Clinical Trials Register

Summary
EudraCT Number:	2018-001678-10
Sponsor's Protocol Code Number:	NL65853.029.18
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-02-20
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

Netherlands - Competent Authority

A.2

EudraCT number

2018-001678-10

A.3

Full title of the trial

Tofacitinib: salvage therapy for patients with RCDII - a pilot study

Tofacitinib: laatste redmiddel voor patiënten met RCDII - een pilot study

A.3.1

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

Research with the drug tofacitinib for patients with refractory celiac disease type II

Onderzoek met het geneesmiddel tofacitinib bij patiënten met refractaire coeliakie type II

A.3.2

Name or abbreviated title of the trial where available

TOF-RCDII

A.4.1

Sponsor's protocol code number

NL65853.029.18

A.5.4

Other Identifiers

Name:

NTR

Number:

7529

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	VU Medical Center
B.1.3.4	Country	Netherlands
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	VU University Medical Center
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	VU University Medical Center
B.5.2	Functional name of contact point	MDL Research
B.5.3	Address:
B.5.3.1	Street Address	De Boelelaan 1117
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1081 HV
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	0031204443522
B.5.5	Fax number	0031204440554
B.5.6	E-mail	mdl.research@vumc.nl

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, INN-tofacitinib citrate
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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.3.8	INN - Proposed INN	TOFACITINIB
D.3.9.1	CAS number	477600-75-2
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	range
D.3.10.3	Concentration number	5 to 10
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

Refractory celiac disease type II

Refractaire coeliakie type II

E.1.1.1

Medical condition in easily understood language

Refractory celiac disease type II

Refractaire coeliakie type II

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

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 evaluate the efficacy of tofacitinib treatment in patients with RCDII with persistent or recurrent villous atrophy (Marsh III ABC) and aberrant IEL T-cells (> 20% as assessed by flow cytometry).

Evaluatie van effectiviteit van tofacitinib bij patiënten met RCDII met persisterende of terugkerende vlokatrofie (Marsh III ABC) en aberrant IEL T-cellen (> 20% aIELS, geanalyseerd mbv flowcytometrie).

E.2.2

Secondary objectives of the trial

- To assess the safety of tofacitinib in patients with RCDII.
- To evaluate the effect of of tofacitinib on quality-of-life of patients with RCDII when treated with tofacitinib.
- To evaluate predictability of response to tofacitinib therapy with an in vitro assay.

- Evaluatie van de veiligheid van tofacitinib bij patiënten met RCDII.
- Evaluatie van het effect van tofacitinib op de kwaliteit van leven bij patienten met RCDII.
- Immunologische veranderingen bekijken bij patineten met RCDII wanneer behandeld met tofacitinib.
- Evaluatie van de voorspelbaarheid van tofacitinib respons met behulp van een in vitro assay.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Adult patients ≥ 18 years old
2. Given informed consent
3. Diagnosis of RCDII
4. Total adherence to a glutenfree diet for at least 6 consecutive months prior to screening. Subjects must also agree to make no changes to their current GFD for the duration of study participation.
5. Anti-tissue transglutaminase (IgA and IgG) at screening < 2x the diagnostic level for celiac disease (weak positive or negative)
6. In case of female fertile patients: negative serum pregnancy test prior to study enrollment; adequate contraception, up to 4 weeks after final dose.
7. Laboratory values:
a) Total WBC > 0.75 x 10^9/L (i.e. > 750/mm3)
n) Hemoglobin > 5.5 mmol/L (i.e. 8.86 g/dL)
c) Absolute neutrophil count > 1 x 10^9 / L (i.e. > 1000 cells/mm3.)
d) Estimated eGFR > 30mL/min/1.73m2 using the Cockcroft-Gault equation.
e) Platelets > 50 x 109/L (i.e. 50000/mm3)
8. PET/CT-scan without signs of abnormalities suggestive for EATL within 3 months.
9. Willingness and ability to comply with study procedures.
10. Willingness to return for all scheduled follow-up visits.

