Clinical Trials Register

Summary
EudraCT Number:	2019-004219-29
Sponsor's Protocol Code Number:	140041
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-02-04
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

2019-004219-29

A.3

Full title of the trial

“Personalized AZithromycin/metronidAZole, in combination with standard induction therapy, to achieve a fecal microbiome community structure and metagenome changes associated with sustained remission in pediatric Crohn’s Disease (CD): a pilot study”

"Gepersonaliseerde Azitromycine/metronidAZole in combinatie met standaard inductie therapie, voor het bereiken van een microbioom structuur en metagenoom veranderingen geassocieerd met aanhoudende remissie bij kinderen met ziekte van Crohn: een pilot studie"

A.3.1

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

Personalized antibiotic therapy in combination with standard therapy to achieve a fecal profile associated with prolonged complaint-free period in pediatric Crohn’s Disease

Gepersonaliseerde antibiotische therapie in combinatie met standaard therapie voor het bereiken van een ontlasting profiel dat geassocieerd is met langere klachtenvrije periode bij kinderen met de ziekte van Crohn

A.3.2

Name or abbreviated title of the trial where available

PAZAZ

A.4.1

Sponsor's protocol code number

140041

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	Amsterdam UMC
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	Wetenschappelijke Adviesraad Emma Children's Hospital
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	Crohn's and Colitis foundation of America
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	Amsterdam UMC
B.5.2	Functional name of contact point	Charlotte Verburgt
B.5.3	Address:
B.5.3.1	Street Address	Meibergdreef 9
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1105 AZ
B.5.3.4	Country	Netherlands
B.5.6	E-mail	c.m.verburgt@amsterdamumc.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	Azithromycin
D.2.1.1.2	Name of the Marketing Authorisation holder	Generic medication
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	Azithromycin
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	Azithromycin
D.3.9.3	Other descriptive name	AZITHROMYCIN
D.3.9.4	EV Substance Code	SUB05660MIG
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	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	Metronidazole
D.2.1.1.2	Name of the Marketing Authorisation holder	Generic medication
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	Metronidazole
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	METRONIDAZOLE
D.3.9.3	Other descriptive name	METRONIDAZOLE
D.3.9.4	EV Substance Code	SUB08922MIG
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

Crohn's Disease

Ziekte van Crohn

E.1.1.1

Medical condition in easily understood language

Chronic bowel inflammation

Chronische darmontsteking

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

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 primary objective is to evaluate the potential efficacy of personalized adjunctive antibiotic therapy in maintaining clinical remission in pediatric subjects undergoing SOC induction therapy for mild to moderate Crohn’s disease who have a relapse-associated microbiome profile

Het primaire doel is het evalueren van de potentiële werkzaamheid van gepersonaliseerde adjunctieve antibiotische therapie voor het handhaven van de klinische remissie bij pediatrische patiënten die CDED-inductietherapie ondergaan voor milde tot matige ziekte van Crohn die een terugval-geassocieerd microbioomprofiel hebben.

E.2.2

Secondary objectives of the trial

The secondary objectives are to evaluate the potential efficacy of personalized adjunctive antibiotic therapy in improving PRO, components of established disease activity measures in remission, as well as ‘biochemical’ remission in pediatric subjects undergoing SOC induction therapy for mild to moderate Crohn’s disease who have a relapse-associated microbiome profile.

The exploratory objective is to investigate relationship between changes in subject microbiome composition and changes in disease activity over time.

De secundaire doelstellingen zijn het evalueren van de potentiële werkzaamheid van gepersonaliseerde adjunctieve antibiotische therapie bij het verbeteren van patiënt-gerapporteerde outcome, componenten van vastgestelde ziekteactiviteit bij remissie, evenals 'biochemische' remissie bij pediatrische patiënten die CDED inductietherapie ondergaan voor milde tot matige ziekte van Crohn met een relaps-geassocieerd microbioomprofiel.

