Clinical Trials Register

Summary
EudraCT Number:	2014-002002-20
Sponsor's Protocol Code Number:	2014METAL1
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2015-05-19
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

2014-002002-20

A.3

Full title of the trial

A multicentre randomized double-blind placebo controlled discontinuation trial of methylphenidate

A.3.1

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

A multicentre randomized double-blind placebo controlled discontinuation trial of methylphenidate

A.3.2

Name or abbreviated title of the trial where available

Methylphenidate discontinuation trial

Methylfenidaat Afbouw Studie bij Kinderen (MASK)

A.4.1

Sponsor's protocol code number

2014METAL1

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	UMCG
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.4.1	Name of organisation providing support	Shire
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	UMCG
B.5.2	Functional name of contact point	methylphenidate trial information
B.5.3	Address:
B.5.3.1	Street Address	postbus 30.001
B.5.3.2	Town/ city	Groningen
B.5.3.3	Post code	9700 RB
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	00310503615589
B.5.6	E-mail	a.f.m.matthijssen@umcg.nl

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	Concerta
D.2.1.1.2	Name of the Marketing Authorisation holder	Jansen-Cilag Limited
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.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	Yes
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	Concerta
D.2.1.1.2	Name of the Marketing Authorisation holder	Jansen-Cilag Limited
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.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	Yes
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: 3
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	Concerta
D.2.1.1.2	Name of the Marketing Authorisation holder	Jansen-Cilag Limited
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.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	Yes
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: 4
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	Concerta
D.2.1.1.2	Name of the Marketing Authorisation holder	Jansen-Cilag Limited
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.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	Yes
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	Capsule, hard
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

attention-deficit/hyperactivity disorder

E.1.1.1

Medical condition in easily understood language

attention-deficit/hyperacitivity disorder (ADHD)

E.1.1.2

Therapeutic area

Psychiatry and Psychology [F] - Behavioral Disciplines and Activities [F04]

MedDRA Classification

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: to investigate the effectiveness of ongoing treatment with methylphenidate beyond two years as prescribed in clinical practice in children and adolescents. We will test the hypothesis that ongoing use of methylphenidate is superior to placebo with regard to ADHD/ODD symptom severity in children and adolescents who have used methylphenidate for two years or longer. Here we will be able to establish whether or not long-term use of methylphenidate is still effective beyond two years of treatment.

E.2.2

Secondary objectives of the trial

Methylphenidate is related to the dopamine neurotransmitter pathway (by increasing attention) so many of the secondary objectives are related to that.
(1) to investigate the effects of discontinuation of methylphenidate on a number of secondary outcome measurements (clinical improvement, withdrawal effects, sleeping behaviour, quality of life, neuropsychological task performance and a number of biomarkers related to dopamine function).
(2) to identify moderators and predictors of treatment discontinuation and long-term outcome six months later. This includes treatment duration and compliance, child factors (age, sex, presence of comorbid psychiatric problems, genetic polymorphisms, cortisol in hair as stress regulation measure and an underaroused temperament) as well as parent factors (socio-economic status, presence of psychiatric problems, parental stress and other family factors).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

In order to be eligible to participate in this study, a subject must meet all of the following criteria:
• Children between the ages of eight to eighteen, any ethnicity or cultural background.
• Children with their first prescription of any form of methylphenidate at least two years ago.
• Children who are for at least the last four weeks the subject has been using methylphenidate in the form of Concerta 36 mg or 54 mg.
• Children with an IQ > 70 (based on a previous IQ test or attending regular education).
• Parents (or the legal guardian) and children (≥ twelve years) have provided informed consent to participate in the study.

E.4

Principal exclusion criteria

Excluded from participation in this study will be:
• Children who have not been using of methylphenidate for a continuous period > 2 months during the last two years.
• Children of parents who are planning to start new psychosocial or pharmacological therapies during the blinded period.
• Children and or parents who are unable to understand or comply with the protocol.
• Children who have any other significant disease or disorder which, in the opinion of the investigator, may either put the participants at risk because of participation in the study, or may influence the result of the study, or the participant’s ability to participate in the study.

E.5 End points

E.5.1

Primary end point(s)

The primary outcome measure will be the clinician based ADHD DSM-5 rating scale. This is an adapted version of the ADHD Rating Scale-IV (Zhang et al., 2005). The adaptation is based on the small changes between the DSM-IV and DSM-5 for the diagnosis of ADHD. The ADHD- IV (5) is a reliable and easy-to-administer instrument both for diagnosing ADHD in children and adolescents and for assessing treatment response. Containing 18 items, the scale is linked directly to DSM-5 diagnostic criteria for ADHD.

E.5.1.1

Timepoint(s) of evaluation of this end point

baseline, after four and seven weeks and after a six months natural follow up.

E.5.2

Secondary end point(s)

Secondary outcome measures:
Rating scales
• The Clinical Global Impression Scale of Improvement (CGI-I).
• The criteria of Oppositional Defiant Disorder (ODD)
• Side effects and withdrawal effects will be evaluated by an adapted version of the Barkley Side Effect Rating scale (BSERS).
• The Sleep Disturbances Scale for Children (SDSC)
• The appetite of the child
• The Retrospective Overt Aggression Scale (R-MOAS)
• The Kindl-R (quality of life)
• The Parental Stress Scale (PSS)
• Questions about family atmosphere questions
• The Parental Frustrations Questionnaire (PFQ)
• The Child Depression Inventory (CDI)
• The Strength and Difficulties Questionnaire (SDQ). We will use the parent, teacher and self-report (ages 11-16) versions.
• The Conners Teacher Rating Scale-Revised: short form (CTRS-R:S).
Physical measures
• Weight, height, blood pressure, pulse
Biomarkers
• Blood draw (ferritin, zinc and cholesterol)
Neuropsychological tests
• Amsterdam Neuropsychological Tasks (three subtests)
• The Monetary incentive delay task for children
Mediators/predictors
• Treatment history, duration and compliance
Child factors
• Sex, age, ethnicity, school type
• Estimation IQ
• Psychiatric diagnoses
• Tanner stage + some questions of Physical Development Scale (PDS)
• Temperament (Behavioural Avoidance and Inhibition Scale [BISBAS], Inventory of Callous and Unemotional traits [ICU], Brief Sensation Seeking Scale [BSSS])
• DNA (blood draw)
• Cortisol in hair
• Stressful events
Parental factors
• Socio-economic factors
• The Egna Minnen Beträffende Uppfostran (EMBU)
• The Adult ADHD Rating scale (AARS)
• The Parenting Sense of Competence Scale (PSOC)
• The Maudsley Marital Questionnaire (MMQ)(subschale Marital adjustment)

E.5.2.1

Timepoint(s) of evaluation of this end point

variable but all at a certain point at the follow ups or baseline. baseline, after four and seven weeks and after a six months natural follow up.

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

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

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

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

The end of the study is defined as the last subject last visit.
The study will be terminated prematurely when in line with the revised CCMO Directive on the Assessment of Clinical Trial Agreements.

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

Yes

F.1.1

Number of subjects for this age range:

120

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

120

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

120

F.1.2

Adults (18-64 years)

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

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

children under the age of twelve.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

120

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

2015-05-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-06-10

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

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