Clinical Trials Register

Summary
EudraCT Number:	2010-023992-24
Sponsor's Protocol Code Number:	MEMAP1
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-05-18
Trial results	View 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

Germany - BfArM

A.2

EudraCT number

2010-023992-24

A.3

Full title of the trial

International randomised double-blind placebo-controlled study on the initial treatment of acute mania with methylphenidate

Internationale randomisierte doppelblinde und Placebo-kontrollierte Studie zur Initialbehandlung der akuten Manie mit Methylphenidat

A.3.1

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

International randomised double-blind placebo-controlled study on the initial treatment of acute mania with methylphenidate

A.3.2

Name or abbreviated title of the trial where available

MEMAP

A.4.1

Sponsor's protocol code number

MEMAP1

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01541605

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	University of Leipzig
B.1.3.4	Country	Germany
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	University of Leipzig, Department of Psychiatry
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Department of Psychiatry of University of Leipzig
B.5.2	Functional name of contact point	Dr Michael Kluge
B.5.3	Address:
B.5.3.1	Street Address	Semmelweisstrasse 10
B.5.3.2	Town/ city	Leipzig
B.5.3.3	Post code	04103
B.5.3.4	Country	Germany
B.5.4	Telephone number	03419724673
B.5.5	Fax number	03419724539
B.5.6	E-mail	michael.kluge@medizin.uni-leipzig.de

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	Medikinet 5 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	MEDICE Arzneimittel Pütter GmbH & Co KG, 58638 Iserlohn/Germany
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Methylphenidate
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	METHYLPHENIDATE
D.3.9.1	CAS number	113-45-1
D.3.9.4	EV Substance Code	SUB08870MIG
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	5 to 5
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	Medikinet 10 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	MEDICE Arzneimittel Pütter GmbH & Co KG, 58638 Iserlohn/Germany
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Methylphenidate
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	METHYLPHENIDATE
D.3.9.1	CAS number	113-45-1
D.3.9.4	EV Substance Code	SUB08870MIG
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	10 to 10
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	Medikinet 20 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	MEDICE Arzneimittel Pütter GmbH & Co KG, 58638 Iserlohn/Germany
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Methylphenidate
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	METHYLPHENIDATE
D.3.9.1	CAS number	113-45-1
D.3.9.4	EV Substance Code	SUB08870MIG
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	5 to 20
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

acute mania and hypomania (ICD-10: F30.0, F30.1, F31.0, F31.1)

E.1.1.1

Medical condition in easily understood language

acute mania

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	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10000852
E.1.2	Term	Acute mania
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

To test the hypothesis that methylphenidate immediate release given twice daily (BID) is significantly superior to placebo in the treatment of manic symptoms in patients with bipolar disorder after 2.5 days of treatment as assessed by the Young Mania Rating Scale (YMRS).

E.2.2

Secondary objectives of the trial

1. Methylphenidate immediate release is significantly superior to placebo in treatment of manic symptoms after 2 hours as assessed by the YMRS and PANSS
2. Change from baseline to endpoint (after 2.5 days of treatment) on the CGI-BP and PANSS-EC
3. 2.5 days of treatment with methylphenidate but not with placebo stabilise vigilance regulation as assessed by the ‘Vigilance Algorithm Leipzig’ (VIGALL)
4. Instability of vigilance regulation predicts response to methylphenidate
5. Methylphenidate immediate release given BID is associated with significantly less movements over the study period than placebo as assessed by actigraphy
6. Methylphenidate is significantly superior to placebo in improving sustained attention as assessed by the “Continuous Performance Test” (CPT)
7. Methylphenidate is significantly superior to placebo in improving cognitive performance as assessed by the “Screen for Cognitive Impairment in Psychiatry” (SCIP)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Diagnosis: Current manic episode according to ICD-10 classification: F30.0, F30.1, F31.0 or F31.1. A previous diagnosis of schizo-affective disorder is NOT an exclusion criterion
2. Male or female >18 years of age
3. YMRS total score ≥ 20 and ≤ 45 points

E.4

Principal exclusion criteria

1. Any other current major psychiatric ICD-10 disorder (except follow: F40-48 Neurotic, stress-related and somatoform disorders, F50-F59 Behavioural syndromes associated with physiological disturbances and physical factors, F60-F69 Disorders of adult personality and behaviour) 2. Contraindications for treatment with methylphenidate except as noted otherwise.
3. Serious non-psychiatric disease (e.g. infectious, autoimmune or metabolic), that may interfere with the objectives of the study or with the safety or compliance of the subject, as judged by the investigator
4. Stable treatment with mood stabilisers including lithium, anticonvulsants (e.g. valproate, carbamazepine) or antipsychotics (e.g. risperidone, olanzapine) or benzodiazepines is NOT an exclusion criterion and will be continued; however, patients receiving more than 2 of this substances are NOT eligible for inclusion
5. Medical history of other disorders of CNS including tics or dyskinesia,
6. Medical history of cardiovascular diseases, moderate to severe hypertension, glaucoma, hyperfunction of the thyroid
7. Patients with congenital or acquired long QT syndrome, or with a familiy history of QT prolongation or other significant inherited cardiac disorders (e.g. family history of hypertrophic cardiomyopathy).
8. History of Electroconvulsive therapy within the last 3 month
9. Known alcohol and drug addiction or abuse, except for patients with abstinence > 3 month. Patients with sporadic abuse of cannabis (products) will not be excluded from the study. That is even true with a positive THC screen in urine.
10. Pregnant or breast-feeding
11. Concomitant participation in other clinical trials or participation during the 30 days prior to screening

E.5 End points

E.5.1

Primary end point(s)

After 2,5 days of treatment to test whether methylphenidate immediate release given twice daily (BID) is significantly superior to placebo in the treatment of manic symptoms in patients with bipolar disorder as assessed by YMRS.

E.5.1.1

Timepoint(s) of evaluation of this end point

After 2,5 days.

E.5.2

Secondary end point(s)

- Methylphenidate immediate release given BID is significantly superior to placebo in the treatment of manic symptoms in patients with bipolar disorder after 2 hours of treatment as assessed by the YMRS and PANSS
- Change from baseline to endpoint (after 2.5 days of treatment) on the CGI-BP and PANSS-EC
- 2.5 days of treatment with methylphenidate but not with placebo stabilise vigilance regulation as assessed by the ‘Vigilance Algorithm Leipzig’ (VIGALL)
- Instability of vigilance regulation as assessed by the VIGALL predicts response to methylphenidate
- Methylphenidate immediate release given BID is associated with significantly less movements over the study period than placebo as assessed by actigraphy
- Methylphenidate is significantly superior to placebo in improving sustained attention as assessed by the “Continuous Performance Test” (CPT)
- Methylphenidate is significantly superior to placebo in improving cognitive performance as assessed by the “Screen for Cognitive Impairment in Psychiatry” (SCIP)

E.5.2.1

Timepoint(s) of evaluation of this end point

After 2 hours respectively after 2,5 days.

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

Yes

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

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)

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

Yes

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

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:

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

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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 treatment is not different from the normal treatment of that condition.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2011-08-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-08-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-02-08

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