 30 -50% the DMC will decide on the continuance of the trial.If the conditional power of any of the three scenarios is above 50% the trial will be continued." 8a) Method used to generate the random allocation sequence NPT: When applicable, how care providers were allocated to each trial group

Does your paper address CONSORT subitem 8a? *
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "The randomization code will be produced by validated programs based on the Statistical Analysis System (SAS)." 8b) Type of randomisation; details of any restriction (such as blocking and block size)

Does your paper address CONSORT subitem 8b? *
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "Fax randomization will be performed within 7 days prior to treatment start.The patient identification code assigned for the trial will be entered on the randomization form and the fully completed form will then be faxed to the Central Randomization Office of the Clinical Trials Unit (CTU).Patients will be randomized to 6 treatment sequences.The block lengths will be documented separately and will not be disclosed.The randomization code will be generated by the CTU using the following procedure to ensure that treatment assignment is unbiased and concealed from patients and investigator staff.Patients will be randomized to 6 treatment sequences according to a Williams design." Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "The patient identification code assigned for the trial will be entered on the randomization form and the fully completed form will then be faxed to the Central Randomization Office of the Clinical Trials Unit (CTU).Patients will be randomized to 6 treatment sequences.The block lengths will be documented separately and will not be disclosed.randomization code will be generated by the CTU using the following procedure to ensure that treatment assignment is unbiased and concealed from patients and investigator staff.Patients will be randomized to 6 treatment sequences according to a Williams design." 10) Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions

Does your paper address CONSORT subitem 10? *
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study Fax randomization will be performed within 7 days prior to treatment start.The patient identification code assigned for the trial will be entered on the randomization form and the fully completed form will then be faxed to the Central Randomization Office of the Clinical Trials Unit (CTU).Patients will be randomized to 6 treatment sequences.Patients are enroled by an investigator prior to randomisation after screening when meeting the inclusion criteria.Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "Blinding Participating patients and (external) observer/raters are blinded.Since stimulation procedure (e.g.start of treatment, treatment switch, adjusting of stimulation parameters/settings) is conducted by an unblinded investigator, who is not involved in data acquisition, blinding will be maintained for patients and for observers/raters." 11a-ii) Discuss e.g., whether participants knew which intervention was the "intervention of interest" and which one was the "comparator" Informed consent procedures (4a-ii) can create biases and certain expectations -discuss e.g., whether participants knew which intervention was the "intervention of interest" and which one was the "comparator".

Does your paper address subitem 11a-ii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "Informed consent Before enrolment in the clinical trial, the patient will be informed that participation in the clinical trial is voluntary and that he/she may withdraw from the clinical trial at any time without having to give reasons and without penalty or loss of benefits to which the patient is otherwise entitled.The treating physician will provide the patient with information about the treatment methods to be compared and the possible risks involved.At the same time, the nature, significance, implications, expected benefits and potential risks of the clinical trial and alternative treatments will be explained to the patient.During the informed consent discussion, the patient will also be informed about the insurance cover that exists and the insured's obligations.The patient will be given ample time and opportunity to obtain answers to any open questions.All questions relating to the clinical trial should be answered to the satisfaction of the patient.In addition, the patient will be given a patient information sheet which contains all the important information in writing.The patient's written consent must be obtained before any trial-specific tests/treatments.For this purpose, the written consent form will be personally dated and signed by the trial patient and the investigator conducting the informed consent discussion."11b) If relevant, description of the similarity of interventions (this item is usually not relevant for ehealth trials as it refers to similarity of a placebo or sham intervention to a active medication/intervention) Does your paper address CONSORT subitem 11b? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study n.a.
12a) Statistical methods used to compare groups for primary and secondary outcomes NPT: When applicable, details of whether and how the clustering by care providers or centers was addressed

