The goal of this clinical trial is to test if patient education or duloxetine can be used to treat multisystem functional somatic disorder (FSD). The main questions it aims to answer are:

• Does duloxetine work better than placebo in the treatment of FSD?
• Does patient education work better than usual treatment for FSD?
• Does the combination of patient education and duloxetine work better than using only one of these treatments?

Participants are patients with FSD. They will receive one of six different treatment combinations:

1. Patient education alone (three individual consultations with a doctor and one group session)
2. Treatment as usual (receiving the diagnosis and a short presentation of what FSD is)
3. Duloxetine
4. Active placebo (a treatment that looks like duloxetine and has similar side effects, but no known effect on FSD)
5. Patient education and duloxetine
6. Patient education and active placebo

Researchers will compare the groups receiving patient education with those receiving only treatment as usual to see if patient education is a better treatment than just receiving a diagnosis and short explanation. Furthermore, researchers will compare the groups receiving duloxetine to those receiving placebo to see if duloxetine works better than placebo. Finally, researchers will compare the groups receiving both patient education and duloxetine to those receiving only one of these treatments to see if the combination works better than the treatments given alone.

The researchers will also collect samples of blood and stool in a biobank to be used in future research.

Background Functional somatic disorders (FSD) are characterized by specific patterns of persistent physical symptoms with a complex etiology involving a multiform interplay between physiological, psychological, and socio-cultural factors. Patients with FSD are prevalent in all medical settings and receive diagnoses such as fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and other functional somatic syndromes (FSS) depending on which medical specialty they consult. Multisystem FSD describes a severely affected subgroup of patients who suffer from symptoms from multiple organ systems. The diagnosis can be operationalized by the criteria for the unifying research diagnosis bodily distress syndrome (BDS).

Multisystem FSD affects 1.3-2.2% of the general population. The condition inflicts suffering and is associated with a substantial socioeconomic impact, involving costly diagnostic examinations and procedures, sick leaves, and long-term disability.

Evidence on treatment options for multisystem FSD is emerging but not yet sufficient. A number of clinical trials investigating non-pharmacological interventions are available and clinical guidelines in some FSS, e.g. fibromyalgia and chronic primary pain, highlight the importance of patient education (PE). PE may support the effect of other treatments by empowering and engaging patients in managing their condition. As a stand-alone treatment, the effect of PE has only sparsely been investigated, yet a PE program targeting multisystem FSD has been tested in an uncontrolled pilot study with promising results.

Pharmacotherapy in FSS includes centrally acting drugs, especially antidepressants. In multisystem FSD, evidence exists for treatment with low-dose tricyclic antidepressants (TCA). Unfortunately, TCAs given in higher, antidepressive doses significantly reduces tolerability and thereby treatment potential for comorbid depression or anxiety which are common in multisystem FSD. Duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI), offers effect sizes similar to low-dose TCA in FSS with a more favorable adverse event profile. Evidence furthermore suggests an effect on cognitive functioning. In addition to reducing symptoms in multisystem FSD, duloxetine could improve cognitive functioning and, if relevant, treat comorbid anxiety and depression.

From a clinical perspective, a synergic effect between a PE program and pharmacological treatment could be hypothesized. On one hand, PE may improve the effect of pharmacological treatment by balancing treatment expectations and enhancing treatment adherence. Conversely, pharmacological treatment may indirectly enhance the effect of PE by improving cognitive functioning and thereby improving the patients' ability to receive and implement relevant educational elements.

As mentioned above, the etiology of FSD is complex and especially the role of biological factors remains largely undiscovered. Research findings support involvement of the immune system, neuroendocrine and neurotransmitter systems, pain processing and gut microbiota. In order to investigate the relevance of such components in multisystem FSD, this study will collect blood, plasma and feces from participants and healthy controls in order to establish a biobank enabling future research in these relevant factors.

Purpose and aim The EDULOX trial aims to investigate the effect of a PE program compared with enhanced usual care (EUC) for patients with multisystem FSD in EDULOX1. Additionally, the study investigates the effect of treatment with duloxetine 60 mg daily against active placebo and explores the effect of combinations of the two interventions in EDULOX2. This is to our knowledge the first study to investigate the combination of medical treatment and PE for patients with multisystem FSD.

By establishing a biobank with blood, plasma and feces from both EDULOX participants and healthy controls, the EDULOX trial furthermore aims to identify possible biomarkers in multisystem FSD and relate these to the outcome measures in the study.

