Effects of a Hypnosis Session Before General Anesthesia on Postoperative Outcomes in Patients Who Underwent Minor Breast Cancer Surgery

Key Points Question What is the benefit of a short hypnosis session before general anesthesia on postoperative outcomes (pain, nausea/vomiting, fatigue, comfort/well-being, anxiety, postanesthesia care unit length of stay, and patient satisfaction) in patients who underwent minor breast cancer surgery? Findings In this randomized clinical trial, 150 women were randomized to receive hypnosis or a control group, and the mean breast pain score before discharge was 1.75 in the control arm vs 2.63 in the hypnosis arm. At discharge, no statistically significant difference in breast pain was reported. Meaning No benefit of hypnosis was found on postoperative breast pain; however, hypnosis seems to have other benefits regarding fatigue, anxiety, and patient satisfaction.


Statistical analyses
A descriptive analysis per group will be performed. The analyses will be performed on an intention-to-treat basis. Data will be described by treatment group. Continuous variables will be described using means with standard deviations, medians with interquartiles (IQ) according to their distribution. For categorical variables, frequencies and percentages will be computed. It will be checked that the baseline characteristics are well-balanced between the two groups, and that they are thus comparable. Efficacy of conversational hypnosis will be assessed comparing the pain severity score of the two groups (bilateral t-test, means and 95% confidence intervals). A similar analysis will be performed using the Student's t-test or the Kruskal-Wallis test to compare the postoperative side-effects measured with a visual analogic scale (discomfort, fatigue, emotional upset) and for all quantitative variables among the secondary endpoints. Standardized values (Δ/σ) will also be presented for each side-effect measured using a VAS. The qualitative secondary endpoints will be compared between the two arms using a Chi-2 test or a Fisher exact test. The analyses will be performed using the Stata v13 software after approval of the statistical analysis plan.   63 Breast cancer is the most frequent cancer in women in France [1]. Surgery is, to date, the key treatment for 64 this disease [2]. During care in the operating room, patient arrival is an anxiety-inducing moment, because 65 breast cancer often affects young women, with light or non-existent medical history, taken in a "hostile" 66 environment: noisy, cold, austere, with unknown care pathway … Breast cancer surgery is a painful 67 moment, associated with cancer disease materialization. It is the time of a sudden awareness of the 68 disease.

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A study published in 1997 showed that perioperative hypnosis significantly decreased postoperative 77 nausea and vomiting (39% versus 68% in the control group) [6]. . 81 Lang et al. [10] reported results in accordance with a reduction of anxiety and pain scores, which were 82 reduced in the empathy and hypnosis groups versus the control groups:

Study design and groups 126
The present study is a prospective randomized multicenter Phase III single-blinded trial comparing two 127 admission/care techniques in operating room for patients eligible for minor cancer surgery.

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The patient will not know, before her admission, which technique will be used for admission in the 129 operating room. The caregiver in charge of assessing outcomes will not know which technique was used. A standardized conversational hypnosis technique will be used. Its objective will be to enhance comfort 141 and well-being of the patient using various techniques. Themes will be proposed to each patient. The 142 choice of a safe place or leisure activity will be done with the patient, and it will be personalized for each 143 patient No theme will be imposed by the medical anesthesiologist, and the patient will be free to follow or 144 not the anesthesiologist on the chosen theme. In case a patient asks to stop communication, the 145 anesthesiologist will have to do so.

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It is recommended that all teams use sensoriality language and paraverbal techniques (slow voice, low tone). The duration of this communication and induction will be reported and will have to be equals or 148 shorter than 15 minutes, except in case of technical problem. During the hypnosis session, only the 149 anesthesiologist talked with the patient in order to individualize the session. The anesthesiologist will 150 choose him/herself the best moment to perfom anesthetic induction.

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Conversational hypnosis will be performed solely by a medical anesthesiologist trained to the technique.

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Only physicians who were trained to hypnosis (hypnosis university or non-university training) and who 153 practiced hypnosis for 1 year or more.

Information and consent
The consent form of the study will be given to the patient by the surgical team at the date of the surgery 195 plannigication (D-30 to D-7), as well as during anesthesia consultation at least 48h before surgery (usually 196 D-7 to D-2).

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The anesthesiologist will check the inclusion and non-inclusion criteria, inform the patient of the study 198 details, give the patient the consent form and validate the patient's consent. A reflection time will be given to the patient between the anesthesia consultation and surgery, at least 201 48h. The patient's decision to participate or not in the study will have to be known at the latest at her 202 admission for surgery. Dated and signed consent will be collected at that time. patients will be randomized.

