Clinical Trials Register

Summary
EudraCT Number:	2016-002584-33
Sponsor's Protocol Code Number:	CINC424C2301
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:	2016-10-20
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

2016-002584-33

A.3

Full title of the trial

A phase III randomized open-label multi-center study of ruxolitinib vs. best available therapy in patients with corticosteroid-refractory acute graft vs. host disease after allogenic stem cell transplantation

A.3.1

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

Safety and efficacy of ruxolitinib versus best available therapy in patients with corticosteroid-refractory acute graft vs. host disease after allogeneic stem cell transplantation

A.4.1

Sponsor's protocol code number

CINC424C2301

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/349/2017

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Novartis Pharma Services AG
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Pharma Services AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Pharma GmbH
B.5.2	Functional name of contact point	Medizinischer Infoservice (MCC)
B.5.3	Address:
B.5.3.1	Street Address	Roonstrasse 25
B.5.3.2	Town/ city	Nürnberg
B.5.3.3	Post code	90429
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49 911 27312100
B.5.5	Fax number	+49 911 27312160
B.5.6	E-mail	infoservice.novartis@novartis.com

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
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm 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	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	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.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

corticosteroid-refractory acute graft vs. host disease after allogeneic stem cell transplantation

E.1.1.1

Medical condition in easily understood language

acute Graft versus host disease

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	20.1
E.1.2	Level	PT
E.1.2	Classification code	10066260
E.1.2	Term	Acute graft versus host disease
E.1.2	System Organ Class	10021428 - Immune system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10066262
E.1.2	Term	Acute graft versus host disease in skin
E.1.2	System Organ Class	10021428 - Immune system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10066264
E.1.2	Term	Acute graft versus host disease in intestine
E.1.2	System Organ Class	10021428 - Immune system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10066263
E.1.2	Term	Acute graft versus host disease in liver
E.1.2	System Organ Class	10021428 - Immune system 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 main objective of the trial is to compare the efficacy of ruxolitinib with best available therapy in patients with corticosteroid refractory acute Graft vs. Host Disease by assessing the overall response rate (either complete or partial response without requiring additional systemic therapies) based on organ stage scoring.

E.2.2

Secondary objectives of the trial

The key secondary objectif of the trial is to measure the durable response rate of patients who are corticosteroid refractory acute graft vs. host disease and to compare those patients treated with ruxolitinib vs. best available therapy.
The other secondary objectives relate to further measurements comparing patients treated with ruxolitinib vs. best available therapy:
Their survival over a 2 year time period.
Whether steroids are successfully tapered to lower doses.
Whether they develop chronic graft vs. host disease, and other standard transplant outcomes including control of their underlying hematologic disease for which the transplant was performed.
The safety of ruxolitinib and best available therapy.
Measurements of each patient’s reported quality of life will be compared in patients treated with ruxolitinib vs. best available therapy for their corticosteroid refractory acute graft vs. host disease.
To estimate the rate of Best Overall Response (BOR)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Have undergone alloSCT from any donor source (matched unrelated donor, sibling, haplo-identical) using bone marrow, peripheral blood stem cells, or
cord blood. Recipients of non- myeloablative, myeloablative, and reduced intensity conditioning are eligible
- Clinically diagnosed Grades II to IV acute GvHD as per standard criteria occurring after alloSCT requiring systemic immune suppressive
therapy. Biopsy of involved organs with aGvHD is encouraged but not required for study screening.
- Confirmed diagnosis of corticosteroid refractory aGvHD (confirmed within 48h prior to study treatment start) defined as:
• Patients administered high-dose systemic corticosteroids (methylprednisolone 2 mg/kg/day [or equivalent prednisone dose 2.5 mg/kg/day]), given alone or combined with calcineurin inhibitors (CNI) and either:
• Progressing based on organ assessment after at least 3 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD,
OR
• Failure to achieve at a minimum partial response based on organ assessment after 7 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD,
OR
• Patients who fail corticosteroid taper defined as fulfilling either one of the following criteria:
• Requirement for an increase in the corticosteroid dose to methylprednisolone ≥2 mg/kg/day (or equivalent prednisone dose ≥2.5 mg/kg/day)
OR
• Failure to taper the methylprednisolone dose to <1 mg/kg/day (or equivalent prednisone dose <1.25 mg/kg/day) for a minimum 7 days.