1. Volwassen patienten (≥ 18 jaar oud)
2. Getekend informed consent
3. Diagnose van RCDII
4. Glutenvrij dieet afgelopen 6 maanden voor screening. Patiënten moeten er ook mee akkoord gaan om geen veranderingen in hun glutenvrije dieet te maken zolang ze meedoen aan de studie.
5. Anti-tissue transglutaminase (IgA and IgG) bij screening < 2x diagnostic levle voor coeliakie (zwak positief of negatief)
6. Bij vrouwelijke patiënten in vruchtbare periode: negatieve serum zwangerschapstest; adequate contraceptie, tot 4 weken na de laatste dosis tofacitinib.
7. Labwaardes:
a) Totaal WBC > 0.75 x 10^9/L (i.e. > 750/mm3)
b) Hemoglobine > 5.5 mmol/L (i.e. 8.86 g/dL)
c) Absolute neutrophil count > 1 x 10^9 / L (i.e. > 1000 cells/mm3.)
d) Geschatte eGFR > 30mL/min/1.73m2 using the Cockcroft-Gault equation.
e) Trombocyten > 50 x 10^9/L (i.e. 50000/mm3)
8. PET/CT-scan zonder tekenen/abnormaliteiten suggestief voor EATL binnen de afgelopen 3 maanden.
9. Bereidheid en mogelijkheid om te voldoen aan de onderzoeksprocedures.
10. Bereidheid om terug te keren voor alle onderzoeksbezoeken.

E.4

Principal exclusion criteria

1. Diagnosis of RCDI, EATL
2. Presence of any of the following diagnosis:
a) Active acute infections, which require systemic treatments (specific attention for treatment with ketoconazol or fluconazole (as well CYP3A4 metabolizers).
b) Severe infection prior to screening
c) Active tuberculosis (TBC) (as confirmed in PET/CT-scan; chest radiography)
d) Untreated or inadequately treated latent TB (as confirmed with a positive IGRA test (QuantiFERON-TB Gold Plus test)).
- NB. Subjects are permitted to enroll in study after ≥ 4 months treatment with rifampicine)
e) History within 3 years of opportunistic infections typical of those seen in immunocomprised patients, such as systemic candida infection.
f) Severe liver insufficiency (Child Pugh Score 10-15)
3. Positive Hep B, Hep C or HIV test results at the time of screening.
4. Vaccination with live, attenuated vaccines (such as varicella zoster vaccine, yellow fever, oral typhoid vaccine) within 2 weeks before start of tofacitinib.
5. History of significant immune suppression:
a) BMT therapy less than 6 months prior to baseline
b) Potent systemic immune suppressants (e.g., azathioprine, within specified time periods per drug type) prior to baseline.
6. Subjects receiving moderate/potent CYP3A inducers or inhibitors in the specified time periods prior to the first dose of study drug:
- Moderate/potent CYP3A inducers, within 28 days of 5 half-lives, whichever is longer, prior to first dose of study drug;
- Moderate/potent CYP3A inhibitors, within 7 days or 5 half-lives, whichever is longer, prior to first dose of study drug.
i. NB.Topical (including skin or mucous membranes) application of antimicriobial and antifungal medications is permitted.
7. Screening 12-lead ECG that demonstrates clinically relevant abnormalities which may affect subject safety or interpretation of study results.
8. History or presence of clinically significant disease that in the opinion of the investigator would confound the subject’s participation and follow-up in the clinical trial or put the subject at unnecessary risk (e.g. uncontrolled cardiac diseases, uncontrolled/chronic pulmonary, renal, endocrine, hematological, gastrointestinal, immunologic, dermatological, neurological or psychiatric dysfunction).
9. History of drug or alcohol abuse that would interfere with the ability to comply with the study protocol.
10. History of clinically significant hypersensitivity to the study drug or to any of the excipients
11. Females who are pregnant, becoming pregnant or are currently breastfeeding.
12. Participation in any other investigational drug study in the past 30 days/5 half-lives.
13. Any additional reason which would endanger safety of the subject for participation in this study, in the opinion of the investigator.

