Clinical Trials Register

Summary
EudraCT Number:	2022-002780-30
Sponsor's Protocol Code Number:	9515
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-10-06
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Denmark - DHMA

A.2

EudraCT number

2022-002780-30

A.3

Full title of the trial

Efficacy of patient education and duloxetine, alone and in combination, for patients with multiorgan bodily distress syndrome: a partial-factorial randomized controlled trial (the EDULOX-trial)

EDULOX 2 - Patientundervisning og medicinsk behandling (duloxetin/aktiv placebo) til patienter med svær funktionel lidelse: et randomiseret, kontrolleret forsøg

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Efficacy of patient education and duloxetine, alone and in combination, for patients with multiorgan bodily distress syndrome: a partial-factorial randomized controlled trial

Patientundervisning og medicinsk behandling (duloxetin/aktiv placebo) til patienter med svær funktionel lidelse: et randomiseret, kontrolleret forsøg

A.3.2

Name or abbreviated title of the trial where available

EDULOX

A.4.1

Sponsor's protocol code number

9515

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Aarhus University Hospital, The Research Clinic for Functional Disorders and Psychosomatics
B.1.3.4	Country	Denmark
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	The Tryg Foundation
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Aarhus University Hospital, The Research Clinic for Functional Disorders and Psychosomatics
B.5.2	Functional name of contact point	Lise Gormsen
B.5.3	Address:
B.5.3.1	Street Address	Palle Juul-Jensens Boulevard 5
B.5.3.2	Town/ city	Aarhus
B.5.3.3	Post code	8200
B.5.3.4	Country	Denmark
B.5.4	Telephone number	004578 46 43 10
B.5.5	Fax number	004578 46 43 40
B.5.6	E-mail	lisgor@rm.dk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Cymbalta
D.2.1.1.2	Name of the Marketing Authorisation holder	Eli Lilly Nederlands, papendorpseweg 83, 3528BJ, Utrecht, Holland
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Cymbalta
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Duloxetine
D.3.9.1	CAS number	116539-59-4
D.3.9.2	Current sponsor code	9515
D.3.9.4	EV Substance Code	SUB06424MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	30 to 60
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Benztropine
D.2.1.1.2	Name of the Marketing Authorisation holder	Par Pharmaceutical Chestnut Ridge, NY 10977, USA
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Benztropine
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Benzatropine mesilate
D.3.9.1	CAS number	86-13-5
D.3.9.2	Current sponsor code	9515
D.3.9.4	EV Substance Code	SUB31964
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Multiorgan Functional somatic disorders (FSD) / bodily disstress syndrome (BDS)

multiorgan Funktionel lidelse

E.1.1.1

Medical condition in easily understood language

Functional somatic disorder

Funktionel lidelse

E.1.1.2

Therapeutic area

Not possible to specify

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10041319
E.1.2	Term	Somatization disorder
E.1.2	System Organ Class	100000004873

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

This study aims to investigate the effect an 8-week treatment with 60 mg duloxetine or the active placebo benztropine on patient-rated physical and overall health. Additionally, the study investigates the effect of a brief patient education program compared with enhanced usual care for patients with multiorgan functional somatic disorders /BDS and explores the effect of combinations of these interventions in a factorial design. The study will provide evidence for the effect of the two treatments, alone and in combination, applicable and suitable for the majority of patients with multi-organ functional somatic disorders / BDS.

E.2.2

Secondary objectives of the trial

Not appicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• A diagnosis of multiorgan BDS.
• Symptoms have been present for at least 1 year at the time of inclusion.
• Multiorgan BDS 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.
• No current or previous diagnosis of mania, bipolar disorder, psychosis, severe agitation, imminent deliria or psychotic symptoms.
• No alcohol, substance or medicine abuse or addiction.
• Age 18-60 years.
• Understands and speaks Danish fluently and is able to follow and benefit from an educational program.
• First-time referral to specialized treatment for functional disorder.
• No participation in psychotherapy or educational programs specifically for FSD within the past 12 months.
• Written and verbal informed consent and letter of authority.
• No current affective disorder requiring fast initiation or continuation of psychiatric pharmacological treatment or psychiatric monitoring.
• No 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 treatment phase.
• No current pregnancy or lactation.
• 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).
• No concomitant use of drugs interacting with or contraindicating duloxetine treatment, i.e., antidepressants, antidiuretics, antihypertensives, and triptanes.
• No treatment with duloxetine for a period of at least 8 successive weeks within the past 6 months
• No concurrency of the following conditions: uncontrolled hypertension, narrow-angle glaucoma, reduced lever function or hepatic insufficiency, renal disease or severe renal impairment, epilepsy, prostatic hypertrophy, tardive dyskinesia, or suicide risk.
• No allergy to study medication or excipients in study medication.
• Written and verbal informed consent and letter of authority.

