Patient Education and Duloxetine, Alone and in Combination, for Patients With Multisystem Functional Somatic Disorder (EDULOX)

Efficacy of Patient Education and Duloxetine, Alone or in Combination, for Patients With Multisystem Functional Somatic Disorder

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.

Study Overview

• Status: Recruiting
• Conditions: Functional Disorder
• Intervention / Treatment: Behavioral: Patient Education; Behavioral: Enhanced usual care; Drug: Duloxetine; Drug: Benztropine Mesylate 0.5 MG and passive placebo RAP

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 424
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Lise Gormsen, MD, PhD; Phone Number: +4578464310; Email: lisgorm@rm.dk
• Study Contact Backup: Name: Cecilia Jespersen, MD; Phone Number: +4578464310; Email: cecijesp@rm.dk

Study Locations

• Denmark
  • Aarhus, Denmark, 8200
    • Recruiting
    • Research Cinic for Functional Disorders
    • Contact: Lise Gormsen; Phone Number: 78464310; Email: lisgorm@rm.dk
    • Contact: Cecilia Pihl; Phone Number: 78464310; Email: cecijesp@rm.dk
    • Principal Investigator: Lise Gormsen, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Patient Education; The patient education program consists of three individual sessions (consultations with the participant's doctor, one to one and a half hour duration each) and one group session (three hours in groups of up to 16 participants). The program focuses on providing patients with a positive and evidence-based understanding of their illness by providing an individualized bio-psycho-social explanation of multisystem functional somatic disorder.	Behavioral: Patient Education; Please see arm desciption
Active Comparator: Enhanced Usual Care; Inclusion consultation and final visit at end of treatment (week 12) are the only contacts provided to participants randomized to receive enhanced usual care.	Behavioral: Enhanced usual care; Please see arm description
Experimental: Duloxetine and Enhanced Usual Care; Duloxetine will be given as capsules orally once daily. Participants will commence with 2 weeks of 30 mg duloxetine and then increase the dose to 60 mg duloxetine (two capsules). If participants are unable to increase in dose due to adverse events, but still tolerate the initial dose of 30 mg duloxetine, this dose is kept for the remaining part of the trial. Treatment will continue for 8 weeks on highest dosis until primary endpoint (end of treatment). The dose is then reduced to 30 mg duloxetine for 1 week after which the study drug is discontinued. In addition, participants will recieve enhanced usual care as described above.	Behavioral: Enhanced usual care; Please see arm description; Drug: Duloxetine; Please see arm description; Other Names: Cymbalta; SNRI
Placebo Comparator: Placebo and Enhanced Usual Care; Participants will recieve the active placebo benztropine mesylate 0,5 mg. In order to best mimic the dosage increase of the duloxetine treatment program a passive placebo RAP will be added for the 8 weeks of high dosage treatment. Benztropine mesylate and passive placebo will be given as capsules orally, and will be re-encapsulated by the hospital pharmacy to assure identical appearance to the duloxetine capsules. Participants will commence with 2 weeks of 0.5 mg benztropine mesylate (one capsule) and continue with 0.5 mg benztropine mesylate and passive placebo RAP (two capsules) for 8 weeks. This will be end of treatment. Participants will then be asked to reduce to one capsule (0.5 mg benztropine mesylate) for 1 week after which the study drug is discontinued. In addition, participants will recieve enhanced usual care as decribed above.	Behavioral: Enhanced usual care; Please see arm description; Drug: Benztropine Mesylate 0.5 MG and passive placebo RAP; Please see arm description
Experimental: Patient Education and Duloxetine; Participants in this arm will recieve patient education as described above. In addition, participants will recieve duloxetine as described above.	Behavioral: Patient Education; Please see arm desciption; Drug: Duloxetine; Please see arm description; Other Names: Cymbalta; SNRI
Experimental: Patient Education and Placebo; Participants in this arm will recieve patient education as described above. In addition, participants will recieve the placebo treatment as described above.	Behavioral: Patient Education; Please see arm desciption; Drug: Benztropine Mesylate 0.5 MG and passive placebo RAP; Please see arm description

