Stigma in functional neurological disorder (FND) - A systematic review.

OBJECTIVE: The purpose of this systematic review was to evaluate stigma and Functional Neurological Disorder (FND) regarding: 1) prevalence and associated factors, 2) the nature and context of stigma in FND, and 3) stigma-reduction interventions. METHODS: We searched four relevant databases from inception to December 2023, using search terms relevant to FND and stigma themes. We employed the method of synthesis by "aggregation and configuration" to synthesise and analyse the data into emergent themes. RESULTS: We found 127 studies, spanning 148 countries, involving 18,886 participants. Of these, 4889 were patients, 13,123 were healthcare professionals, and 526 were caregivers. Quantitatively, stigma has been mainly studied in patients with functional seizures, and was higher than patients with epilepsy in three studies. Stigma experienced by patients is associated with poorer quality of life and caregiver burden. We found 10 themes and 29 subthemes revealing stigma as a systemic process, with intrapersonal, interpersonal and structural aspects. Few studies examined the perspective of caregivers, the public or online community. We identified six anti-stigma interventions. CONCLUSION: Stigma in FND is a layered process, and affects patient quality of life and provision of care. Stigma needs to be addressed from the top structures, at governmental level, so that appropriate care pathways can be created, giving patients with FND parity of esteem with other medical conditions.

Challenging the current hypothesis that thrombosis is responsible for the post-COVID-19 condition.

People with the post-COVID-19 condition suffer symptoms that persist beyond 12 weeks following acute COVID-19 infection. Fatigue, shortness of breath, and cognitive dysfunction ("brain fog") are common. Scientists, clinicians, and patients debate the pathophysiology. One pathophysiological hypothesis is that prothrombotic changes associated with acute COVID-19 persist, causing clots that lead to symptoms. This theory, arising from a research team in South Africa and supported by a paper in Nature Medicine, has been widely disseminated on social media and entered the public narrative as a cause of the post-COVID-19 condition. We describe the development of this theory, examine the findings of a Cochrane review that critically appraises the "microclot" beliefs, and critically appraise the influential study relating clotting biomarkers to cognitive deficits. We conclude the inferences for the hypothesis are not based on evidence, unlicensed use of antithrombotic medication is not justified, and apheresis should not be considered outside of a well-designed clinical trial.

Reflections on the CODES trial for adults with dissociative seizures: what we found and considerations for future studies.

The COgnitive behavioural therapy versus standardised medical care for adults with Dissociative non-Epileptic Seizures multicentre randomised controlled trial is the largest, fully-powered study to test the clinical and cost-effectiveness of a psychotherapeutic intervention in this population. We also explored predictors or moderators of outcomes and investigated mechanisms of change in therapy. In this current review of findings, we discuss issues related to the design of the trial and consider the study's nested qualitative studies which were undertaken not only to shed light on the original research questions but to provide insights and recommendations for other researchers in the field of functional neurological disorder. Finally, we consider issues relating to the possible clinical application of our study findings.

Specialist physiotherapy for functional motor disorder in England and Scotland (Physio4FMD): a pragmatic, multicentre, phase 3 randomised controlled trial.