Hypothesis EDULOX1:

The primary hypothesis is that the PE program is superior to EUC in improving patient-rated health-related quality of life measured by a Short-Form Health Survey (SF-36) aggregate score and patient-rated overall health measured by the Clinical Global Improvement Scale (CGI).

Hypothesis EDULOX2:

The primary hypothesis is that duloxetine is superior to active placebo in improving the SF-36 aggregate score, the CGI and cognitive functioning measured by Cognitive Failures Questionnaire (CFQ) at end of treatment.

Exploratory hypothesis:

There is a synergistic effect of receiving both PE and duloxetine, i.e. participants receiving both interventions show larger improvement in SF-36 aggregate score and CGI, than would be expected from simple additive effect of each intervention.

Hypothesis biobank We hypothesize that the immune system, hypothalamic-pituitary-adrenal axis, neurotransmitter levels, symptom- and/or pain processes are changed, and that the gut microbiota is disturbed. Changes are correlated to the severity of symptoms.

Methods For study design please see separate segment in the clinical trial registration.

Setting The project is initiated and managed by the Research Clinic for Functional Disorders and Psychosomatics (RCF), Aarhus University Hospital (AUH), Denmark. Participants will be recruited from eligible patients from the RCF, AUH or patients referred to the RCF for possible participation from the Pain and Headache Clinic, AUH, Center for Functional Disorders, the Hospital Lillebælt, and the Center for Functional Disorders, Aalborg University Hospital.

Interventions Please see Arms and Interventions segment of the clinical trial registration.

Data sources and effect measures Data sources include patient-rated outcomes, clinician-rated outcomes, and a qualitative evaluation consisting of 10-15 patient interviews examining acceptability and patient experiences regarding the PE intervention.

Questionnaire data will be collected at 5 time points:

• T0: Baseline (before inclusion)
• T1: Week 0 (before randomization)
• T2: Week 6 (during treatment)
• T3: Week 12 (end of treatment, primary endpoint)
• T4: 3-months follow-up after end of treatment

Naturalistic follow-up measurements are collected at 12 and 24 months from randomization (T5 and T6).

Please see further details in the Outcome Measures segment of the clinical trial registration.

Acceptability and feasibility measures Acceptability and feasibility measures will be collected from the first 40 participants. Reasons for non-participation, drop-out and breaking protocol will be analyzed. These data will be used to identify any major obstacles for the smooth running of the EDULOX. Patient acceptancy will be investigated through the Experience of Service Questionnaire and through a qualitative interview study with 10-15 planned semi-structured interviews.

Feasibility criteria are based on prior studies and will include:

• Inclusion rate more than 85% on the PE trial and 45% on the duloxetine trial.
• Drop-out will be less than 15% (reasons for drop out will be analyzed)
• More than 90% of the participants allocated to receive PE completes the PE program by attending at least two individual sessions and the group PE session
• Missing data will be less than 15%
• Questionnaire response-rate of minimum 90% at baseline and minimum 85% for the endpoint questionnaires (12 weeks, T3)
• PE will prove acceptable to patients with a patient satisfaction score of moderate to high
• Blinding in the duloxetine trial will be sufficient

Safety and monitoring The safety profile of duloxetine is well-described for patients with fibromyalgia and patients will be informed about the most common and the most severe adverse events for both duloxetine and benztropine mesylate.

Safety is assessed by collecting information on adverse events by the clinician (final visit, all contacts regarding adverse events). Patients are instructed to contact the project nurse by phone if experiencing any problems with the study drug. The nurse will have access to advice from medical doctors. Project workers can be contacted by telephone at all times if acute unblinding is required.

The project will be conducted in accordance with the Helsinki Declaration (II). General procedures for quality control and quality assurance will be followed. All protocol violations will be recorded. The quality and safety of the project are monitored by the Good Clinical Practise GCP unit at Department of Clinical Medicine, Aarhus University.

Discussion Solid and rigidly designed intervention studies for patients suffering from severe functional somatic disorders are highly needed. A documented positive effect of duloxetine will provide clinicians with an easily delivered pharmacological treatment option, and furthermore, new cost-effective treatment approaches arise if study results suggest a synergic effect of the combination of duloxetine and PE.

Such results could support the development of a stepped care model securing better treatment faster for those who can benefit from treatment in less specialized settings. This is of great significance since many clinics currently have waiting lists of more than a year, risking possible chronification of symptoms while patients wait for relevant treatment.