E.4

Principal exclusion criteria

• SCAN interview or clinical diagnosis of moderate to severe depression, anxiety and other mental disorders. Referral to relevant treatment options is initiated, and the patient is immediately terminated from the trial.
• Risk of suicide: The patient is immediately referred to relevant treatment options, and the patient is immediately terminated from the trial.
• Pregnancy and breastfeeding.
• The patient wants to leave the trial.
• The patient cannot cooperate during the experiment.
• Development of serious side effects or allergic reactions/hypersensitivity to the trial drug or any of the inactive substances.
• Development of depression or other condition requiring psychiatric treatment: The patient is immediately referred to relevant treatment.
• Failure to comply with the trial conditions with regard to taking trial medication and filling in trial questionnaires.
• Taking pain and/or antidepressant medication, which is not included in the trial.
• The trial staff believe that it is in the patient's best interest to stop.
• The trial is stopped. This happens if an unexpectedly large number of unwanted events occur. This will be in collaboration with the authorities.

E.5 End points

E.5.1

Primary end point(s)

Difference in patient-rated physical health measured by an aggregate score of the SF-36 subscales "physical functioning", "bodily pain" and "vitality" at endpoint (12 weeks-T3). This outcome measures physical health domains usually affected in multiorgan BDS.
And
- Patient-rated overall health improvement measured by the 5-point Clinical Global Improvement Scale (CGI) at end point (week 12-T3). Patients rate their general health as "much worse", "worse", "unchanged", "better" or "much better" in response to the following question: "How do you consider your health status now compared with when you first came to the clinic?" This simple and global scale correlates with other specific outcomes in this population, including physical functioning and symptom scores.

E.5.1.1

Timepoint(s) of evaluation of this end point

Outcome measures are collected at 4 time points: before clinical assessment and inclusion, T0; before treatment, T1; during treatment (after the group session/during drug treatment 6 weeks after inclusion, T2); and at trial endpoint (after completion of the patient education program and/or after 8 weeks of 60 mg of study drug, T3) before tapering out of study drug. Time between inclusion and endpoint will be 12 weeks. Patient-rated follow-up data is collected 3 months after endpoint (T4). During the 3-month period patients are not offered other specialized treatments. Naturalistic follow-up measurements are collected at 12 and 24 months from treatment initiation (T5 and T6).

E.5.2

Secondary end point(s)

Difference between groups at endpoint in:
- symptoms of BDS measured by the BDS Checklist and the somatization subscore of the 92-item Danish version of the Symptom Checklist (SCL-92)
- symptom intensity, symptom interference, and pain intensity measured by the numeric rating scale
- symptoms of anxiety and depression measured by relevant subscores of the Symptom Checklist (SCL-92)
- illness worry measured by Whiteley-7
- physical, mental and social health measured by relevant subscales of the Short Form 36 Health Survey (SF-36) and the component summaries

Treatment target measures:
Difference between groups at endpoint in:
- illness perception measured by Brief-IPQ
- illness behavior measured by BRIQ
- cognitive functioning measured by the Cognitive Failures Questionnaire (CFQ)
- psychological Inflexibility in Pain Scale (PIPS)
Clinician-rated secondary outcome measures:
Clinician-rated improvement measured by the 5-point CGI scale (12 weeks)
Clinicians’ rating of biopsychosocial awareness and readiness to change
Diagnostic reassessment.
Adverse events (manualized patient interview)
Other measures:
- Patients expectations of treatment effects measured by the Credibility/Expectancy Questionnaire (CEQ) at inclusion and endpoint [44]and, for the patients receiving study drug, expected effect of the study drug on their overall wellbeing (10-point NRS)
- Patients' and clinicians' relationship measured by the Working Alliance Inventory-Short revised (WAI-SR)at endpoint.
- Negative effects of psychotherapy measured by the Inventory for the Assessment of Negative Effects of Psychotherapy (INEP)at 3-month follow-up.
- Health-economic measures: European Quality of Life – 5 dimensions (EQ-D5) and data from Danish National Registries (use of health care (primary and secondary care visits), sick-leave and social benefits, prescriptions) at inclusion and 1- and 2 year-follow-up.
- Patients’ recollection of the educational content and impression of treatment effect at follow-up.

E.5.2.1

Timepoint(s) of evaluation of this end point

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

212

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

212

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

The patient will have the usual care at a specialiced center of functional somatic disorders

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2022-12-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-11-15

P. End of Trial
P.	End of Trial Status	Ongoing

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