BACKGROUND: Functional motor disorder-the motor variant of functional neurological disorder-is a disabling condition that is commonly associated with poor health outcomes. Pathophysiological models have inspired new treatment approaches such as specialist physiotherapy, although evidence from large randomised controlled trials is absent. We aimed to assess the clinical effectiveness of a specialist physiotherapy intervention for functional motor disorder compared with treatment as usual. METHODS: In this pragmatic, multicentre, phase 3 randomised controlled trial at 11 hospitals in England and Scotland, adults with a clinically definite diagnosis of functional motor disorder, diagnosed by a neurologist, were included. Participants were randomly assigned (1:1, stratified by site) using a remote web-based application to either specialist physiotherapy (a protocolised intervention of nine sessions plus follow-up) or treatment as usual (referral to local community neurological physiotherapy). Individuals working on data collection and analysis were masked to treatment allocation. The primary outcome was the physical functioning domain of the 36-item short form health questionnaire (SF36) at 12 months after randomisation. The primary analysis followed a modified intention-to-treat principle, using a complete case approach; participants who were unable to receive their randomised treatment due to the suspension of health-care services during the COVID-19 pandemic were excluded from the primary analysis. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN56136713, and is completed. FINDINGS: Recruitment occurred between Oct 19, 2018, and March 11, 2020, pausing during the COVID-19 lockdown, and resuming from Aug 3, 2021, to Jan 31, 2022. Of 355 participants who were enrolled, 179 were randomly assigned to specialist physiotherapy and 176 to treatment as usual. 89 participants were excluded from the primary analysis due to COVID-19 interruption to treatment (27 were assigned to specialist physiotherapy and 62 to treatment as usual). After accounting for withdrawals (n=11) and loss to follow-up (n=14), the primary analysis included data from 241 participants (138 [91%] assigned specialist physiotherapy and 103 [90%] assigned treatment as usual). Physical functioning, as assessed by SF36, did not differ significantly between groups (adjusted mean difference 3·5, 95% CI -2·3 to 9·3; p=0·23). There were no serious adverse events related to the trial interventions. 35 serious adverse events were recorded in the specialist physiotherapy group by 24 participants (17·0%), and 24 serious adverse events were recorded in the treatment as usual group by 18 participants (17·0%); one death occurred in the specialist physiotherapy group (cause of death was recorded as suicide). All were considered unrelated to specialist physiotherapy. INTERPRETATION: Although more participants who were assigned specialist physiotherapy self-rated their motor symptoms as improved and had better scores on subjective measures of mental health, the intervention did not result in better self-reported physical functioning at 12 months. Both the specialist and community neurological physiotherapy appeared to be a safe and a valued treatment for selected patients with functional motor disorder. Future research should continue to refine interventions for people with functional motor disorder and develop evidence-based methods to guide treatment triage decisions. FUNDING: National Institute for Health and Care Research and Health Technology Assessment Programme.

Perspectives on the diagnosis and management of functional cognitive disorder: An international Delphi study.

BACKGROUND: Current proposed criteria for functional cognitive disorder (FCD) have not been externally validated. We sought to analyse the current perspectives of cognitive specialists in the diagnosis and management of FCD in comparison with neurodegenerative conditions. METHODS: International experts in cognitive disorders were invited to assess seven illustrative clinical vignettes containing history and bedside characteristics alone. Participants assigned a probable diagnosis and selected the appropriate investigation and treatment. Qualitative, quantitative and inter-rater agreement analyses were undertaken. RESULTS: Eighteen diagnostic terminologies were assigned by 45 cognitive experts from 12 countries with a median of 13 years of experience, across the seven scenarios. Accurate discrimination between FCD and neurodegeneration was observed, independently of background and years of experience: 100% of the neurodegenerative vignettes were correctly classified and 75%-88% of the FCD diagnoses were attributed to non-neurodegenerative causes. There was <50% agreement in the terminology used for FCD, in comparison with 87%-92% agreement for neurodegenerative syndromes. Blood tests and neuropsychological evaluation were the leading diagnostic modalities for FCD. Diagnostic communication, psychotherapy and psychiatry referral were the main suggested management strategies in FCD. CONCLUSIONS: Our study demonstrates the feasibility of distinguishing between FCD and neurodegeneration based on relevant patient characteristics and history details. These characteristics need further validation and operationalisation. Heterogeneous labelling and framing pose clinical and research challenges reflecting a lack of agreement in the field. Careful consideration of FCD diagnosis is advised, particularly in the presence of comorbidities. This study informs future research on diagnostic tools and evidence-based interventions.

Chronic idiopathic urinary retention: Comorbidity and outcome in 102 individuals.

OBJECTIVES: Chronic Idiopathic urinary retention is poorly understood. One small study suggests higher than expected rates of functional neurological disorder and pain comorbidity which may have implications for understanding the disorder. We investigated the frequency of functional neurological disorder, chronic pain other medical and psychiatric comorbidity, triggers of urinary retention, results of urodynamic assessment, medication history, management, and outcome in patients with chronic idiopathic urinary retention. METHODS: A consecutive retrospective electronic notes analysis was undertaken of patients with chronic idiopathic urinary retention presenting to a secondary care urology clinic between Jan 2018-Jan 2021, with follow-up to their most recent urological appointment. RESULTS: 102 patients were identified (mean age of 41.9 years, 98% female). 25% had functional neurological disorder (n = 26), most commonly limb weakness (n = 19, 19%) and functional seizures (n = 16, 16%). Chronic pain (n = 58, 57%) was a common comorbidity. Surgical and medical riggers to urinary retention were found in almost half of patients (n = 49, 48%). 81% of patients underwent urodynamic assessment (n = 83). Most frequently no specific abnormality was reported (n = 30, 29%). Hypertonic urethral sphincter was the most identified urodynamic abnormality (n = 17, 17%). We noted high levels of opioid (n = 50, 49%) and benzodiazepine (n = 27, 26%) use. Urinary retention resolved in only a small number of patients (n = 6, 6%, median follow up 54 months), in three cases spontaneously. CONCLUSION: This preliminary data suggests idiopathic urinary retention is commonly comorbid with functional neurological disorder, and chronic pain, suggesting shared mechanisms.