1. Diagnosis van RCDI, EATL
2. Aanwezigheid van een de volgende diagnoses:
a) Actieve acute infecties waarvoor systemische behandeling wordt gegeven (met name attentie voor behandeling met ketoconazol en fluconazol (en andere CYP3A4 metabolizers)
b) Ernstige infectie voorafgaand aan screening
c) Actieve tuberculose (TBC)
d) Onbehandelde of onvoldoende behandelde latente TB (zoals bevestigd met een positieve IGRA test (QuantiFERON-TB Gold Plus test)).
e) Voorgeschiedenis in afgelopen 3 jaar van opportunistische infecties die typisch worden gezien bij immuungecompromitteerde patienten, zoals systemische candida infecties.
f) Ernstige leverinsufficiëntie (Child Pugh Score 10-15)
3. Positieve Hep B, Hep C of HIV test resultaten t.t.v. screening.
4. Vaccinatie met levende, verzwakte vaccines (zoals varicella zoster vaccin, gele koorts of oraal buiktyfus vaccin), 2 weken voorafgaand aan de eerste inname van tofacitinib.
5. Voorgeschiedenis van significante immuunsuppressie:
a) Beenmergtransplantatie minder 6 maanden voorafgaand aan baseline.
b) Potente systemische immuunsuppressiva (e.g. azathioprine, in tijdsperiodes specifiek per medicijn) voor baseline.
6. Proefpersonen die matig-sterke CYP3A4 remmers of sterke CYP3A4 remmers gebruiken in de gespecificeerde tijdsperiodes voor de eerste dosis van tofacitinib:
- Matige/sterke CYP3A inducers, binnen 28 dagen of 5 half-lives, welke langer is, voor de eerste dosis van tofacitinib;
- Matige/sterke CYP3A remmers, binnen 7 dagen of 5 half-lives, welke langer is, voor de eerste dosis van tofacitinib.
7. Screening 12-kanaals ECG welke klinische relevante afwijkingen laten zien die eventueel de patiënt in gevaar kunnen brengen; interpretatie van de studieresultaten kunnen beïnvloeden.
8. Voorgeschiedenis of aanwezigheid van klinisch significante ziekte die naar mening van de onderzoeker, de deelname en follow-up van de participant in de klinische trial zou kunnen verstoren of de participant onnodig in gevaar zou kunnen brengen. (e.g. ongecontroleerde cardiale ziektes, ongecontroleerde/chronische long-, nier-, endocriene, hematologische, gastrointestinale, immunologische, dermatologische, neurologische of psychiatrische dysfunctie.
9. Voorgeschiedenis van medicijn- of alcoholmisbruik dat ervoor zou kunnen zorgen dat de participant niet het vermogen heeft om te voldoen aan het onderzoeksprotocol.
10. Voorgeschiedenis van klinisch significante overgevoeligheid voor het onderzoeksmedicijn of een van de hulpstoffen in het medicijn.
11. Vrouwen die zwanger zijn, zwanger worden of borstvoeding geven.
12. Participatie in een ander geneesmiddelenonderzoek in de laatste 30 dagen/ 5 halfwaardetijden van dat medicijn.
13. Elke andere additionele reden die de veiligheid van de potentiele kandidaat in gevaar zou kunnen brengen, naar mening van de onderzoeker.

E.5 End points

E.5.1

Primary end point(s)

Primary efficacy endpoint:

- Immunological response, as defined by:
reduction from baseline of aberrant IELs (%) with respect to total IELs in duodenal biopsies at week 12, as assessed by flow cytometry.