Het verkennende doel is om de relatie tussen veranderingen in de samenstelling van het microbioom van het onderwerp en veranderingen in ziekteactiviteit in de tijd te onderzoeken.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

microbiome changes associated with maintenance of remission

Personalized AZithromycin/metronidAZole, in combination with standard induction therapy, to achieve a fecal microbiome community structure and metagenome changes associated with sustained remission in pediatric Crohn’s Disease (CD): a pilot study - Protocol v1.5

E.3

Principal inclusion criteria

1. Provision of signed and dated informed consent form (and assent form, as applicable)
2. Stated willingness to comply with all study procedures and availability for the duration of the study
3. Male or female, aged 3 to 17 years
4. Diagnosed with CD according to standard clinical and histological criteria, within 36 months of week 0
5. Exhibiting mild to moderate symptoms of active disease, as determined by a PCDAI score >10 (or >7.5 excluding the height item) and ≤37.5
6. Evidence of active inflammation based on either: fecal calprotectin level >=250 microgram/g (local laboratory or pre-arranged sponsor testing) within 30 days prior to week 0 visit; or according to accepted endoscopic and histologic evidence obtained during an endoscopy procedure completed within 30 days prior to Week 0 Visit.

1. Gedateerd en ondertekend informed consent formulier met toestemming voor deelname
2. Akkoord met deelname onderzoek en bereidheid om deel te nemen aan alle studie procedures gedurende de gehele duur van het onderzoek
3. Man of vrouw, tussen 3-17 jaar oud
4. Gediagnostiseerd met ziekte van Crohn volgens de standaard klinische en histologische criteria, met bevestiging van diagnose in uiterlijk 36 maanden voor week 0 van het onderzoek
5. Symptomen passend bij mild tot matige ziekte van Crohn, gedefinieerd als een PCDAI score >10 (of >7.5 zonder lengte) en ≤ 37.5
6. Bewijs van inflammatie gebaseerd op een van de volgende: faeces calprotectine >= 250 microgram/g in 30 dagen voor week 0 of volgens endoscopisch en histologisch bewijs verkregen aanwijzingen tijdens een endoscopie binnen 30 dagen voorafgaand aan week 0

E.4

Principal exclusion criteria

1.Current or previous use of anti-TNF or other biologic therapy
2.Presence of stricturing, penetrating (intestinal or perianal) and/or fistulizing CD.
3.Pregnancy or lactation
4.Have undergone intestinal resection
5.Laboratory diagnosis of Clostridium Difficile Infection (CDI), if performed for clinical indication
6.Treatment with another investigational drug or other intervention within 30 days before week 0
7.Risk factors for arrhythmia including history of prolonged QTc, hypokalemia or hypomagnesemia, resting bradycardia, or concurrent treatment with other drugs with potential for QT prolongation.
8.History of Cockayne syndrome
9.Prior diagnosis of any hematologic condition/blood dyscrasia which may result in leukopenia (even if leukocyte count is normal at screening)
10.Known allergy or intolerance to azithromycin or metronidazole
11.Subjects who received IV anti-infective within 35 days prior to week 0 visit or oral anti-infectives within 14 days prior to the week 0 visit.
12.Subject on oral aminosalicylates who has not been on stable doses for greater than, or discontinued within, at least 14 days prior to week 0.
13.Subject on cyclosporine, tacrolimus or mycophenolate mofetil. Stable doses (no change within 14 days prior to week 0) of Azathioprine, 6-mercaptopurine or MTX are not a reason for exclusion.
14.Subject who received fecal microbial transplantation within 35 days prior to week 0 visit.
15.Screening laboratory and other analyses show any of the following abnormal results:
o AST, ALT > 2 X upper limit of the reference range (as determined locally at each site)
o Urea, Creatinine > 1.5X upper limit of the reference range (as determined locally at each site)
o White blood cell (WBC) count < 3.0 X 109/L
o Total bilirubin >= 20 micromol/liter (1.17mg/dl); except for subjects with isolated elevation of indirect bilirubin relating to Gilbert syndrome
o Hemoglobin < 80 gram/liter
o Platelets < 100,000/μL