How stigma unfolds for patients with Functional Neurological Disorder.

OBJECTIVE: The aim of this study was to explore experiences of stigma in Functional Neurological Disorder (FND) from the perspective of the patient as it manifests from the onset of symptoms, up to diagnosis and subsequently. BACKGROUND: The existing literature clearly shows that stigma exists for many patients with FND, and is associated with poorer quality of life. However, it is less clear how stigma unfolds, and how it can be alleviated. METHODS: We performed a qualitative interview study with patients who were diagnosed with FND, using data based on semi-structured interviews. Participants were recruited purposively via outpatient clinics. We analysed the data using a reflexive thematic analytic approach, through the lens of recognised stigma frameworks. RESULTS: 15 participants were included in the study, aged between 19 and 68 years, with varying presentations of FND. We identified six themes and 16 subthemes relevant to their stigma trajectory. We found that stigma unfolds through four main domains: 1) through their symptom experience; 2) through "othering" by the healthcare system; 3) through everyday interactions; and 4) from within the self. Across these four domains was a central theme of 5) stages of knowledge, which both fuelled and countered stigma. Lastly, 6) validation of the patient experience emerged as a theme that alleviated stigma. CONCLUSIONS: Stigma did not unfold as a linear process, rather it came from multiple interacting sources. Interventions to target stigma could take the form of improved clinician training, communication, especially around point of diagnosis, and public interventions, co-produced with patients with FND.

Cognitive domains affected post-COVID-19; a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: This review aims to characterize the pattern of post-COVID-19 cognitive impairment, allowing better prediction of impact on daily function to inform clinical management and rehabilitation. METHODS: A systematic review and meta-analysis of neurocognitive sequelae following COVID-19 was conducted, following PRISMA-S guidelines. Studies were included if they reported domain-specific cognitive assessment in patients with COVID-19 at >4 weeks post-infection. Studies were deemed high-quality if they had >40 participants, utilized healthy controls, had low attrition rates and mitigated for confounders. RESULTS: Five of the seven primary Diagnostic and Statistical Manual of Mental Disorders (DSM-5) cognitive domains were assessed by enough high-quality studies to facilitate meta-analysis. Medium effect sizes indicating impairment in patients post-COVID-19 versus controls were seen across executive function (standardised mean difference (SMD) -0.45), learning and memory (SMD -0.55), complex attention (SMD -0.54) and language (SMD -0.54), with perceptual motor function appearing to be impacted to a greater degree (SMD -0.70). A narrative synthesis of the 56 low-quality studies also suggested no obvious pattern of impairment. CONCLUSIONS: This review found moderate impairments across multiple domains of cognition in patients post-COVID-19, with no specific pattern. The reported literature was significantly heterogeneous, with a wide variety of cognitive tasks, small sample sizes and disparate initial disease severities limiting interpretability. The finding of consistent impairment across a range of cognitive tasks suggests broad, as opposed to domain-specific, brain dysfunction. Future studies should utilize a harmonized test battery to facilitate inter-study comparisons, whilst also accounting for the interactions between COVID-19, neurological sequelae and mental health, the interplay between which might explain cognitive impairment.

Pain and functional neurological disorder: a systematic review and meta-analysis.

