Study setting {9}
This study will be conducted in a tertiary university hospital in Dublin (Mater Misericordiae University Hospital), Republic of Ireland. The hospital performs over 500 breast cancer surgeries per year.
Eligibility criteria {10}
Inclusion criteria are:
- Female patients
- Aged 18-75
- Undergoing breast cancer surgery (either wide local excision with magseed or full mastectomy)
- Pain Catastrophising Scale (PCS) score of 24 or higher
Exclusion criteria are:
- Pain Catastrophising Scale score below 24
- Surgery for benign breast disease
- Patient non-consent
- Plans to undergo major surgery within six months after current breast surgery
- Comorbid severe psychiatric conditions such as schizophrenia or personality disorder
- Known or suspected non-compliance
- Known or suspected drug or alcohol abuse problems within past 3 months
- Inability to follow the study procedures e.g. dementia or non-fluency of English
- The presence of any serious medical comorbidity that might cause disability or worsen the patient’s general health condition
- Pregnancy
- An opioid intrathecal pump
- Cognitive behavioural therapy in the past 12 months.
- Inability to complete at least one psychological session prior to breast cancer surgery
Who will take informed consent? {26a}
The senior pain psychologist (DL) delivering the perioperative interventions for this trial will screen for potential trial participants, after breast cancer surgery clinic nurses identify potential candidates for the study. Patients that meet the eligibility criteria will be contacted, and informed consent will be obtained. All potential participants will have the opportunity to withdraw at any time point during the study period.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Not applicable. No data and biological specimens will be collected for use in ancillary studies
Interventions
Explanation for the choice of comparators {6b}
CBT is a form of psychological treatment that is widely used to treat various mental health disorders. We aim to examine its effectiveness in reducing pain intensity and development of chronic post-surgical pain (CPSP) three months post-breast cancer surgery. To achieve this, we have designed our trial to compare CBT with an active control arm, a pain education and mindfulness programme. By taking this approach, the study is controlled for the following factors: time exposure to the psychologist, pain education content and mindfulness practice. This will help to specifically isolate the potential effects of CBT on those participants in that arm of the study.
Intervention description {11a}
1. Group 1: Cognitive Behavioural Therapy for chronic pain (CBT-CP)
The CBT intervention will be delivered by a Senior Psychologist with seventeen years of hospital psychology experience including seven in the treatment of chronic pain patients. Sessions will be delivered in one-hour, individual therapy appointments to patients, and there will be an emphasis on mindfulness based stress reduction, cognitive restructuring, exercise and pacing, behavioural activation, improving sleep, and anger management. Standardized worksheets and homework assignments are an important part of CBT-CP, and these will be given to patients who will be asked to read and complete in terms of complementing the consultations. A total of four sessions will be delivered during the perioperative period, with at least one of these taking place prior to surgery. Further details of each individual session and its content are provided in Table 1. This intervention has been developed with reference to two sources: A successful national implementation of CBT-CP using video teleconferencing format (12) and an evidence-based CBT manual specifically designed to treat chronic pain (13).
2. Group 2: Pain Education and Mindfulness (PEM)
To control for the potential effects of additional time spent with a professional, pain education and mindfulness input between the two interventions, patients in the education and mindfulness group will also have four perioperative psychology sessions, at least one of which will take place before the surgery. As the same person will be providing the CBT-CP and educational interventions, this potential confounding factor will also be controlled for. The control intervention consists of discussing pain education, as derived from the self-management section of the chronic pain Ireland website (https://www.chronicpain.ie/our-services/self-management) and the persistent pain section of the pain toolkit website (https://www.paintoolkit.org/persistent-pain). Four mindfulness-based stress reduction exercises will be completed including an introductory session on mindful breathing, a guided meditation, progressive muscle relaxation and a body scan. These sessions will each last less than one hour.
Criteria for discontinuing or modifying allocated interventions {11b}
Criteria for discontinuing the allocated interventions are:
- Patient withdrawal of consent at any point of study
- Worsening mental health or psychological well-being of patient
Strategies to improve adherence to interventions {11c}
All participants for this trial will receive a total of four psychological based interventions (see ‘interventions description’ part 11a). Each intervention session lasts for approximately 60 minutes. To ensure patient adherence to the study interventions during the trial period, all participants will be well-informed during the consent process. The study participation burden, such as duration and timing of each psychology session, and completion of primary outcome questionnaires at one and, three months post-surgery will be explained. The senior pain psychologist responsible for screening potential study participants will record all eligible candidates, and those that don’t proceed with the study due to ineligibility, non-consent, or withdrawal. In so far as it is possible, only eligible, and fully willing individuals will proceed to randomisation and allocation of the patient to either the CBT-CP or PEM group.
