Clinical Trials Register

Summary
EudraCT Number:	2017-003766-27
Sponsor's Protocol Code Number:	848015011
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-06-05
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

Netherlands - Competent Authority

A.2

EudraCT number

2017-003766-27

A.3

Full title of the trial

The DREAMING study: Efficacy of low dose amitriptyline and mirtazapine
for insomnia disorder: a double-blind, randomized, placebo-controlled trial
in general practice

A.3.1

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

The DREAMING study: Efficacy of low dose amitriptyline and mirtazapine
for insomnia disorder

A.3.2

Name or abbreviated title of the trial where available

DREAMING study

A.4.1

Sponsor's protocol code number

848015011

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	VU University Medical Centre
B.1.3.4	Country	Netherlands
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	ZonMw
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	VU University Medical Centre
B.5.2	Functional name of contact point	Department General Practice
B.5.3	Address:
B.5.3.1	Street Address	Van der Boechorststraat 7
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1081 HV
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	31204448199

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	amitriptyline
D.2.1.1.2	Name of the Marketing Authorisation holder	not fixed in protocol
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	amitriptyline
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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	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	mirtazapine
D.2.1.1.2	Name of the Marketing Authorisation holder	not fixed in protocol
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	mirtazapine
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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	Film-coated 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

Insonnia disorder

E.1.1.1

Medical condition in easily understood language

Sleeping disorder

E.1.1.2

Therapeutic area

Psychiatry and Psychology [F] - Mental Disorders [F03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10078083
E.1.2	Term	Insomnia 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

Primary Objective: Our primary objective is to assess the efficacy of a
16-week treatment period of low dose amitriptyline (10-20 mg nightly)
or mirtazapine (7.5 – 15 mg nightly) on subjective sleep quality
compared to placebo added to usual care in patients with insomnia
disorder with sleep maintenance problems in general practice.

E.2.2

Secondary objectives of the trial

Secondary objectives are to assess (a) the post-treatment efficacy on
subjective sleep quality and sleep indices (up to 12 month), (b) the
efficacy regarding daytime symptoms and functioning both during and
after treatment (up to 12 months), (c) that the treatment indeed is well
tolerated (safe) and (d) whether treatment is sufficient or that
additional sleep medication is requested during or after the treatment
period (up to 12 months).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Adults aged 18-85 years and registered as patient in one of the
participating general practices.
- Presence of insomnia disorder conform DSM-5, i.e. sleep problems
(including problems maintaining sleep) in at least 3 nights a week
during at least 3 months, with consequences for daytime functioning.
- Request for long-term and/or frequent sleep medication put to their
GP because non-pharmacological treatment according to the Dutch
(NHG) general practice guideline is deemed insufficient by patient and
GP.

E.4

Principal exclusion criteria

General exclusion criteria
- Isolated problem falling asleep (without problems maintaining sleep)
- Insomnia secondary to another medical condition, e.g. OSAS, comorbid major depression, chronic pain
- Habitual shift worker doing night shifts
- Wish to continue (over-the-counter) melatonin
- Use of off-label amitriptyline or mirtazapine for insomnia in the past year
- Terminal illness
- Suicide risk
- Pregnancy, lactation or wish to become pregnant in the coming 6 months
- Vulnerability due to unstable health situation according to GP.
- Being unable to follow study instructions and fill out the study questionnaires (in Dutch)
- Participation in other interventional medical scientific studies

Contra-indications
- Allergy for amitriptyline or mirtazapine
- Cardiac arrhythmia / blockade / Long QT syndrome / Brugada syndrome / Family history of acute cardiac death
- Recent myocardial infarction (within the past 90 days) / Angina pectoris / coronary insufficiency
- Severe renal insufficiency (GFR < 10)
- Severe liver dysfunction
- Epilepsy
- Ocular Hypertension / Glaucoma
- Bipolar affective disorder
- Current alcohol or drug abuse/addiction

Potential drug-drug interactions
- Current use of psychopharmaceuticals (including anxiolytics as e.g. benzodiazepines, antidepressants including St John’s wort and, anticonvulsants )
- Current use of antimycotics (all types)
- Certain enzyme inductors, antiretroviral drugs, cimetidine and clonidine. (All of these are not commonly used and will be excluded by the prescription check by the GP and/or the final check by the pharmacist).

E.5 End points

E.5.1

Primary end point(s)

The primary outcome of the study is the insomnia severity as measured
by the Insomnia Severity Index (ISI) (Morin e.a. 2011). The ISI is a 7-
item questionnaire scored on a 5-point Likert scale reflecting the
severity of both nighttime and daytime aspects of insomnia disorder as
perceived by the participant in the last 2 weeks with scores ranging from
0 (no insomnia) to 28 (severe insomnia). The ISI is the recommended
outcome measure in insomnia trials (Buysse e.a. 2006). Previous
research has indicated that it is a valid and reliable instrument as
outcome measurement. It possesses adequate internal consistency and
is sensitive to changes in perceived sleep difficulties over time (Bastien
e.a. 2001; Morin e.a. 2011). The total score can be interpreted as
follows: absence of insomnia (0–7); sub-threshold insomnia (8–14);
moderate insomnia (15–21); and severe insomnia (22–28) (Morin e.a.
2011). ISI will be evaluated at each time point: baseline, 6 weeks, 12
weeks, 20 weeks and 12 months.