BACKGROUND: Functional neurological disorder (FND) is characterised by neurological symptoms, such as seizures and abnormal movements. Despite its significance to patients, the clinical features of chronic pain in people with FND, and of FND in people with chronic pain, have not been comprehensively studied. METHODS: We systematically reviewed PubMed, Embase and PsycINFO for studies of chronic pain in adults with FND and FND in patients with chronic pain. We described the proportions of patients reporting pain, pain rating and timing, pain-related diagnoses and responsiveness to treatment. We performed random effects meta-analyses of the proportions of patients with FND who reported pain or were diagnosed with pain-related disorders. RESULTS: Seven hundred and fifteen articles were screened and 64 were included in the analysis. Eight case-control studies of 3476 patients described pain symptoms in a higher proportion of patients with FND than controls with other neurological disorders. A random effects model of 30 cohorts found that an estimated 55% (95% CI 46% to 64%) of 4272 patients with FND reported pain. Random effects models estimated diagnoses of complex regional pain syndrome in 22% (95% CI 6% to 39%) of patients, irritable bowel syndrome in 16% (95% CI 9% to 24%) and fibromyalgia in 10% (95% CI 8% to 13%). Five studies of FND diagnoses among 361 patients with chronic pain were identified. Most interventions for FND did not ameliorate pain, even when other symptoms improved. CONCLUSIONS: Pain symptoms and pain-related diagnoses are common in FND. Classification systems and treatments should routinely consider pain as a comorbidity in patients with FND.

Non-motor symptoms in motor neuron disease: prevalence, assessment and impact.

People with motor neuron disease often experience non-motor symptoms that may occur secondary to, or distinct from, motor degeneration and that may significantly reduce quality of life, despite being under-recognized and evaluated in clinical practice. Non-motor symptoms explored in this population-based study include pain, fatigue, gastrointestinal issues, poor sleep, low mood, anxiety, problematic saliva, apathy, emotional lability, cognitive complaints and sexual dysfunction. People registered on the Clinical Audit Research and Evaluation of motor neuron disease platform, the Scottish Motor Neuron Disease Register, were invited to complete a questionnaire on non-motor symptoms and a self-reported Amyotrophic Lateral Sclerosis Functional Rating Scale. The questionnaire comprised a pre-defined list of 11 potential non-motor symptoms, with the opportunity to list additional symptoms. A total of 120 individuals participated in this cross-sectional study, a 39% response rate of those sent questionnaires (n = 311); 99% of participants recruited (n = 120) experienced at least one non-motor symptom, with 72% (n = 120) reporting five or more. The symptoms most often reported were pain and fatigue (reported by 76% of participants, respectively). The symptoms reported to be most impactful were gastrointestinal issues (reported as 'severe' by 54% of participants who experienced them), followed by pain and problematic saliva (51%, respectively). Lower Amyotrophic Lateral Sclerosis Functional Rating Scale scores, indicating more advanced disease and being a long survivor [diagnosed over 8 years ago; Black et al. (Genetic epidemiology of motor neuron disease-associated variants in the Scottish population. Neurobiol Aging. 2017;51:178.e11-178.e20.)], were significantly associated with reporting more symptoms; 73% of respondents were satisfied with the frequency that non-motor symptoms were discussed in clinical care; 80% of participants indicated they believe evaluation of non-motor symptom is important to include as outcomes in trials, independent of their personal experience of these symptoms. The preferred method of assessment was completing questionnaires, at home. The overwhelming majority of people with motor neuron disease report non-motor symptoms and these frequently co-occur. Pain, fatigue, gastrointestinal issues, sleep, mood, anxiety, problematic saliva, apathy, emotional lability, cognitive complaints and sexual dysfunction are prevalent. People with motor neuron disease who had worse physical function and those who were long survivors were more likely to report more symptoms. Where reported, these symptoms are frequent, impactful and a priority for people with motor neuron disease in clinical care and trial design.

Factors impacting trial participation in people with motor neuron disease.

Motor neuron disease (MND) is a rapidly progressive neurodegenerative disorder with limited treatment options. Historically, neurological trials have been plagued by suboptimal recruitment and high rates of attrition. The Motor Neuron Disease-Systematic Multi-Arm Randomised Adaptive Trial (MND-SMART) seeks to identify effective disease modifying drugs. This study investigates person-specific factors affecting recruitment and retention. Improved understanding of these factors may improve trial protocol design, optimise recruitment and retention. Participants with MND completed questionnaires and this was supplemented with clinical data. 12 months after completing the questionnaires we used MND-SMART recruitment data to establish if members of our cohort engaged with the trial. 120 people with MND completed questionnaires for this study. Mean age at participation was 66 (SD = 9), 14% (n = 17) were categorised as long survivors, with 68% (n = 81) of participants male and 60% (n = 73) had the ALS sub-type. Of the 120 study participants, 50% (n = 60) were randomised into MND-SMART and 78% (n = 94) expressed interest an in participating. After the 1-year follow-up period 65% (n = 39) of the 60 randomised participants remained in MND-SMART. Older age was significantly associated with reduced likelihood of participation (OR = 0.92, 95% CI = 0.88-0.96, p = 0.000488). The findings show that people with MND are highly motivated to engage in research, but older individuals remain significantly less likely to participate. We recommend the inclusion of studies to explore characteristics of prospective and current participants alongside trials.