A biobank with relevant biological samples may enable future research into important etiological factors of FSD which remains largely uncovered. Insight into such possible biomarkers and their relation to the severity of the disorder could open up new possibilities for targeted treatment.

Inclusion criteria for the parent trial:

• A diagnosis of multisystem functional somatic disorder (operationalized as fulfilling the criteria for the research diagnosis multiorgan bodily distress syndrome)
• Symptoms present for at least six months at the time of inclusion
• Multisystem functional somatic disorder is the predominant health complaint, i.e. concurrent physical or psychiatric illness is stable and well controlled and symptoms can be separated from BDS symptoms
• Understands and speaks Danish fluently and is able to follow and benefit from an educational program
• First-time referral to specialized treatment for functional somatic disorder

Additional inclusion criteria for the nested study drug trial:

• Use of efficient contraception for women in the fertile age (contractive pills, intrauterine device, deposit injections of gestagen, subdermal implant, hormone vaginal ring, or transdermal deposit plaster)
• Men with a pregnant or non-pregnant female partner in the fertile age must use a condom in the full length of the trial plus a minimum of one week after end of study drug treatment

Exclusion criteria for parent trial:

• Participation in psychotherapy or educational programs specifically for FSD within the past 12 months
• Current or previous diagnosis of mania, bipolar disorder, psychosis, severe agitation, imminent deliria or psychotic symptoms
• SCAN or clinical diagnosis of moderate to severe depression, anxiety or other psychiatric disorders
• Current affective disorder requiring fast initiation or continuation of psychiatric pharmacological treatment or psychiatric monitoring
• Alcohol, substance or medicine abuse or addiction

Additional exclusion criteria for the nested trial

• Treatment with duloxetine for a period of at least 8 successive weeks within the past 6 months
• Allergy to study medication or excipients in study medication
• Serious or unstabile somatic illness, e.g. stroke, Alzheimers disease, ischemic heart disease, epilepsy, fructose intolerance, glucosegalactose malabsorption, invertase-isomaltase insufficiency, increased intraocular pressure, uncontrolled narrow-angle glaucoma, hemodialysis, hemophilia, reduced platelet function, increased bleeding tendency, Raynaud's phenomenon, uncontrolled hypertension, prostate hypertrophy, urin retension or previous anaphylactic shock
• Severe renal impairment with creatinine clearance <30 ml / min. (risk of increased plasma concentration of duloxetine)
• Liver disease with reduced function with affected blood tests (risk of increased plasma concentration of duloxetine)
• Sweat gland disorder (risk of hyperthermia in high temperatures related to use of benztropine)
• Current pregnancy or lactation
• Concomitant use of CNS-acting drugs (drugs with pain-modulating or antidepressant properties and others) besides paracetamol and ibuprofen (escape medication in restricted doses). When clinically relevant and safe, the prohibited medication is gradually titrated down at the time of study inclusion, and treatments are discontinued at least 2 weeks before the study drug treatment begins)
• Concomitant use of drugs interacting with or contraindicating duloxetine treatment, e.g. serotonergic antidepressants (SSRI og TCA præparater, e.g. clomipramine or amitriptyline), dietary supplement St. John's wort (Hypericum perforatum), venlafaxine, MAO inhibitants or triptanes, tramadol, pethidin and tryptophan (risik of serotonin syndrome)
• Concomitant use of potent CYP1A2-inhibitants, e.g. fluvoxamine, ciprofloxacine og enoxacine (risk of increased plasma concentration of duloxetine)
• Concomitant use of non-selective, irreversible or selective, reversible monoaminoxidase (MAO) inhibitants; at least 14 days between termination of treatment with MAO-inhibitants and beginning of treatment with duloxetine. Additionally, treatment with MAO-inhibitants are not allowed before duloxetine treatment has been terminated for 5 days (risk of serotonin syndrome)

Before and during the study the Study protocol, statistical analysis plan and inform consent form can be shared.

2024-2027

independent researcher in the area.

Randomization for both the open-label parent trial and the nested blinded study drug trial will be carried out using REDCap. The randomization code will be generated by an independent employee through REDCap. Coded (numbered) packs of study drug and active placebo will be produced according to the randomization schedule. Patients, clinicians, investigators, and all other staff involved in the conduct or data analysis of the nested trial will be masked to study drug treatment allocation for the duration of the study and throughout all data analysis. Patients and clinicians will be asked to guess allocated treatment (duloxetine or active placebo) and indicate reason at endpoints to evaluate blinding efficacy.