Clinical Trials Register

Summary
EudraCT Number:	2014-003150-13
Sponsor's Protocol Code Number:	TUD-DELTA1-063
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:	2015-01-29
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

2014-003150-13

A.3

Full title of the trial

A randomized placebo-controlled phase 2 study of decitabine with or without eltrombopag in AML patients ≥65 years of age not eligible for intensive chemotherapy

Randomisierte Placebo-kontrollierte Phase-II-Studie zu Decitabin in Kombination mit oder ohne Eltrombopag bei AML-Patienten ≥65 Jahre, für die eine intensive Chemotherapie nicht in Frage kommt

A.3.1

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

A randomized placebo-controlled phase 2 study of decitabine with or without eltrombopag in patients with acute myeloid leukemia ≥65 years of age not eligible for intensive chemotherapy

Randomisierte Placebo-kontrollierte Phase-II-Studie zu Decitabin in Kombination mit oder ohne Eltrombopag bei Patienten mit akuter myeloischer Leukämie ≥65 Jahre, für die eine intensive Chemotherapie nicht in Frage kommt

A.3.2

Name or abbreviated title of the trial where available

DELTA

A.4.1

Sponsor's protocol code number

TUD-DELTA1-063

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	Technische Universität Dresden
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	GlaxoSmithKline GmbH & Co KG
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	Universitätsklinikum Dresden, Med. Klinik und Poliklinik I
B.5.2	Functional name of contact point	coordinating investigator
B.5.3	Address:
B.5.3.1	Street Address	Fetscherstraße 74
B.5.3.2	Town/ city	Dresden
B.5.3.3	Post code	01307
B.5.3.4	Country	Germany
B.5.4	Telephone number	04903514582583
B.5.5	Fax number	04903514584367
B.5.6	E-mail	uwe.platzbecker@uniklinikum-dresden.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	Revolade
D.2.1.1.2	Name of the Marketing Authorisation holder	GlaxoSmithKline Trading Services Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Eltrombopag
D.3.2	Product code	SB-497115
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ELTROMBOPAG
D.3.9.1	CAS number	496775-61-2
D.3.9.2	Current sponsor code	SB-497115 (Eltrombopag)
D.3.9.4	EV Substance Code	SUB30140
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	50
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	No
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	Eltrombopag
D.3.2	Product code	SB-497115
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ELTROMBOPAG
D.3.9.1	CAS number	496775-61-2
D.3.9.2	Current sponsor code	SB-497115 (Eltrombopag)
D.3.9.4	EV Substance Code	SUB30140
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	100
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

acute myeloid leukemia
AML

Akute myeloische Leukämie
AML

E.1.1.1

Medical condition in easily understood language

acute myeloid leukemia
AML

Akute myeloische Leukämie
AML

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

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	10000880
E.1.2	Term	Acute myeloid leukaemia
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To study whether supportive treatment with eltrombopag improves treatment change-free survival (TCFS) in AML patients ≥65 years of age when added to standard treatment with DAC

Einfluss einer zusätzlichen palliativen Behandlung mit Eltrombopag zur Standardtherapie mit Decitabin auf das behandlungsänderungsfreie Überleben von AML Patienten ≥ 65 Jahre

E.2.2

Secondary objectives of the trial

• overall survival (OS)
• relapse free survival (RFS)
• overall response rate (CR, PR, SD)
• number of bone marrow blasts after 5, 9 and 12 months
• quality of life (QLQ-C30 and SF-36)
• bleeding events
• median platelet counts
• number of platelet transfusions
• hospitalization rate
• safety and tolerability of treatment with EPAG / placebo
• impact of comorbidities on predicting overall survival

• Gesamtüberleben (OS)
• Rezidiv-freies Überleben (RFS)
• Gesamtansprechrate (CR, PR, SD)
• Blastengehalt im Knochenmark nach 5, 9 und 12 Monaten
• Lebensqualitätsfragebögen (QLQ-C30 and SF-36)
• Inzidenz von Blutungen
• mediane Thrombozytenzahl
• Anzahl an Thrombozytentransfusionen
• Hospitalisierungsrate
• Sicherheit und Verträglichkeit der EPAG / Placebo-Behandlung
• Einfluss von Komorbiditäten auf die Vorhersage des Gesamtüberlebens

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Newly diagnosed AML (including therapy-related or after antecedent MDS) other than APL according to WHO criteria, i.e. bone marrow aspirate or biopsy must contain ≥20% blasts of all nucleated cells or differential blood count must contain ≥20% blasts. In AML defined by cytogenetic aberrations according to WHO the proportion of blasts may be <20%
• Age ≥ 65 years
• ECOG performance status 0-3
• Patients not eligible for intensive induction therapy
• Planned therapy with DAC
• Platelet count <75 Gpt/L taken within 4 weeks prior to randomization
• Signed Informed Consent
• Adequate liver function as assessed by the following laboratory requirements:
o Total bilirubin ≤ 3 times the upper limit of normal (except for Gilbert’s Syndrome)
o ALT and AST ≤ 3 times upper limit of normal

