Clinical Trials Register

Summary
EudraCT Number:	2013-002132-25
Sponsor's Protocol Code Number:	12-181
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:	2015-02-03
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

2013-002132-25

A.3

Full title of the trial

RUXOlitinib versus BEst Available Therapy in patients with high-risk polycythemia vera or high-risk essential thrombocythemia – The RUXO-BEAT Trial

Ruxolitinib im Vergleich zur besten verfügbaren Therapie in Patienten mit Hoch-Risiko Polycythemia vera oder Hoch-Risiko Essentieller Thrombozythämie – Die RUXO-BEAT Studie

A.3.1

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

RUXOlitinib versus BEst Available Therapy in patients with high-risk polycythemia vera or high-risk essential thrombocythemia – The RUXO-BEAT Trial

Ruxolitinib im Vergleich zur besten verfügbaren Therapie in Patienten mit Hoch-Risiko Polycythemia vera oder Hoch-Risiko Essentieller Thrombozythämie – Die RUXO-BEAT Studie

A.3.2

Name or abbreviated title of the trial where available

Ruxo-BEAT

A.4.1

Sponsor's protocol code number

12-181

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02577926

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 Hospital Aachen AöR, represented by the executive board, represented by the Dean of the Medical Faculty
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.4.1	Name of organisation providing support	Department of Oncology, Haematology and Stem Cell Transplantation (Medical Clinic IV), University Hospital RWTH Aachen
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	Center for Translational & Clinical Research Aachen (CTC-A)
B.5.2	Functional name of contact point	CTC-A
B.5.3	Address:
B.5.3.1	Street Address	Pauwelsstrasse 30
B.5.3.2	Town/ city	Aachen
B.5.3.3	Post code	52074
B.5.3.4	Country	Germany
B.5.4	Telephone number	004902418080092
B.5.5	Fax number	00490241803380092
B.5.6	E-mail	ctca-regaffairs@ukaachen.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	Jakavi® 5 mg tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Ltd.
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	Ruxolitinib
D.3.2	Product code	INC424
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	Ruxolitinib
D.3.9.1	CAS number	1092939-17-7
D.3.9.2	Current sponsor code	INC424
D.3.9.3	Other descriptive name	RUXOLITINIB-Phosphate
D.3.9.4	EV Substance Code	SUB32273
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
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	Jakavi® 20 mg tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Ltd.
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	Ruxolitinib
D.3.2	Product code	INC424
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	Ruxolitinib
D.3.9.1	CAS number	1092939-17-7
D.3.9.2	Current sponsor code	INC424
D.3.9.3	Other descriptive name	RUXOLITINIB PHOSPHATE
D.3.9.4	EV Substance Code	SUB32897
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	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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Myeloproliferative Neoplasms (MPN): high-risk Polycythemia Vera (PV) and high-risk Essential Thrombocythemia (ET)

E.1.1.1

Medical condition in easily understood language

Patients with myeloproliferative blood disorders may suffer an overproduction of red blood cells, white blood cells or platelets.

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

E.2 Objective of the trial

E.2.1

Main objective of the trial

The objective of the Ruxo-BEAT trial is to assess the feasibility, safety, and efficacy of administration of ruxolitinib vs. best available therapy in patients with high-risk PV or high-risk ET.

Primary Endpoint
• The rate of complete clinicohematologic responses (CHR) at month 6 compared to baseline as defined by Barosi et al., 2009.