Primaire effectiviteits eindpunten:

- Immunologische respons, gedefinieerd door:
vermindering van baseline in aberrante IELs (%) in verhouding tot totaal IELs, in duodenumbiopten, in week 12, geanalyseerd m.b.v. flow cytometrie.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 weeks

12 weken

E.5.2

Secondary end point(s)

Secondary efficacy endpoints:
- Histological response, as defined by: improvement from baseline in histology scores for celiac disease, as defined by Marsh classification.
- Clinical response: changes from baseline in clinical symptoms, as assesed by:
Bristol Stool Forming Scale (BSFS), gastrointestinal symptom rating scale (GSRS), which includes the celiac disease GSRS (CeD)-GSRS, Celiac Disease Patient Reported Outcome (CeD-PRO), Celiac Disease Symptom Diary (CDSD).

Safety endpoints

Exploratory endpoints:
- Safety of tofacitinib for patients with RCDII
- Changes in quality-of-life when using tofacitinib, as evaluated by questionnaire EQ-5D-5L.
- Immunological changes: by tracking of immune subsets in duodenal biopsies and blood after tofacitinib treatment (single-cell CyTOF) and tracking histological changes in the small intestine after tofacitinib treatment (IHC; Vectra, imaging CyTOF).
- In vitro tofacitinib assay: to evaluate predictability of tofacitinib responsiveness with an in vitro assay (FACS) vs. in vivo immunological response (primary efficacy endpoint)

Secundaire effectiviteits eindpunten:
- Histologische respons, gedefinieerd door:
verbetering vanaf baseline in histologische scores voor coeliakie, zoals gedefinieerd door Marsh classificatie.
- Klinische respons: veranderingen vanaf baseline in klinische symptomen, geëvalueerd door:
Bristol Stoelgangschaal, gastrointestinal symptom rating scale (GSRS) inclusief coeliakie GSRS (CeD-GSRS), door de patiënt gerapporteerde uitkomsten van de ziekte coeliakie (CeD-PRO; CDSD).

Veiligheid van tofacitinib bij patienten met RCDII

Exploratieve eindpunten:
- Verandering in kwaliteit van leven bij gebruik van het middel tofacitinib, geevalueerd door vragenlijst (EQ-5D-5L).
- Immunologische veranderingen, geevalueerd door veranderingen in immunsubsets te bekijken in duodenumbiopten en blood na tofacitinib behandeling (single-cell CyTOF) en histologische veranderingen in de dunne darm te bekijken na tofacitinib behandeling (IHC; Vectra; imaging CyTOF).
- In vitro tofacitinib assay: om de voorspelbaarheid van tofacitinib respons te evalueren met behulp van een in vitro assay (FACS) vs. in vivo immunologische response (7.1.1. Primair effectiviteits eindpunt)

E.5.2.1

Timepoint(s) of evaluation of this end point

- Histology: 12 weeks
- Clinical: continuously
- Safety: continuously
- Quality of life: 12 weeks
- Immunological changes: 12 weeks

- Histologie: 12 weken
- Klinisch: continu
- Veiligheid: continu
- Kwaliteit van leven: 12 weken
- Immunologische veranderingen: 12 weken

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

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.8.3

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

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

Last visit of the last subject in study

Laatste visite van de laatste participant in de studie

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.4.2

For a multinational trial

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)

If it turns out tofacitinib is effective for treatment of RCDII patients, Pfizer will provide tofacitinib for treatment of RCDII patients. In the meantime, the sponsor (VUmc) will request off-label approval at the local drug regulatory authorority (College ter Beoordeling Geneesmiddelen) in the Netherlands.

Als tofacitinib effectief blijkt te zijn voor behandeling van RCDII patienten, dan zal Pfizer tofacitinib blijven geven voor de behandeling van RCDII patienten. Ondertussen zal de sponsor (VUmc) off-label approval aanvragen bij het College ter Beoordeling Geneesmiddelen.

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

2019-02-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-06-06

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

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