The Standard Protocol Items: Recommendations for Intervention Trials (SPIRIT) 2013 checklist that supports this study can be consulted in Additional file 1.
The study is conducted at the Instituto Português de Oncologia do Porto (IPOP; Portuguese Oncology Institute of Porto), a reference hospital for cancer in northern Portugal. Data are being collected from Portuguese patients of this hospital. Public data about this trial can be obtained on the website of the project funding this study (https://mindgap-fet-open.eu). The majority of the interactions with participants are being conducted via internet-based platforms.
The inclusion criteria are summarized in Table 1. It is noteworthy that breast, prostate, and colorectal cancer diseases were selected, as they are the most common cancers in Portugal, with both sexes included (88). Completion of primary treatments was also considered to minimize the impact of cancer treatment on biological markers, also considering that psychological distress may still be present in people who have had cancer, regardless of survival stage (at least up to five years) (89).
In addition, participants must have significant distress at the time of inclusion, defined by a score of 4 or higher on the National Comprehensive Cancer Network (NCCN) Distress Thermometer (8), as used in previous MBI studies (30), and considering that this cut-off score indicates moderate distress related to cancer (90,91).
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Two main strategies are planned to reach the target population. The first is based on obtaining a list of potential participants from the hospital’s Research Outcome Laboratory, filtered by relevant criteria, such as type of cancer and treatments. These potential participants receive an informative email inviting them to visit the official website of the MindGAP project (https://mindgap-fet-open.eu). This website provides participants with more information about the study, including how to register. In the second variant, IPOP’s social networking sites (e.g., Facebook; Instagram; Institutional website) will be used to conduct regular dissemination and invite potential participants to visit the MindGAP’s website.
In any case, participants can request more information by email or phone. Once contacted, participants receive a link to an online eligibility screening survey. This survey consists of an informed consent form and sociodemographic and health-related questions. If eligibility criteria are met, participants are invited to proceed in the study and to complete the baseline assessment. If any risk is identified (e.g., suicidal ideation), participants are informed about how to access specialist care services.
Informed consent is obtained directly from potential participants, via the online survey mentioned earlier. Specifically, participants are asked to confirm that they have read the information provided and are willing to collaborate, by checking a box. They will also be asked to authorize the research team to contact them regarding this study, access individual clinical records, and record the intervention sessions. Alternatively, participants will have the option to check a box to end their collaboration.
Sample size estimation.
Because no previous study has examined circulating EVs in relation to MBIs and cancer, we could not use a specific effect size in estimating the sample size. Nonetheless, a recent systematic review examining the effects of Internet-based MBIs on psychological distress (anxiety and depression) found a median Cohen’s d value between 0.38 and 0.42 for the other primary outcome, psychological distress (18). By using G*Power-3.1 statistical software (92) and considering repeated-measures ANOVA related to within-between interaction (group x time interaction), with an alpha significance level of 0.05 and an effect size of 0.38 (as calculated in (93)), a sample of 84 participants would allow for a power of 0.80. Additionally, previous studies showed dropout rates ranging from 12.1 to 32% for the intervention group and from 6 and 17.4% for the control group, when considering the period immediately following the intervention (30,40,49,52,59,60,94). At follow-up, dropout rates were about 30.8% in the intervention group and 19.6% in the control group (60). Considering the highest dropout rate (32%), 27 participants should be added to the estimated sample, resulting in a minimum of 111 participants to be included in the study.
A schematic representation of the study design from recruitment to the final follow-up time point is provided in Figure 1. Briefly, after enrolling in the study, participants must complete the baseline survey, which consists of both biological and self-assessments. It is worthy to note that the self-reported measures are being completed via online surveys, while the biomarkers require the participants to visit the hospital for a blood sample collection. The blood samples will be preferably collected during routine clinic visits that occur in all recovered patients. After completing the baseline, participants will be randomized to one of the study conditions, internet-based MBCT or TAU. Subsequent study time points are at 4, 8, 24, and 52 weeks after baseline.
The MBCT program (95) is a manualized group-based training program that combines aspects of cognitive-behavioural therapy and aspects of the MBSR program (96). It was originally developed to reduce the risk of relapse and recurrence associated with major depression, but has also been used for other clinical conditions (e.g., cancer; chronic pain; vascular disease) with satisfactory results (see (97) for an overview). We selected this program as it has been used in cancer patients with moderate to high levels of distress and has also shown promising results in an online setting (39,53,54,94,98,99).
During the program, participants learn mindfulness skills to bring attention to the present moment and foster increasing awareness of body sensations, thoughts, and feelings. This includes recognizing and accepting negative and unwanted thoughts, as well as the transitory quality of feelings. The idea is to allow the mind to move from automatic and spiralling patterns to a more conscious processing of mental and physical activities (11,17,100). Overall, the awareness of the usual patterns of the self, shall help to manage and accept unwanted thoughts and feelings.
