Protocol for a randomised controlled feasibility trial of an integrated psychosexual intervention for sexual difficulties in people with Multiple Sclerosis: the PIMS trial

Abstract

Background

Multiple Sclerosis (MS) is a long-term condition that significantly diminishes quality of life (QoL). Sexual difficulties (SDs) are common, but often overlooked symptom, affecting 50–80% of people with MS (PwMS). The emergence of SDs in MS results from the intricate interplay of disease processes, treatments, and psychosocial factors, contributing to a further decline in QoL and adverse effects on body image, relationships, and psychological well-being. Despite the limited treatment options, which mainly include medications and physiotherapy, there is promise in psychological interventions for addressing SDs in PwMS, although integrating them into routine care poses challenges. This protocol details the trial assessing the acceptability and feasibility of an eight-session, clinicians supported integrated Psychosexual Intervention for people with Multiple Sclerosis (PIMS).

Methods

This is a multicentre interventional two-arm randomized feasibility trial with a nested qualitative study to gather preliminary data about the intervention and the feasibility of conducting a full-scale trial. We aim to recruit 50 PwMS across three research sites in England’s National Health Service (NHS). Participants will be randomised to either the PIMS intervention (comprised of 8 sessions: 6 self-led and 2-facilitator led over the course of 12 weeks) or psychosexual education (one appointment with a facilitator to discuss treatment options). Feasibility will be assessed by collecting descriptive data on recruitment and retention rates and willingness to be randomised according to Consolidated Standards of Reporting Trials (CONSORT) feasibility and pilot trial guidelines. Patient reported outcomes (e.g., measures of sexual functioning and distress, psychological functioning, and quality of life) will be measured at baseline and follow up 14-weeks after randomisation. We will also use a nested qualitative study will use inductive thematic analysis to identify barriers to engagement with and delivery of the intervention, and to make appropriate modifications to PIMS.

Discussion

The PIMS intervention will be the first integrated psychosexual intervention developed for people with Multiple Sclerosis in the UK. Assessing the feasibility of PIMS is an important first step to establishing future implementation and efficacy via a definitive randomised controlled trial.

Trial registration

This trial is registered at ISRCTN: 12202900.

Registration date: 28th February 2023; Retrospectively registered.

IRAS identification: 305830.

NIHR award reference: NIHR202006.

Trial sponsorship: This trial is co-sponsored by South London and Maudsley NHS Foundation Trust and King’s College London. Contact: slam-ioppn.research@kcl.ac.uk.

Protocol version: 2.0, 10th February, 2025

Background and rationale

Multiple Sclerosis (MS) is a long-term condition (LTC) with a substantial impact on quality of life (QoL) [1, 2]. Sexual difficulties (SDs) are a common and distressing symptom of MS, with a 2023 systematic review and meta-analysis reporting a global prevalence of 62.5% in women with MS [3] and estimates of 50–90% in men with MS [4, 5]. SDs in MS negatively impact QoL, relationship satisfaction, body image, and can exacerbate symptoms of depression and anxiety with moderate effect [4,5,6,7]. In a large study (N = 6183 people with MS) sexual dysfunction had a greater impact on the psychological components of QoL than the severity of disability [8]. Longitudinal studies show that for both men and women with MS, the number of SD symptoms increases significantly over time after diagnosis (e.g., vaginal dryness or erectile dysfunction becomes more severe or additional SDs develop) [9, 10].

SDs in MS arise from the complex interplay of disease processes, disability, side effects of medications, and psychosocial factors [11]. However, current treatments for people with MS (PwMS) are largely limited to medications which treat SDs caused by disease mechanisms (e.g., erectile dysfunction; reduced genital sensation). A Cochrane review of trials of medications for erectile dysfunction in MS show mixed efficacy and adverse side effects were commonly reported [12]. There are no medications that target ejaculatory problems or the psychological or biological contributory factors for the development and maintenance of other SDs in men. Pharmacological treatments for women with SDs are even more limited and are not MS-specific (e.g., Filbanserin for low sexual desire). Research suggests the most effective type of treatment protocol for SDs in PwMS is multidisciplinary given the biopsychosocial nature of the difficulties. This is optimally designed in collaboration with neurologists, specialist nurses, psychologists, and psychosexual clinicians [13]. Clinical specialists and other health care professionals working with PwMS (MS specialist nurses, physiotherapists, continence nurses) are best placed to deliver an intervention for sexual difficulties given their expertise and existing relationships with PwMS [13, 14].

A systematic review of controlled clinical trials shows good efficacy of psychological interventions for diagnosed sexual dysfunctions (ICD-coded rather than SDs more generally) in men and women in the general population, with most studies showing small to moderate effects [15]. Similarly, Cochrane reviews show evidence for the treatment of sexual dysfunctions with psychotherapeutic interventions in people with cardiovascular disease [16], after cancer [17], and for men with erectile dysfunction [18]. A 2021 systematic review with meta-analysis supports the efficacy of mindfulness-based therapies in the treatment of men and women with SDs, with moderate effect sizes [19]. All reviews call for higher quality studies to evaluate the efficacy of psychological interventions in the treatment of SDs, as many have varying outcome measures, therapeutic approaches, high risk of bias, and small sample sizes.

