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

NCT06232473 | Recruiting Phase 4 DMC

• 1 other identifier: 9515
• Study Type: interventional
• Target: 424
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Functional Disorder

Keywords

Patient Education; Duloxetine; Medically Unexplained Symptoms; SNRI; Bodily Distress Syndrome; Functional Somatic Symptoms; Functional Somatic Disorders; Randomized Controlled Trial; Biobank; Biomarker

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (11)

• 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)

  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

  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

  T1(before randomization), T2 (week 6, mid-treatment), T3 (primary endpoint, 12 weeks)

• Mean difference between groups in Whiteley-6-R score

  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

  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)

Other Outcomes (15)

• Mean score on a patient-rated Numeric Rating Scale (NRS) regarding expected effect of study drug

  T1(before randomization)

• Mean score on a clinician-rated Numeric Rating Scale (NRS) regarding expected effect of study drug

  T1(before randomization)

• Mean score on Spiritual Needs Questionnaire (SNQ)

  T1(before randomization)

Study Arms (6)

Patient Education

EXPERIMENTAL

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

Enhanced Usual Care

ACTIVE COMPARATOR

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

Duloxetine and Enhanced Usual Care

EXPERIMENTAL

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.

Drug: Duloxetine; Behavioral: Enhanced usual care

Placebo and Enhanced Usual Care

PLACEBO COMPARATOR

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.

Drug: Benztropine Mesylate 0.5 MG and passive placebo RAP; Behavioral: Enhanced usual care

Patient Education and Duloxetine

EXPERIMENTAL

Participants in this arm will recieve patient education as described above. In addition, participants will recieve duloxetine as described above.

Behavioral: Patient Education; Drug: Duloxetine

Patient Education and Placebo

EXPERIMENTAL

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; Drug: Benztropine Mesylate 0.5 MG and passive placebo RAP

Interventions

Patient Education BEHAVIORAL

Please see arm desciption

Patient Education; Patient Education and Duloxetine; Patient Education and Placebo

Duloxetine DRUG

Please see arm description

Also known as: Cymbalta, SNRI

Duloxetine and Enhanced Usual Care; Patient Education and Duloxetine

Benztropine Mesylate 0.5 MG and passive placebo RAP DRUG

Please see arm description

Patient Education and Placebo; Placebo and Enhanced Usual Care

Enhanced usual care BEHAVIORAL

Please see arm description

Duloxetine and Enhanced Usual Care; Enhanced Usual Care; Placebo and Enhanced Usual Care

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• A diagnosis of multisystem functional somatic disorder (operationalized as fulfilling the criteria for the research diagnosis multiorgan bodily distress syndrome)
• 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
• 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

You may not qualify if:

• 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
• 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 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)

Sponsors & Collaborators

• Aarhus University Hospital: lead
• Central Denmark Region: collaborator
• University of Aarhus: collaborator
• Vejle Hospital: collaborator
• Aalborg University Hospital: collaborator
• TrygFonden, Denmark: collaborator
• Independent Research Fund Denmark: collaborator

Study Sites (1)

Research Cinic for Functional Disorders

Aarhus, 8200, Denmark

RECRUITING

Related Publications (47)

• Burton C, Fink P, Henningsen P, Lowe B, Rief W; EURONET-SOMA Group. Functional somatic disorders: discussion paper for a new common classification for research and clinical use. BMC Med. 2020 Mar 3;18(1):34. doi: 10.1186/s12916-020-1505-4.

  PMID: 32122350 BACKGROUND

• Roenneberg C, Sattel H, Schaefert R, Henningsen P, Hausteiner-Wiehle C. Functional Somatic Symptoms. Dtsch Arztebl Int. 2019 Aug 9;116(33-34):553-560. doi: 10.3238/arztebl.2019.0553.

  PMID: 31554544 BACKGROUND

• Henningsen P, Zipfel S, Sattel H, Creed F. Management of Functional Somatic Syndromes and Bodily Distress. Psychother Psychosom. 2018;87(1):12-31. doi: 10.1159/000484413. Epub 2018 Jan 6.

  PMID: 29306954 BACKGROUND

• Petersen MW, Schroder A, Jorgensen T, Ornbol E, Dantoft TM, Eliasen M, Carstensen TW, Falgaard Eplov L, Fink P. Prevalence of functional somatic syndromes and bodily distress syndrome in the Danish population: the DanFunD study. Scand J Public Health. 2020 Jul;48(5):567-576. doi: 10.1177/1403494819868592. Epub 2019 Aug 14.

