Clinical Trials Register

Summary
EudraCT Number:	2014-000265-43
Sponsor's Protocol Code Number:	München/CS04
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Temporarily Halted
Date on which this record was first entered in the EudraCT database:	2017-11-20
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

Germany - BfArM

A.2

EudraCT number

2014-000265-43

A.3

Full title of the trial

A randomized, placebo-controlled trial comparing the treatment effect of Pegvisomant and the SSRI Escitalopram on depressive acromegalic patients

Doppelblinde, Randomisierte, Plazebo-kontrollierte Studie zum Vergleich der Behandlungseffekte von Pegvisomant und des selektiven Serotonin-Wiederaufnahmehemmers Escitalopram bei depressiven akromegalen Patienten

A.3.1

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

Pegvisomant and Escitalopram in acromegalic depressive patients

Pegvisomant und Escitalopram bei akromegalen depressiven Patienten

A.4.1

Sponsor's protocol code number

München/CS04

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	Max-Planck-Institut für Psychiatrie
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	Pfizer Pharma GmbH
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	DFG grant JU-2817/3-1
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	Max-Planck-Institut für Psychiatrie
B.5.2	Functional name of contact point	Kathrin Popp
B.5.3	Address:
B.5.3.1	Street Address	Kraepelinstr. 10
B.5.3.2	Town/ city	München
B.5.3.3	Post code	80804
B.5.3.4	Country	Germany
B.5.4	Telephone number	00498930622270
B.5.5	Fax number	004989206227460
B.5.6	E-mail	kathrin_popp@psych.mpg.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	Somavert 20 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Pharma GmbH, 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.3.4	Pharmaceutical form	Powder and solution for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PEGVISOMANT
D.3.9.1	CAS number	218620-50-9
D.3.9.4	EV Substance Code	SUB03668MIG
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	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Escitalopram Hexal 10 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Hexal AG
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	Escitalopram 10 mg
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	ESCITALOPRAM
D.3.9.2	Current sponsor code	86610.00.00
D.3.9.4	EV Substance Code	SUB16425MIG
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
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	Solution for injection/infusion
D.8.4	Route of administration of the placebo	Subcutaneous use
D.8 Placebo: 2
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

Acromegalie with depression

Akromegalie mit Depression

E.1.1.1

Medical condition in easily understood language

Acromegalie with depression

Akromegalie mit Depression

E.1.1.2

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10000599
E.1.2	Term	Acromegaly
E.1.2	System Organ Class	10014698 - Endocrine disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to evaluate and compare the placebo-controlled depression improvements of Pegvisomant and SSRI Escitalopram in acromegalic patients during 8 weeks of therapy in the three therapeutic arms.

Der primäre Endpunkt der Studie ist die Erfassung und der Vergleich der Verbesserungen der Depression zwischen einer Plazebobehandlung, der Therapie mit Pegvisomant und dem selektiven Serotonin-Wiederaufnahmehemmer Escitalopram bei Akromegalen in der 8-wöchigen Therapie (3-armig).

E.2.2

Secondary objectives of the trial

The secondary objectives are
• to access and compare the placebo-controlled effects of Pegvisomant and SSRI Escitalopram on quality of life during 8 weeks treatment.
• to access and compare the placebo-controlled effects of Pegvisomant and SSRI Escitalopram on health outcome during 8 weeks treatment
• to access and compare the placebo-controlled effects of Pegvisomant and SSRI Escitalopram on depression severity during 8 weeks treatment.
• to access and compare the placebo-controlled effects of Pegvisomant and SSRI Escitalopram on pain experience during 8 weeks treatment.

• to access and compare placebo-controlled effect of Pegvisomant and SSRI Escitalopram on metabolic changes during 8 weeks treatment.