The online MBCT program that is being used in this study will be as close as possible to a face-to-face version. It consists of eight weekly 2-hour sessions in a group setting (usually 12 participants), follow-up sessions, and an online retreat that addresses meditation skills and is led by a mindfulness teacher (19,95). The general structure of the MBCT program is as follows: the first four sessions are devoted to promoting basic mindfulness skills and psychoeducation regarding unhelpful thoughts; the last four sessions promote an accepting attitude towards unhelpful thoughts and feelings. Each session usually begins with mindfulness and meditation exercises, followed by group discussion, a review of homework activities, and the introduction to new exercises. A summary of the program can be found in Table 2.
Synchronous sessions and interactions will be conducted via videoconference with the teacher and other group members (maximum of 12 participants). In addition to the online sessions, participants will be encouraged to complete daily asynchronous homework assignments using support materials created and provided by the program. For this purpose, participants will be provided with audio-guided exercises shared via an online file hosting service and mp3 players. Participants will be expected to complete daily practices of 10-40 minutes six times per week. Home practice will be monitored weekly using online surveys. A 4-hour online retreat is proposed after the fifth week of intervention, and 4 monthly booster and consolidation sessions of 2 hours are scheduled after the synchronous sessions.
The mindfulness instructor(s) responsible for the intervention will be mental health professionals with training and clinical experience in MBCT and following UK good practice guidelines from the mindfulness-based teacher trainer network (101). A random pool of sessions from different phases of the program will be transcribed and compared to the original protocol to assess the level of adherence to the intervention protocol by the therapist(s). For this purpose, sessions will be recorded with the consent of the participants and the mindfulness instructor(s). These recordings can be used to support supervision or intervention by the mindfulness instructor(s) (16).
Treatment as usual (TAU).
Participants in TAU group will follow the routine intervention protocol established by the hospital for needs assessment, referral, follow-up, and management of individuals with significant distress difficulties. Participants will be monitored for recurrence of cancer or other health problems, changes related with pharmacological and non-pharmacological interventions, and the occurrence of other major life events.
Criteria for discontinuing intervention.
In the group receiving MBCT, along with the weekly daily practice survey, participants will be asked to rate their participation in the program, from harmful to helpful. This will allow monitoring, identifying, and preventing unwanted effects associated to the intervention. If a negative effect is identified, the difficulties will be explored and could result in the intervention being discontinued for those participants. In addition, all participants have the right to terminate their participation at any time. Whenever possible, information about the main reason(s) for dropping out will be requested and recorded.
Adherence and feasibility.
Implementing strategies to promote adherence and prevent dropout is of paramount importance, especially considering dropout rates ranging from 12.1% to 32% in intervention groups (30,40,49,52,59,60,94) and variability in adherence in online programs ranging from 52% to 83% (18). Such strategies are also relevant when considering adherence in daily practice. Although current data are heterogeneous regarding the frequency and timing of home practice in online MBIs (18), MBIs are estimated to have an adherence rate of approximately 60% (102,103). In addition, studies reported that participants completed between 2 to 4 home exercises per week for online MBIs (58,104). Other studies documented reasons underlying for dropping out of online MBIs (28,52,60), including technical problems, insufficient technology-related skills, perceived high intensity of the program, time commitment, lack of motivation, and cancer recurrence or other physical problems.
To avoid technological issues, efforts will be made to provide participants with information on how to complete the online surveys; what is required and how to participate in the videoconference sessions; steps to request specific assistance; in addition to answers to other questions that arise during the study that will be compiled and delivered to participants. Written instructions with step-by-step help information and links to online tutorials will be provided. In addition, interested participants may test the videoconference program, equipment and internet in a short session prior to the start of the intervention program.
Issues such as the intensity and time commitment required by the program and the compatibility of the program with daily activities have been identified in the literature as significant barriers to participation (31,42). Therefore, flexibility in daily practice is expected. Previous findings suggested that participants prefer short, 10-minute mindfulness meditations and more frequently employ body-scan exercises, followed by formal sitting meditations, loving-kindness meditations, mindful yoga, and silent meditations (59). This highlights the need to adapt home practice to a daily routine and offer different exercises with varying lengths to easily accommodate individual preferences (51,56,59).
Motivation during the program is supported and intensified in synchronous group sessions led by instructors, as interpersonal interactions and peer group support have been identified as relevant aspects in online MBIs (28,39,42,61). Previous studies indicated that participants need to receive reminders about daily training (56). MBIs that include reminders have been shown to be more likely to have greater effects on outcome measures than MBIs without reminders (36). Reminders may also lead to better completion rates (105). However, there is a lack of evidence in the literature about how often these reminders should be given to promote engagement and not an opposite effect (see (18) for a discussion). In this study, we will adopt some of the strategies reported in previous studies, including twice-weekly email reminders (59), reinforced reminders during the synchronous sessions (106), and additional reminders to unresponsive participants (29,30). In addition to these interventions, four booster sessions will be implemented to avoid the feelings of disengagement that participants may experience after weekly sessions (107).