  PMID: 31409218 BACKGROUND

• Fink P, Schroder A. One single diagnosis, bodily distress syndrome, succeeded to capture 10 diagnostic categories of functional somatic syndromes and somatoform disorders. J Psychosom Res. 2010 May;68(5):415-26. doi: 10.1016/j.jpsychores.2010.02.004.

  PMID: 20403500 BACKGROUND

• Hauser W, Hausteiner-Wiehle C, Henningsen P, Brahler E, Schmalbach B, Wolfe F. Prevalence and overlap of somatic symptom disorder, bodily distress syndrome and fibromyalgia syndrome in the German general population: A cross sectional study. J Psychosom Res. 2020 Jun;133:110111. doi: 10.1016/j.jpsychores.2020.110111. Epub 2020 Apr 11.

  PMID: 32305723 BACKGROUND

• Fink P, Toft T, Hansen MS, Ornbol E, Olesen F. Symptoms and syndromes of bodily distress: an exploratory study of 978 internal medical, neurological, and primary care patients. Psychosom Med. 2007 Jan;69(1):30-9. doi: 10.1097/PSY.0b013e31802e46eb.

  PMID: 17244846 BACKGROUND

• Budtz-Lilly A, Vestergaard M, Fink P, Carlsen AH, Rosendal M. Patient characteristics and frequency of bodily distress syndrome in primary care: a cross-sectional study. Br J Gen Pract. 2015 Sep;65(638):e617-23. doi: 10.3399/bjgp15X686545.

  PMID: 26324499 BACKGROUND

• Rask MT, Rosendal M, Fenger-Gron M, Bro F, Ornbol E, Fink P. Sick leave and work disability in primary care patients with recent-onset multiple medically unexplained symptoms and persistent somatoform disorders: a 10-year follow-up of the FIP study. Gen Hosp Psychiatry. 2015 Jan-Feb;37(1):53-9. doi: 10.1016/j.genhosppsych.2014.10.007. Epub 2014 Oct 22.

  PMID: 25456975 BACKGROUND

• Schroder A, Ornbol E, Jensen JS, Sharpe M, Fink P. Long-term economic evaluation of cognitive-behavioural group treatment versus enhanced usual care for functional somatic syndromes. J Psychosom Res. 2017 Mar;94:73-81. doi: 10.1016/j.jpsychores.2017.01.005. Epub 2017 Jan 10.

  PMID: 28183406 BACKGROUND

• 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;2014(11):CD011142. doi: 10.1002/14651858.CD011142.pub2.

  PMID: 25362239 BACKGROUND

• Schroder A, Rehfeld E, Ornbol E, Sharpe M, Licht RW, Fink P. Cognitive-behavioural group treatment for a range of functional somatic syndromes: randomised trial. Br J Psychiatry. 2012 Jun;200(6):499-507. doi: 10.1192/bjp.bp.111.098681. Epub 2012 Apr 26.

  PMID: 22539780 BACKGROUND

• Fjorback LO, Arendt M, Ornbol E, Walach H, Rehfeld E, Schroder A, Fink P. Mindfulness therapy for somatization disorder and functional somatic syndromes: randomized trial with one-year follow-up. J Psychosom Res. 2013 Jan;74(1):31-40. doi: 10.1016/j.jpsychores.2012.09.006. Epub 2012 Oct 1.

  PMID: 23272986 BACKGROUND

• Agger JL, Schroder A, Gormsen LK, Jensen JS, Jensen TS, Fink PK. Imipramine versus placebo for multiple functional somatic syndromes (STreSS-3): a double-blind, randomised study. Lancet Psychiatry. 2017 May;4(5):378-388. doi: 10.1016/S2215-0366(17)30126-8. Epub 2017 Apr 10.

  PMID: 28408193 BACKGROUND

• Pedersen HF, Agger JL, Frostholm L, Jensen JS, Ornbol E, Fink P, Schroder A. Acceptance and Commitment group Therapy for patients with multiple functional somatic syndromes: a three-armed trial comparing ACT in a brief and extended version with enhanced care. Psychol Med. 2019 Apr;49(6):1005-1014. doi: 10.1017/S0033291718001666. Epub 2018 Jun 26.