Die sekundären Endpunkte sind die Erfassung und der Vergleich

• der plazebokontrollierten Effekte von Pegvisomant und Escitalopram auf die Lebensqualität in der 8-wöchigen Therapiephase
• der plazebokontrollierten Effekte von Pegvisomant und Escitalopram auf das allgemeine Outcome in der 8-wöchigen Therapiephase
• der plazebokontrollierten Effekte von Pegvisomant und Escitalopram auf den Schweregrad der Depression in der 8-wöchigen Therapiephase
• der plazebokontrollierten Effekte von Pegvisomant und Escitalopram auf das Schmerzempfinden in der 8-wöchigen Therapiephase
• der plazebokontrollierten Effekte von Pegvisomant und Escitalopram auf Stoffwechselveränderungen in der 8-wöchigen Therapiephase

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Adult patients between 18 and 65 years
2) Female and male
3) Confirmed diagnosis of acromegaly
4) Under stable therapy and stable hormonal substitution for at least three months
5) Biochemically controlled acromegaly (confirmed by normal IGF-1 values for age and gender) with side effects of the current medication.
6) Psychiatric diagnosis of unipolar depression (according to S3-Leitlinie Nationale Versorgungsleitlinie unipolare Depression) with an BDI-II: 14-19
7) Signed informed consent by patient

1) Erwachsene Patienten zwischen 18 und 65 Jahren
2) Männer und Frauen
3) Bestätigte Diagnose einer Akromegalie
4) Stabile medikamentöse Therapie und stabile hormonelle Substitution für mindesten 3 Monate
5) Biochemisch kontrollierte Akromegalie (normale alters- und geschlechtsspezifische IGF-1 Werte mit Nebenwirkungen der aktuellen Therapie
6) 6) Psychiatrische Diagnose einer unipolanen Depression (nach der S3 Leitlinie (Nationale Versorgungsleitlinie unipolare Depression (BDI-II: 14-19
7) Schriftliche Einwilligungserklärung des Patienten

E.4

Principal exclusion criteria

1. Female patients who are pregnant or lactating, or are of childbearing potential as well as men of childbearing potential and not practicing a medically acceptable method of birth control. Women of childbearing potential who are sexually active with opposite partners have to perform adequate contraception with a combination of a highly effective method of birth control and additional barrier contraception. [Highly effective method of birth control is defined as those, alone or in combination, that result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly for the entire study duration: combined (oestrogen and gestagen) oral contraceptives, hormone implants, hormone injectables, or hormone containing intrauterine device that needed to be in place for a period of at least 2 months prior to screening. Additional barrier contraception (at least the following methods are allowed: condom of the male, diaphragm with spermicide, portio cap with spermicide) has to be used for the duration of the trial, defined as from the time of screening to the end of double-blind treatment phase. A single barrier method is not acceptable. Women of non-childbearing potential can be included if surgically sterile (documented complete hysterectomy or bi-tubal ligations) or postmenopausal >1 year
2. Men of reproductive potential must use condoms. In addition, the female partner should also be on a safe hormonal contraception (e.g. combined oral contraceptives, hormone implant hormone injectables or hormone containing intrauterine device) or use a barrier contraception (e.g. intrauterine device, diaphragm or portio cap with spermicide), if she is of childbearing potential.
3. Previous (within last 6 months) or concomitant therapy with antidepressants or PegvisomantConcomitant medication with dopamine agonists
4. Patients with epilepsy and increased risk of bleeding
5. Patients with the risk of suicide
6. Known history of long QT-syndrome, arrhythmias or relevant diseases of the heart
7. Suspected or known hypersensitivity to Escitalopram or Pegvisomant
8. Any physical condition which interferes with the recommendation in the SMPC of Escitalopram or Pegvisomant (see also not allowed concomitant medication)
9. Suspected or known drug or alcohol abuse
10. Any condition which in the opinion of the investigator makes the patient unsuitable for inclusion.
11. Participation in another clinical trial
12. Planned treatment or changes in established treatment with any other drug which might influence outcome
13. Severe disturbances in articulation, visual faculty or hearing
14. Any elective surgery or medical treatment planned in the observation period
15. Unable to give consent to study participation
16. Intensive Care treatment
17. Patients with insuline-dependent type 2 diabetes mellitus or type 2 diabetes mellitus with antidiabetic medication with a risk of hypoglycaemia