Does your paper address CONSORT subitem 12a? *
Copy and paste relevant sections from the manuscript (include in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "Biostatistical planning and analysis Before the start of the final analysis a detailed statistical analysis plan (SAP) will be prepared.This will be completed during the 'blind review' of the data, at the latest.This blind review, i.e. a checking and assessment of the data, will be performed before the futility analysis and the planned follow-up period without looking at the randomized treatment for each patient.If the SAP contains any changes to the analyses outlined in the trial protocol, they will be marked as such, and reasons for amendments will be given.All statistical programming for analysis will be performed with the Statistical Analysis System (SAS®).Sample size calculation: Based on the standard error of PDQ-39 total score in the EARLYSTIM trial (N Eng J Med 2013;368:610-22), we anticipate a within-person standard deviation of about 14.4 score points for the difference between two treatments.If 3×6=18 patients are allocated to each of the 6 sequences, a two-sided t-test (ANOVA for difference of means in crossover designs) at significance level 5% has 80% power to detect a difference if the true mean difference between STN+Vim/DRT-DBS and STN-DBS (or Vim/DRT-DBS) is 10.2 points (effect size: 0.71; nQuery Advisor version 7.0).""Description of the primary efficacy analysis and population: Analysis of the primary endpoint will be done by intention to treat in a linear mixed model with baseline score, treatment, period and sequence included as fixed effects [18], and within-patient correlation modelled by a compound symmetry covariance matrix to account for the random subject effect.The sequence effect will be dropped if nonsignificant at the 5%-level.In the final model, treatment comparisons will be based on contrasts estimated by least-squares means with two-sided 95% confidence intervals.For confirmatory analysis, a closed test procedure will be applied: First, the null-hypothesis of equal means in the three arms will be tested at a significance level of 5%.Only if it can be rejected will the three pairwise treatment comparisons be carried out in a confirmatory fashion.This multiple test procedure assures control of the multiple type I error rate of 5%.In addition, all fixed effects will be tested descriptively at the two-sided 5%-level."

12a-i) Imputation techniques to deal with attrition / missing values
Imputation techniques to deal with attrition / missing values: Not all participants will use the intervention/comparator as intended and attrition is typically high in ehealth trials.Specify how participants who did not use the application or dropped out from the trial were treated in the statistical analysis (a complete case analysis is strongly discouraged, and simple imputation techniques such as LOCF may also be problematic [4]).
1 2 3 4 5 subitem not at all important essential Does your paper address subitem 12a-i?* Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "Recruitment will be stopped after 12 patients have been randomized and treated.Then, a futility analysis will be carried out by means of a conditional power analysis.The conditional probability to attain a significant result for STN+Vim/DRT-DBS versus STN-DBS and Vim/DRT-DBS, respectively, after recruitment of another 6 patients, given the results of the first 12 patients, will be estimated.Three scenarios will be considered: One in which the effect size for the 6 patients to follow will be estimated from the results of the first 12 patients, one in which the upper (optimistic) limits of the 95% confidence intervals for the treatment effects estimated from the first 12 patients will be used, and one in which the treatment effect for the 6 patients to follow will be assumed to be 10.2 points as anticipated in the sample size calculation.The optional possibility to stop the trial prematurely for futility after this interim analysis does not inflate the type one error rate.If the conditional power is below 30% in all three chosen scenarios the trial will be stopped.If the conditional power of any of the three scenarios is between 30 -50% the DMC will decide on the continuance of the trial.If the conditional power of any of the three scenarios is above 50% the trial will be continued." 12b) Methods for additional analyses, such as subgroup analyses and adjusted analyses Does your paper address CONSORT subitem 12b? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study na. in the publication of a protocol.
X26) REB/IRB Approval and Ethical Considerations [recommended as subheading under "Methods"] (not a CONSORT item)

X26-i) Comment on ethics committee approval
1 2 3 4 5 subitem not at all important essential

Does your paper address subitem X26-i?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study

x26-ii) Outline informed consent procedures
Outline informed consent procedures e.g., if consent was obtained ooine or online (how?Checkbox, etc.?), and what information was provided (see 4a-ii).See [6] for some items to be included in informed consent documents.
1 2 3 4 5 subitem not at all important essential Does your paper address subitem X26-ii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "Informed consent Before enrolment in the clinical trial, the patient will be informed that participation in the clinical trial is voluntary and that he/she may withdraw from the clinical trial at any time without having to give reasons and without penalty or loss of benefits to which the patient is otherwise entitled.
The treating physician will provide the patient with information about the treatment methods to be compared and the possible risks involved.At the same time, the nature, significance, implications, expected benefits and potential risks of the clinical trial and alternative treatments will be explained to the patient.During the informed consent discussion, the patient will also be informed about the insurance cover that exists and the insured's obligations.The patient will be given ample time and opportunity to obtain answers to any open questions.All questions relating to the clinical trial should be answered to the satisfaction of the patient.In addition, the patient will be given a patient information sheet which contains all the important information in writing.The patient's written consent must be obtained before any trial-specific tests/treatments.For this purpose, the written consent form will be personally dated and signed by the trial patient and the investigator conducting the informed consent discussion."