  PMID: 29941062 BACKGROUND

• Hauser W, Ablin J, Perrot S, Fitzcharles MA. Management of fibromyalgia: practical guides from recent evidence-based guidelines. Pol Arch Intern Med. 2017 Jan 4;127(1):47-56. doi: 10.20452/pamw.3877. Epub 2017 Jan 4.

  PMID: 28075425 BACKGROUND

• Carville S, Constanti M, Kosky N, Stannard C, Wilkinson C; Guideline Committee. Chronic pain (primary and secondary) in over 16s: summary of NICE guidance. BMJ. 2021 Apr 21;373:n895. doi: 10.1136/bmj.n895. No abstract available.

  PMID: 33883123 BACKGROUND

• Clauw DJ. Fibromyalgia: a clinical review. JAMA. 2014 Apr 16;311(15):1547-55. doi: 10.1001/jama.2014.3266.

  PMID: 24737367 BACKGROUND

• Ford AC, Lacy BE, Talley NJ. Irritable Bowel Syndrome. N Engl J Med. 2017 Jun 29;376(26):2566-2578. doi: 10.1056/NEJMra1607547. No abstract available.

  PMID: 28657875 BACKGROUND

• 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.

  PMID: 20920834 BACKGROUND

• Christensen SS, Frostholm L, Ornbol E, Schroder A. Changes in illness perceptions mediated the effect of cognitive behavioural therapy in severe functional somatic syndromes. J Psychosom Res. 2015 Apr;78(4):363-70. doi: 10.1016/j.jpsychores.2014.12.005. Epub 2014 Dec 13.

  PMID: 25541119 BACKGROUND

• Gruman J, Rovner MH, French ME, Jeffress D, Sofaer S, Shaller D, Prager DJ. From patient education to patient engagement: implications for the field of patient education. Patient Educ Couns. 2010 Mar;78(3):350-6. doi: 10.1016/j.pec.2010.02.002. Epub 2010 Mar 3.

  PMID: 20202780 BACKGROUND

• Hoving C, Visser A, Mullen PD, van den Borne B. A history of patient education by health professionals in Europe and North America: from authority to shared decision making education. Patient Educ Couns. 2010 Mar;78(3):275-81. doi: 10.1016/j.pec.2010.01.015. Epub 2010 Mar 1.

  PMID: 20189746 BACKGROUND

• Frolund Pedersen H, Holsting A, Frostholm L, Rask C, Jensen JS, Hoeg MD, Schroder A. "Understand your illness and your needs": Assessment-informed patient education for people with multiple functional somatic syndromes. Patient Educ Couns. 2019 Sep;102(9):1662-1671. doi: 10.1016/j.pec.2019.04.016. Epub 2019 Apr 17.

  PMID: 31023608 BACKGROUND

• Kleinstauber M, Witthoft M, Steffanowski A, van Marwijk H, Hiller W, Lambert MJ. Pharmacological interventions for somatoform disorders in adults. Cochrane Database Syst Rev. 2014 Nov 7;2014(11):CD010628. doi: 10.1002/14651858.CD010628.pub2.

  PMID: 25379990 BACKGROUND

• Welsch P, Uceyler N, Klose P, Walitt B, Hauser W. Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia. Cochrane Database Syst Rev. 2018 Feb 28;2(2):CD010292. doi: 10.1002/14651858.CD010292.pub2.

  PMID: 29489029 BACKGROUND

• Hirase T, Hirase J, Ling J, Kuo PH, Hernandez GA, Giwa K, Marco R. Duloxetine for the Treatment of Chronic Low Back Pain: A Systematic Review of Randomized Placebo-Controlled Trials. Cureus. 2021 May 22;13(5):e15169. doi: 10.7759/cureus.15169.

  PMID: 34046287 BACKGROUND

• Rodrigues-Amorim D, Olivares JM, Spuch C, Rivera-Baltanas T. A Systematic Review of Efficacy, Safety, and Tolerability of Duloxetine. Front Psychiatry. 2020 Oct 23;11:554899. doi: 10.3389/fpsyt.2020.554899. eCollection 2020.

  PMID: 33192668 BACKGROUND

• Rosenblat JD, Kakar R, McIntyre RS. The Cognitive Effects of Antidepressants in Major Depressive Disorder: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. Int J Neuropsychopharmacol. 2015 Jul 25;19(2):pyv082. doi: 10.1093/ijnp/pyv082.