E.5.1.1

Timepoint(s) of evaluation of this end point

baseline, 6 weeks, 12 weeks, 20 weeks and 12 months.

E.5.2

Secondary end point(s)

Other sleep parameters
A secondary sleep outcome will be sleep quality as measured and
quantified according to the Consensus sleep diary (Carney e.a. 2012),
minimum version, during one week. The sleep estimates (calculated
based on the sleep diary) are amongst others: Sleep Onset Latency
(number of minutes to fall asleep after going to bed), Sleep Efficiency
(percentage of time slept from the total amount of time spent in bed),
Number of Awakenings, Wake After Sleep Onset (total minutes awake
after sleep onset), Total Sleep Time and Sleep Quality (a number
between 1 and 5 for each night). The Dutch translation of the consensus
sleep diary of Carney and colleagues (2012) with some minor consensus
adaptations achieved by co Dutch group of sleep researchers (a.o. prof.
Dr. A. Van Straten) will be used.
Participants will keep the sleep diary prospectively for one week at
baseline (before the start of the trial medication), one week during the
intervention (week 6) and for one week after the intervention (week
20). In addition to these sleep estimates based on week dairies,
participants will be asked to recall their sleep over the past two weeks (i.e. referring to the same time period as the other questionnaires) by
means of items 1-4 of the Pittsburgh Sleep Quality Index (PSQI) (Buysse
e.a. 1989; Backhaus e.a 2002) at each measurement time point, i.e. to
estimate Sleep Onset Latency, Total Sleep Time, Sleep Efficiency, and the
number of nights per week in which the participant experienced sleep
problems. Finally, a global rate of change (sleep problem compared to
baseline) is assessed at 6, 12, and 20 weeks.
Daytime functioning related to insomnia
The impact of insomnia on daytime functioning will be measured using
the Work and Social Adjustment Scale (WSAS) (Mundt e.a. 2002). The
WSAS is a 5-item questionnaire on a 8-point Likert scale. The usual
timeframe (1 year) is adjusted to the past 2 weeks.
In addition, the Glasgow Sleep Impact Index (GSII) will be used, i.e. a
patient-centred measure to assess sleep-related quality of life
impairment in insomnia disorder (Kyle e.a. 2013). Participants are asked
to rank their own top 3 impacts of the sleep problem on their life (in
their own words) and subsequently to rate how much they suffered from
these impacts in the past two weeks.
Daytime symptoms: fatigue and mood
Fatigue will be measured by the Multidimensional Fatigue Inventory
(MFI) (in Dutch: Meervoudige Vermoeidheidsindex) (Smets e.a. 1995).
The MFI is a 20-item questionnaire on a 5-point Likert scale measuring
five subscales of fatigue dimensions over the previous days. For each
scale (general fatigue, physical fatigue, mental fatigue, reduced
motivation and reduced activity) the score varies between 4 and 20, with
a higher score indicating more severe fatigue. The internal consistency
and construct validity of the scale are adequate. In addition, 2 items of
the Flinders Fatigue Scale will be used to assess the number of days per
week and severity of daytime fatigue (Gradisar e.a. 2007). Mood,
including symptoms of depression, anxiety and distress, will be
evaluated with the 14-item Hospital Anxiety and Depression Scale
(HADS)( Olsson e.a. 2005).
Safety: Side-effects, withdrawal and rebound effects
Side-effects will be measured using the Antidepressant Side-Effect
Checklist (ASEC) (Uher ea 2009) at baseline (symptom rate before trial
medication) and at 6 weeks and 12 weeks during treatment. The ASEC
consists of 21 symptom items, of which the severity scored on a 4-points
scale (absent to severe). During treatment participants indicate per
symptom they experienced whether or not they think it is related to the
treatment. Room for comments and additional side-effects is provided.
We will use the Dutch translation from the PAINDIP study (de Heer e.a.
2013) with some adaptions; i.e. translating medical jargon to common
language and the layout to self-administration format. In addition, given
our treatment aim and dosage is not depression but insomnia, we
changed "sleep problems" into "difficulty waking up", "sleepiness in the
morning", "sleepiness in the afternoon", "vivid dreams/disturbed sleep".
Withdrawal will be measured by the Dutch translation of the 43-item
Discontinuation-Emergent Signs and Symptoms (DESS) checklist
(Rosenbaum e.a 1998) adjusted to self-administration format.
Participants will be asked whether they have experienced one of the
listed signs or symptoms during the first week after they have
discontinued the treatment, but not during treatment. The number of
newly occurring DESS events will be used to measure the effect of
discontinuation (compared to placebo). This will be assessed
retrospectively (week 20), as has been done previously (Geffen e.a.
2005). Treatment evaluation: adherence, satisfaction, and additional insomnia
treatment

E.5.2.1

Timepoint(s) of evaluation of this end point

baseline, 6 weeks, 12 weeks, 20 weeks and 12 months.

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

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

Yes

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)

Yes

E.7.4

Therapeutic use (Phase IV)

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

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in 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

last questionnaire of last patient

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:

104

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

156

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)

None

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

2018-06-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-07-18

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2022-06-28

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