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Patient randomisation will be performed at the end of the anesthesia consultation. The inclusion form will 209 be completed and signed by the investigator (Appendix 1). The form will be sent by fax at the following: The anesthesilogist will be appointed to the patient after randomisation, depending on the allocated 215 group. 216 6.6. Operating room admission and anesthesia 217 No premedication is allowed to be given to the patient, who will have fasted for 4h for liquids. If any 218 premedication was given, it should be recorded.

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At operating room admission, the two groups are to perform an oral questionnaire, the safety check-up 220 (legal requirement from the Haute Autorité de Santé). Then :

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-For the control group, physicians and all caregivers will behave "as usual"

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-For the hypnosis group, patient will be welcomed by a specific anesthesiologist trained for 223 hypnosis, who will start the hypnosis technique as soon as the patient is admitted in the operation All drugs used perioperatively will be standardized and will not differ in the two groups. 253

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At the end of surgery, the patient will be brought in PACU.

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PACU discharge will be allowed when the ALDRETE score will be >12/14 (see Appendix 2).

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Discharge from the center to home will be allowed:

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-In outpatient surgery, after approval by the anesthesiologist or the surgeon. If the patient is not 258 allowed the discharge, the reason should be recorded.

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-In classic surgery on day 1. If the patient is not allowed the discharge, the reason should be 260 recorded. The main characteristics measured are:

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A descriptive analysis per group will be performed. The analyses will be performed on an intention-to-treat 322 basis. Data will be described by treatment group. Continuous variables will be described using means with 323 standard deviations, medians with interquartiles (IQ) according to their distribution. For categorical 324 variables, frequencies and percentages will be computed.

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It will be checked that the baseline characteristics are well-balanced between the two groups, and that 326 they are thus comparable.

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Efficacy of conversational hypnosis will be assessed comparing the pain severity score of the two groups 328 (bilateral t-test, means and 95% confidence intervals).

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A similar analysis will be performed using the Student's t-test or the Kruskal-Wallis test to compare the 330 postoperative side-effects measured with a visual analogic scale (discomfort, fatigue, emotional upset) and 331 for all quantitative variables among the secondary endpoints.

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Standardized values (Δ/σ) will also be presented for each side-effect measured using a VAS.

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The qualitative secondary endpoints will be compared between the two arms using a Chi-2 test or a Fisher 334 exact test.

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The analyses will be performed using the Stata v13 software after approval of the statistical analysis plan.  347 Only Adverse Events (AEs) imputable to conversational hypnosis will be reported.

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*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 375 managing money, etc. **Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 377 and not bedridden.   The risk-benefit balance of the study is evaluated continuously by the ICM Clinical Research 411 Pharmacovigilance Unit and this risk-benefit balance will be discussed in the periodic safety reports. These 412 reports will contain all required regulatory aspects and will be submitted to the competent authorities.
In the present study, all SAEs imputable to surgery, to cancer treatment or to any concomitant treatment 414 will not be notified to the study Sponsor. Only the SAEs linked to the study procedures will be reported to 415 the study Sponsor. All data obtained in the study described in the protocol will be recorded on CRF. The CRF for each subject 422 will be presented in a folder. The CRF will be completed chronologically and updated regularly in order to 423 reflect the most recent data on the subject included in the study.  Although subjects may be interviewed by a CRA, the Investigator must verify that all data entries are 431 accurate and correct, including verification that the subject fulfils the criteria for entrance into the study 432 before study medication is dispensed. Physical examinations have to be performed by a registered medical 433 practitioner.

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The End of Treatment Form must be completed for each subject either finishing the study or dropping out 435 from it.

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The Investigator will add to the subject trial file, after completion of the study, any relevant post-trial 437 information brought to his attention. This information will be sent to the Sponsor within one year after 438 ending the trial or more if the need arises.

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Original forms and the first two copies of these forms are the property of the Sponsor.  persons with access to confidential information will ensure confidentiality of all data (treatment, research, persons and patients, especially patient ID, study results). They are all subject to professional and medical 448 secrecy.

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The present materials (protocol, CRF, investigator's brochure) contain confidential information. Except as 450 may otherwise be agreed to in writing with the study monitor, the investigator agrees to hold such 451 information in confidence, and not to disclose it to others (except where required by applicable laws and 452 regulations). All information from this study (excluding data from informed consent) will be entered into a 453 database by the sponsor in accordance with the French law,"Loi Informatique et Libertés" (art. 40, January 454 6, 1978) and with the European Directive 95/46/CE. All data will be anonymized (first letter of the first 455 name and surname, inclusion number, center number).

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The sponsor will be responsible for ensuring that all patients participating in the study have given their 457 informed consent for individual access to their personal information.   465 The investigator will be responsible for the conduct of the study trial according to the following texts and  All these texts remind that a written consent is to be given by all patients before their participation in the 476 study.  478 The "Declaration of Helsinki" recommends that consent should be obtained from each potential subject in 479 biomedical research trials after the aims, methods, anticipated benefits, and potential hazards of the trial, 480 and discomfort it may entail, are explained to the individual by the physician. The potential study subject 481 should also be informed of his or her right to not participate or to withdraw from the trial at any time.