  PMID: 26209859 BACKGROUND

• Barber AJ, Tischler VA, Healy E. Consumer satisfaction and child behaviour problems in child and adolescent mental health services. J Child Health Care. 2006 Mar;10(1):9-21. doi: 10.1177/1367493506060200.

  PMID: 16464930 BACKGROUND

• Fink P. Syndromes of bodily distress or functional somatic syndromes - Where are we heading. Lecture on the occasion of receiving the Alison Creed award 2017. J Psychosom Res. 2017 Jun;97:127-130. doi: 10.1016/j.jpsychores.2017.04.012. Epub 2017 Apr 25. No abstract available.

  PMID: 28606492 BACKGROUND

• Petersen MW, Schroder A, Jorgensen T, Ornbol E, Meinertz Dantoft T, Eliasen M, Benros ME, Fink P. Irritable bowel, chronic widespread pain, chronic fatigue and related syndromes are prevalent and highly overlapping in the general population: DanFunD. Sci Rep. 2020 Feb 24;10(1):3273. doi: 10.1038/s41598-020-60318-6.

  PMID: 32094442 BACKGROUND

• Kallesoe KH, Schroder A, Jensen JS, Wicksell RK, Rask CU. Group-based Acceptance and Commitment Therapy (AHEAD) for adolescents with multiple functional somatic syndromes: A randomised trial. JCPP Adv. 2021 Dec 8;1(4):e12047. doi: 10.1002/jcv2.12047. eCollection 2021 Dec.

  PMID: 37431406 BACKGROUND

• Wallace DJ, Linker-Israeli M, Hallegua D, Silverman S, Silver D, Weisman MH. Cytokines play an aetiopathogenetic role in fibromyalgia: a hypothesis and pilot study. Rheumatology (Oxford). 2001 Jul;40(7):743-9. doi: 10.1093/rheumatology/40.7.743.

  PMID: 11477278 BACKGROUND

• Vaeroy H, Helle R, Forre O, Kass E, Terenius L. Elevated CSF levels of substance P and high incidence of Raynaud phenomenon in patients with fibromyalgia: new features for diagnosis. Pain. 1988 Jan;32(1):21-26. doi: 10.1016/0304-3959(88)90019-X.

  PMID: 2448729 BACKGROUND

• Tsilioni I, Russell IJ, Stewart JM, Gleason RM, Theoharides TC. Neuropeptides CRH, SP, HK-1, and Inflammatory Cytokines IL-6 and TNF Are Increased in Serum of Patients with Fibromyalgia Syndrome, Implicating Mast Cells. J Pharmacol Exp Ther. 2016 Mar;356(3):664-72. doi: 10.1124/jpet.115.230060. Epub 2016 Jan 13.

  PMID: 26763911 BACKGROUND

• Thompson T, Gallop K, Correll CU, Carvalho AF, Veronese N, Wright E, Stubbs B. Pain perception in Parkinson's disease: A systematic review and meta-analysis of experimental studies. Ageing Res Rev. 2017 May;35:74-86. doi: 10.1016/j.arr.2017.01.005. Epub 2017 Feb 4.

  PMID: 28179128 BACKGROUND

• Rodriguez-Pinto I, Agmon-Levin N, Howard A, Shoenfeld Y. Fibromyalgia and cytokines. Immunol Lett. 2014 Oct;161(2):200-3. doi: 10.1016/j.imlet.2014.01.009. Epub 2014 Jan 23.

  PMID: 24462815 BACKGROUND

• Papadopoulos AS, Cleare AJ. Hypothalamic-pituitary-adrenal axis dysfunction in chronic fatigue syndrome. Nat Rev Endocrinol. 2011 Sep 27;8(1):22-32. doi: 10.1038/nrendo.2011.153.

  PMID: 21946893 BACKGROUND

• Neeck G, Riedel W. Neuromediator and hormonal perturbations in fibromyalgia syndrome: results of chronic stress? Baillieres Clin Rheumatol. 1994 Nov;8(4):763-75. doi: 10.1016/s0950-3579(05)80047-0.

