Clinical Trials Register

Summary
EudraCT Number:	2012-002318-37
Sponsor's Protocol Code Number:	INCB18424-357
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-12-11
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2012-002318-37

A.3

Full title of the trial

Polycythemia Vera Symptom Study Evaluating Ruxolitinib Versus Hydroxyurea in a Randomized, Multicenter, Double-Blind, Double-Dummy, Phase 3 Efficacy and Safety Study of Patient Reported Outcomes

Studio dei sintomi della policitemia vera per la valutazione dell'efficacia e della sicurezza di ruxolitinib verso idrossiurea in uno studio randomizzato, multicentrico, in doppio cieco, a doppia simulazione di Fase 3 dei risultati riferiti dai pazienti (studio RELIEF)

A.3.1

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

Randomized Polycythemia Vera Symptom Study comparing the effectiveness and patient assessed effects of Ruxolitinib with Hydroxyurea in a Phase 3 trial

Studio randomizzato di commutazione terapeutica da idrossiurea a ruxolitinib per ALLEVIARE i sintomi della policitemia vera: Studio RELIEF

A.3.2

Name or abbreviated title of the trial where available

The RELIEF Study

A.4.1

Sponsor's protocol code number

INCB18424-357

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	INCYTE
B.1.3.4	Country	United States
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	Incyte Corporation
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Incyte Corporation
B.5.2	Functional name of contact point	Incyte Call Centre
B.5.3	Address:
B.5.3.1	Street Address	Rt 141 & Henry Clay Road
B.5.3.2	Town/ city	Wilmington
B.5.3.3	Post code	DE 19880
B.5.3.4	Country	United States
B.5.4	Telephone number	+1 855 4633463
B.5.5	Fax number	+1 302 4252734
B.5.6	E-mail	regaffairs@incyte.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	Jakafi
D.2.1.1.2	Name of the Marketing Authorisation holder	Incyte Corporation
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	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.3.10	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	Comparator
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	Par Hydroxyurea
D.2.1.1.2	Name of the Marketing Authorisation holder	Par Pharmaceutical Inc
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Capsule, hard
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	Hydroxyurea
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	500
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	Tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, hard
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

Polycythemia Vera

Policitemia vera

E.1.1.1

Medical condition in easily understood language

Polycythemia Vera

Policitemia vera

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	14.1
E.1.2	Level	HLGT
E.1.2	Classification code	10018865
E.1.2	Term	Haematopoietic neoplasms (excl leukaemias and lymphomas)
E.1.2	System Organ Class	10005329 - Blood and lymphatic system disorders

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 compare the efficacy of ruxolitinib and HU for reducing the cluster of
symptoms defined by tiredness, itching, muscle aches, night sweats, and
sweats while awake in subjects with PV.ml+xm

Comparare l’efficacia di ruxolitinib e idrossiurea (Hydroxyurea, HU) per la riduzione dell’insieme di sintomi definiti da affaticamento, prurito, dolori muscolari, sudorazioni notturne e sudorazioni da svegli in soggetti con policitemia vera (PV)

E.2.2

Secondary objectives of the trial

To compare the efficacy of ruxolitinib and HU for reducing the following
individual symptoms:
- Tiredness
- Itching
- Muscle aches
- Night sweats
- Sweats while awake
• To evaluate the durability of symptomatic improvement in subjects
experiencing relief from the cluster of symptoms that includes tiredness,
itching, muscle aches, night sweats, and sweats while awake, and for
each of these symptoms individually.
• To evaluate the safety of ruxolitinib and HU.

Comparare l’efficacia di ruxolitinib e HU per la riduzione dei seguenti sintomi individuali:
- Affaticamento
- Prurito
- Dolori muscolari
- Sudorazioni notturne
- Sudorazioni da svegli
• Valutare la durata del miglioramento sintomatico in soggetti che sperimentano sollievo dall’insieme di sintomi che includono affaticamento, prurito, dolori muscolari, sudorazioni notturne e sudorazioni da svegli e per ognuno di questi sintomi individualmente.
• Valutare la sicurezza di ruxolitinib e HU in soggetti con PV

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Men or women aged . 18 years with a confirmed diagnosis of PV
according to the revised World Health Organization criteria.
. Subjects must currently be reporting symptoms on a stable dose of HU
monotherapy and be eligible to continue HU on study after
randomization. Before screening, the subject must have been receiving
HU for at least 12 weeks and on the same dose for the last 4 weeks.
. Subjects must have completed the modified MPN-SAF screening
symptom form and have a screening total symptom score (TSS) of . 8
for the cytokine-related symptoms, or symptom cluster C (TSS-C):
tiredness, itching, muscle aches, night sweats, and sweats while awake.
. Subjects should meet at least one of the following criteria with respect
to phlebotomy and splenomegaly:
. No more than 1 phlebotomy within the 6 months before screening OR
. No palpable splenomegalym
• Subjects must have a hematocrit that can be controlled within 35% to
48% (inclusive) before randomization. (A phlebotomy may be performed
during the screening phase to achieve this target range.)
• Subjects must have recovered from all side effects associated with
phlebotomy, and at least 1 week must have elapsed between the
phlebotomy and the beginning of the baseline phase.
• Subjects with Eastern Cooperative Oncology Group performance status
of 0, 1, or 2 at screening.