The following feasibility measures are considered: recruitment rates (e.g., the proportion of individuals who responded with interest to our invitation; the proportion of individuals who agreed to participate in the study, regardless of eligibility; the proportion of individuals who completed the first assessment point – T1 – and began the intervention); adherence to practice (e.g., number of attended sessions; the number of homework assignments completed per week; the average time spent practicing at home each day); program completion and dropout rates; and program satisfaction.
Program satisfaction will be monitored through several approaches: (1) at the third data collection point, participants will receive an online written semi-structured questionnaire; (2) mindfulness instructor(s) will be invited to participate in a focus group with the research team; (3) a subset of participants will be invited to complete an online adaptation of the Client Change Interview (CCI, (108); European Portuguese adaptation by (109)). The CCI qualitatively assesses how participants experienced the intervention, perceived changes during the intervention, what these changes are due to, positive and negative aspects related to the intervention, and suggestions. In this interview, participants use three 5-point Likert-type scales to rate: expected change (1 - very much expected; 5 - very much surprised by it); change without intervention (1 - clearly would not have happened; 5 - clearly would have happened anyway); the value of the change (1 - not at all important; 5 - extremely important).
The primary and secondary outcomes collected via self-report measures are briefly described and summarized in Table 3. For each self-report measure, the total score obtained for scale and/or subscales will be used as outcomes. Measures examining the eligibility criteria and the sociodemographic and health-related information are also reported in this table.
To determine EVs cargo, total EVs will be isolated from platelet-free plasma samples by ultracentrifugation, followed by a purification step for CNS-derived EVs by immunoprecipitation with CNS-specific antibodies. Since we are interested in CNS-derived EVs, brain-related microRNAs will be measured to verify the origin of the EVs. This is achieved by isothermal nucleic acid amplification method. Results are measured by luminescence.
To evaluate the biochemical markers, inflammatory response biomarkers (IL-1, IL-6, IL-8, IL-10, IFN-γ, TNF) will be detected in serum by multiplex immunoassay (MILLIPLEX® Multiplex Assays Using Luminex®). Similarly, various cancer antigens (CA 15-3 and CA 19.9 in units/mL, PSA in ng/mL, CEA in ng/mL) will also be detected by immunoassay to monitor cancer recurrence. Other health-related biomarkers will include c-reactive protein (mg/L), telomerase activity, erythrocytes number (million/mm3), adrenocorticotropic hormone (pg/mL via immunoassay analyzer), and glycosylated haemoglobin (mmol/mol via high performance liquid chromatography).
The timing of these measures is shown in Table 4. All psychosocial measures employed at baseline are used at T3, T4, and T5. In the fourth week after the baseline (the fourth session in the case of the intervention group), self-reported measures of distress and mindfulness will be used. This intermediate point (T2) was considered as previous studies have suggested that four sessions are the minimum satisfactory intervention dose (18,60,94,99). Few measures were selected at T2 to avoid participant burden.
The plan is to collect biological samples at T1, T3, and T4. Collection at T5 would be important for assessing the long-term impact of online MBIs in the studied markers but will not be done due to limited resources. Of note, participants will receive financial compensation for the costs they incur traveling to IPOP to participate in the blood collections.
Assignment of intervention
Participants will be randomly assigned to one of the two arms: MBCT or TAU groups (1:1 allocation ratio). Randomization blocks will be created using informatic tools and the entire process will be overseen by an investigator who will not be directly involved in the intervention or assessments. This investigator will inform the research team of the final allocation of each participant.
Prior to randomization, individuals involved in the study (participants, study coordinators, mindfulness instructor(s), research assistants, statistician) will be blinded to the study conditions. After randomization, the research team will inform participants about group membership. Similar to previous studies in the field (18), and given the specificities and resources available in the current study, it is impossible to guarantee further blinding of staff and participants.
Data collection and management
After registration, participants will be assigned randomly generated identification codes. They will be asked to keep and use the code to avoid inserting sensitive personal data during their participation. Correspondence between the code and participant’s personal information (e.g., name; contact information; clinical identification in IPOP) is stored in a metadata file that is encrypted with a password and accessible only through the IPOP’s computer, which is protected by institutional security measures.
Data on sociodemographic and health self-report, screening, and primary and secondary outcome measures will be stored in the online survey service used here, LimeSurvey, which adheres to user privacy policies. Data will be periodically copied to an IPOP computer, where they are processed and inserted into excel files. These files will only be accessible to members of the IPOP research team via passwords or physical keys to open specific doors in the case of paper-based documentation, which will be kept in cabinets and locked.
