Clinical Trials Register

Summary
EudraCT Number:	2014-000174-19
Sponsor's Protocol Code Number:	9345
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2014-09-01
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

2014-000174-19

A.3

Full title of the trial

Efficacy and Safety of Eltrombopag in Patients with Acquired Moderate Aplastic Anemia (EMAA) who are treated with Ciclosporin A

Prospective Randomized Multicenter Study comparing Thrombopoetin-Receptor agonist Eltrombopagwith Placebo in Patients with Acquired Moderate Aplastic Anemia who are treated with Ciclosporin A

Wirksamkeit und Sicherheit von Eltrombopag in Kombination in Patienten mit Erworbener Moderater Aplastischer Anämie (EMAA), die mit Ciclosporin A behandelt werden

Eine prospektive, randomisierte, multizentrische klinische Studie zum Vergleich des Thrombopoetinrezeptor-Agonist Eltrombopag mit Placebo in Patienten mit Erworbener Moderater Aplastischer Anämie (EMAA), die mit Ciclosporin behandelt werden

A.3.1

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

Efficacy and Safety of Eltrombopag in Patients with Acquired Moderate Aplastic Anemia (EMAA) who are treated with Ciclosporin A

Prospective Randomized Multicenter Study comparing Thrombopoetin-Receptor agonist Eltrombopag with Placebo in Patients with Acquired Moderate Aplastic Anemia who are treated with Ciclosporin A

A.3.2

Name or abbreviated title of the trial where available

EMAA

A.4.1

Sponsor's protocol code number

9345

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	Universitätsklinikum Ulm
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	Novartis Pharma GmbH
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 Ulm
B.5.2	Functional name of contact point	Britta Höchsmann
B.5.3	Address:
B.5.3.1	Street Address	Helmholtzstraße 10
B.5.3.2	Town/ city	Ulm
B.5.3.3	Post code	89081
B.5.3.4	Country	Germany
B.5.4	Telephone number	0049731150560
B.5.5	Fax number	0049731150500
B.5.6	E-mail	b.hoechsmann@blutspende.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 75 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Pharma GmbH
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	SB497115
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	496775-62-3
D.3.9.2	Current sponsor code	SB497115
D.3.9.3	Other descriptive name	ELTROMBOPAG OLAMINE
D.3.9.4	EV Substance Code	SUB30141
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	75
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

Moderate Aplastic Anemia (MAA)

E.1.1.1

Medical condition in easily understood language

Moderate Aplastic Anemia (MAA) is a non-malignant blood disorder.

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

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

The aim of this trial is to improve treatment of Moderate Aplastic Anemia (MAA) by evaluating the safety and efficiency
of Eltrombopag as a new treatment option in patients with MAA requiring therapy.

The primary objective of this trial is the evaluation of the superiority of Eltrombopag on top of background treatment
with Ciclosporin (CSA) regarding hematologic response (PR +CR) at 6 months in comparison with treatment with CSA alone in untreated MAA patient.

E.2.2

Secondary objectives of the trial

The secondary objective of this trial is to investigate the impact of Eltrombopag added to background therapy with
CSA on all outcome measures, safety and quality of life in untreated MAA patients. As well as the evaluation of telomere
lengths and telomerase mutations as biomarkers for response to Eltrombopag therapy in MAA and the evaluation of the new Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria (PNH) specific quality of life questionnaire QLQ-AA/PNH.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Current diagnosis of a Moderate Aplastic Anemia requiring standard treatment with CSA without prior specific therapy.

MAA is defined as Aplastic Anemia fulfilling the following criteria:
• no evidence for other disease, causing marrow failure
• hypocellular bone marrow for age
• depression of at least two out of three peripheral blood counts below the normal values in two different blood samples in a time span from at least two weeks:
• absolute neutrophil count (ANC) < 1.2 G/L
• platelet count < 70 G/L
• absolute reticulocyte count < 60 G/L21
• without fulfilling the criteria for SAA (hypocellularity of bone marrow 25 % and depression of two of the three peripheral counts: ANC < 0.5 G/L, platelet count < 20 G/L, reticulocyte count < 20 G/L)

2. In this study need for treatment with CSA is defined as:
a. transfusion-independent MAA and:
• ANC < 1.0 G/L
• or hemoglobin < 8.5 g/dl and reticulocyte count < 60 G/L
• or platelet count < 30 G/L
• or significant clinical symptoms (infections, bleeding, anemia)
b. transfusion-dependent MAA:
• Platelet transfusion dependency is defined as prophylactic transfusion (platelet counts < 10 G/L with no bleeding) or therapeutic transfusion in the 12 weeks prior to study entry.
• Red blood cell transfusion dependency is defined as transfusion of at least 4 units of packed red blood cell
concentrates (PRBC) in the 12 weeks prior to study entry.
3. A signed and dated informed consent is necessary before the conduct of any study-specific procedure.

