Patients' Conscious Experience and Psychological Consequences of Awake Surgery for Intracerebral Lesions

ETHICAL AND REGULATORY ASPECTS

Ethical Conduct of Study

The research project will be carried out in accordance to the research plan and with principles enunciated in the current version of the Declaration of Helsinki (DoH), the Essentials of Good Epidemiological Practice issued by Public Health Switzerland (EGEP), the Swiss Law and Swiss regulatory authority's requirements as applicable. The EC and regulatory authorities will be informed about project start and termination.

The Project Leader of this Project Leader initiated Trial acknowledges his responsibilities as both the Investigator and the Project Leader.

Risk categorisation

Risk category A: Enroled patients are not exposed to additional risks, as intraoperative mapping of brain functions using electrical stimulation in awake patients is actually considered the gold standard of treatment in intracerebral lesions in the immediate vicinity or within eloquent brain regions.

Ethics Committee (EC)

Before the project will be conducted, the project plan, the proposed participant information and consent form as well as other project-specific documents shall be submitted to a competent Ethics Committee (EC). The regular end, premature end or interruption of the research project is reported to the EC within 90 days upon completion of the project (HRO Art. 22).

Participant Information and Informed Consent

Consecutive ongoing recruitment through investigator(s) in daily clinical practice (consultations). The subjects will receive the consent form with an address and phone number indicated where further questions regarding the study can be discussed directly with the project leader. This will take place at least one week before the hospitalisation.

Participant privacy and safety

The Project Leader affirms and upholds the principle of the participants' right to dignity, privacy and health and that the project team shall comply with applicable privacy laws. Especially, anonymity of the participants shall be guaranteed when presenting the data at scientific meetings or publishing them in scientific journals.

Individual participant medical information obtained as a result of this research project is considered confidential and disclosure to third parties is prohibited. Participant confidentiality will be further ensured by utilising identification code numbers to correspond to medical information in the computer files.

For data verification purposes, authorised representatives of the Project Leader, a competent ethics committee may require direct access to parts of the medical records relevant to the project, including participants' medical history.

Early termination of Project

The Project Leader (and any competent authority) may terminate the project prematurely according to certain circumstances (insufficient participant recruitment, change of project leader or any other reason that would prevent the project execution according to the research plan). The premature end or interruption of the research project would be reported to the EC within 90 days upon completion of the project (HRO Art. 22).

Amendments, Changes

Significant changes to the project plan would be communicated to relevant parties (e.g., investigators, EC). The Project Leader would submit to the EC any application documents, which are affected by the change. At the same time, the project leader would provide information on the reasons for the change. Substantial amendments are only implemented after approval of the EC.

BACKGROUND

Intraoperative mapping of brain functions using electrical stimulation in awake patients has been proven to be a safe technique that enables increased tumor removal while preserving the functional status of the patients. Former studies reported that the conscious experienced procedure is generally well tolerated and psychological sequelae due to awake craniotomy seem to be rare (Milian et al., 2014). Fear, anxiety and pain are the most commonly seen phenomena intraoperatively (Milian et al., 2014). It is also known that fear and anxiety may aggravate pain perception (Keefe et al., 2001). The investigators hypothesize that patients with less preoperative anxiety experience less intraoperative pain.

Rationale for the research Project

Potential postoperative psychological sequelae could be considered and affected patients could benefit of early recognition and treatment.

Risk-Benefit Assessment

Enroled patients are not exposed to additional risks, as intraoperative mapping of brain functions using electrical stimulation in awake patients is actually considered the gold standard of treatment in intracerebral lesions in the immediate vicinity or within eloquent brain regions. Potential postoperative psychological sequelae could be considered and affected patients could benefit of early recognition and treatment.

PROJECT DESIGN

Type of research and general project design

Research project in which health-related personal data is collected. Data will be pseudonymized. Prospective, monocentric, descriptive, cohort study. Overall study duration will be about one year. Patients are recruited at the investigators in daily clinical practice, which can be days to weeks prior to surgery. Once the surgery is started the study duration for each patient will last 6 months post-surgery.

Procedures

Standardized questionnaires will be completed by the selected patients as follows:

1st day preoperatively: MMSE, NRS-anxiety, HADS-D, PDS-1, BPI, PHQ-D, BDI. Intraoperatively: NRS for anxiety and pain at three timepoints during surgery: before skin incision, after removal of the bone flap, after tumor resection.

3rd day postoperatively: HADS-D, PHQ-D, PDS-1, BPI, NRS for pain. 6 months postoperatively at the outpatient clinics: PHQ-D, BDI, HADS-D, PDS-1, BPI.

Recruitment and Screening

Consecutive ongoing recruitment through investigator(s) in daily clinical practice (consultations). The subjects will receive the consent form with an address and phone number indicated where further questions regarding the study can be discussed directly with the project leader. This will take place at least one week before the hospitalisation.

Methods of minimising bias

The use of validated questionnaires. Blinding is not necessary as there are no randomized/different therapies offered. Additional factors to be considered as they influence primary and secondary endpoints: Assessment of gender and age.