Functional Cognitive Disorder: Diagnosis, Treatment, and Differentiation from Secondary Causes of Cognitive Difficulties.

Functional cognitive disorder is an increasingly common cause of referral to the memory clinic. As a substantial source of disability, clinicians involved in the management of patients with cognitive complaints need to familiarize themselves with this important differential diagnosis. Our approach focuses on the identification of positive features of internal inconsistency (historical and clinical clues alongside patterns of performance) instead of an exclusionary approach. Although effective treatments are desperately needed, promising therapies include metacognitive retraining and cognitive-behavioral therapy modalities. Future research should focus on a better understanding of disease trajectories and outcomes as well as the development of evidence-based interventions.

Setting up Functional Neurological Disorder Treatment Services: Questions and Answers.

Functional neurologic disorder (FND) is commonly encountered across outpatient and inpatient medical settings. Given the potential for a high burden of disability in some patients and mounting evidence for the efficacy of FND-specific multidisciplinary treatment services, expanding clinical services for this population is a necessity. In this perspective article, we discuss considerations for creating FND services, including the types of services that exist, how to start, how to identify appropriate referrals, and how to develop and monitor individualized treatment plans. In addition, we discuss how this effort can be done sustainably - balancing patient needs with limited healthcare resources.

Psychiatric sequelae of traumatic brain injury - future directions in research.

Despite growing appreciation that traumatic brain injury (TBI) is an important public health burden, our understanding of the psychiatric and behavioural consequences of TBI remains limited. These changes are particularly detrimental to a person's sense of self, their relationships and their participation in the wider community, and they continue to have devastating individual and cumulative effects long after TBI. This Review relates specifically to TBIs that confer objective clinical or biomarker evidence of structural brain injury; symptomatic head injuries without such evidence are outside the scope of this article. Common psychiatric, affective and behavioural sequelae of TBI and their proposed underlying mechanisms are outlined, along with a brief overview of current treatments. Suggestions for how scientists and clinicians can work together in the future to address the chasms in clinical care and knowledge are discussed in depth.

Clinical signs in functional cognitive disorders: A systematic review and diagnostic meta-analysis.

OBJECTIVE: Functional cognitive disorder (FCD) accounts for around a third of patients attending specialized memory clinics. It is also overrepresented in patients with other functional and somatic diagnoses. So far, no long-term diagnostic validity studies were conducted, and a positive diagnostic profile is yet to be identified. We aimed to review the literature on diagnostic signs and symptoms that allow for a discrimination between FCD and neurodegeneration. METHODS: Systematic review of Ovid-Medline®, Embase and PsycINFO databases. Relevant clinical features were extracted including demographics, symptom history, comorbidities, language and interaction profiles and cognitive assessments. Studies with quantifiable diagnostic accuracy data were included in a diagnostic meta-analysis. RESULTS: Thirty studies (N = 8602) were included. FCD patients were younger, more educated, and more likely to have a family history of older onset dementia, abrupt symptom onset, and higher rates of anxiety, depression and sleep disturbance. Promising language profiles include longer duration of spoken answer, elaborated examples of memory failures, ability to answer compound and personal questions, and demonstration of working memory during interaction. The pooled analysis of clinical accuracy of different signs revealed that attending alone and bringing a handwritten list of problems particularly increase the odds of a FCD diagnosis. Current evidence from neuropsychometric studies in FCD is scarce. CONCLUSIONS: Our systematic review reinforces that positive signs contribute for an early differentiation between FCD and neurodegeneration in patients presenting with memory complaints. It is the first to attain quantitative value to clinical observations. These results will inform future diagnostic decision tools and intervention testing.