Given the burden of SDs in PwMS, there is increased interest in designing MS specific interventions targeting this troubling symptom. A systematic review of 12 clinical trials (N = 611) found that sex therapy, mindfulness, and physiotherapy showed some efficacy in treating sexual difficulties in MS [20]. One intervention (N = 70) combined non-specific mindfulness meditation and pelvic floor exercises [21], where mindfulness groups showed greater increase in sexual functioning and satisfaction compared to wait-list controls. However, these and other interventions have been tested exclusively in women and took varying approaches (e.g., exclusively non-specific psychotherapies, psychosexual therapy, and physiotherapy) [22,23,24,25,26,27,28,29,30,31] and would be difficult to integrate into regular care in the National Health Service (NHS; or other nationalised healthcare systems) for four primary reasons:

• 1) they require highly skilled clinical practitioners (typically psychologists or physiotherapists) to deliver the intervention,

• 2) they provide no information about including men with MS, and

• 3) they require significant additional appointment time with healthcare practitioners (HCPs)

• 4) mechanisms for improvement of SDs are not clearly specified or linked to theory

Additionally, previous intervention trials frequently have no active control condition, so any effects may relate to time and attention rather than intervention mechanisms. Thus, we aim to investigate, for the first time, a theory-informed treatment using a more scalable delivery format that can be embedded in NHS MS services.

Specifically, our integrated Psychosexual Intervention for sexual difficulties in people with Multiple Sclerosis (PIMS) comprises components from sex education tailored to PwMS (including practical/medical advice specific to MS care), psychosexual therapy (e.g., improving sexual communication), and ACT, including mindfulness (present moment awareness) and values for enhancing motivation to engage in sex and intimacy [32,33,34]. To do this, we first developed a working theoretical model of disease etiological factors of SDs in MS based on existing empirical evidence. Identified mechanisms were then mapped onto possible medical and psychosexual treatment techniques. We then used experience-based co-design (EBCD) to 1) determine areas of importance and 2) finalize content for a self-directed intervention that could be delivered in routine care. Through these systematic methods, we created an integrative 8-session manualized Psychosexual Intervention for people with Multiple Sclerosis (PIMS): 6 sessions are self-guided and 2 are facilitated by trained MS HCPs.

We will assess the acceptability of the intervention to HCPs and PwMS within the NHS in England and the feasibility of running a future NHS based fully powered randomised controlled trial. To do this, we will be assessing the adapted PIMS intervention alongside a standard care arm within a feasibility RCT.

This protocol was prepared using the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist and Consolidated Standards of Reporting Trials (CONSORT) feasibility and pilot trial guidelines. See Appendix C for full checklist.

Objectives

The primary objective is to evaluate the feasibility of a larger randomised controlled trial based on eligibility and recruitment rates, retention, and adherence.

Feasibility objectives: People with Multiple Sclerosis

• 1. Determine eligibility rates (proportion of those screened who meet inclusion criteria)

• 2. Recruitment rates (proportion of eligible PwMS consented to trial)

• 3. Assess retention of participants (% participants who complete 14-week follow up assessment)

• 4. Assess participant adherence

  • a. Average number of appointments attended

  • b. Average number of self-guided sessions completed

• 5. Acceptability as indicated by:

  • a. Average acceptability ratings according to eight items on a theoretical framework of acceptability questionnaire [35, 36]

  • b. Acceptability of self-reported outcome measures for a future trial (i.e., completion rates, reliability, item-level missing data, floor/ceiling effects, participant validity rating of sex-related outcomes)

Feasibility objectives: NHS Sites

• 1. Recruitment rates

  • a. Number of NHS sites recruiting for trial

  • b. Number of facilitators recruited from neurology services to deliver the intervention

• 2. Facilitator adherence

  • a. Proportion of required session material covered during appointments

Secondary objectives

• 1) To explore the differences in means on self-reported outcomes between trial arms and at between pre-post randomisation time points

• 2) To qualitatively explore the participant perceptions of the acceptability and usefulness of the PIMS/psychosexual education (PSE; comparator group) packages and identify areas of improvement for a full-scale trial

• 3) To qualitatively explore HCPs perceptions of acceptability and usefulness of the PIMS/PSE packages and barriers/facilitators to delivery

• 4) To explore the feasibility of collecting health economic estimates of: 1) the costs of the psychosexual intervention, and 2) assessment of the feasibility of collecting data on health service utilisation and health-related quality of life for sexual difficulties in people with multiple sclerosis

Trial design

This is a multicentre interventional two-arm randomized feasibility trial with a nested qualitative study to gather preliminary data about the intervention and the feasibility of conducting a full-scale trial. Fifty PwMS will be randomised to either the PIMS intervention (comprised of 8 sessions: 6 self-led and 2-facilitator led over the course of 12 weeks) or psychosexual education (one appointment with a facilitator based on NICE guidelines to discuss treatment options).

Methods: Participants, intervention, and outcomes

Study setting

This is a multicentre trial at 3 NHS trusts (two hospitals, one community clinic) in England within neurology or specialist MS services. Participants will be recruited from these services when attending routine appointments by the MS clinicians including MS nurses, neurologists, occupational and physiotherapists. Facilitators of both intervention arms will be trained MS clinicians within these services. Where possible, appointments will be scheduled at times to suit the participant (during usual clinic hours) and will be conducted in a private environment either remotely (telephone or video conferencing) or at one of the NHS sites depending on patient/facilitator availability.

Self-report questionnaires and informed consent will be completed online via Qualtrics (https://qualtrics.kcl.ac.uk/). This is a confidential survey software that is complaint with General Data Protection Regulations (GDPR). The interviews for the nested qualitative study, conducted by members of the research team, will be run remotely and audio/video recorded and transcribed.

Eligibility criteria

Inclusion criteria

For PwMS in the intervention study:

• Confirmed diagnosis of Multiple Sclerosis

• Attending the Neurology clinic at one of the participating research sites

• Aged ≥ 18

• Affirmative response to the following question:

  • ◦ Are you currently experiencing any sort of sexual or intimacy difficulty?

• Able and willing to provide informed consent

For facilitators participating in nested qualitative study:

• Clinical staff at research sites that work with people with Multiple Sclerosis

Exclusion criteria

For PwMS in the intervention study

• Severe visual or hearing impairments which will impact the ability to engage in the intervention.

