Clinical Trials Register

Summary
EudraCT Number:	2013-003295-12
Sponsor's Protocol Code Number:	15022013
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-10-28
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

Denmark - DHMA

A.2

EudraCT number

2013-003295-12

A.3

Full title of the trial

Combination Therapy Interferon Alpha + JAK1-2 Inhibitor in The Ph-Negative Chronic Myeloid Neoplasms

A.3.1

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

Kombinationsbehandling med Interferon og JAK1-2 Hæmmer i behandlingen af Ph-Negativ Myeloprolifertiv Cancer

A.4.1

Sponsor's protocol code number

15022013

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	Roskilde University Hospital
B.1.3.4	Country
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Roskilde Hospital
B.5.2	Functional name of contact point	Mads Emil Bjørn
B.5.3	Address:
B.5.3.1	Street Address	Koegevej 7-13
B.5.3.2	Town/ city	Roskilde
B.5.4	Telephone number	004526223678
B.5.6	E-mail	hans.hasselbalch@dadlnet.dk

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
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Information not present in EudraCT
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Jakavi
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.3.9.3	Other descriptive name	RUXOLITINIB
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	range
D.3.10.3	Concentration number	10 to 40
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)	Information not present in EudraCT
	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	Pegasys 135 microgram
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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
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	PEGINTERFERON ALFA-2A
D.3.9.1	CAS number	198153-51-4
D.3.9.4	EV Substance Code	SUB16452MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	45
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	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: 3
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	PegIntron 50 microgram
D.2.1.1.2	Name of the Marketing Authorisation holder	MSD
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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
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.3.9.3	Other descriptive name	PEGINTERFERON ALFA-2B
D.3.9.4	EV Substance Code	SUB12549MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	30
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.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

E.1.1.1

Medical condition in easily understood language

Polycythemia vera

Hyperproliferativ myelofibrosis

E.1.1.2

Therapeutic area

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

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10028538
E.1.2	Term	Myelofibrosis with myelometaplasia
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10036061
E.1.2	Term	Polycythemia vera
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10053134
E.1.2	Term	Osteomyelofibrosis
E.1.2	System Organ Class	100000004864

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

Primary Objectives
1. To describe the effect of combination therapy with IFN-alpha (Pegasys, PegIntron) and JAK1-2-inhibitor treatment (ruxolitinib) evaluated by hematological parameters (Hb, hematocrit, white blood cell count, platelet count, LDH, reduction in JAK2V617-mutation allele burden) and quality of life score, which indirectly will also reflect the remission of the IFN-alpha-induced side effects

E.2.2

Secondary objectives of the trial

Secondary Objectives
1. To investigate whether additional treatment with JAK1-2-inhibitor (ruxolitinib) to patients who show intolerance (due to adverse events) during treatment with interferon-alpha (IFN-alpha) (Pegasys, PegIntron) can improve the efficacy based on individual contribution of the two agents regarding that the JAK1-2 inhibitor through its very potent anti-inflammatory efficacy profile may dampen the impact of the systemic inflammatory response mediated by IFN-alpha.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

3.1 Inclusion Criteria
1. Male or female patients> 18 years.
2. Patients with early prefibrotic myelofibrosis /post-ET myelofibrosis , PV, Post-PV myelofibrosis or hyperproliferative PMF according to WHO classification.
3. Active disease defined by one or more of the following criteria, at some time before study enrollment and accordingly not necessarily at the time or weeks before enrollment :
a) Need for venesection (hematocrit> 0.42 in females and > 0.45 in males)
b) White blood cell counts > 10 MIA/L in the absence of infection / inflammation.
c) Platelet count> 400 MIA/L in the absence infection / inflammation.
d) Hypermetabolic symptoms such as weight loss (> 10% within 6 months), night sweats and subfebrilia (temperature> 38 º C for more than 2 weeks without signs of infection)
e) Pruritus
f) Symptomatic splenomegaly
g) Presence of previous thrombosis.