STATISTICAL METHODOLOGY

The study is a non-interventional, monocentric cohort study. The scores which will be analysed as primary and secondary endpoints are in general not assumed to follow a normal distribution. Differences in the raw (untransformed) scores and for changes of the scores over time, will be described by descriptive statistics. The hypotheses of the primary and secondary endpoints described below, will not be examined by any statistical tests.

Hypothesis

The investigators hypothesize that intraoperative pain perception, measured by the NRS, in patients with less preoperative fear and anxiety must be lower. The scores listed as secondary endpoints are hypothesized not to change between pre- and post-operative measurement.

As the expected sample size is not large enough to carry out a statistical test with adequate power, no hypothesis testing will be carried out for this study. The evidence for differences in the scores of the primary and secondary endpoints will be discussed based on the descriptive statistics.

Determination of Sample Size

The primary objective of this study is of descriptive nature, i.e., to assess the conscious experience and experience and psychological consequences of awake surgery among the patient collective at the Cantonal Hospital St. Gallen (Kantonsspital St. Gallen, KSSG). The number of included patients is governed by the duration of the study, which is planned to be one year. Within this year it is expected that around 20 patients, recruited at the KSSG, will be included in the study.

Statistical criteria of termination of Trial

There will be no statistical criteria, which would trigger early termination of this trial, as long as the data gathering process is not impaired.

Planned Analyses

The following measures will be reported: mean, standard deviation, 95% confidence interval, median, 1st and 3rd quartile, minimum, and maximum.

Further the same descriptive statistics will be reported for patient characteristics on continuous scale (e.g. age) and percentages will be reported for categorical variables (e.g. gender). The Spearman rank correlation, which is a non-parametric measure for correlations, for the same scores measured at different occasions, will be reported for the scores in the primary and secondary endpoint.

Datasets to be analysed, analysis populations

The analysis population includes all eligible patients which were recruited in the study. Patients will be included in the analysis if they have included any of the questionnaires. Characteristics of patients which did not meet the inclusion criteria will be reported separately. If a patient has a missing value, or missed a follow-up visit, only the observed measurements will be included and no data imputation will be applied. This implies that the data will be analysed according to the intention to treat principle, which should not be problematic as no intervention is planned in this study.

Essentially no subgroup analyses are planned but under the assumption of equal group sizes, a descriptive analysis of the examined scores for subgroups of gender and age will complement the analysis.

Primary Analyses

Descriptive statistics will be displayed for the NRS score and for the changes in the NRS score between the pre-operative and intra-operative and the pre-operative and post-operative measurements.

Secondary Analyses

For the measures of the secondary analysis (PHQ-D, BDI, MMSE, HADS-D, PDS-1 and BPI) descriptive statistics for each measurement occasion and for the changes in the measures will be carried out.

Interim Analyses

No interim analysis is planned. The duration of the study will be one year. However, interim analyses are possible if requested by the investigator, as the data will be analysed with descriptive statistics only and no intervention is planned.

Deviations from the original statistical plan

Deviations from the planned statistical analysis will be documented and justified in the final statistical report.

Handling of missing data and drop-outs

Patients who have not submitted any of the questionnaires will be excluded from the analysis. However, patient characteristics for patients submitting and not or only partially submitting questionnaires will be compared to determine if there are any statistically significant or clinically relevant differences between the two groups. This may affect how the results of the study should be interpreted.

DATA AND QUALITY MANAGEMENT

Data handling and record keeping / archiving

All data will be recorded in an excel-file, only accessible by authorised personnel, such as Werner Surbeck, Hejrati Nader. The questionnaires will be saved by Werner Surbeck in his locked bureau during the study. On the Case Report Forms (CRF) and other project specific documents, subjects are not identified by their names, but by a unique subject number (UPN).

Confidentiality, Data Protection

Project data will be handled with uttermost discretion and is only accessible to authorized personnel who require the data to fulfil their duties. On the CRFs and other project specific documents, subjects are not identified by their names, but by a unique subject number (UPN). UPN will not consist of initials of the subjects or their date of birth.

The UPN will be distributed to all subjects to whom the questionnaires will be given and used from this moment on exclusively. Subject identification list will be compiled and stored by Dr W. Surbeck in an Excel sheet only on his personal laptop secured by a strong password. A regular backup of the subject identification list will be stored on a Universal Serial Bus (USB) device by Dr Surbeck and locked securely in his office. All alterations in the list will be done by Dr W. Surbeck exclusively.

Coding

On the CRFs and other project specific documents, subjects are not identified by their names, but by a unique subject number (UPN).

Archiving and Destruction

All trial data, including documents necessary for patient identification and post-trial care, will be archived for a minimum of 10 years upon premature- or trial termination.

ANNNOUNCEMENTS AND REPORTS

In the event of serious announcements, they will be performed according to Art. 21 (HFV).

PUBLICATION AND DISSEMINATION POLICY

Publication of results

Publication of the study results is planned. An acknowledgement to the Clinical Trials Unit (CTU) St. Gallen is enclosed in any publication that will result from this study. The study will be registered at clinicaltrials.gov.

FUNDING AND SUPPORT

No funding necessary.

INSURANCE

In the event of study-related damage or injuries, the public liability insurance of the Sponsor (i.e. the Kantonsspital St. Gallen) provides compensation, except for claims that arise from wilful misconduct or gross negligence.