• Severe mental health disorder (e.g., psychosis) which will impact the ability to engage in the intervention.

• Receiving psychotherapy for sex or intimacy difficulties or are participating in any other psychological intervention trial during the time they will be in the study.

• Insufficient verbal and/or written proficiency in English.

For facilitators participating in nested qualitative study:

• Unable or unwilling to consent to participate in the follow up interviews.

Interventions

No modifications will be made to the interventions during the trial. All participants in each arm will receive the same intervention, but advice, referrals, and treatment options from HCPs will be tailored to the individual needs of participants (e.g., based on presenting issue, sexual orientation, age, gender, etc.).

PIMS

PIMS is an adapted psychosexual intervention that is primarily self-directed with support from trained MS HCPs. The purpose of this intervention is to target biological, cognitive, emotional, and behavioural aspects of sexual difficulties for people with MS.

Development

First, we developed a working theoretical model of etiological factors of SDs in MS based on existing empirical evidence, which states there are three primary causal levels of SDs in PwMS: primary (caused by disease mechanisms), secondary (caused by disease symptoms and treatment side effects) and tertiary (caused by psychosocial factors) [37]. We then mapped each of these etiological pathways onto possible medical and psychosexual treatment techniques such as Acceptance and Commitment Therapy (ACT) and psychosexual education. We also drew on previous mindfulness-based interventions treating 1) sexual difficulties in people with MS and spinal cord injuries [38] and 2) women with low sexual desire [39].

Next, we used experience-based co-design (EBCD) to 1) determine areas of importance and 2) finalize content for a self-directed intervention that could be delivered in routine care. EBCD is a systematic method for working with patients and HCPs to improve healthcare delivery and outcomes via workshops and interviews with [40]. We then iteratively worked with a group of 7 PwMS to finalize the intervention manual. Grounded in theory and supported by patient and public involvement, we created an integrative 8-session manualized Psychosexual Intervention for people with Multiple Sclerosis (PIMS): 6 sessions are self-guided and 2 are facilitated by trained MS HCPs.

There are three components of PIMS:

• 1. Psycho- and sexual- education

  • This will help provide a knowledge base about the interaction between MS and possible biological changes affecting sexual functioning, psychological functioning, and sexual wellbeing.

• 2. Acceptance and Commitment Therapy (ACT)

  • These techniques will be used to support PwMS developing present-moment awareness of and openness to MS-related challenges to enable engagement in personally meaningful sex, intimacy, and relationship activities. A growing number of trials support the use of ACT in LTCs [41].

• 3. Psychosexual therapy techniques

  • Sex and relationship therapy techniques, such as sensate focus therapy [42] and enhancing communication, will be integrated into the intervention to target difficulties in navigating sexual relationships after an MS diagnosis

Table 1 outlines the topics and tasks for each session.

Table 1 Summary of PIMS sessions

Training and supervision

Facilitators will be clinicians who work with PwMS in the neurology services recruited for this study. Training before intervention delivery will be two half-day sessions. Session 1 will focus on trial protocol, education on techniques being used/ manual navigation, and discussion of case studies. Before session 2, all facilitators will work with a member of our patient and public involvement group to practice a facilitated session. This will be audio/video recorded and individual feedback will be provided by the trial manager. The second training session will act as an introduction to supervision sessions, where practice participants will be discussed, and peer feedback will be given.

Facilitators will be expected to attend clinical supervision sessions every 2–4 weeks, led by the study PI and trial manager who developed the intervention, and a clinical collaborator who specialises in ACT. One-on-one supervision will be provided ad-hoc based-on facilitator needs.

Delivery

If randomised to the PIMS treatment arm, participants will be provided with a structured PIMS therapy manual including worksheets and between-session tasks. The manual will be provided as a pdf upon randomisation confirmation and a hard copy will be posted after participants provide their mailing address. The PIMS manual will have six self-guided sessions (designed to take around 50 min each) and two facilitator-led sessions (designed to last approximately 30 min; see Table 1 above). Participants will be expected to complete all eight sessions within 12 weeks of randomisation.

Facilitated sessions will be delivered either on site or remotely (via telephone), based on participant/facilitator availability and preferences. These sessions will be designed to last 30 min and are focused on goal setting, treatment/referral options, and participants’ progress through the PIMS manual. We will use the PACT approach to goal setting: goals should be Purposeful, Actionable, Continuous, and Trackable. This was chosen over the traditional ‘SMART’ goal method (Specific, Measurable, Achievable, Relevant, And Time-Bound) typically employed in health-related interventions [43, 44] as PACT goals are more relevant to creating longer term goals with a focus on what can be controlled by the goal-setter; this is also more in line with ACT principles of committed action.

At the end of each appointment, facilitators will complete an online log that details 1) preparation for the session, 2) material covered during session, 3) date/duration/mode of delivery, and 4) any notes of concern to be brought to the research team.

Psychosexual education

Development

We developed our comparator treatment based on NICE guidelines for MS symptom management [45] which states that treatment options for sexual dysfunction should be discussed with HCPs. Despite this being the formal recommendation by NICE, PwMS (including our patient and public involvement group) report that this is rarely discussed during appointments and that clinicians are often inconsistent and uncomfortable having these discussions. For the purposes of this study, our Psychosexual Education (PSE) comparator will be designed as a one-off appointment with an MS HCP of approximately 30 min to discuss 1) basic psychosexual education (such as sexual anatomy and response), and 2) possible treatment options (along with any relevant referrals). This will be an appropriate comparator as it allows all participants to receive treatment and helps us examine feasibility and acceptability of our intervention against what is advised to be ‘standard care’. We will use currently available resources for PwMS experiencing sexual and intimacy challenges along with input from PPI and MS HCPs to create an information leaflet to be used during appointments. This is consistent with NICE guidelines and recommendations for managing sexual and intimacy challenges put forth by the MS Society [46] and MS Trust [47, 48].