X26-iii) Safety and security procedures
Safety and security procedures, incl.privacy considerations, and any steps taken to reduce the likelihood or detection of harm (e.g., education and training, availability of a hotline) 1 2 3 4 5 subitem not at all important essential Does your paper address subitem X26-iii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "Safety Adverse Events (AEs) will be documented in the CRF and in the patient's medical chart (source documents).Serious Adverse Events (SAEs) will be reported according to the provisions set forth in the German Medical Devices Safety Plan Ordinance.Data monitoring committee (DMC) The Data Monitoring Committee (DMC) will consist of the coordinating investigator and the unblinded investigators.As stated above the trial will be stopped if the conditional power is below 30% in all three scenarios; the trial will continue if the conditional power of any of the three scenarios is above 50%.If the conditional power is between 30 -50% the DMC will decide on the continuance of the trial.For this purpose the DMC will receive unblinded trial data and will discuss whether or not continuation of the trial is ethically justified.The DMC will also receive data on severe intra-cranial hemorrhages or ischemias or infections and/or severe neurological deteriorations.
In case of higher occurrence rates than expected the DMC will discuss whether the trial should be stopped prematurely."

RESULTS
13a) For each group, the numbers of participants who were randomly assigned, received intended treatment, and were analysed for the primary outcome Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study Does not apply in a publication of the study protocol.

13b-i) Attrition diagram
Strongly recommended: An attrition diagram (e.g., proportion of participants still logging in or using the intervention/comparator in each group plotted over time, similar to a survival curve) or other Ugures or tables demonstrating usage/dose/engagement.

Does your paper address subitem 13b-i?
Copy and paste relevant sections from the manuscript or cite the Ugure number if applicable (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study 14a) Dates deUning the periods of recruitment and follow-up Does your paper address CONSORT subitem 14a? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study Does not apply in a publication of the study protocol.
14a-i) Indicate if critical "secular events" fell into the study period Indicate if critical "secular events" fell into the study period, e.g., signiUcant changes in Internet resources available or "changes in computer hardware or Internet delivery resources" 1 2 3 4 5 subitem not at all important essential Does your paper address subitem 14a-i?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study 14b) Why the trial ended or was stopped (early)

15-i) Report demographics associated with digital divide issues
In ehealth trials it is particularly important to report demographics associated with digital divide issues, such as age, education, gender, social-economic status, computer/Internet/ehealth literacy of the participants, if known.
1 2 3 4 5 subitem not at all important essential Does your paper address subitem 15-i?* Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study na.
16) For each group, number of participants (denominator) included in each analysis and whether the analysis was by original assigned groups

16-i) Report multiple "denominators" and provide deZnitions
Report multiple "denominators" and provide deUnitions: Report N's (and effect sizes) "across a range of study participation [and use] thresholds" [1], e.g., N exposed, N consented, N used more than x times, N used more than y weeks, N participants "used" the intervention/comparator at speciUc pre-deUned time points of interest (in absolute and relative numbers per group).Always clearly deUne "use" of the intervention.
1 2 3 4 5 subitem not at all important essential Does your paper address subitem 16-i?* Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study Does not apply in a publication of the study protocol.

16-ii) Primary analysis should be intent-to-treat
Primary analysis should be intent-to-treat, secondary analyses could include comparing only "users", with the appropriate caveats that this is no longer a randomized sample (see 18-i).
1 2 3 4 5 subitem not at all important essential Does your paper address subitem 16-ii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study 17a) For each primary and secondary outcome, results for each group, and the estimated effect size and its precision (such as 95% conUdence interval) Does your paper address CONSORT subitem 17a? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study Does not apply in a publication of the study protocol.

17a-i) Presentation of process outcomes such as metrics of use and intensity of use
In addition to primary/secondary (clinical) outcomes, the presentation of process outcomes such as metrics of use and intensity of use (dose, exposure) and their operational deUnitions is critical.This does not only refer to metrics of attrition (13-b) (often a binary variable), but also to more continuous exposure metrics such as "average session length".These must be accompanied by a technical description how a metric like a "session" is deUned (e.g., timeout after idle time) [1] (report under item 6a).