Anomalies in the review process and interpretation of the evidence in the NICE guideline for chronic fatigue syndrome and myalgic encephalomyelitis.

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disabling long-term condition of unknown cause. The National Institute for Health and Care Excellence (NICE) published a guideline in 2021 that highlighted the seriousness of the condition, but also recommended that graded exercise therapy (GET) should not be used and cognitive-behavioural therapy should only be used to manage symptoms and reduce distress, not to aid recovery. This U-turn in recommendations from the previous 2007 guideline is controversial.We suggest that the controversy stems from anomalies in both processing and interpretation of the evidence by the NICE committee. The committee: (1) created a new definition of CFS/ME, which 'downgraded' the certainty of trial evidence; (2) omitted data from standard trial end points used to assess efficacy; (3) discounted trial data when assessing treatment harm in favour of lower quality surveys and qualitative studies; (4) minimised the importance of fatigue as an outcome; (5) did not use accepted practices to synthesise trial evidence adequately using GRADE (Grading of Recommendations, Assessment, Development and Evaluations trial evidence); (6) interpreted GET as mandating fixed increments of change when trials defined it as collaborative, negotiated and symptom dependent; (7) deviated from NICE recommendations of rehabilitation for related conditions, such as chronic primary pain and (8) recommended an energy management approach in the absence of supportive research evidence.We conclude that the dissonance between this and the previous guideline was the result of deviating from usual scientific standards of the NICE process. The consequences of this are that patients may be denied helpful treatments and therefore risk persistent ill health and disability.

Functional neurological disorder is common in patients attending chronic pain clinics.

BACKGROUND AND PURPOSE: Chronic pain is a common comorbidity in those with functional neurological disorder (FND); however, the prevalence and characteristics of FND in those with chronic pain is unknown. METHODS: A retrospective electronic records review was made of consecutive new patients attending a chronic pain clinic of a regional service. Clinical features, medication for and outcome of chronic pain, any lifetime diagnoses of functional disorders, FND, and psychiatric disorders, and undiagnosed neurological symptoms were recorded. RESULTS: Of 190 patients attending the chronic pain clinic, 32 (17%) had a lifetime diagnosis of FND and an additional 11 (6%) had undiagnosed neurological symptoms. Pain patients with comorbid FND were more likely to have chronic primary pain (88% with FND, 44% without FND, p < 0.0001), widespread chronic primary pain (53%, 15%, p < 0.00001), and depression (84%, 52%, p < 0.005) and less likely to have a pain-precipitating event (19% vs. 56%, p < 0.001). However, there was no significant difference between these patients in opiate prescription, benzodiazepine prescription, or pain outcome. CONCLUSIONS: This first study of FND in a chronic pain patient population found a remarkably high prevalence of FND (17%) and is possibly an underestimation. The size of the overlap indicates that FND and chronic pain research fields are likely to have a lot to learn from each other.

COVID-19 and the Physio4FMD trial: Impact, mitigating strategies and analysis plans.

Introduction: Functional motor disorder (FMD) is a common cause of disabling neurological symptoms such as weakness and tremor. Physio4FMD is a pragmatic, multicentre single blind randomised controlled trial to evaluate effectiveness and cost effectiveness of specialist physiotherapy for FMD. Like many other studies this trial was affected by the COVID-19 pandemic. Methods: The planned statistical and health economics analyses for this trial are described, as well as the sensitivity analyses designed to assess the disruption caused by COVID-19. The trial treatment of at least 89 participants (33%) was disrupted due to the pandemic. To account for this, we have extended the trial to increase the sample size. We have identified four groups based on how participants' involvement in Physio4FMD was affected; A: 25 were unaffected; B: 134 received their trial treatment before the start of the COVID-19 pandemic and were followed up during the pandemic; C: 89 were recruited in early 2020 and had not received any randomised treatment before clinical services closed because of COVID-19; D: 88 participants were recruited after the trial was restarted in July 2021. The primary analysis will involve groups A, B and D. Regression analysis will be used to assess treatment effectiveness. We will conduct descriptive analyses for each of the groups identified and sensitivity regression analyses with participants from all groups, including group C, separately. Discussion: The COVID-19 mitigation strategy and analysis plans are designed to maintain the integrity of the trial while providing meaningful results. Trial registration: ISRCTN56136713.