Training and supervision

We will hold a half-day training session for facilitators who delivered the PSE treatment arm. To reduce possible contamination effects, facilitators of the PSE arm will not receive information about the psychological intervention strategies used in PIMS (e.g., mindfulness). Training will largely cover possible treatments, both those available on the NHS and privately. Referral pathways and availability of additional services will also be discussed (e.g., urogynaecology or psychosexual clinics). Supervision will be held every 6–8 weeks with the trial manager, along with individual ad hoc meetings as requested.

Delivery

The PSE treatment will be a single 30-min session with a trained facilitator. Sessions will be held in clinic or remotely based on facilitator/participant availability and preference. The appointment will involve facilitators asking standardised questions about sexual difficulties, discussing medication, and signposting to other resources. At the time of randomisation, participants will be emailed a pdf of the PSE leaflet; they will also receive a hard copy if they attend their appointment in clinic.

As with the PIMS arm, facilitators will be asked to complete an online log that details 1) preparation, 2) material covered, 3) appointment details, and 4) any notes of concern to be brought to the research team.

Outcomes

Primary feasibility parameters

Feasibility will be assessed by collecting descriptive data on recruitment and retention rates and willingness to be randomised according to Consolidated Standards of Reporting Trials (CONSORT) feasibility and pilot trial guidelines [49]. The outcomes will be collected by someone separate to the facilitator. We will determine the following:

• Eligibility and recruitment rates

  • ◦ This will allow us to determine whether our eligibility criteria are appropriate, and whether those eligible to participate (i.e., complete screening) are willing to be randomised.

• Follow up/retention rates

  • ◦ Proportion of participants who were randomised that completed follow up assessment.

  • ◦ If participants drop out, we will attempt to contact them to investigate reasons for doing so.

• Treatment adherence rates

  • ◦ Total number of appointments attended/completed.

  • ◦ Number of appointments attended with facilitator.

  • ◦ Number of self-guided sessions completed.

    • ▪ At least one activity completed per session will be considered partial completion.

    • ▪ Number of activities completed by session.

  • ◦ Adherence will be defined as attending at least one facilitated session and completing at least 3 self-guided sessions.

• Acceptability of the intervention

  • ◦ This will be evaluated based on constructs identified as being part of a theoretical framework for acceptability that have been developed into an 8-item scale for use in feasibility trials [35, 36, 50]. Items are on 5-point Likert response scales, though scale points differ based on the item. Wording of the items will be adapted for this study, as is directed by the scale authors. Participants in the PSE and PIMS arm will both respond to the scale.

• Health Economics

  • ◦ We will examine the feasibility of collecting data in interviews with trial participants and via a modified Adult Service Use Schedule (ADSUS).

  • ◦ For health-related quality of life, we will measure the completion rate and item missingness for the EQ-5D-5L.

    ◦ To estimate the cost of the psychosexual intervention, we will collect details on training, to include materials and the time costs of those attending and training, alongside the time average duration and number of treatment sessions.

• Nested qualitative study

  • ◦ We will investigate patients’ and facilitators’ experience with the intervention

Patient reported outcomes

Sex- and intimacy-related outcomes

We will assess multiple measures of sex and intimacy to determine which are most appropriate outcomes measures for a full-scale trial. This will be measured via reliability, validity, change scores, and floor/ceiling effects.

The Sexual Function Evaluation Questionnaire (SFEQ) [51] will be used to assess level of sexual functioning. This was designed and validated as a clinical tool to assess patients with sexual difficulties; it shows good internal and external validity and reliability. The SFEQ has 16 items with one general score and four sub-scale scores (problem distress, partner relationship, sex life, and sexual confidence). Subsequent items are triggered if respondents indicate having difficulties in items relating to the four domains in the past month via a binary yes/no response. Higher scores indicate more negative outcomes.

The Multiple Sclerosis Intimacy and Sexuality Questionnaire (MSISQ-19) [52] was designed to assess MS-specific sex and intimacy related difficulties. Sum scores will be generated for each level of causation of SDs in MS (primary, secondary, and tertiary). Nineteen items will be responded on a scale of 1 (never) to 5 (always), with respondents stating how often each issue (e.g., tremors or shaking, concentration difficulties, bladder symptoms) has interfered with sexual activity or satisfaction in the past 6 months. The MSISQ-19 shows good psychometric properties across samples [53,54,55,56].

The Female Sexual Distress Scale-Revised (FSDS-R) will assess sexual distress. The FSDS-R shows good psychometric properties in clinical samples of women with sexual dysfunction. Thirteen items will assess how much a problem (e.g., feeling inferior because of sexual problems) has bothered or distressed respondents in the past month on a scale from 0 (never) to 4 (always). This scale will be used for both male and female participants as it has been validated in both [57,58,59] – items do not contain any female-specific wording (despite the title). An overall score will be used in between-group analysis.

The New Sexual Satisfaction Scale – Short form (NSSS-S) [60, 61] is a 12 item measure assessing overall sexual satisfaction. Respondents will be asked to indicate how satisfied they are with certain aspects of their sex life (such as ‘my mood after sexual activity’) in the past six months on a scale of 1 (extremely satisfied) to 7 (extremely dissatisfied). The scale shows good psychometric properties across samples [62, 63]. An overall score will be generated for between-group analysis.

