Clinical Trials Register

Summary
EudraCT Number:	2018-003162-13
Sponsor's Protocol Code Number:	WI232128
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-11-08
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2018-003162-13

A.3

Full title of the trial

A Study to investigate Bone turnover Markers in patients planned to receive tofacitinib

Uno studio per indagare marcatori di turnover osseo in pazienti in procinto di avviare
la terapia con tofacitinib

A.3.1

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

A Study to investigate Bone turnover Markers in patients planned to receive tofacitinib

Uno studio per indagare marcatori di turnover osseo in pazienti in procinto di avviare
la terapia con tofacitinib

A.3.2

Name or abbreviated title of the trial where available

WI232128

A.4.1

Sponsor's protocol code number

WI232128

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	AZIENDA OSPEDALIERA UNIVERSITARIA INTEGRATA VERONA
B.1.3.4	Country	Italy
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	Pfizer S.r.l.
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AOUI Verona
B.5.2	Functional name of contact point	Unità Ricerca Clinica
B.5.3	Address:
B.5.3.1	Street Address	P.le Stefani 1
B.5.3.2	Town/ city	Verona
B.5.3.3	Post code	37126
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390458127043
B.5.5	Fax number	00390458122814
B.5.6	E-mail	supporto.noprofit@aovr.veneto.it

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	XELJANZ 5 mg film-coated tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Limited
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Xeljanz 5mg
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	TOFACITINIB
D.3.9.1	CAS number	477600-75-2
D.3.9.2	Current sponsor code	TOFACITINIB
D.3.9.4	EV Substance Code	SUB33104
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

Rheumatoid arthritis

Artrite reumatoide

E.1.1.1

Medical condition in easily understood language

Rheumatoid arthritis

Artrite reumatoide

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10039073
E.1.2	Term	Rheumatoid arthritis
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue 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 our study is to investigate the effect of tofacitinib on serum
levels of bone turnover markers (CTX ng/ml, P1NP ng/ml, BAP ng/ml) and modulators
(DKK1 pmol/L, Sclerostin pmol/L, OPG pmol/L, RANKL pmol/L, PTH pg/ml, 25 OH vitamin D
ng/ml)

L'obiettivo principale del nostro studio è di studiare l'effetto di Tofacitinib sui
livelli sierici dei marker di turnover osseo (CTX ng / ml, P1NP ng / ml, BAP ng / ml)
e modulatori del turnover osseo (DKK1 pmol / L, Sclerostin pmol / L, OPG pmol / L,
RANKL pmol / L, PTH pg / ml, 25 OH vitamina D ng / ml)

E.2.2

Secondary objectives of the trial

1. changes versus baseline in hip and lumbar bone mineral density (BMD) by Dual X-ray
Absorptiometry (DXA), hand BMD by DXR, bone erosions and anti-citrullinated peptides
antibodies (ACPA),
2. to investigate the correlations between ACPA, bone turnover markers and modulators
(BTM), bone mineral density (BMD) by Dual X-ray Absoptiometry (DXA), metacarpal index
(MCI) and Bone Health Index (BHI) by and Digital X-ray Radiogrammometry (DXR), and
bone erosions in patients with RA with short disease duration.
3. to evaluate the influence of tofacitinib on those outcomes and determinate if they
are related to the effect on ACPA titer

1. variazioni rispetto al basale della densità minerale ossea (BMD) dell'anca e
lombare mediante Dual X-ray Absorptiometry (DXA), della BMD della mano mediante DXR,
delle erosioni ossee e degli anticorpi anti-citrullinati (ACPA)
2. indagare le correlazioni tra ACPA, marcatori e modulatori del turnover osseo (BTM),
densità minerale ossea (BMD) mediante Dual X-ray Absoptiometry (DXA), metacarpal index
(MCI) e Bone Health Index (BHI) mediante Digital X-ray Radiogrammometry (DXR) e
erosioni ossee in pazienti con AR con breve durata della malattia.
3. valutare l'influenza di tofacitinib su questi outcomes e determinare se sono
correlati all'effetto sul titolo anticorpale di ACPA

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age = 18 years
• Signed and dated informed consent
• RA diagnosis according to ACR/EULAR 2010 criteria
• Disease onset within 3 years
• Tofacitinib oral therapy required due to synthetic or biologic DMARD
failure/intolerance according to EULAR recommendations
• Glucocorticoid daily dose stable for at least 3 months and = 5 mg/day of
prednisolone equivalent.
• Unregarding ACPA status (both positive and negative included).
• Wash out from previous biologic agent = 3 half lives of the biologic agent and at
least 3 months.
• women of childbearing age must have a negative urine pregnancy test within 7 days
before beginning treatment and they will be informed of the need of an efficacy
contraceptive method during the administration and after 4 weeks from the last dose of
tofacitinib
• patients must be negative to screening exam for latent infections ( HIV, HCV, HBV,
quantiferon, chest x-rays)