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean difference between groups in Short-Form Health Survey (SF-36) aggregate score	Patient-rated health-related quality of life is measured by an aggregate score of the SF-36 subscales "physical functioning", "bodily pain" and "vitality" at endpoint (week 12). Minimum score is 15 and maximum score is 62 with lower scores indicating worse health related quality of life. Primary outcome will be measured as the change from baseline to primary endpoint (12 weeks), but data will be collected on several timepoints to describe the development on the score	T0 (baseline, before assessment), T1(after inclusion, before randomization), T2 (week 6, mid-treatment), T3 (primary endpoint, week 12), T4 (3-month after end of treatment), T5 (1-year follow-up), T6 (2-year follow-up)
Mean difference between groups in Clinical Global Improvement Scale (CGI) score	Patient-rated overall health improvement measured by the 5-point CGI. General health is rated as "much worse", "worse", "unchanged", "better" or "much better" in response to the question: "How do you consider your health status now compared with when you first came to the clinic?".	T3 (primary endpoint, 12 weeks), T4 (3-month follow-up), T5 (1-year follow-up), T6 (2-year follow-up)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean difference between groups in the Symptom Checklist (SCL-92) score on subscales somatic symptoms (SCL-som), anxiety and depression (SCL-anx 4, SCL-depr 6)	Health related physical and psychological functioning will be measured using relevant subscales of the Somatisation score measured using the SCL-92. SCL-som contains 12 items, SCL-anx 4 and SCL-depr 6 contains a total of 10 items. All items are scored on a 5 point Likert scale. Higher scores indicates more symptoms.	T0 (baseline, before assessment), T1(before randomization), T2 (week 6, mid-treatment), T3 (primary endpoint, 12 weeks), T4 (3-month follow-up), T5 (1-year follow-up), T6 (2-year follow-up)
Mean difference between groups in the Bodily Distress Syndrome (BDS) check-list score	The BDS check-list will be used to measure the severity of FSD symptoms. The BDS symptom score ranges from 0-100, with each of the 25 symptoms being scored on a Likert scale from 0-4. A higher score indicates more symptoms.	T0 (baseline, before assessment), T1(before randomization), T3 (primary endpoint, 12 weeks), T4 (3-month follow-up), T5 (1-year follow-up), T6 (2-year follow-up)
Mean difference between groups in Cognitive Failures Questionnaire (CFQ) score	Cognitive functioning will be measured using the 25 item CFQ. The total score ranges from 0-100 with a higher score indicating a more impaired cognitive functioning.	T1(before randomization), T2 (week 6, mid-treatment), T3 (primary endpoint, 12 weeks)
Mean difference between groups in Whiteley-6-R score	Whiteley-6-R is used to measure illness worry. This 6 item score ranges from 0-24 with a higher score indicating more illness worry.	T0 (baseline, before assessment), T1(before randomization), T2 (week 6, mid-treatment), T3 (primary endpoint, 12 weeks), T4 (3-month follow-up), T5 (1-year follow-up), T6 (2-year follow-up)
Mean difference between groups in Patients' Endorsement of a Biopsychosocial Model of Pain/Persistent Somatic Symptoms (PEB) score	The participants' bio-psycho-social understanding of their symptoms will we measured using the 11 item PEB questionnaire. The PEB is developed to measure patients' specific beliefs regarding pain. The scale has been adjusted to include a broader spectrum of physical symptoms relevant to functional somatic disorder instead of focusing on pain alone. Items are rated on a 4-point Likert scale resulting in a total score ranging from 11-44 with higher scores indicating a better bio-psycho-social understanding.	T1(before randomization), T2 (week 6, mid-treatment), T3 (primary endpoint, 12 weeks), T4 (3-month follow-up), T5 (1-year follow-up), T6 (2-year follow-up)
Mean difference between groups in Numeric Rating Scale (NRS) on symptom intensity and symptom interference	Symptom intensity and symptom interference is measured on a NRS ranging 0 to 10 on 2 items. This results in scores ranging from 0 to 20 with higher scores meaning worse symptoms.	T0 (baseline, before assessment), T1(before randomization), T2 (week 6, mid-treatment), T3 (primary endpoint, 12 weeks), T4 (3-month follow-up), T5 (1-year follow-up), T6 (2-year follow-up)
Mean difference between groups in Numeric Rating Scale (NRS) on pain intensity	Pain intensity is measured on a NRS ranging 0 to 10 on 1 item. A higher score indicates higher pain intensity.	T0 (baseline, before assessment), T1(before randomization), T2 (week 6, mid-treatment), T3 (primary endpoint, 12 weeks), T4 (3-month follow-up), T5 (1-year follow-up), T6 (2-year follow-up)
Mean difference between groups in Brief-Illness Perception Questionnaire (b-IPQ)	Illness perception is measured using b-IPQ, containing 8 items each scored on a 11-point scale from 0 to 10. This results in a total score ranging from 0 to 80 with higher scores indicating more negative illness perception.	T0 (baseline, before assessment), T1(before randomization), T2 (week 6, mid-treatment), T3 (primary endpoint, 12 weeks), T4 (3-month follow-up), T5 (1-year follow-up), T6 (2-year follow-up)
Mean difference between groups in Behavioural Responses to Illness Questionnaire (BRIQ)	Illness behaviour is measured using the BRIQ containing 13 items scored on a 5 point Likert scale. This results in a total score from 13 to 65 with higher scores indicating more negative illness behaviour.	T0 (baseline, before assessment), T1(before randomization), T2 (week 6, mid-treatment), T3 (primary endpoint, 12 weeks), T4 (3-month follow-up), T5 (1-year follow-up), T6 (2-year follow-up)
Mean difference between groups in clinician-rated Clinical Global Improvement Scale (CGI) score	Clinician-rated overall health improvement measured by the 5-point CGI. Clinicians are asked to rate the patient's general health as "much worse", "worse", "unchanged", "better" or "much better" in response to the question: "How do you consider your patient's health status now compared with when the patient first came to the clinic?"	T3 (primary endpoint, 12 weeks)
Mean difference between groups in diagnosis based on a clinical diagnostic reassessment	Doctors will evaluate if the diagnostic criteria for multisystem functional somatic disorder, operationalized using the criteria for multiorgan bodily distress syndrome.	T3 (primary endpoint, 12 weeks)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean score on a patient-rated Numeric Rating Scale (NRS) regarding expected effect of study drug	For participants in the study drug trial, expected effect of the study drug on their overall wellbeing will be measured using a 11-point NRS ranging from 0 to 10 with higher scores meaning higher expectations to the effect of the study drug.	T1(before randomization)