Does your paper address subitem 17a-i?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study 17b) For binary outcomes, presentation of both absolute and relative effect sizes is recommended

18-i) Subgroup analysis of comparing only users
A subgroup analysis of comparing only users is not uncommon in ehealth trials, but if done, it must be stressed that this is a self-selected sample and no longer an unbiased sample from a randomized trial (see 16-iii).
1 2 3 4 5 subitem not at all important essential Does your paper address subitem 18-i?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study 19) All important harms or unintended effects in each group (for speciUc guidance see CONSORT for harms)

Does your paper address CONSORT subitem 19? *
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "Safety Adverse Events (AEs) will be documented in the CRF and in the patient's medical chart (source documents).Serious Adverse Events (SAEs) will be reported according to the provisions set forth in the German Medical Devices Safety Plan Ordinance."

19-i) Include privacy breaches, technical problems
Include privacy breaches, technical problems.This does not only include physical "harm" to participants, but also incidents such as perceived or real privacy breaches [1], technical problems, and other unexpected/unintended incidents."Unintended effects" also includes unintended positive effects [2].

Does your paper address subitem 19-i?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study 19-ii) Include qualitative feedback from participants or observations from staff/researchers Include qualitative feedback from participants or observations from staff/researchers, if available, on strengths and shortcomings of the application, especially if they point to unintended/unexpected effects or uses.This includes (if available) reasons for why people did or did not use the application as intended by the developers.
1 2 3 4 5 subitem not at all important essential Does your paper address subitem 19-ii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study Restate study questions and summarize the answers suggested by the data, starting with primary outcomes and process outcomes (use).
1 2 3 4 5 subitem not at all important essential Does your paper address subitem 22-i?* Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study Does not apply in a publication of the study protocol.

22-ii) Highlight unanswered new questions, suggest future research
Highlight unanswered new questions, suggest future research.
1 2 3 4 5 subitem not at all important essential Does your paper address subitem 22-ii?
Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study Does not apply in a publication of the study protocol.Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study Does not apply in a publication of the study protocol.Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study Does not apply in a publication of the study protocol.Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study