1. Schwangere oder stillenden weibliche Patientinnen, oder Patientinnen im gebärfähigen Alter, die keine adäquate Methode zur Empfängnisverhütung anwenden (doppelte Barrieremethode, sichere Methode mit einer weiteren Barrieremethode, weitere Detailbeschreibung siehe Originalprotokoll). Post-menopausale Frauen  1 Jahr.
2. Männer im gebärfähigen Alter, die keine Kondome anwenden wollen (ebenfalls doppelte Barrieremethode bei Partnerinnen im gebärfähigen Alter (weitere Detailbeschreibung siehe Originalprotokoll)
3. Vorangegangene (innerhalb der letzten 6 Monate) oder Begleittherapie mit Antidepressiva oder Pegvisomant. Begleitmedikation Dopaminagonisten.
4. Patienten mit Epilepsie oder gesteigertem Blutungsrisiko
5. Patienten mit Suizidrisiko
6. Bekannte Vorgeschichte eines langen QT - Syndroms, Arrhythmien oder andere relevanten Herzerkrankungen
7. Verdacht auf bzw. bekannte Hypersensitivität auf Escitalopram oder Pegvisomant
8. Physische Konditionen die gegen die Behandlungsempfehlungen in der Fachinformation von Escitalopram oder Pegvisomant stehen (einschließlich unerlaubter Begleitmedikamente)
9. Verdacht auf, bzw. bekannter Drogen- oder Alkoholmissbrauch.
10. Jeder Gesundheitszustand, der nach Meinung des Arztes eine Studienteilnahme unmöglich macht
11. Teilnahme an einer anderen klinischen Studie
12. Geplante Behandlungsänderungen der etablierten Therapie die das Outcome verändern könnten
13. Schwere Artikulationsstörungen, Hörverminderung oder Wahrnehmungsstörungen
14. Elektive Operationen oder Eingriffe im Beobachtungszeitraum
15. Unfähigkeit zur Einwilligung
16. Behandlung auf einer Intensivstation
17. Patienten mit insulinpflichtigem Typ 2 DM oder Typ 2 DM unter antidiabetischer Behehandlung mit dem Risiko einer Hypoglycämie

E.5 End points

E.5.1

Primary end point(s)

The primary variable will be the change in depression score from baseline to 8 weeks measured by the Beck Depression Inventory (BDI-II)

Die primäre Zielgröße ist die Veränderung im Depressionsscore (Becks Depressionsinventar, BDI-II) zwischen der Basiserfassung und nach 8 Wochen Therapie.

E.5.1.1

Timepoint(s) of evaluation of this end point

after 8 weeks fo therapy

nach 8 Wochen Therapie

E.5.2

Secondary end point(s)

Secondary outcome measure
• Changes (Δ) in the quality of life from baseline to week 8 using AcroQuol and EQ 5D.
• Changes (Δ) in depression severity from baseline to week 8 using Hamilton Rating Scale for Depressoin (HAMD).
• Changes in pain experience from baseline to week 8 using the PainDetect.
• Changes in blood levels IGF-I, fasting gucose ans HbA1c from baseline to week 8.
Safety endpoint:
• Changes in QT-Time in ECG according to flow chart

• Veränderungen (Δ) in der Lebensqualität zwischen der Basiserfassung und nach 8 Wochen Therapie (AcroQuol und EQ 5D).
Sekundäre Zielgrößen:
• Veränderungen (Δ) in der Depressionsintensität zwischen der Basiserfassung und nach 8 Wochen Therapie (Hamilton Rating Skala, HAMD)).
• Veränderungen (Δ) im Schmerzempfinden zwischen der Basiserfassung und nach 8 Wochen Therapie (PainDetect).
• Veränderungen (Δ) in den Blutwerten IGF-I, Nüchterglukose, und HbA1c zwischen der Basiserfassung und nach 8 Wochen Therapie
Sicherheitsendpunkt:
• Veränderungen in der QT-Zeit im EKG nach Ablaufplan

E.5.2.1

Timepoint(s) of evaluation of this end point

saftey endpoint weekly, secondary endpoint after 8 weeks of therapy

Sicherheitsendpunkt wöchentlich, Sekundärparameter nach 8 Wochen

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:

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.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 continuation of Escitalopram treatment after the end of the study is possible according to current registration and reimbursement status and will be decided individually by the treating physician. For the Pegvisomant group a continuation of therapy is only possible under certain circumstances: current registration and reimbursement status does allow a therapy of acromegalic patients experiencing side effects under somatostatin analogues.

Die Fortsetzung der Therapie mit Escitalopram ist nach augenblicklichem Zulassungs- und Erstattungsstatus möglich und wird individuell vom behandelnden Arzt entschieden. Für die Pegvisomantgruppe ist eine Therapiefortführung unter bestimmten Bedingungen möglich, nämlich bei Auftreten von Nebenwirkungen unter Somatostatinanaloga

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

2018-05-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-12-15

P. End of Trial
P.	End of Trial Status	Temporarily Halted

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