Secondary outcomes

The Guy’s Neurological Disability Scale [64] will assess 12 categories of MS-specific disability: cognitive, mood, visual, speech and communication, swallowing, upper limb, lower limb, bladder, bowel, sexual, fatigue, and miscellaneous disability (e.g., dizziness, medication side effects). Each domain has between 2–10 yes or no (binary) items. All domains begin with the question ‘do you have any problems with [domain]?’. Responding yes to this item will trigger subsequent items. Each domain is scored on a scale of 0–5, with 0 indicating no problems and 5 indicating total loss of function (e.g., full time wheelchair user). The GNDS shows good content and face validity, and inter-rater and test–retest reliability; these results have been replicated across studies [65, 66]. A total score and a subscale score for sexual dysfunction will be calculated for use in between-group analysis.

The EQ-5D-5L measures health-related quality of life in five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), with five severity levels for each dimension [67]. This is a revised version of previous EQ-5D, with more sensitivity to changes in health decrements and simplified instructions. This is a self-report measure with a single item for each dimension asking for respondents to describe their health at present. Each item has 5 possible responses, with these increasing in severity. There is a final sixth item, asking for respondents to rate their overall health on the day on a sliding scale of 0 (‘the worst health you can imagine’) to 100 (‘the best health you can imagine’). The EQ-5D-5L is widely used and well validated in clinical and non-clinical populations [68, 69]. An overall score and the self-rated heath score will be used in between-group analysis.

Depression symptoms will be measured via the Patient Health Questionnaire-9 (PHQ-9) [70] and anxiety symptoms will be measured via the Generalised Anxiety Disorders-7 questionnaire (GAD-7) [71]. These are 9 and 7 item measures, respectively, asking about symptoms over the past two weeks, with higher scores indicating more severe symptoms. They have been widely validated in clinical populations. Sum scores will be generated for both measures.

Plausible process variables

Mindfulness is often operationalised as having five facets 1) observing; 2) describing; 3) awareness of actions; 4) non-judgement; and 5) non-reactivity. In the context of sex and relationships, studies [72, 73] link the ‘awareness of actions’ and ‘non-judgement’ facets to increased sexual and relationship satisfaction. To measure this, we will use these two sub-scales from the Five Facet Mindfulness Questionnaire (FFMQ) [74]. The FFMQ show good psychometric properties that have been replicated across cultures [75, 76] and in LTC patient groups [77]. Both subscales are comprised of 8 items that are responded to on a 5-point Likert scale ranging from ‘never or very rarely true’ to ‘very often or always true’. An average score will be computed for the two subscales being used for this study.

The Dyadic Sexual Communication Scale (DSC) [78] is a 13-item measure assessing comfort in discussing sex with partners. Respondents indicate how much they agree with statements such as ‘I seldom feel embarrassed when talking about the details of our sex life with my partner’ considering their current relationships on a scale of 1 (strongly agree) to 5 (strongly disagree). Higher sum scores indicate stronger sexual communication. The DSC has shown good psychometric properties across samples [79] and is predictive of sexual outcomes (e.g., satisfaction) [80]. A total sore will be used in between-group analysis.

Safety assessment and event reporting

If suicidal ideation is detected during screening/data collection, as indicated by a score of > 1 on the depression PHQ9 item ‘Thoughts that you would be better off dead, or of hurting yourself’, then a risk assessment will be performed to determine the urgency of referral to liaison psychiatry. This will also be done if a participant reports suicidal ideation during intervention sessions. Level of risk will be assessed in line with the King’s Health Partners ‘Integrating Mental and Physical healthcare: research, training and services’ (IMPARTS) risk assessment protocol [81]. This will include enquiring about degree of suicidal ideation, whether active plans are present, the patient’s history of suicide attempts, recent life stressors, protective factors, and current social support. The risk assessment will be carried out by a trained member of the research team.

If risk is deemed to be low, we will determine if the participant needs more support and ask if they are willing to inform their GP; they will be given a letter to give to their GP regarding their risk assessment outcome. If risk is high, this will be escalated to relevant mental health services.

If deterioration in the participants’ mental health at any stage of the trial, and these needs are outside the scope of the intervention, this will be discussed with the CI and an appropriate referral plan to psychiatry or psychology will be made.

Given that intervention material may lead to participants reflecting on past experiences of sex and intimacy, there will be the potential for participants to disclose past experiences of sexual assault or domestic violence. Facilitators, who have all undergone safeguarding training, will be able to signpost them to relevant supports should this be requested. Facilitators will also be given additional information regarding this during intervention training. If there is suspected/disclosed ongoing abuse, a brief safeguarding assessment will be made and this will be discussed with the CI or trial investigator and the clinician in charge of the patient to determine if a safeguarding report needs to be made, in line with NHS safeguarding guidance [79].

Adverse events (AE), adverse reactions (AR), and serious adverse events/reactions, verified by site PI, will be sent immediately to the CI, who will report this to the REC and sponsor within 15 days of becoming aware of the event. Participants will be asked to self-report AEs in follow up data collection; If relevant the team will discuss AEs (e.g., other contact with health services, major life events) with the TSC/DMC to determine if these are AR related to the intervention.

Other data collected

Health economics

For health-related quality of life, we will measure the completion rate and item missingness for the EQ-5D-5L, which would be used as the primary outcome measure for cost-effectiveness analysis in a subsequent full RCT. For the feasibility of collecting data on broader health service use, we will modify and test a version of the Adult Service Use Schedule (ADSUS) and will assess the measure’s comprehensiveness in capturing all relevant services, and specifically identify items which were redundant, or important services that had been omitted.