E.4

Principal exclusion criteria

3.2 Exclusion Criteria
1. Childbearing potential patients without a negative pregnancy test prior to initiation of study drug and / or non-acceptance of the use of effective contraceptive methods *
2. Other active malignancy within the past 5 years (except basal cell carcinoma of the skin).
3. ECOG function scores> / = 3
4. Serum creatinine more than 2 x ULN
5. Total serum bilirubin greater than 1.5 x ULN
6. Plasma ALT more than 3 x ULN
7. Former psychiatric disorder (depression diagnosed by a psychiatrist)
8. Uncontrolled metabolic disease.
9. Severe heart disease (heart failure NYHA class 3-4).
10. Severe myelosuppression. (leucocyte count<1.5 Mill/L, Platelet count<100)
11. Chronic hepatitis with decompensated cirrhosis.
12. Chronic hepatitis in patients who have been or recently (within 6 months) has been treated with immunosuppressive drugs with the exception of corticosteroid treatment.
13. Epilepsy and / or other serious CNS disorders.
14. Known hypersensitivity to recombinant interferon (Pegasys or PegIntron) and JAKAVI, or to one or more of these preparations .
* Spiral, birth control pills, implants, transdermal patch, vaginal ring or transdermal injection.
Sterile / infertile subjects are exempt from the use of contraception. In order to be considered sterile or infertile, one must generally be surgically sterilized (vasectomy, bilateral tubectomy, hysterectomy or ovariectomy) or be postmenopausal, defined as absent menstruation for at least 12 months before study enrollment.

E.5 End points

E.5.1

Primary end point(s)

ENDPOINTS
Objective Endpoint related to objective
To describe the effect of combination therapy with IFN-alpha (Pegasys, PegIntron) and JAK1-2-inhibitor treatment (ruxolitinib) Change in hematological parameters (Hb, hematocrit, white blood cell count, platelet count, LDH, reduction in JAK2V617-mutation allele burden) and
Change in quality of life score from baseline (MPN-SAF)

To investigate whether additional treatment with JAK1-2-inhibitor (ruxolitinib) to patients who show intolerance (due to adverse events) during treatment with interferon-alpha (IFN-alpha) (Pegasys, PegIntron) can improve the efficacy based on individual contribution of the two agents regarding that the JAK1-2 inhibitor through its very potent anti-inflammatory effect profile may dampen the systemic inflammatory response mediated by IFN-alpha. Difference in number of IFN-related adverse events compared to matched group in the Dahlia study

The compliance to the treatment, as measured by the number of patients who discontinue ruxolitinib/IFN for AE, and the safety of the treatment, as measured by the number and the type of SAE during Ruxolitinib/IFN alpha treatment.
To investigate whether additional treatment with JAK1-2-inhibitor (ruxolitinib) to patients who exhibit lack of efficacy of treatment (IFN-alpha) (Pegasys, PegIntron) can establish / re-establish treatment response regarding that the JAK1-2 inhibitor through its very potent anti-inflammatory effect profile may reduce / eliminate the systemic inflammation response - mediated by IFN-alpha and MPN disease per se – and thereby potentially may facilitate the inhibition of clonal expansion (by down-regulation of inflammatory cytokines - TNF-alpha 2, IL-6 etc. - and perhaps through an enhancement of IFN-alpha's effects on the immune cells of interest for intact "Tumor Immune Surveillance "(for example, NK cells, dendritic cells, cytotoxic T cells, regulatory T cells)
Number of patients with complete hematological response compared to matched group in DAHLIA study
To investigate whether combination therapy with JAK1-2 inhibitor results in elimination of interferon antibodies (IFN-ab) and thus induction of efficacy in treatment refractory patients with evidence of antibody formation to recombinant interferon Level of interferon antibodies (IFN-ab) compared to baseline

E.5.1.1

Timepoint(s) of evaluation of this end point

Study end (LPLV): February 2019

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

Study end (LPLV): February 2019

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

E.6.4

Safety

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

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

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Single group non-randomized combination study

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

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

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)

None

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

2013-10-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-09-09

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-05-15

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