Mean score on a clinician-rated Numeric Rating Scale (NRS) regarding expected effect of study drug	Clinicians will be asked to evaluate their expectations for the effect of the study drug on the overall health improvement for participants in the study drug trial. This will be measured using an 11-point NRS ranging from 0 to 10 with higher scores meaning higher expectations to the effect of the study drug.	T1(before randomization)
Mean score on Spiritual Needs Questionnaire (SNQ)	The existential needs of the patient is measured using the SNQ. Participants will rate 20 items representing their spiritual needs on four domains: Religious needs, existential needs, inner peace needs, and generativity needs. Items are rated from 0 (No) to 3 (Very big). This results in a total score ranging from 0 to 60 with higher scores indicating higher spiritual needs. The participants will additionally be asked to rate if they felt like such needs were adressed in the assessment, if they felt like such a focus was missing from the assessment, if they found such a focus to be relevant, if they felt like a doctor should adress such needs and if they found that others (presented in a list) would be more relevant to adress such needs with.	T1(before randomization)
Mean difference between groups on the Credibility/Expectancy Questionnaire (CEQ)	Patients expectations of treatment effects (both PE and study drug treatment) will be measured by the CEQ containing 6 items rated from 1 to 10 resulting in a total score from 6 to 60 with higher scores indicating higher confidence in the treatment offered.	T2 (week 6, mid-treatment)
Mean score on Inventory for the Assessment of Negative Effects of Psychotherapy (INEP)	The Inventory for the assessment of Negative Effects of Psychotherapy (INEP) contains 21 items covering e.g. relationships problems, dependence on the therapist, and financial worries. Respondents are asked to indicate on a 4-point scale to what extent they agree or disagree with these statements. Other items are answered on a 3-point scale, e.g. "I feel…": "better", "unchanged/not applicable" or "worse". Negative effects of psychological treatment is measured by the INEP with 21 items with some items rated on a 4 point scale and others on a 3 points scale. Higher scores indicate experience of more negative effects.	T3 (primary endpoint, 12 weeks)
Mean score on Working Alliance Inventory-Short revised (WAI-SR)	Patients and clinicians relationship will be measured by the 12 item WAI-SR questionnaire. Items will be scored on a 7 point scale with higher scores indicating a better working alliance.	T2 (week 6, mid-treatment) and T3 (primary endpoint, 12 weeks)
European Quality of Life - 5 dimensions (EQ-D5)	Data on health economic measures will be calculated by use of the EQ-D5 quality of life measure.	T1(before randomization), T2 (week 6, mid-treatment), T3 (primary end-point, 12 weeks), T5 (1-year follow-up), T6 (2-year follow-up)
Mean difference between groups in participants' recollection of the content of patient education (PE) program	For participants in the PE intervention, six questions on participant's recollection of the content of the PE program will be scored on a three point scale.	T3 (primary endpoint, 12 weeks)
Mean difference between groups on the Sources of Meaning and Meaning in Life, Danish version) (SoMe-Da) score	Experience of meaning in life and crisis is measured using the 10 item SoMe-Da. Items are rated on a 6 point scale with higher scores indicating more experience of meaning in life.	T1(before randomization), T3 (primary endpoint, 12 weeks), T4 (3-month follow-up)
Mean score on the Experience of Service Questionnaire (ESQ)	Participants' satisfaction with the interventions will be measured using the ESQ. It is a 15-item questionnaire made up of 12 statements (about facilities, staff, how well the patient was treated, confidence in staff, and overall satisfaction with the service) and three additional questions which invite free text responses: 'What was really good about your care?'; 'Was there anything you didn't like or anything that needs improving?'; and 'Is there anything else you want to tell us about the service you received?'. The 12 statements are rated on a Likert scale to determine the level of agreement (certainly true, scoring 1; partly true, scoring 0; not true, scoring -1, and don't know, not scored); scores range from 12 (very satisfied) to -12 (very dissatisfied).	T3 (primary endpoint, 12 weeks)
Change in blood pressure following study drug treatment	As hypertension is a known side effect to duloxetin, blood pressure will be meassured before and during study drug treatment and this measure will be reported.	Before study drug treatment initiation, at visits at the clinic in week 3, week 7 or 8 and week 12.
Concentration of duloxetine in serum	A blood test will be taken in order to measure serum duloxetine in all participants in the study drug trial to evaluate compliance. The results will be analyzed at the end of the trial and remain blinded from all study personel throughout data analysis.	T3 (primary endpoint, 12 weeks)
Differences between groups in concentration of biomarkers in blood samples	2 glasses of 10 ml will be drawn for coagulation blood and 2 glasses of 10 ml for EDTA-blood to investigate biomarkers for functional disorder. Participants will have been fasting for 12 hours or more when samples are collected. Analysis will include concentration of proinflammatory cytokines and such as IL-1RA, IL-6, and IL-8 and chemokines such as CCL17, CCL22, CXCL9, and CXCL11. Additionally, biomarkers indicating an over-activated kynurenine pathway and C-reactive protein (CRP) and the specialized pro-resolving lipid mediators (SPM) will be meassured. Neuroendocrine dysfunction will be investigated by meassuring the corticotropin-releasing hormone (CRH), the monoamines serotonin, noradrenaline, and dopamine and their metabolites 5-HIAA, DOPAC, and HVA, as well as the neuropeptide Substance P and tumor necrosis factor (TNF).	Week 3 and week 12
Diary of diet and medication	Participants will be asked to write a diary of their diet and medication three days prior to the collection of biological samples	3 days prior to collection of biological material in week 3 and week 12
Differences between groups in biomarkers in feces samples	The participant will bring feces samples from home for investigation of the mikrobiota. This will be done exploratively through laboratory analysis of different signaling molecules such as metabolites, neuromodulators, neuropeptides, and neurotransmitters.	Week 3 and week 12