Sociodemographic and clinical data

• Date of birth

• Gender

• Sex assigned at birth

• Post code

• Level of education (based on highest qualification achieved)

• Relationship status

• Ethnicity

• Sexual orientation

• Type of MS (relapse remitting, secondary progressive, or primary progressive)

• Length of time since MS diagnosis

Qualitative assessment

The primary aim of the nested qualitative study will be to gather participants’ and facilitators’ experiences of PSE, PIMS, and facilitators’ experiences of training/intervention delivery. This will enable us identify barriers to engagement with and delivery of the intervention, and to make appropriate modifications to PIMS, facilitator training, and trial design. We will also explore barriers to participation by interviewing participants who drop out at different points (e.g., pre-intervention vs. mid-intervention). Data (minimum of 20 interviews with participants, and all facilitators) will be collected via semi-structured interviews (audio-recorded, telephone, or face-to-face). Interviewers will be independent of study facilitators.

Participant timeline

From date of randomisation, participants are expected to be in the study for 14 weeks; see Fig. 1.

Fig. 1

Anticipated flow of participants through the study. Number of patients referred for screening, assessed for eligibility, and consented will be recorded. Eligible and consented participants will be invited to complete baseline measures (T0). After baseline, participants will be randomised. The PIMS arm will receive the intervention over 12 weeks. The PSE arm will have their one-off session by week 12. All participants will complete follow-up measures at 14 weeks post-randomisation (T1). Participants in both arms will be invited to take part in qualitative interview at the end

Sample size

A sample of 50 is within the recommended sample size for feasibility trials [82]. As significance testing is not used in trials of this nature, the sample size is based on the precision with which the key parameters are estimated. A sample size of 50 will allow us to estimate recruitment rates with a 95%CI of width ± 8% assuming 50% recruitment (width will be narrower if recruitment lower) and drop-out rates with a 95%CI with maximum width ± 14% overall and ± 20% within each group. A sample size of 50 will also provide an estimate of the standard deviation in the study population that is sufficiently accurate to be used in the sample size estimation for a definitive trial.

Between three study sites we will expect to recruit 17 participants from each. Over a 9-month recruitment period, this will require a recruitment rate of approximately 2–3 participants per month per site. This recruitment period was extended based on study timelines and clinician availability. The date of randomisation of the first participant was February 8th, 2023. Recruitment will close on February 29th, 2024.

Recruitment

There are three ways in which participants will be approached for recruitment:

• 1. During their regular neurology clinic visit by their MS HCP

• 2. By contacting the research team via flyers posted in clinic waiting areas

• 3. By contacting the research team after receiving a copy of the information sheet via post (clinicians will identify potential participants to send these to)

The research team will only approach potential participants about the study and to complete screening if they have provided consent to contact. Consent to contact will be gained either by 1) consent given to the healthcare team during their initial approach or 2) if potential participants reach out directly to the research team and provide this consent.

To determine if people meet the inclusion/exclusion criteria, a brief screening questionnaire will be done (via Qualtrics) with a member of the research team.

We have chosen not to use a standardised measure as a screening tool as it can act as a barrier to recruitment (e.g., through scoring cut-offs) and can produce a regression to the mean effect across groups. We will explore the possibility of using a standardised measure (e.g., the Female Sexual Distress Inventory) as a screening tool in a later RCT.

Intervention facilitators (clinical staff) will be invited to take part in the nested qualitative study. All intervention facilitators will be invited for the interviews; we expect for all facilitators to take part.

Methods: Assignment of interventions

Allocation

Participants will be randomised to the intervention or control group following a 1:1 ratio using randomly varying block sizes to maintain similar numbers across each group during the period of recruitment. Randomisation will be stratified by centre and three gender groups: 1) cisgender men, 2) cisgender women, and 3) transgender/nonbinary. There will be an equal probability of being randomised to the PIMS or PSE arm for groups 1 and 2, and a 100% chance of being randomised to the PIMS treatment group for those in group 3.

Randomisation will take place after baseline measures have been completed using the King’s Clinical Trial Unit (KCTU) online randomisation service. The system will be online and managed independent of the trial team. Only the trial manager will have full access to the KCTU randomisation system and will generate trial allocation. Research assistants who help with participant assignment (e.g., mailing out the PIMS manual/ emails about trial allocation) will have access to the randomisation outcome; they will not be performing any full trial analysis.

Individuals who identify as transgender or nonbinary will not be randomised. Research suggests that 1% or less of the population identifies as transgender or non-binary [83], we do not expect to have more than 1 participant in this category. They will not be randomised and will be included in the PIMS arm to assess acceptability. Thus, data regarding treatment outcomes from those who identify as non-binary or transgender will not contribute to randomised comparisons but will inform retention and acceptability through the qualitative interview. Given this is a feasibility trial we have decided to prioritise information concerning the acceptability of the intervention in this group, rather than maximising the precision of between group comparisons which are not to be tested statistically anyway.

Blinding

Group allocation will be concealed for the trial statistician who will undertake the primary between group analysis. The CI and members of the research team that are solely responsible for screening/data collection will also be blinded. The trial manager and facilitators are the main points of contact for safeguarding concerns and will all be unblinded throughout the study; the CI may be unblinded for any serious safeguarding concerns or adverse event. The trial steering committee (TSC), which includes a statistician and is acting jointly as the data monitoring committee (DMC), will be able to review unblinded data as part of a closed meeting where there are adverse events to consider. This will allow the trial analyst to remain blind during the primary analysis.

Group allocation will be stored in a separate database from baseline and follow-up data; a mimic randomisation and analysis write-up will be performed before unblinding after all data has been collected.

Methods: Data collection, management, and analysis

Data collection

Trial procedures by timepoint, according to SPIRIT guidelines, can be seen in Table 2. All quantitative measures at baseline and follow-up will be collected via Qualtrics. Interviews will be conducted remotely or face-to-face and audio transcribed verbatim. See secondary feasibility parameters for details on outcomes.