Biological marker data will be obtained from blood samples collected from participants using a 21 to 23-gauge needle into 3 EDTA tubes (≤ 12 mL) and 1 nonadditive tube (4 mL). The standard tubes are stored at 4ºC for a maximum of 180 minutes. Tubes will be centrifuged at 2500g for 30 minutes at 4ºC. The upper third of plasma will be transferred to sterilized 2 mL tubes, and the plasma samples will be aliquoted and stored at – 80ºC in the hospital biobank until further use. The tubes will be labelled with a reference to the MindGAP project and a participant identification code to ensure anonymization during the blood collection and processing. Prior to EVs isolation, a centrifugation step at 5000 g for 15 minutes is performed in thawed plasma samples, to remove most of the remaining platelets.
For both self-reported and biological data, a privacy impact assessment has already been submitted, analysed, and approved by the IPOP’s Data Protection Officer. In addition, given the nature and the resources available to conduct this study, no Data Monitoring Committee was designated. Nevertheless, the IPOP’s research team meets regularly to assess the conduct and progress of this study and to ensure compliance with the study protocol. Similarly, regular consortium meetings are planned with the MindGAP project research partners to discuss the developments within this study.
Screening data for errors and missing values is the first step in the data analysis plan. Missing data will be managed and avoided during the data collection by using mandatory fields in the online surveys and retrieving the data from participants when possible. Data from participants who completed fewer than 4-weekly online MBCT sessions will not be considered further, as four sessions were set as the minimum number required for participation (18).
For each group (MBCT and TAU), a summary of baseline sociodemographic and health-data will be provided, including number and percentages, mean, standard deviation, median, first and third quartiles, minimum and maximum. Using the socio-demographic and health data, as well as the primary and secondary measures, comparisons will be made between groups to examine whether there are differences between groups at baseline. Similarly, differences at baseline between participants who will complete the study and those who will drop out will be examined. The presence of differences in variables may warrant the need to examine and/or adjust for their influence on outcome changes in the primary analyses. This summary also presents the within-group effect sizes (Cohen’s d – equation 11.10, from (110)) for each outcome across time (i.e., T1 to T2; T1 to T3; T1 to T4; T1 to T5).
The total scores of each primary and secondary measures will be used as outcomes in multiple linear mixed models (LMMs). Each model will include the interaction between group and time, while participants will be treated as a random effect. The visual inspection of Q-Q plots will be conducted to check the normal distribution of residuals. Examination of factors such as sex, type of cancer, cancer stage will be approached by running separate models for each factor. LMM analyses can be employed using, for instance, lmer4 (111) and lmerTest (112) in R software (113).
Descriptive statistics for feasibility indicators (see adherence and feasibility section) will be documented. In the case of program satisfaction, a qualitative analysis of the information collected in the semi-structured interview, focus groups, and CCI will be conducted (108). For this purpose, a computer-assisted thematic analysis will be used, following Braun and Clarke’s 6-step approach (114) (see also (115,116)): (i) familiarization with the data (transcribing the non-written data to a written format and carefully reading all the material several times to become familiar with it); (ii) initiation of the coding process (identifying emergent units of meaning - codes - that are relevant to the research and can be used to tag similar data); (iii) generation of potential and broader themes (codes can be categorized according to the themes and a thematic map that contains associations between themes, including major and sub-themes, and between codes); (iv) review the themes (themes are reviewed to verify if they fit the coded data so that they can be deleted, modified, merged and/or separated; also, the accuracy of the thematic map is reviewed); (v) description of themes (provide a name, characterization, and a scope, and refine the themes step by step); (vi) report of analysis (write and describe in detail the process of analysis using data supporting the themes and discuss the results in light of the literature and research goals). As recommended, steps 1-3 will be conducted by at least two independent researchers and later brought into the group discussion to promote thematic and code reliability (117).
Oversight and monitoring
Participants in the intervention group will be monitored weekly for their experience in the intervention sessions. The aim is to detect adverse events associated with the intervention (see (18,31) for some examples), to discontinue the intervention or, if necessary, to make a referral to specialist care services. Such incidents will be documented in the participant flow diagram.
Changes to the study protocol will first be submitted to the IPOP Ethics Committee and after approved updated accordingly in clinicaltrials.gov.
The activities and results of the MindGAP project are updated on the project website (https://mindgap-fet-open.eu) and disseminated on the project’s social networking platforms (Facebook, Twitter, LinkedIn, YouTube), which are linked on the project homepage. The public can interact with the research team through the former channels. The results of the study will be presented in scientific meetings and published in open-access journals. By the end of this study, it is planned to present the results to participants, healthcare professionals, and the community in an open session organized at IPOP. Social and traditional media platforms could also be used to reach a wider audience.