Relevant concomitant care permitted or prohibited during the trial {11d}
All patients will receive standard peri-operative surgical and anaesthesia care during this trial. These include:
- Pre-operative assessment: This may involve optimization of underlying medical conditions (e.g., Blood pressure or glucose control)
- Intra-operative interventions: All patients will receive a general anaesthesia as part of their surgical management. This may be complemented with regional anaesthesia techniques (e.g., PEC Block) for post-operative pain management, this will be under the discretion of the treating anaesthesiologist.
- Post-operative interventions: All patient will have a post-operative analgesia plan. Again, this will be under the discretion of the treating anaesthesiologists. Standard post-operative analgesia that may be prescribed but are not limited to include paracetamol, Non-steroidal anti-inflammatory drug, morphine, fentanyl and gabapentin.
Provisions for post-trial care {30}
All participants that are enrolled into this study are covered by indemnity for negligent harm, through the standard Health Service Executive (HSE) indemnity arrangements. If any participant suffers from any stress or mental health complications arising directly from either intervention during or after the trial, then the participant will be offered further psychological management in line with standard care. This will be offered by a different clinical psychologist, that has no direct or indirect involvement with this trial. The research team for this study will liaise with clinical staff attached to the breast cancer surgery teams in order to make these arrangements.
Outcomes {12}
Primary outcome:
- Brief Pain Inventory Short form: average pain severity score. [ Time Frame: 3 months postoperative].
- Brief Pain Inventory (BPI) Short form will be used to assess for CPSP after Breast Cancer Surgery. This assessment will be conducted by a member of the research team. BPI assess for quality of life and pain and its scale is measured between 0 - 10, where '0' indicates no pain and '10' indicates severe pain. A decrease in the BPI score of 2 or more from the baseline score is considered clinically significant and indicates an improvement in severity of the patient’s cancer and or non-cancer pain (14)
Secondary outcomes:
Secondary outcomes of the study include pain interference, quality of recovery from surgery, levels of pain catastrophising, reported depressed mood and levels of anxiety. These will be measured as follows:
- Brief Pain Inventory Short form: average pain interference score. [ Time Frame: 3 months postoperative].
- BPI average pain interference score assess for interference the pain has on the patient’s functioning. BPI is measured between 0-10, where ‘0’ indicates no interference and ‘10’ indicates severe interference with quality of life (14).
- Quality of Recovery-15 (QoR-15)[Time Frame: 24-48 hours, post-operative]
- QoR-15 is a 15-item questionnaire which is used as a tool to assess overall patient recovery and pain after surgery. Participant will be asked to complete this questionnaire within 24-48 hours after their surgery. It is scored between 0 and 150, where the greater the number indicates excellent post-operative recovery (15).
- Pain Catastrophising Scale (PCS).[Time Frame: 1 and 3 months, post-operative]
- PCS is a 13-item questionnaire designed to measure levels of pain-catastrophizing. The scale comprises 13 items which yield an overall catastrophising score, which is a composite of magnification, rumination, and helplessness subscales. An overall score of greater than 24 is significant for pain catastrophising (6, 9, 16)
- Hospital Anxiety and Depression Scale (HADS). [Time Frame: 1 and 3 months, post-operative]
- HADS is a 14 item self-report questionnaire that was developed and found to be a reliable for detecting states of depression and anxiety in hospital patients, including those with cancer. A depression or anxiety score of greater than 10 is considered significant (17).
Participant timeline {13}
Time schedule of enrolment, interventions, assessments, and visits for participants are illustrated in Table 2.
Table 2: Time schedule for various points during study period.
|
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STUDY PERIOD
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|
Enrolment
|
Allocation
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Post-allocation
|
Primary & Secondary outcomes
|
TIMEPOINT
|
-t1
|
0
|
14 days pre-op
|
7 days pre- op
|
Intra-operative
|
24-48
hours post-op
|
7 days post- op
|
14 days post- op
|
30 days
|
90 days
|
ENROLMENT:
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|
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Eligibility screen (Inclusion & exclusion criteria)
|
X
|
|
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|
|
|
|
|
|
Informed consent
|
X
|
|
|
|
|
|
|
|
|
|
Baseline PCS
(>24: eligible to enrol)
|
X
|
|
|
|
|
|
|
|
|
|
Randomisation
|
|
X
|
|
|
|
|
|
|
|
|
INTERVENTIONS
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|
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|
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CBTsession group
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|
|
X
|
X
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|
|
X
|
X
|
|
|
PEM session group
|
|
|
X
|
X
|
|
|
X
|
X
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|
|
|
|
|
|
|
|
|
|
|
|
|
ASSESSMENTS:
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Patient demographics and characteristics
|
X
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Intraoperative data
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|
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|
X
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BPI
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X
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|
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|
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|
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X
|
X
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QoR-15
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|
|
|
|
|
X
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PCS
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X
|
X
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HADS
|
|
|
|
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|
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|
|
X
|
X
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PCS- Pain Catastrophising Scale, CBT- Cognitive Behavioural Therapy, PEM- Pain Education & Mindfulness, BPI: Brief Pain Inventory score, QoR-15- Quality of Recovery-15 score, HADS- Hospital anxiety and Depression Scale
Sample size {14}
The primary outcome is the difference in the BPI average pain severity score between the study groups, three months after surgery. A clinically important difference on the BPI is 2 raw score reduction on the 11-point Numerical Pain Rating Scale (NRS) (18-20)The standard deviation (SD) of BPI scores after breast surgery is in the order of 2.3 (21) on this scale. Taking a BPI score reduction of 2 as being clinically significant, then n=21 patients would be required each arm if Type I error=0.05 and Type II error is 0.2 (power 80%). Taking into account of dropouts, we propose to enrol 24 eligible patients in each group (N=48 total).