E.4

Principal exclusion criteria

- Has received more than one systemic treatment for steriod refractory aGvHD,
- Clinical presentation resembling de novo chronic GvHD or GvHD overlap syndrome with both acute and chronic GvHD features (as defined by Jagasia, et al. 2015)
- Presence of an active uncontrolled infection including significant bacterial, fungal, viral or parasitic infection requiring treatment. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no signs of progression are present. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection.
Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
- Evidence of uncontrolled viral infection including CMV, EBV, HHV-6, HBV, or HCV based on assessment by the treating physicial.
- Presence of relapsed primary malignancy, or who have been treated for relapse after the alloHSCT was performed, or who may require rapid immune suppression withdrawal as pre-emergent treatment of early malignancy relapse.
Other protocol-defined inclusion/exclusion criteria may apply.

E.5 End points

E.5.1

Primary end point(s)

Overall Response Rate (ORR)
• ORR is defined as the proportion of patients with a best overall response defined as complete response or partial response without requirement for additional systemic therapy for an early progression, mixed response, or non response.

E.5.1.1

Timepoint(s) of evaluation of this end point

28 Days

E.5.2

Secondary end point(s)

1. Durable Overall Response Rate
o Proportion of all patients in each arm who achieve a complete response (CR) or partial response (PR) at Day 28 and maintain a CR or PR at Day 56.
2.Proportion of patients who achieved OR (CR+PR) at Day 14.
3. Duration of response
o DOR is the time from first response until aGvHD progression or the date of additional systemic therapies for aGvHD.
4. Cumulative steroid dose
o Weekly cumulative steroid dose for each subject up to Day 56 or end of treatment
5. Overall Survival (OS)
o OS is defined as the time from the date of randomization to the date of death due to any cause.
6. Event-free survival
o Event-free survival, defined as the time from the date of randomization to the date of hematologic disease relapse/progression, graft failure, or death due to any cause.
7. Failure-Free survival (FFS)
o FFS is defined as the time from the date of randomization to date of hematologic disease relapse/progression, non- relapse mortality, or addition of new systemic aGvHD treatment.
8. Non Relapse Mortality (NRM)
o NRM is defined as the time from date of randomization to date of death not preceded by hematologic disease relapse/progression
9. Malignancy Relapse/Progression (MR)
o MR is defined as the time from date of randomization to hematologic malignancy relapse/progression.
Calculated for patients with underlying hematologic malignant disease.
10. Incidence of cGvHD
o cGvHD, defined as the diagnosis of any cGvHD including mild, moderate, severe
11.Best Overall Response (BOR), defined as proportion of patients who
achieved RO(CR+PR) at any time pointup to and including D28 and
before the start of additional systemic therapy for aGvHD
12. Pharmacokinetics (PK) of ruxolitinib in Steroid Refractory -acute GvHD patients
o Ruxolitinib plasma concentrations after a single dose and at steady state.
13. Exposure-response relationship of ruxolitinib in SR-aGvHD
o Pharmacokinetics (exposure) and efficacy (ORR, OS or other relevant
endpoints) relationship. Pharmacokinetics (exposure) and safety (AEs) relationship.
14. Patient Reported Outcomes (PROs): Change in FACT-BMT from baseline, only in adults
15. Patient Reported Outcomes (PROs): Change in EQ-5D-5L from baseline

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Day 56
2. Day 14
3. Up to 24 weeks
4. 56 Days
5. Up to 24 months
6. Up to 24 months
7. Up to 24 months
8. Up to 24 months
9. Up to 24 months
10. Up to 24 months
11. Up to Day 28
12. 168 Days
13. 168 Days
14. Baseline, Up to 30 day follow-up visit
15. Baseline, Up to 30 day follow-up visit

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

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)

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

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

Best available therapy (BAT)

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

104

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

Argentina

Australia

Austria

Bulgaria

Canada

Czechia

Denmark

France

Germany

Greece

Hong Kong

Hungary

Israel

Italy

Japan

Korea, Republic of

Netherlands

Norway

Poland

Portugal

Russian Federation

Saudi Arabia

Spain

Sweden

Taiwan

Turkey

United Kingdom

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

End of Study (EoS) will occur when all patients have reached Month 24 (2 years from randomization), unless the patient withdraws consent.

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

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

281

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

226

F.4.2.2

In the whole clinical trial

308

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)

Patients who are still receiving ruxolitinib at their end of study
(approximately 2 years from randomization), and deriving clinical
benefit from ruxolitinib as assessed by the Investigator, will be given
the possibility to continue ruxolitinib outside the study from another
source, where permitted by and in accordance to local laws and
regulations.

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

2016-12-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-01-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-04-23

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