E.4

Principal exclusion criteria

1. Age < 18 years
2. Constitutional Aplastic Anemia (i.e. Fanconi anemia or Dyskeratosis congenita)
3. Clonal myeloid disorders based on cytogenetic findings performed within 12 weeks of study entry. Especially patients with cytogenetic abnormalities which are recurrent in MDS are not eligible for the
study.
4. Bone marrow reticulin fibrosis of grade 3 or greater
5. Severe concurrent diseases precluding the patient's ability to tolerate protocol therapy
6. ALT > 3 times the upper limit of normal if this elevation is progressive, or persistent during the 4 weeks before study entry or accompanied by increased direct bilirubin, or accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation
7. Infection not adequately responding to appropriate therapy
8. HIV-positivity (patients with Hepatitis B or Hepatitis C are only in combination with hepatic failure - see
criteria 7- excluded)
9. Moribund status with a likely death within 3 months.
10. History of malignancy other than localized tumors diagnosed more than one year previously and treated surgically with curative intent (for instance squamous cell or other skin cancers, stage 1, breast cancer in
situ, cervical carcinoma in situ...).
11. Prior specific treatment of Aplastic Anemia with immuno-suppression or androgens or interleukin2- receptor-antibodies. The use of these drugs in context with other disorders before diagnosis of aplastic anemia is not an exclusion criteria if these treatments were finished longer than 6 months before study entry.
12. Treatment with other hematological effective drugs (including erythropoetin) within 3 months before study
entry as well as treatment with corticosteroids and GCSF within 3 weeks before enrollment.
13. Known hypersensitivity to Eltrombopag or its components
14. Known hypersensitivity to Ciclosporin.
15. Current nursing, pregnancy, or unwillingness to take oral contraceptives or use a barrier method of birth
control to refrain from pregnancy as well as a missing or positive pregnancy test within the last 14 days before inclusion for women of childbearing potential during the course of this study.
16. Inability to understand the investigational nature of the study or to give informed consent.
17. Renal failure with creatinine > 2× upper limit of normal.
18. Uncontrolled hypertension.
19. Participation in any study using an investigational drug or treatment with an investigational drug within 30 days preceding the first dose of study medication.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of the study is the hematologic response rate (CR + PR) at 6 months.

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months

E.5.2

Secondary end point(s)

Secondary endpoints are:
• Trilineage (CR and PR) and single lineage hematological response rate at 3, 6, 12 and 18 months.
• cumulative incidence of response
• time to best hematological trilineage and single lineage response
• Proportion of patients with need for transfusions and number of units transfused (PRBC and PC) since start of treatment
• cumulative incidence of progress to SAA/VSAA or intensive immunosuppressive treatment with ATG
• toxicity profile as measured using the CTCAE criteria
• relapse rate at 6, 12 and 18 months
• cumulative incidence of relapse (from best trilineage hematological response)
• overall survival
• failure-free survival
• telomere lengths and presence of telomerase mutations as biomarkers for response.
• quality of life as assessed by quality of life instruments (FACIT-F SCALE and EORTC QLQ-C30, QLQAA/PNH)

Pharmacokinetic studies for assessment of dose dependency regarding efficiency and safety in a subgroup of patients.

E.5.2.1

Timepoint(s) of evaluation of this end point

• Trilineage hematological response rate (CR and PR) at 3, 6, 12 and 18 months.
• single lineage response at 3, 6, 12 and 18 months
• relapse rate at 6, 12 and 18 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

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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)

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

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

France

Switzerland

Germany

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

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

E.8.9.2

In all countries concerned by the trial 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.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)

After conclusion of the trial patients will receive further standard medical care as usual for this kind of disease.

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

2015-01-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-11-10

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

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