Table 2 Summary of trial procedures by key timepoint/visit

We will promote participant retention by consistent communication with participants. For example, we will call participants after allocation to ensure they understand the trial process/treatment manual use and send text message reminders of appointments. We will also attempt contact with those that have met eligibility criteria and have expressed interest but have not completed baseline data up to three times (email, phone, and text). At follow up, we will email participants a personal Qualtrics link to provide follow up data. If this has not been completed within a week, we will send a follow up email and call to ensure they have received this. If we are unable to reach participants via email, a member of the research team will call to fill out the questionnaire with them via telephone. We will be requesting follow up data from all participants at 14-weeks post randomisation, regardless of intervention adherence. For those that withdraw, we will attempt to complete an informal interview about reasons for withdrawal.

Participants who wish to partake in the interview study will be required to submit follow up data before the interview can take place. We will be offering a £20 Love2Shop voucher for participants who complete interviews; this is noted at the time of consent and on the information sheet.

Data management

A central recruitment log will be securely stored to track potential participants who have given consent to contact. At the end of study, aggregate data (e.g., number screened vs recruited) will be collected and identifiable data will be deleted.

Participants will complete questionnaires electronically through Qualtrics If participants request paper copies of questionnaires, these will be mailed to them. When returned to the research team, these will be inputted into the Qualtrics form within 10 working days and then permanently destroyed.

Pseudonymised data, including group allocation, will be kept on REDCap [84, 85]. This will include study ID, dates of each key trial procedure, and trial arm. Identifiable information will only be stored on Qualtrics; this does not contain treatment allocation information. Both systems will be managed by the trial manager. After data collection has ended, Qualtrics data will be downloaded, and the online data will be permanently deleted. Identifiable information, with the exception of full post code, will be deleted once downloaded. After a deprivation index is calculated, the post code will also be deleted.

The quantitative data will be analysed by a statistician at King’s College London; they will also oversee database management. The trial manager will prepare reports on screening and recruitment and assess adherence. The statistician will complete the between-group analyses, scale completeness and psychometric assessments, and assessment of retention. For all quantitative analyses, the statistician will be blind to treatment allocation, as they will be using the dataset without allocation information.

The qualitative interview data will be transcribed and analysed by the trial manager with assistance from MSc Health Psychology and DClinPsy Students at King’s College London. Research data will be stored for 10 years after the study has ended, in line with King’s College London Guidelines. Research data will be deposited in the King’s Research Data Management system for long term preservation after the study has ended. Once the assigned retention period for the research has passed, the principal investigator and the research data management team at King’s College London will ensure the secure disposal of any confidential records. Hard copy data will not be archived; it will be destroyed after it has been transferred to the electronic database.

Analysis plan

Descriptives

Descriptive statistics of patients screened, eligible, consented, and randomised will be computed, in line with CONSORT feasibility and pilot study guidelines [49]. Demographic descriptors and reasons for non-consent, exclusion, and drop out will be recorded and reported. Standard deviations will be computed for the outcome measures for each trial arm to estimate sample size for a future efficacy trial.

Progression criteria

The key analyses undertaken will inform the decision to progress to a definitive trial based on the acceptability and feasibility analyses described below for the variables listed as primary outcomes. Progression will be judged via a commonly used traffic light system shown below (Table 3).

• 1. Green- feasible to proceed to a full RCT with the current trial design/procedures

• 2. Amber- modifications are required before proceeding to a definitive trial

• 3. Red- not feasible to proceed to a definitive trial

Table 3 Progression criteria for full-scale efficacy trial

Where all criteria are observed to be green, the recommendation will be that a full-scale trial is feasible without major modifications to the intended protocol (i.e., progress). Where there is a mixture of green and amber criteria, the recommendation will be that a full-scale trial is feasible only if modifications can be made to the relevant domain such that the green judgment is likely to be achieved. It is anticipated that these modifications will then need to be confirmed as part of an internal pilot for the full-scale trial. Where any of the criteria are observed to be red, the recommendation will be that a full-scale trial is not feasible (i.e., do not progress) and that major modifications to the protocol are needed and a further feasibility study likely to be necessary.

Acceptability and feasibility

Acceptability will be based on objective behavioural measures (e.g., dropout rates, attendance), self-report measures of attitudes towards the intervention, and qualitative reports on experiences with the intervention in addition to reasons for withdrawal [36]. These will be summarised as n(%) with 95%CIs. Using a mixed methods approach, we will determine intervention-specific challenges. This includes identifying the optimal number of sessions for both participants and HCPs, assessing HCP intervention fidelity, and overall satisfaction of participants and HCPs. Assessing issues related to recruitment and retention rates, suitability of selected outcome measures, and other intervention-specific issues will help us determine whether to proceed to a larger RCT. Such findings will inform the design of a future trial, such as primary outcome measure selection, sample size estimation, and protocol adaptations. Missing data will not be imputated.

Psychometrics of instruments

The psychometric quality of self-report instruments will be assessed for patient reported outcome measures. Given the noted criticism of using Cronbach’s alpha [86], we will assess reliability using McDonalds Omega, with a minimum accepted cut off of ω = 0.70 and a preference for values ω > 0.80. Reliability calculations will also be computed for sub-scales where relevant. Potential issues with floor and ceiling effects will be considered, particularly where these might impact responsiveness in the definitive trial. Individual items will be checked to ensure that there are no problematic items for this patient population. To assess face validity, participants will rate how well they feel each of the sex and intimacy related outcomes captured their SDs from ‘strongly agree’ to ‘strongly disagree’.