E.2.2

Secondary objectives of the trial

•Safety of both regimens
•The rate of complete clinicohematologic responses at month 12 & 24 as defined by Barosi et al. 2009 (with the clinical modification that splenomegaly assessment may be done by ultrasound or palpation)
•To determine the complete response rate at month 6 as defined by Barosi et al. 2013 (revised ELN response criteria)
•The efficacy as assessed by both the absence of phlebotomy (Hct <45%) and reduction in spleen size (palpable spleen that is reduced by > 50% from baseline measured by palpation or ultrasound) OR platelet count < 600 x 109/l (ET) at month 6 & 24
•The proportion of subjects achieving both durable absence of phlebotomy eligibility and durable spleen size reduction measured by palpation (PV) OR durable platelet count < 600 x 109/l (ET) (durable defined as > 3 months) (Barosi et al. 2009/2013) at month 6, 12 & 24
•The rate of overall clinicohematologic responses (CR+PR) according to both guidelines (Barosi et al. 2009 and 2013) at month 6 & 24

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Substudy to establish and prospectively validate cold-shock protein Ybx1 as diagnostic marker in MPN (August 10, 2016)

Concept and Specific Aims:
We aim to prospectively validate Ybx1 as a diagnostic and putative prognostic marker for MPN (PV and ET) within the Ruxo-BEAT trial.
Specific Aims (SA):
SA1: Assessment of Ybx1 expression in diagnostic samples (bone marrow biopsies) from patients registered and screened for the Ruxo-BEAT trial.
SA2: Analysis of Ybx1 mRNA expression in erythro-lysed peripheral blood samples derived from patients registered and screened for the Ruxo-BEAT trial.
SA3: Correlation of immunohistochemical stainings (multiplied M-score) and mRNA expression with mutational status, disease burden, response to therapy and prognostic & clinical data.

E.3

Principal inclusion criteria

1. Subjects must provide written informed consent prior to study-specific procedures or assessments which are not routinely performed for diagnosis or monitoring of PV or ET, and the subjects must be willing to comply with treatment and to follow up assessments and procedures
2. Patient must be 18 years of age or older
3. Patient´s ECOG performance status must be 0-2
4. Patient must fulfill WHO 2008 diagnostic criteria for either polycythemia vera (PV) or essential thrombocythemia (ET). Moreover, PV- and ET-patients have to be classified as high risk according to defined criteria as outlined below.
- For patients with high risk PV OR PV with indication for cytoreductive therapy due to progressive myeloproliferation, AT LEAST ONE of the following must be fulfilled (according to DGHO onkopedia) (Barbui, et al., 2011), (Passamonti, 2009):
• Age > 60 years
• Previous documented thrombosis or thromboembolism
• Platelet count > 1500 x 109/l
• Poor tolerance of phlebotomy or frequent phlebotomy requirement
• Symptomatic or progressive splenomegaly
• Severe disease-related symptoms (according to the investigators definition)
• Progressive leukocytosis with leukocyte count > 20 x 109/l
- For patients with high risk ET, AT LEAST ONE of the following must be fulfilled (according to DGHO guidelines):
• Age > 60 years
• Platelet count > 1500 x 109/l
• Previous thrombosis or thromboembolism
• Previous severe hemorrhage related to ET (defined as decrease of Hgb of at least 2 g/dl)
5. Patients must fulfill the following criteria regarding prior therapy:
PV patients:
Never treated with cytoreductive drugs except hydroxyurea, anagrelide, or interferon for up to 6 weeks maximum (phlebotomy and/or aspirin are allowed)
ET patients:
Naïve and pretreated patients may be entered in this trial.
6. Patient must have adequate liver function as indicated by a total bilirubin, AST, and ALT ≤ 2 of the institutional upper limit of normal (ULN) value, unless directly attributable to the patient’s MPN
7. Patient must have a creatinine clearance >40ml/min calculated according to the modified formula of Cockcroft and Gault, eGFR, or directly measured after 24h-urine collection
8. Patient must be able to swallow and retain oral medication