Uomini o donne di età ≥ 18 anni con una diagnosi confermata di PV secondo i criteri rivisti dell’Organizzazione Mondiale della Sanità.
• I soggetti devono attualmente riferire sintomi con una dose stabile di monoterapia con HU ed essere idonei a proseguire con HU nello studio dopo la randomizzazione. Prima dello screening il soggetto deve ricevere HU da almeno 12 settimane e allo stesso dosaggio nelle ultime 4 settimane.
• I soggetti devono aver completato il modulo modificato MPN-SAF di screening dei sintomi e avere un punteggio di screening dei sintomi totale (TSS) ≥ 8 per i sintomi correlati alle citochine, o l’insieme C di sintomi (TSS-C): affaticamento, prurito, dolori muscolari, sudorazioni notturne e sudorazioni da sveglio.
• I soggetti devono rispondere ad almeno uno dei seguenti criteri riguardo la flebotomia e la splenomegalia:
− non più di 1 flebotomia nei 6 mesi precedenti lo screening; OPPURE
− assenza di splenomegalia palpabile.
• I soggetti devono avere un ematocrito che può essere controllato tra il 35% e il 48% (inclusi) prima della randomizzazione. (Può essere effettuata una flebotomia durante la fase di screening per raggiungere questo intervallo target).
• I soggetti devono essersi ripresi da tutti gli effetti collaterali associati alla flebotomia e deve essere trascorsa almeno 1 settimana tra la flebotomia e l’inizio della fase basale.
• Soggetti con uno stato di prestazione Eastern Cooperative Oncology Group di 0, 1 o 2 allo screening

E.4

Principal exclusion criteria

Subjects with inadequate liver or renal function at screening as
demonstrated by:
. Encephalopathy . Grade 2 as per Child-Pugh System
. Hepatocellular disease
. Total bilirubin > 2 ~ upper limit of normal (ULN), unless direct
bilirubin is < 2 ~ ULN
. Alanine aminotransferase > 2.5 ~ ULN
. Modification of Diet in Renal Disease estimated glomerular filtration
rate < 30 mL/min/1.73 m2 or on dialysis
. Subjects with platelet count < 100 ~ 10^9/L or an absolute neutrophil
count of < 1 ~ 10^9/L
. Subjects with peripheral blood blast count of > 0% at screening.

Soggetti con funzione epatica o renale inadeguata allo screening come dimostrato da:
. Encefalopatia . grado 2 secondo il sistema Child-Pugh
. Malattia epatocellulare
. Bilirubina totale > 2 x il limite superiore del normale (ULN), a meno che la bilirubina diretta sia < 2 x ULN
. Alanina aminotransferasi (ALT) > 2,5 ~ ULN
. Modifica della dieta nella malattia renale con tasso di filtrazione glomerulare stimato < 30 ml/min/1,73 m2 o in dialisi
. Soggetti con conta piastrinica < 100 x 109/l o conta assoluta dei neutrofili < 1 x 109/l
. I soggetti con conta di blasti nel sangue periferico > 0% allo screening

E.5 End points

E.5.1

Primary end point(s)

Proportion of subjects with ≥50% reduction in the TSS-C (tiredness,
itching, muscle aches, night sweats, and sweats while awake) at Week
16 compared to baseline, as measured by the modified MPN-SAF diary.S

Proporzione di soggetti con ≥50% di riduzione del TSS-C (affaticamento, prurito, dolori muscolari, sudorazioni notturne e sudorazioni da svegli) alla settimana 16 rispetto al basale, come misurato dal diario modificato MPN-SAF.

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 16

16a SETTIMANA

E.5.2

Secondary end point(s)

Proportion of subjects with ≥50% reduction in individual symptoms at
Week 16 compared to baseline, as measured by the modified MPN-SAF
diary for the following items:
. Tiredness
. Itching
. Muscle aches
. Night sweats
. Sweats while awake
Noncomparative Secondary Endpoints
. Proportion of subjects in Arm A who achieve a durable response,
defined as a ≥50% reduction in TSS-C at Week 16 that is maintained at
Week 48.
. Proportions of subjects in Arm A who achieve a durable response,
defined as a ≥50% reduction in the individual symptoms in TSS-C
(tiredness, itching, muscle aches, night sweats, and sweats while
awake) at Week 16 that is maintained at Week 48.
. Safety of ruxolitinib and HU.

Proporzione di soggetti con ≥50% di riduzione dei punteggi di sintomo individuale alla settimana 16 rispetto al basale, come misurato dal diario MPN-SAF modificato per quanto segue:
. Affaticamento
. Prurito
. Dolori muscolari
. Sudorazioni notturne
. Sudorazioni da svegli
. Proporzione di soggetti randomizzati al braccio A di trattamento che raggiungono una risposta duratura, definita come ≥50% di riduzione del TSS-C alla settimana 16 che rimane invariata alla settimana 48.
. Proporzione di soggetti randomizzati al braccio A di trattamento che raggiungono una risposta duratura, definita come ≥50% di riduzione del TSS-C (affaticamento, prurito, dolori muscolari, sudorazioni notturne e sudorazioni da svegli) alla settimana 16 che rimane invariata alla settimana 48.
. Sicurezza di ruxolitinib e HU.

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 16 and week 48

16a E 48a SETTIMANA

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

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)

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

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

Yes

E.8.2.3.1

Comparator description

Idrossiurea

Hydroxyurea

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

United States

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

Subjects who remain on study at the end of the formal data collection period (when all enrolled subjects have reached Week 48 on study or have been withdrawn) will be withdrawn from the study.

I soggetti che rimangono nello studio alla fine del periodo di raccolta dati formali(in cui tutti i soggetti arruolati hanno raggiunto la 48° settimana di studio o sono stati ritirati) saranno ritirati dallo studio.

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

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)

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

100

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)

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

2012-12-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-11-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-06-24

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Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
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