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The patient should be told that material from her/his tumor will be stored and potentially used for 483 additional studies not described in this protocol.
Informed consent for each subject will be obtained prior to initiating any trial procedures according to the 485 current regulation (directive ICH E6, 1995). 486 The One copy of the informed consent must be given to each subject and one signed original copy must be 487 retained in the investigator's trial records. The informed consent form must be available in the case of data 488 audits.

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If the subject is in a dependent relationship to the physician or gives consent under duress, the informed 490 consent should be obtained by an independent physician. By signing this protocol, the investigator agrees 491 to conduct the trial in accordance with the "Declaration of Helsinki".

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The study data will be recorded directly by the identified and declared persons of each center, via the 506 eCRF, and will be controlled and validated according to specific procedures.

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At the end of the study and once all the eCRF data are validated, the investigator will log in and sign all the 508 pages in order to validate the data entered for each patient.

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The sponsor will create and send an electronic copy (PDF file) to the investigator. This copy must be 510 printed and signed by the investigator, to be archived at the investigator's site. In case of missing data, coding to be used will be specified in the CRF.

Patient files 522
The investigator will be responsible for source data for each patient (paper or digital data).

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A substantial modification request is sent by the sponsor to the CPP for an opinion. Upon receipt of the 556 favorable opinion, the amended version of the protocol is then forwarded for information to the ANSM 557 and forwarded to all investigators by the sponsor.

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A non-substantial change to the protocol is a minor change or unrestricted clarification of the conduct of 559 the test. These modifications will not be submitted to the competent authorities but will be subject to an 560 agreement between the sponsor and the investigator and will be clearly documented in the follow-up file 561 of the study and will be forwarded to the CPP for information.

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Prior to the enrollment of any subject at a site, the investigator will review the protocol, investigator 566 brochure, the procedure for obtaining informed consent, and procedures for reporting adverse events.

Conventions 167
Time to events will be calculated from the date of inclusion.

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For any calculation of time between two dates, the following convention will be applied:

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For any calculation of duration between two dates, the following convention will be applied:

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To convert a number of days to year or month, the following convention will be applied:

Missing data 176
Unless otherwise stated, missing values will not be imputed.

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If the day of a date is missing, it will be replaced by 15.

Subjects disposition 182 183
The following will be summarized: The datalistings will be edited and appended in the final report.

Stratification factors 189
The stratification factor "Center", collected at the randomization will be described..

Baseline characteristics 191 192
The initial characteristics (Baseline evaluation) will be described by arms and globally. It will be 193 evaluated between D-30 and D-2.

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It corresponds to the demographics (age, education level, socio-economic class), vital signs 196 (height, weight, BMI, blood pressure and pulse), patient characteristics (manual preference,

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Calculated (and categorized) variables are presented in the following

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The following items reported will be described only for patients in the hypnosis arm.

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The following items will be described for each arm and for the overall population.

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The following items will be described for each arm and for the overall population. All adverse events of grade ≥ 3 will be described by toxicity type. Severity of the Aes will be 258 graded according to the NCI-CTCAE scale (version 4.0).

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AEs will be described by patient.

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The number of patients who underwent at least one AE will be described.
262 Every AE will be described according to the following groups :

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If an AE is reported more than once during treatment, the higher grade will be reported for that 266 given patient.

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Datalistings will be edited and reported in appendix in the final report. The primary criterion defined in subsection 2.1 (critère quantitatif) will be analyzed according to

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Means and medians for the pain VAS scores at all times will be compared between the two arms. The number of patients with at least one concomitant treatment will be described.

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The datalistings will be edited and appended in the final report.

STATISTICAL METHODS 286
The analyzes will be carried out by treatment arm and globally (phase III).

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All statistical tests are bilateral and the significance threshold is set at 5% (ie p <0.05).

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Statistical analyses will be carried out using the STATA v13.0 software and a statistical report will 290 be provided. The continuous variables will be described by the number of observations (N), the median, the 294 minimum, the maximum, the mean and the standard error. Student t test and Kruskal-Wallis test 295 will be used to compare the quantitative variables distribution.

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Pain VAS scores between Day 0 (or Day 1) and D7 will be compared in each group using a 297 Wilcoxon test (case-matched samples)

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Optional: longitudinal analyses with linear mixt models will be performed for the pain VAS scores. The categorical variables will be described by the number of observations (N) and the frequency 301 (%) of each modality. The missing categories will be counted.

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Percentages will be calculated in relation to the total population excluding missing data.

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The Chi-2 test will be used to compare proportions (or Fisher's exact test if the expected 304 frequencies are less than 5).