Quantitative analysis of clinical outcomes

Between-group differences at baseline and 14-week follow-up outcome assessments will be estimated with 95%CIs using linear regression models. Baseline level of the outcome and stratification factors will be adjusted for. Given the study is not powered to determine superiority of the intervention versus control, p-values for between group differences will not be reported and interpretation will be based on 95%CIs indicating the range of plausible effect sizes supported by the data. Standard deviations for the plausible primary outcomes of a larger trial (SFEQ, MSISQ-19, FSDS-R, DSC, and NSSS-S; see details on sex and intimacy-related outcomes) will be computed to inform estimation of the sample size of a definitive trial. We will determine the primary outcome for a definitive trial based on psychometric properties and quantitative reports from participants regarding face validity (see details on psychometrics of instruments above), in addition to patient advisory group focus groups to be held during future research set-up.

Qualitative acceptability and process analysis

The primary aim of the nested qualitative study will be to gather participants’ and facilitators’ experiences of standard-care, PIMS, and facilitators’ experiences of training. This will enable us identify barriers to engagement with and delivery of the intervention, and to make appropriate modifications to PIMS, facilitator training and trial design We will also explore barriers to participation by interviewing participants who drop out at different points (e.g., pre-intervention vs. mid-intervention). Data (minimum of 16 interviews with participants, and all facilitators) will be collected via semi-structured interviews (audio-recorded, telephone, or face-to-face) by members of the research team. Purposive maximum variation sampling will be employed to ensure participants are interviewed across a range of characteristics [87], in particular: age, gender, ethnicity, MS subtype, degree of intervention adherence, relationship status, and site. In line with recommendations for multi-site qualitative studies, we will aim to do 8–10 interviews per trial arm [88, 89]. Interviews will be transcribed verbatim and analysed using inductive thematic analysis using NVivo software. This form of qualitative analysis will identify recurrent themes and patterns from the interviews, and we will developing a coding manual.

Economic data analysis

An evaluation of the feasibility of data collection for a future economic evaluation in a full-scale trial will include: 1) asking facilitators to provide feedback on the feasibility of collecting service use data, 2) identifying and costing the resources associated with treatment-as-usual via service use data collection, 3) developing an estimate of intervention cost through collection of detailed information on the intervention and its implementation in practice, and 4) identifying and testing the sensitivity of the EQ-5D-5L quality of life measure, which is preferred by NICE for the calculation of QALYS, in this population.

Ethics and dissemination

Ethical approval

The trial will be conducted in compliance with the principles of the Declaration of Helsinki (1996), the principles of GCP and in accordance with all applicable regulatory requirements including but not limited to the UK policy framework for health and social care research and the Mental Capacity Act 2005. This trial received full ethical approval from the Health Research Authority, Harrow Research Ethics Committee reference 22/LO/0441, on 24th June 2022.

Protocol amendments

All protocol amendments will be communicated to relevant bodies, e.g., NHS trusts. Amendments will first be approved by the sponsor before submitting the amendment tool and any amended documents via the Integrated Research Application System (IRAS) amendment portal. The REC will review amendment if needed. All relevant NHS Trust R&Ds, the sponsor, and other parties (e.g., ISRCTN) will be notified.

Consent

Informed consent will be obtained from all participants (see Appendix A).

Confidentiality

Information regarding data confidentiality is included in the participant information sheet (see Appendix B). General Data Protection Regulation guidance (GDPR) will be followed for all data collection and analysis. Only the immediate healthcare team will have access to medical records and personal details, except in the event of an audit or inspection by regulatory authorities. No NHS records will be transferred. Data will be transferred via the KCL network (e.g., transferring data from Qualtrics to the database). Writing up the qualitative interview transcripts involves publication of direct quotations from participants. We will ensure this remains anonymous and no identifiable information is included in quotations.

Access to data

The datasets generated during and/or analysed during the current study will be available from the CI on reasonable request. The CI [blinded for review] will be the contact to approve and send out copies of any data. Any data shared will be de-identified. Only data from participants who have consented to their data being shared/used in future research studies will be shared. A data file will be made at the end of the trial where the possibility of identification has been minimized and includes only data from those who have consented to this. Both quantitative and qualitative data may be requested. Data will only be shared for the purpose of research.

Ancillary and post-trial care

Given that intervention material may lead to participants reflecting on their overall wellbeing, there will be the potential for participants to experience some distress. Facilitators, who have all undergone safeguarding training, will be able to signpost them to relevant supports should this be requested. We provide additional information about mental health resources on both the baseline and follow-up questionnaires. We do not expect to deliver any additional post-trial care.

Dissemination policy

Results will be fed back to participants and disseminated through public engagement events (arranged with our patient and public involvement working group), academic publications, and presented at international conferences. Study results will also be disseminated via public engagement events and through relevant MS charities/organisations, such as the MS Trust.

Discussion

Given that the burden on sexual difficulties in MS are high, an evidence-based intervention that can be integrated into current health systems is needed. Research has found elements of mindfulness, psychosexual therapy, and physiotherapy are useful in managing sexual difficulties for PwMS [20]. However, previous interventions were mainly tested in women, required highly skilled practitioners, and lacked clear mechanisms for improvement. The PIMS intervention addresses these limitations by 1) having clear links between theory and the model of treatment, 2) being clinician supported and largely self-led, and 3) being applicable to people of all genders, sexual orientations, and relationship configurations. Specifically, PIMS combines MS-specific sex education, psychosexual therapy, and ACT in an 8-session manualised intervention. This intervention was co-developed alongside MS clinicians and PwMS to ensure balance between patient needs and clinician availability. Despite the potential benefits of PIMS, the feasibility is unknown.

We will use a randomised controlled feasibility trial, with a nested qualitative study, to assess the feasibility of the PIMS intervention. If feasible, data from this trial will help inform a definitive efficacy RCT, including determining primary outcome measures and adapting PIMS for implementability within existing healthcare systems.