• Età = 18 anni
• Consenso informato firmato e datato
• Diagnosi di AR secondo criteri ACR/EULAR 2010
• Esordio di malattia entro 3 anni
• Necessità di avviare terapia orale con tofacitinib per fallimento o intolleranza
di DMARD sintetici e/o biologici in accordo con le raccomandazioni EULAR
• Dose stabile di glucocorticoidi da almeno 3 mesi e = 5 mg/die di prednisone
equivalenti.
• status sieropositivo e sieronegativo di ACPA (anticorpi anti-peptidi citrullinati)
• Wash out dal precedente biologico = 3 emivite o almeno 3 mesi.
• Donne in età fertile devono avere un test di gravidanza sulle urine negative entro
i 7 gg antecedenti l’inizio della terapia e devono essere informate sulla necessità di
un metodo contraccettivo efficace durante la somministrazione e fino a 4 settimane dopo
l’ultima somministrazione di tofacitinib.
• I pazienti devono essere negativi agli esami di screening per infezioni latenti
(HIV, HCV, HBV, quantiferon, Rx torace)

E.4

Principal exclusion criteria

• Other rheumatic diagnosis other than RA
• Bone diseases other than osteoporosis
• Severe liver or kidney disease
• Not-controlled endocrine disease
• Contraindication to tofacitinib (concomitant recurrent or chronic infections,
tumor in the previous 5 years)
• Previous treatment with other biologic agents within 3 months or 3 half lives of
the last one
• Concomitant (or before 12 months, except for zoledronate that is before 24
months) treatment with bisphosphonate, strontium ranelate, teriparatide, selective
estrogen receptor modulators (SERM) or denosumab.
• Intra-articular injections at MCPs or MTPs in the 3 months before.
• Pregnancy or breast feeding status
• Prisoners or subjects who are compulsory detained

• Presenza di altre diagnosi reumatologiche oltre all’artrite reumatoide
• Malattie metaboliche ossee diverse dall’osteoporosi
• Significativa compromissione renale o epatica
• Malattie endocrinoogiche non controllate
• Controindicazioni a tofacitinib (infezioni ricorrenti o croniche, neoplasie negli
ultimi 5 anni)
• Precedente trattamento con farmaci biologici nei tre mesi precedenti o 3 emivite
del farmaco.
• Trattamento concomitante o nei precedenti 12 mesi (o 24 mesi per lo zoledronato)
con bisfosfonati, ranelato di stronzio, teriparatide, modulatori selettivi dei recettori
per estrogeni (SERM) o denosumab.
• Iniziezioni intrarticolari a livello delle articolazioni metacarpo-falangea nei
precedenti tre mesi.
• Stato di gravidanza o allattamento.
• Carcerati

E.5 End points

E.5.1

Primary end point(s)

Serum levels of bone turnover markers (CTX ng/ml, P1NP ng/ml, BAP ng/ml) and
modulators (DKK1 pmol/L, Sclerostin pmol/L, OPG pmol/L, RANKL pmol/L, PTH pg/ml, 25 OH
vitamin D ng/ml) serum levels at multiple timepoints (M1, M2, M3, M6, M9 e M12) versus
pre-treatment levels (M0)

Livelli sierici dei marker di turnover osseo (CTX ng / ml, P1NP ng / ml, BAP ng / ml)
e dei suoi modulatori (DKK1 pmol / L, Sclerostin pmol / L, OPG pmol / L, RANKL pmol/L, PTH pg / ml, 25 OH vitamina D ng / ml) a più timepoints (M1, M2, M3, M6, M9 e M12)
rispetto ai livelli pre-trattamento (M0)

E.5.1.1

Timepoint(s) of evaluation of this end point

M0 vs M1, M2, M3, M6, M9, M12

E.5.2

Secondary end point(s)

Systemic BMD (lumbar e femoral T and Z-scores) and hand MCI/BHI, evaluation of bone
erosions (Sharp van der Heijde Score), RF U/ml, ACPAU/ml at multiple timepoints (M0,
M1, M2, M3, M6, M9 e M12). These endpoints refers to secondary objectives 1., 2., 3

BMD sistemica (T e Z-scores lombare e femorale) e MCI/BHI della mano, valutazione
erosioni ossee (Sharp van der Heijde Score), fattore reumatoide U/ml, Anti- CCP U/ml a
più timepoints (M0, M1, M2, M3, M6, M9 e M12). Tali endpoint si rifanno agli obiettivi
secondari 1., 2., 3

E.5.2.1

Timepoint(s) of evaluation of this end point

M0, M1, M2, M3, M6, M9, M12

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

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

Yes

E.6.13.1

Other scope of the trial description

To evaluate the effect of Tofacitinib on bone metabolism

Valutare l'effetto di Tofacitinib sul metabolismo osseo

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)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

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

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.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

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)

Patients will be treated according to the best clinical practice

I pazienti saranno trattati come da migliore pratica clinica

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

2019-01-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-01-23

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

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