21-ii
1a-iii) Primary condition or target group in the title Mention primary condition or target group in the title, if any (e.g., "for children with Type I Diabetes") Example: A Web-based and Mobile Intervention with Telephone Support for Children with Type I Diabetesall important essential Does your paper address subitem 1a-iii?* Copy and paste relevant sections from manuscript title (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study 1 a, iii) Mention primary condition or target group in the title: "for patients with tremor dominant idiopathic Parkinson syndrome" 1b) ABSTRACT: Structured summary of trial design, methods, results, and conclusions NPT extension: Description of experimental treatment, comparator, care providers, centers, and blinding status.1b-i) Key features/functionalities/components of the intervention and comparator in the METHODS section of the ABSTRACT Mention key features/functionalities/components of the intervention and comparator in the abstract.If possible, also mention theories and principles used for designing the site.Keep in mind the needs of systematic reviewers and indexers by including important synonyms.(Note: Only report in the abstract what the main paper is reporting.If this information is missing from the main body of text, Does your paper address subitem 1b-i?* 1b-iii) Open vs. closed, web-based (self-assessment) vs. face-to-face assessments in the METHODS section of the ABSTRACT Mention how participants were recruited (online vs. ooine), e.g., from an open access website or from a clinic or a closed online user group (closed usergroup trial), and clarify if this was a purely web-based trial, or there were face-to-face components (as part of the intervention or for assessment).Clearly say if outcomes were self-assessed through questionnaires (as common in web-based trials).Note: In traditional ooine trials, an open trial (open-label trial) is a type of clinical trial in which both the researchers and participants know which treatment is being administered.To avoid confusion, use "blinded" or "unblinded" to indicated the level of blinding instead of "open", as "open" in web-based trials usually refers to "open access" (i.e.participants can self-enrol).(Note: Only report in the abstract what the main paper is reporting.If this information is missing from the main body of text, consider adding it) (QoL)  obtained by the Parkinson's disease Questionnaire (39 items; PDQ-39) for each stimulation modality.Secondary objectives include tremor reduction (obtained by Fahn-Tolosa-Marin tremor rating scale (FTMTRS) including video recording, Unified Parkinson's disease rating scale (UPDRS, part III) and by tremor analysis), psychiatric assessment of patients and to assess safety of intervention."1b-v)CONCLUSIONS/DISCUSSION in abstract for negative trialsConclusions/Discussions in abstract for negative trials: Discuss the primary outcome -if the trial is negative (primary outcome not changed), and the intervention was not used, discuss whether negative results are attributable to lack of uptake and discuss reasons.(Note: Only report in the abstract what the main paper is reporting.If this information is missing from the main body of text, consider adding it) INTRODUCTION 2a) In INTRODUCTION: ScientiUc background and explanation of rationale 2a-i) Problem and the type of system/solutionDescribe the problem and the type of system/solution that is object of the study: intended as standalone intervention vs. incorporated in broader health care program?Intended for a particular patient population?Goals of the intervention, e.g., being more cost-effective to other interventions, replace or complement other solutions?(Note: Details about the intervention are provided in "Methods" under 5address subitem 2a-i?* Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "In younger patients with tremor dominant IPS STN-DBS rather than thalamic DBS appears to be the better option because early onset IPS is known to enter motor fluctuations in a later stage of the disease.These symptoms will likely respond to STN-DBS.In turn, older patients who suffer from tremor dominant IPS are less likely to develop motor fluctuations.Because of the higher complication rate of stimulation of the STN in this patient group[2], thalamic DBS is typically recommended.However, especially older patients receiving thalamic DBS might -in a later stage of the disease -suffer from insufficient symptom control and these patients might benefit from additional subthalamic surgery[10].At this time, however, these patients might already be in a risk group for subthalamic DBS[2].With this study we will try to understand if the latter patient group will benefit from a one path thalamic subthalamic implantation of DBS electrodes and a possibly combined stimulation strategy for both target regions that is adjustable for the distinct target regions and over time."2a-ii) ScientiZc background, rationale: What is known about the (type of) systemScientiUc background, rationale: What is known about the (type of) system that is the object of the study (be sure to discuss the use of similar systems for other conditions/diagnoses, if appropiate), motivation for the study, i.e. what are the reasons for and what is the context for this speciUc study, from which stakeholder viewpoint is the study performed, potential impact of Undings[2].Briepy justify the choice of the comparator.address subitem 2a-ii?* Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "First studies have shown that thalamic DBS, which targets the ventral intermediate nucleus of thalamus (Vim), can effectively (95%) reduce Parkinson's disease (PD) tremor.In larger cohorts, this number was reduced to 85% favorable outcome[5,6].It was also reported that the other symptoms of IPS are not favorably influenced with thalamic DBS and while tremor can be nicely controlled over years, bradykinesia and rigidity are not well controlled under stimulation[6]."2b)In INTRODUCTION: SpeciUc objectives or hypothesesDoes your paper address CONSORT subitem 2b? *Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "With this study we will try to understand if the latter patient group"... (patients tremor dominant IPS with less expected development of motor fluctuations, typically treated with thalamic DBS with the risk of reqiuring additional STN stimulation later)..." will benefit from a one path thalamic subthalamic implantation of DBS electrodes and a possibly combined stimulation strategy for both target regions that is adjustable for the distinct target regions and over time." METHODS 3a) Description of trial design (such as parallel, factorial) including allocation ratio Does your paper address CONSORT subitem 3a? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "This is a randomized, 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.The trial flow is illustrated in Figure1.This monocentric study will be conducted at the Department of Stereotactic and Functional Neurosurgery in close collaboration with the Department of Neurology, both at the Freiburg University Medical Center, Germany."3b) Important changes to methods after trial commencement (such as eligibility criteria), with reasons Does your paper address CONSORT subitem 3b? * criteria for participants Does your paper address CONSORT subitem 4a? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "Inclusion criteria: Male or female patients aged ≥ 35 and ≤ 75 years with a life expectancy of at least 5 years Patients with Parkinson's disease according to the criteria of the British Brain Bank as diagnosed by a neurologist specialized in movement disorders 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.Absence of postural instability (which could be aggravated under STN DBS) Hoehn & Yahr stage 1-3.After stadium 3 patients will show increased incidence of falling that can be aggravated by (typical) STN DBS 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 PDQ-39 to be completed within 42 days prior to surgery Written informed consent" [7].The use of subthalamic (STN) DBS shows effects on tremor either, but typically has no such dramatic initial effects, as Vim-DBS while it also reduces the other cardinal symptoms of IPS [8] [9].There are anecdotal reports on the lack of pure subthalamic stimulation to effectively reduce tremor with the need to additionally stimulate the thalamic region.However, in recent years, subthalamic stimulation has become the main treatment option for refractory IPS.The main indication for STN-DBS remains fluctuations in movement after long-standing dopaminergic medication[3].Patients who suffer from tremor on top of these symptoms (equivalent type IPS) and who show some improvement with dopaminergic medication are likely to improve under STN DBS[8].However, different considerations apply for tremor dominant IPS with therapy refractory tremor:In younger patients with tremor dominant IPS STN-DBS rather than thalamic DBS appears to be the better option because early onset IPS is known to enter motor fluctuations in a later stage of the disease.These symptoms will likely respond to STN-DBS.In turn, older patients who suffer from tremor dominant IPS are less likely to develop motor fluctuations.Because of the higher complication rate of stimulation of the STN in this patient group[2], thalamic DBS is typically recommended.However, especially older patients receiving thalamic DBS might -in a later stage of the disease -suffer from insufficient symptom control and these patients might benefit from additional subthalamic surgery[10].At this time, however, these patients might already be in a risk group for subthalamic DBS[2]." complete pre-therapeutic work-up includes a physical examination including a neurological examination and vital signs (incl.weight and height), medical history, demography, a pregnancy test in women of childbearing potential, Mattis Dementia Rating Scale, PDQ-39, UPDRS, FTMTRS with Video recording, , CGI-I, tremor analysis, psychiatric assessment, PD medication, concomitant medication, L-Dopa equivalent dose (LED) and a cMRI."5-viii) Mode of delivery, features/functionalities/components of the intervention and comparator, and the theoretical frameworkDescribe mode of delivery, features/functionalities/components of the intervention and comparator, and the theoretical framework [6] used to design them (instructional strategy [1], behaviour change techniques, persuasive features, etc., see e.g.,[7, 8]  for terminology).This includes an in-depth description of the content (including where it is coming from and who developed it) [1]," whether [and how] it is tailored to individual circumstances and allows users to track their progress and receive feedback"[6].This also includes a description of communication delivery channels and -if computermediated communication is a component -whether communication was synchronous or asynchronous[6].It also includes information on presentation strategies [1], including page design principles, average amount of text on pages, presence of hyperlinks to other resources, etc. [1]. 1 2 3 4 5 subitem not at all important essential Does your paper address subitem 5-viii?*