E.4

Principal exclusion criteria

1. Patients who meet criteria for post PV-MF or post ET-MF (IWG-MRT)
2. Patients who have received previous ruxolitinib treatment
3. Patients who have a history of anaphylaxis following exposure to the BAT drug of choice
4. Patients who have an inadequate bone marrow reserve as demonstrated by ANC ≤ 1 x 109/l OR platelet count <50 x 109/l
5. Patients who have known hepatitis B or C or HIV infection
6. Patients who suffer from other severe, concurrent diseases, including tuberculosis, serious cardiac functional dysfunction (class III or IV as defined by the New York Heart Association Classification), uncontrolled diabetes, uncontrolled hypertension, severe pulmonary disease (i.e. COPD with hypoxemia), or major organ malfunction that could interfere with the patient’s ability to participate in the study
7. Patients who have history of active substance or alcohol abuse within the last year
8. Female patients who are pregnant or nursing
9. Patients who have participated in another interventional trial and/or used investigational agents or concurrent anticancer treatment for concomitant disease within the last 4 weeks of registration
10. Any circumstance at the time of study entry that would preclude completion of the study or the required follow-up prohibits inclusion into this study
11. Subjects who have had an active malignancy during the previous 3 years except for treated cervical intraepithelial neoplasia, basal cell carcinoma of the skin, or squamous cell carcinoma of the skin, each with no evidence for recurrence in the past 3 years
12. Patients who have uncontrolled bacterial, viral, or fungal infection
13. Patients who have any medical condition requiring prolonged use of oral corticosteroids with a dose of more than 20 mg per day (> 1 month)
14. Patients who have severe cerebral dysfunction and/or legal incapacity
15. Patients who have had active splanchnic vein thrombosis within the last 3 months (includes Budd-Chiari, portal vein, splenic and mesenteric thrombosis)
16. Patients who have thyroid dysfunction which is not adequately controlled
17. Fertile men or women of childbearing potential cannot be included unless they are:
-surgically sterile or > 2 years after the onset of menopause and/or
-willing to use a highly effective contraceptive method (Pearl Index <1) such as oral contraceptives, intrauterine device, sexual abstinence, or barrier method of contraception (i.e. condoms) in conjunction with spermicidal jelly during study treatment
18. Patients who are taking any of the following prohibited medication:
-clarithromycin, telithromycin, troleandomycin (antibiotics)
-ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, lopinavir (HIV protease inhibitors)
-itraconazole, ketoconazole, voriconazole, fluconazole (antifungals)
19. Patients with a diagnosis of galactose or lactose intolerance or a glucose-galactose-malabsortion

E.5 End points

E.5.1

Primary end point(s)

• The rate of complete clinicohematologic responses (CHR) at month 6 compared to baseline as defined by Barosi et al 2009

E.5.1.1

Timepoint(s) of evaluation of this end point

EOT

E.5.2

Secondary end point(s)

• Safety of both regimens
• The rate of complete clinicohematologic responses (CHR) at month 12 and month 24 as defined by Barosi et al. Blood 2009 (with the clinical modification that splenomegaly assessment may be done by ultrasound or palpation)
• To determine the complete response (CR) rate at month 6 as defined by Barosi et al. Blood 2013 (revised ELN response criteria, see section 15.6) (Barosi, et al., 2013)
• The efficacy as assessed by both the absence of phlebotomy (Hct <45%) and reduction in spleen size (palpable spleen that is reduced by > 50% from baseline measured by palpation or ultrasound) OR platelet count < 600 x 109/l (ET) at month 6 and month 24
• The proportion of subjects achieving both durable absence of phlebotomy eligibility and durable spleen size reduction measured by palpation (PV) OR durable platelet count < 600 x 109/l (ET) (durable defined as > 3 months) (Barosi et al. 2009/2013) at month 6, month 12 and month 24
• The rate of overall clinicohematologic responses (CR + PR) according to both guidelines (Barosi et al. 2009 and 2013) at month 6 and month 24

E.5.2.1

Timepoint(s) of evaluation of this end point

EOT

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

e.g. Hydroxyurea, Interferon, Anagrelide, Pipobroman, Busulfan

Control group will receive Best Available Therapy based on the investigator’s best judgment.

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

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:

380

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

380

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

380

F.4.2

For a multinational trial

F.4.2.1

In the EEA

380

F.4.2.2

In the whole clinical trial

380

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)

For patients failing BAT at the 6 month time point, crossover is possible (see section 7.17 for crossover requirements).

After study completion, all subjects are followed up in a MPN registry

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

2015-03-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-06-29

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

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