  PMID: 7850879 BACKGROUND

• Liu L, Wu Q, Chen Y, Ren H, Zhang Q, Yang H, Zhang W, Ding T, Wang S, Zhang Y, Liu Y, Sun J. Gut microbiota in chronic pain: Novel insights into mechanisms and promising therapeutic strategies. Int Immunopharmacol. 2023 Feb;115:109685. doi: 10.1016/j.intimp.2023.109685. Epub 2023 Jan 24.

  PMID: 37278059 BACKGROUND

• Hagelberg N, Jaaskelainen SK, Martikainen IK, Mansikka H, Forssell H, Scheinin H, Hietala J, Pertovaara A. Striatal dopamine D2 receptors in modulation of pain in humans: a review. Eur J Pharmacol. 2004 Oct 1;500(1-3):187-92. doi: 10.1016/j.ejphar.2004.07.024.

  PMID: 15464032 BACKGROUND

• Groven N, Reitan SK, Fors EA, Guzey IC. Kynurenine metabolites and ratios differ between Chronic Fatigue Syndrome, Fibromyalgia, and healthy controls. Psychoneuroendocrinology. 2021 Sep;131:105287. doi: 10.1016/j.psyneuen.2021.105287. Epub 2021 May 27.

  PMID: 34090138 BACKGROUND

• 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.

  PMID: 1659582 BACKGROUND

• Cleare AJ. The neuroendocrinology of chronic fatigue syndrome. Endocr Rev. 2003 Apr;24(2):236-52. doi: 10.1210/er.2002-0014.

  PMID: 12700181 BACKGROUND

• Amin OA, Abouzeid SM, Ali SA, Amin BA, Alswat KA. Clinical association of vitamin D and serotonin levels among patients with fibromyalgia syndrome. Neuropsychiatr Dis Treat. 2019 May 27;15:1421-1426. doi: 10.2147/NDT.S198434. eCollection 2019.

  PMID: 31239680 BACKGROUND

• Jespersen CP, Pedersen HF, Kleinstauber M, Fink P, Wellnitz KB, Ornbol E, Schroder A, Agger JL, Vase L, Finnerup NB, Gormsen LK. Efficacy of patient education and duloxetine, alone and in combination, for patients with multisystem functional somatic disorder: Study protocol for the EDULOX trial. Contemp Clin Trials. 2024 Jun;141:107524. doi: 10.1016/j.cct.2024.107524. Epub 2024 Apr 9.

  PMID: 38604496 DERIVED

Related Links

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

MeSH Terms

Conditions

Medically Unexplained Symptoms

Interventions

Patient Education as Topic; Duloxetine Hydrochloride; Serotonin and Noradrenaline Reuptake Inhibitors; Benztropine

Condition Hierarchy (Ancestors)

Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Health Education; Preventive Health Services; Health Services; Health Care Facilities Workforce and Services; Thiophenes; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Neurotransmitter Agents; Physiological Effects of Drugs; Tropanes; Azabicyclo Compounds; Aza Compounds; Alkaloids; Bridged Bicyclo Compounds, Heterocyclic; Heterocyclic Compounds, Bridged-Ring

Study Officials

• Lise K Gormsen, MD, PhD

  Department of Funtional disorders, Aarhus University Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Lise Gormsen, MD, PhD

CONTACT

+4578464310; lisgorm@rm.dk

Cecilia Jespersen, MD

CONTACT

+4578464310; cecijesp@rm.dk

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a nested design. The parent trial (EDULOX 1) is an open-labelled randomized controlled trial comparing patient education (PE) with enhanced usual care (EUC). The parent trial nests a concomitantly running, two-by-two factorial, double-blinded, randomised controlled trial (EDULOX 2) comparing duloxetine with active placebo in combination with the PE program or EUC. Participants in the parent trial will be randomized (open-label) to receive either EUC or the PE program. Participants in the nested trial will be randomized (open-label + blinded) to receive either EUC or PE along with either duloxetine or active placebo. This will result in a total of six randomization groups for the full EDULOX trial. A total of 424 participants will be recruited for the EDULOX parent trial, of these 212 participants will participate in the nested study drug trial. Biological material for the biobank will be collected from all participants and an additional 75 healthy controls.

Study Record Dates

• First Submitted: January 2, 2024
• First Posted: January 30, 2024
• Study Start: January 1, 2024
• Primary Completion (Estimated): November 1, 2027
• Study Completion (Estimated): November 1, 2029
• Last Updated: January 30, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: 2024-2027
• Access Criteria: independent researcher in the area.

Locations

DK (1)