)
Describe any co-interventions (incl.training/support) Describe any co-interventions (incl.training/support): Clearly state any interventions that are provided in addition to the targeted eHealth intervention, as ehealth intervention may not be designed as standalone intervention.This includes training sessions and support [1].It may be necessary to distinguish between the level of training required for the trial, and the level of training for a routine application outside of a RCT setting (discuss under item 21 -generalizability. 1 2 3 4 5 subitem not at all important essential Does your paper address subitem 5-xii?* Effects and side effects (= therapeutic window) will be noted in a standardized protocol.Stimulation settings will then follow the randomization of the area which has to be stimulated (Vim/DRT, STN or, Vim/DRT-STN).Stimulation parameters are set empirically on the estimation on the investigator based on the testing phase of electrode contacts with tremor being the primary target symptom.Week 6, 8 and 12 These visits can be performed either via telephone or at the clinical 6a-i) Online questionnaires: describe if they were validated for online use and apply CHERRIES items to describe how the questionnaires were designed/deployed If outcomes were obtained through online questionnaires, describe if they were validated for online use and apply CHERRIES items to describe how the questionnaires were designed/deployed [9

6b)
Any changes to trial outcomes after the trial commenced, with reasons Does your paper address CONSORT subitem 6b? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study "Discontinuation criteria The coordinating investigator is under obligation to monitor the progress of the clinical trial with regard to safety-relevant developments and, if necessary, initiate the premature termination of a treatment arm or the entire clinical trial.Premature termination of one of the treatment arms or the entire trial A treatment arm or the entire clinical trial must be terminated prematurely if:

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Sample size calculation: Based on the standard error of PDQ-39 total score in the EARLYSTIM trial (N Eng J Med 2013;368:610-22), we anticipate a within-person standard deviation of about 14.4 score points for the difference between two treatments.If 3×6=18 patients are allocated to each of the 6 sequences, a two-sided t-test (ANOVA for difference of means in crossover designs) at significance level 5% has 80% power to detect a difference if the true mean difference between STN+Vim/DRT-DBS and STN-DBS (or Vim/DRT-DBS) is 10.2 points (effect size: 0.71; nQuery Advisor version 7.0)."7b) When applicable, explanation of any interim analyses and stopping guidelines Does your paper address CONSORT subitem 7b? *