Recruitment {15}
Patients eligible for participation will be evaluated approximately two weeks before surgery and asked for informed consent, and then asked to complete the Pain Catastrophising Scale (PCS) questionnaire (6, 9, 16) by a member of the research team. Patients with high pain catastrophising, defined as a score of ≥24 on the PCS, and who satisfy all other eligibility criteria, will proceed for randomisation to either perioperative CBT or PEM groups. This cut-off is based on a previous study that showed a pre-treatment score of 24 or higher on the PCS best predicted follow-up chronic pain ratings and work status after multidisciplinary treatment (22) and has since been selected as an appropriate score cut-off in a perioperative CBT intervention in lumbar surgery patients (23). More recently, this cut-off was also suggested to obtain the highest sensitivity and specificity to predict unfavourable outcomes after spinal surgery (24).
Assignment of interventions: allocation
Sequence generation {16a}
Patients will be randomised after they are included in the study, having consented, and completed the PCS (and scoring scored ≥24), and two preoperative appointments will be scheduled with the patients in the intervention and control groups. Patients will be randomised to either ‘CBT-CP’ or ‘PEM groups by using an online computer-generated block randomisation.
Concealment mechanism {16b}
Patient study number and group allocation will be typed onto separate pages and concealed in sequentially numbered sealed opaque envelopes.
Implementation {16c}
The randomisation process will be performed by an independent third party. The randomisation key/seed will also be held by an independent third party and investigators will not have access to this key/seed until the study has been completed, with the exception of the treating psychologist (DL) assigned to this trial as will have the responsibility in enrolling study participants and collecting baseline data. DL will allocate patients to either study intervention only after opening the sealed envelopes prospectively as participants are enrolled. DL will not have any additional involvement in data collection or analysis.
Assignment of interventions: Blinding
Who will be blinded {17a}
The treating psychologist will not be blinded as he is required to deliver both interventions associated with this trial. All other members of the research team involved in data collection and analysis will be blinded to the group allocation. In addition, patients will also be blinded because they will not be informed if they are receiving CBT or PEM other than that they are receiving one of two types of psychological interventions.
Procedure for unblinding if needed {17b}
Un-blinding of trial participants to fellow research team members will occur only after creation of a final locked analysis dataset when the last patient has provided data at 3-month follow-up and after data has been statistically analysed by (MBC and DB).=
Data collection and management
Plans for assessment and collection of outcomes {18a}
There will be three time points in which data collection will occur (preoperative, intraoperative, and postoperative). Data will be obtained from electronic and paper patient records. In addition, various questionnaires will be used to gather data to assess for the primary and secondary outcomes outlined for this trial (see section 12-outcomes).
Plans to promote participant retention and complete follow-up {18b}
During the screening process, potential participants will receive an extensive patient information leaflet about the study. The senior pain psychologist involved in this study will emphasise the importance of patient participation and the expectation to complete the study interventions and the various follow up questionnaires at the time of screening and enrollment to optimise retention and meaningful data collection.
Data management {19}
All data will be recorded on a study specific Case Report Form (CRF) that has the patient’s unique study identifier code on each page. Study investigators will enter the data from CRF’s into a designed study specific REDCap database that is password protected. Data will be entered primarily by one study investigator (AM) and verified by a different study investigator (CE) to minimize data entry errors (e.g., incorrect, or duplicate data). Both researchers will be blinded to group allocation.
The data collected and all the research-related documents (both hard copies and electronic copies) will be stored securely in a locked office in the Principal Investigator’s office at the Mater Misericordiae University Hospital (MMUH). Only the principal investigator and the co-investigators can have access to these documents. The records will be kept for 5 years following study closure. All electronic files will be encrypted and accessed via password protected computers.
The electronic REDCap database also allows for specified ranges and automatic calculations to reduce entry errors. The study REDCap database will have automatic calculations for study questionnaires and specified ranges entered for each questionnaire response to ensure accurate data entry. Data will be cleaned by investigators upon completion of data collection to ensure good quality data.