Collaborators and Investigators

• Sponsor: Aarhus University Hospital
• Collaborators: University of Aarhus; Central Denmark Region; Vejle Hospital; TrygFonden, Denmark; Aalborg University Hospital; Independent Research Fund Denmark
• Investigators: Principal Investigator: Lise K Gormsen, MD, PhD, Department of Funtional disorders, Aarhus University Hospital

Publications and helpful links

General Publications

• Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi MJ, Chrousos GP, Gold PW. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab. 1991 Dec;73(6):1224-34. doi: 10.1210/jcem-73-6-1224.
• van Dessel N, den Boeft M, van der Wouden JC, Kleinstauber M, Leone SS, Terluin B, Numans ME, van der Horst HE, van Marwijk H. Non-pharmacological interventions for somatoform disorders and medically unexplained physical symptoms (MUPS) in adults. Cochrane Database Syst Rev. 2014 Nov 1;(11):CD011142. doi: 10.1002/14651858.CD011142.pub2.
• Kleinstauber M, Witthoft M, Hiller W. Efficacy of short-term psychotherapy for multiple medically unexplained physical symptoms: a meta-analysis. Clin Psychol Rev. 2011 Feb;31(1):146-60. doi: 10.1016/j.cpr.2010.09.001. Epub 2010 Sep 16.
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Helpful Links

• US Natl Inst Health. Current medication information for benztropine mesylate, A.a. Accessed August 2020.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2024
• Primary Completion (Estimated): November 1, 2027
• Study Completion (Estimated): November 1, 2029

Study Registration Dates

• First Submitted: January 2, 2024
• First Submitted That Met QC Criteria: January 22, 2024
• First Posted (Actual): January 30, 2024

Study Record Updates

• Last Update Posted (Actual): January 30, 2024
• Last Update Submitted That Met QC Criteria: January 22, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Biomarker; Randomized Controlled Trial; Biobank; Duloxetine; Patient Education; SNRI; Bodily Distress Syndrome; Medically Unexplained Symptoms; Functional Somatic Symptoms; Functional Somatic Disorders
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Analgesics; Sensory System Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Dopamine Agents; Serotonin and Noradrenaline Reuptake Inhibitors; Dopamine Uptake Inhibitors; Antiparkinson Agents; Anti-Dyskinesia Agents; Duloxetine Hydrochloride; Benztropine
• Other Study ID Numbers: 9515

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Before and during the study the Study protocol, statistical analysis plan and inform consent form can be shared.
• IPD Sharing Time Frame: 2024-2027
• IPD Sharing Access Criteria: independent researcher in the area.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No