9)
Mechanism used to implement the random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned Does your paper address CONSORT subitem 9? * 11a) If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how NPT: Whether or not administering co-interventions were blinded to group assignment 11a-i) Specify who was blinded, and who wasn't Specify who was blinded, and who wasn't.Usually, in web-based trials it is not possible to blind the participants [1, 3] (this should be clearly acknowledged), but it may be possible to blind outcome assessors, those doing data analysis or those administering co-interventions (if any).
not at all important essential Does your paper address subitem 11a-i?*

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An adequate subject insurance contract has been taken out.The study protocol has been approved by the independent Ethics Committee of the University of Freiburg (reference number EK 38/15) and by the Federal Institute for Drugs and Medical Devices (reference number 94.1.04-5660 -9558).The study will be conducted in accordance with the ethical principles of the Declaration of Helsinki, the DIN EN ISO 14155 and applicable regulatory requirements (e.g.German Medical Devices Act, Ordinance on Clinical Trials with Medical Devices).The OPINION trial has been registered in the publicly available registries www.ClinicalTrials.gov(http:// www.clinicaltrials.gov)(NCT02288468) and German Clinical Trials Register (DRKS00007526)"

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Secondary objectives are: • To show advantage of combined STN+Vim/DRT-DBS in tremor reduction in comparison to Vim/DRT-DBS or STN-DBS obtained by Fahn-Tolosa-Marin tremor rating scale (FTMTRS) including video recording, Unified Parkinson's disease rating scale (UPDRS, part III, items 20 & 21) and by tremor analysis • To show superiority of combined STN+Vim/DRT-DBS in motor symptoms of Parkinson's disease in comparison to Vim/DRT-DBS or STN-DBS obtained by Unified Parkinson's disease rating scale (UPDRS, part III except items 20 & 21)

DISCUSSION 22 )
Interpretation consistent with results, balancing beneUts and harms, and considering other relevant evidence NPT: In addition, take into account the choice of the comparator, lack of or partial blinding, and unequal expertise of care providers or centers in each group 22-i) Restate study questions and summarize the answers suggested by the data, starting with primary outcomes and process outcomes (use) 20) Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses20-i) Typical limitations in ehealth trialsTypical limitations in ehealth trials: Participants in ehealth trials are rarely blinded.Ehealth trials often look at a multiplicity of outcomes, increasing risk for a Type I error.Discuss biases due to non-use of the intervention/usability issues, biases through informed consent procedures, unexpected events.
21) Generalisability (external validity, applicability) of the trial Undings NPT: External validity of the trial Undings according to the intervention, comparators, patients, and care providers or centers involved in the trial 21-i) Generalizability to other populations Generalizability to other populations: In particular, discuss generalizability to a general Internet population, outside of a RCT setting, and general patient population, including applicability of the study results for other organizations 1 2 3 4 5 subitem not at all important essential Does your paper address subitem 21-i?
) Discuss if there were elements in the RCT that would be different in a routine application setting Discuss if there were elements in the RCT that would be different in a routine application setting (e.g., prompts/reminders, more human involvement, training sessions or other co-interventions) and what impact the omission of these elements could have on use, adoption, or outcomes if the intervention is applied outside of a RCT setting.Does your paper address subitem 21-ii?

Does your paper address CONSORT subitem 13b? (NOTE: Preferably, this is shown in a CONSORT bow diagram) *
The number of care providers or centers performing the intervention in each group and the number of patients treated by each care provider in each centerCopy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study NPT:

Does your paper address CONSORT subitem 14b?
quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study Does not apply in a publication of the study protocol.
*Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct quotes from your manuscript), or elaborate on this item by providing additional information not in the ms, or briepy explain why the item is not applicable/relevant for your study Does not apply in a publication of the study protocol.15)Atable showing baseline demographic and clinical characteristics for each groupNPT: When applicable, a description of care providers (case volume, qualiUcation, expertise, etc.) and centers (volume) in each group Does your paper address CONSORT subitem 15? * Copy and paste relevant sections from the manuscript (include quotes in quotation marks "like this" to indicate direct