Confidentiality {27}
All the data collected will remain anonymous and confidential. A unique subject number will be provided to each individual patient participating in the study. The front page of the CRF which will be labelled with both the randomisation number and patient information will be stored separately to the remainder of the CRF containing data about the patient to ensure data is re-identifiable. Only study investigators will have access to the data as CRF forms will be stored in a locked office that only study investigators have access to.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Not applicable, no samples will be collected.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Outcome analyses will be conducted by researchers (MBC and DB) who will be blinded to treatment group allocation. Descriptive statistics will be calculated for all outcome measures at each time point, including for continuous variables: means, standard deviations, or medians with ranges of scores; and for categorical variables: frequencies and percentages.
Descriptive and inferential statistics will be obtained using the appropriate statistical methods required to address the study objectives. The primary analysis will compare the effect of the interventions on the primary outcomes; average pain severity at 3 months post-surgery. Outcome analyses will be conducted according to an intention to treat principle i.e. all randomised participants will be included in the main analysis and will be analysed as randomised, regardless of protocol adherence. Secondary analysis will involve the analysis of the secondary outcomes: QoR-15 at 24 hours post-surgery, PCS, HADS and average pain interference on the BPI short form at 3-months post-surgery. Linear mixed models on the outcome measures over time will be fitted to evaluate the effectiveness of both interventions, which intrinsically adjusts for baseline scores. Statistical significance will be assessed from a p-value < 0.05 from the group by time interaction term. For all tests, 2-sided p-values will be used, which will be reported to 4 decimal places with p-values less than 0.001 reported as p< 0.001. In the case of a significant result, contrasts of the group effects at each assessment timepoint will be used to investigate the direction and pattern of effects. Irrespective of statistical significance, the mean changes and confidence intervals will be reported. An up-to-date version of SPSS will be used to conduct analyses.
Interim analyses {21b}
No interim analyses will be conducted.
Methods for additional analyses (e.g. subgroup analyses) {20b}
A per-protocol analysis will exclude participants found to be ineligible after randomization and those who did not receive the intervention. Both intention to treat and per-protocol analyses will be reported and superiority will be determined only if demonstrated with the primary intention to treat analysis.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Careful attention will be paid to ensure that all participants are fully assessed at all time points to minimise missing data. We do not plan to use additional statistical methods such as multiple imputation as studies have demonstrated that linear mixed modelling is sufficient to control for missing data (25, 26)
Plans to give access to the full protocol, participant level-data and statistical code {31c}
The collated data collected by the investigators will be retained for a maximum 5 years after analysis has been completed. We will deliver a completely de-identified data set an appropriate data upon reasonable request and in agreement with the principal investigator and data protection officer.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
This is a single centre study. The trial steering committee will consist of the principal investigator (DB), trial coordinator (HK) and personnel responsible for data entry & data management (AM, CE & MBC). In addition, a research nurse employed by the institution, will also be a member of this committee (HK). This committee will meet monthly to evaluate the progress of the trial, address ongoing organizational and logistical issues and consider any adverse effects.
Composition of the data monitoring committee, its role and reporting structure {21a}
During the process of obtaining ethical approval for this single site study, a data protection impact assessment (DPIA) screening tool was completed. This was analyzed by the hospital’s data protection officer (DPO) in MMUH. It was deemed that this study posed a low risk to the rights and freedoms of natural persons and therefore a formal DPIA was not needed. Recruitment of participants is expected to be completed within less than nine months or once the required number of participants needed is fulfilled. Due to the rapid expected inclusion of participants and the known minimal inherited risks associated with this trial, a data monitoring committee was not appointed.
Adverse event reporting and harms {22}
The study interventions associated with this trial does not involve any physical interventions and all patients will receive standard of care during their perioperative period. Therefore, it is not expected that any participants that volunteer to take part in this trial will suffer from any physical complications directly related from this study. However, some participants may find the study interventions (Cognitive Behavioural Therapy or Education and Mindfulness) distressing. This is not expected, but in the event if this occurs, it will be reported to the principal investigator. The participant will be removed from the trial if merited and further support will be provided.
Frequency and plans for auditing trial conduct {23}
A research nurse affiliated with MMUH anaesthesiology department but not involved in the trial by means patient recruitment, data collection, data entry and analysis will undertake an auditing process for trial conduct. This will occur every three months and would include: exploring the REDCap database for accuracy, proper data entry, duplicate data and adhering to data protection guidelines.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
Approval for any study protocol amendments will be sought from the relevant IRB. Participant information leaflets will be updated accordingly and any changes to the published protocol will be reported in full in any future publications.
Dissemination plans {31a}
The results from this clinical trial will be fully disclosed by means of publication in an international peer-reviewed journal and by oral/poster presentations at national and international scientific meetings. Both positive and negative findings will be disclosed.