• neu diagnostizierte AML (einschließlich Therapie-assoziiert oder nach vorangegangenem MDS) außer APL nach WHO Kriterien; d. h. Knochenmarkaspirat- oder biopsie muss ≥20% Blasten unter allen kernhaltigen Zellen aufweisen oder im Differentialblutbild müssen ≥20% Blasten nachgewiesen werden. Bei einer durch zytrogenetische Aberationen definierte AML können die Blasten auch <20% betragen.
• Alter ≥ 65 Jahre
• ECOG performance status 0-3
• nicht geeignet für intensive Induktionstherapie
• geplante Therapie mit DAC
• Thrombozytenzahl <75 Gpt/L (Befund innerhalb 4 Wochen vor Randomisierung)
• unterzeichnete Einwilligungserklärung nach Aufklärung
• adäquate Leberfunktion; folgende Voraussetzungen sind einzuhalten:
o Gesamt-Bilirubin ≤ 3-faches des oberen Normalwertes (außer Gilbert’s Syndrome)
o ALT und AST ≤ 3-faches des oberen Normalwertes

E.4

Principal exclusion criteria

• Acute promyelocytic leukemia (APL)
• History of MDS or AML treatment with TPO-R agonists (Revolade, NPlate or other TPO-R agonists), hypomethylating agents or intensive chemotherapy
• NYHA stage ≥ 2 due to heart insufficiency
• Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results
• Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication
• Active and uncontrolled infections
• positive Human Immunodeficiency Virus (HIV) or positive Hepatitis B or C serology
• Patients unable to swallow medication
• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to eltrombopag or DAC or excipients that contraindicate their participation.

• Akute Promyelozytenleukämie (APL)
• Bekanntes Hochrisiko-MDS oder vorherige Behandlung der AML mit einem TPO-R-Agonisten (z. B. Revolade, NPlate oder andere TPO-R-Agonisten), hypomethylierende Medikamente oder intensive Chemotherapie
• NYHA-Stadium ≥ 2 (aufgrund von Herzinsuffizienz)
• aktueller Drogen- oder Alkoholabusus
• Behandlung mit einem Prüfmedikament innerhalb von 30 Tagen bzw. 5 Halbwertszeiten (je nach dem welches länger dauert) vor Erhalt der ersten Studienmedikation
• aktive unkontrollierte Infektion
• Patienten, die nicht in der Lage sind Tabletten zu schlucken
• positive HIV- oder Hepatitis-Serologie (Hepatitis B und C)
• bekannte Überempfindlichkeit gegenüber der Prüfmedikation oder stukturverwandte Substanzen

E.5 End points

E.5.1

Primary end point(s)

Treatment change-free survival (TCFS)

Behandlungsänderungs-freies Überleben

E.5.1.1

Timepoint(s) of evaluation of this end point

date of treatment change or death

Datum der Änderung der Behandlung oder Tod

E.5.2

Secondary end point(s)

• Overall Survival (OS) in presence of competing risk treatment change
• Overall response rate (CR, PR, SD)
• Relapse free survival (RFS)
• Median platelet counts
• Number of platelet transfusions during cycles 1-4
• Incidence of bleeding events
• Number of bone marrow blasts from baseline and after 5, 9 and 12 months
• Hospitalization rate (days in hospital)
• Safety and tolerability of treatment with EPAG / placebo
• Quality of life
• impact of comorbidities on predicting overall survival

• Gesamtüberleben (OS)
• Gesamtansprechrate (CR, PR, SD)
• Rezidiv-freies Überleben (RFS)
• Mediane Thrombozytenzahl
• Anzahl Thrombozytentransfusionen während der Zyklen 1-4
• Inzidenz von Blutungen
• Anzahl an Knochenmarkblasten zur Baseline; sowie nach 5, 9 und 12 Monaten
• Rate an Hospitalisierungen (Krankenhaustage)
• Sicherheit und Verträglichkeit der Behandlung mit EPAG / Placebo
• „Quality of life“
• Einfluss von Komorbiditäten auf die Vorhersage des Gesamtüberlebens

E.5.2.1

Timepoint(s) of evaluation of this end point

• whole study
• date of relapse, death
• cycles 1-4, 5, 9 and 12
• follow up after treatment discontinuation: week 2, month 3, 6, 9, 12, 24, 36, and 48

• während der gesamten Studiendauer
• Datum des Rezidives, Todes
• Zyklus 1-4, 5, 9 und 12
• Follow Up nach Abbruch/Ende der Behandlung: Woche 2, Monat 3, 6, 9, 12, 24, 36, 48

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

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

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

Yes

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

Letzte Visite des letzten Patienten

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

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)

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

238

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

238

F.4.2

For a multinational trial

F.4.2.1

In the EEA

238

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)

After discontinuation of study treatment, patients will pass the end of study visit and survival will further be observed during follow up for a maximum of 4 years after randomization. Following discontinuation of EPAG, thrombocytopenia is likely to reoccur. Therefore, platelet counts should be monitored weekly for 4 weeks. Upon discontinuation from assigned study treatment, subjects may receive additional (non protocol) therapy at the discretion of the treating physician.

Nach Beendigung der Studienbehandlung erfolgt eine Abschlussvisite. Im Rahmen eines Follow Ups wird das Überleben der Patienten bis maximal 4 Jahre nach Randomisierung weiter beobachtet. Nach Absetzen von EPAG kann eine Thrombozytopenie erneut auftreten. Daher sollte die Anzahl der Thrombozyten im ersten Monat wöchentlich überwacht werden. Die Folgetherapie und weitere Behandlung ist nicht Gegenstand der Studie und liegt im Ermessen des behandelnden Arztes.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	SAL - Study Alliance Leukemia
G.4.3.4	Network Country	Germany

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-03-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-01-09

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-12-26

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