1. Actueel of voormalig gebruik van TNF-alfa remmers of andere biologicals
2. Aanwezigheid van stricturen, penetrerende (intestinale of perianale) en/of fistulerende ziekte van Crohn
3. Zwangerschap of lactatie
4. Het hebben ondergaan van intestinale resectie
5. Diagnose met Clostridium Difficile infectie (indien uitgevoerd voor klinische indicatie)
6. Behandeling met een andere geneesmiddel of interventie voor onderzoeksdoeleinden in de 30 dagen voorafgaand aan week 0 bezoek
7. Risicofactoren voor arytmie, lang QTc in voorgeschiedenis, hypokaliemie, hypomagnesiemie, bradycardie (in rust), inname van medicatie geassocieerd met QT verlenging
8. Voorgeschiedenis met Cockayne syndroom
9. Hematologische aandoening in de voorgeschiedenis die kan resulteren in leukopenie (zelfs indien leukocyten bij screening normaal zijn)
10. Bestaande allergie of intolerantie voor azytromycine of metronidazol
11. Gebruik van intraveneuze anti-infectieuze middelen in de 35 dagen voorgaand week 0 bezoek of orale anti-infectieuze middelen 14 dagen voor week 0 bezoek
12. Gebruik van orale aminosalicylaten die geen stabiele dosis voor langer dan, of gestopt in, de 14 dagen voorafgaand aan week 0 bezoek
13. Gebruik van cyclosporine, tacrolimus of mycofenolaat mofetil. Stabiele doses (geen verandering in 14 dagen voorafgaand aan week 0) van azathioprine, 6-mercaptoourine of MTX zijn geen reden voor exclusie
14. Feacestransplantatie in 35 dagen voor week 0 bezoel
15. Screenende labwaarden of andere analyses die een van de volgende resultaten laat zien:
- ASAT, ALAT >2x bovenste grenswaarde (lokale grenswaarden)
- Ureum, creatinine> 1.5 keer bovenste grenswaarde (lokale grenswaarden)
- White blood cell (WBC) count < 3.0 x 109 /L
- Totale bilirubine >=20 micromol/liter (1.17 mg/dl); behalve voor deelnemers met geïsoleerde elevatie van indirect bilirubine gerelateerd aan syndroom van Gilbert
- Hemoglobine <80g/L
- Trombocyten <100.000/μL

E.5 End points

E.5.1

Primary end point(s)

Primary Outcome variable: Sustained remission defined as no need of re-induction for clinical flare (new course of nutritional therapy, need to start steroids), steroid dependence, biologic (anti-TNF) use, and/or intestinal surgery by 12 months.

Primaire uitkomstvariabele: aanhoudende remissie gedefinieerd als geen behoefte aan re-inductie voor klinische opvlamming (zoals nieuw verloop van voedingstherapie, noodzaak om steroïden te starten), steroïde afhankelijkheid, biologisch (anti-TNF) gebruik en / of darmchirurgie in periode van 12 maanden.

E.5.1.1

Timepoint(s) of evaluation of this end point

52 weeks

52 weken

E.5.2

Secondary end point(s)

Secondary Outcome variables: Longitudinal (clustered and with respect to baseline) changes in disease activity indices (PCDAI: 0-100) components and inflammatory markers in stool and blood at each study visit up to 12 months. Longitudinal (clustered and with respect to baseline) changes in patient-reported outcomes (PRO) by 12 months.
Exploratory Outcome variable: Longitudinal (clustered and with respect to baseline) changes in fecal microbiome taxonomic composition or in total gene (metagenome) content. The changes will be analyzed for association with changes in disease activity (e.g. relapse or sustained remission) over time up to 12 months.

Secundaire uitkomstvariabelen: Longitudinale (geclusterd en ten opzichte van baseline) veranderingen in ziekteactiviteitindices (PCDAI: 0-100), componenten en ontstekingsmarkers in ontlasting, en bloed bij elk studiebezoek tot 12 maanden. Daarnaast ook nog longitudinale (geclusterde en ten opzichte van baseline) veranderingen in door de patiënt gerapporteerde uitkomsten (PRO) gedurende 12 maanden.

Verkennende uitkomstvariabele: longitudinale (geclusterde en ten opzichte van baseline) veranderingen in de fecale microbioom samenstelling of in het totale metagenoom. De veranderingen zullen worden geanalyseerd op verband met veranderingen in ziekteactiviteit (bijv. terugval of aanhoudende remissie) in de periode tot 12 maanden.

E.5.2.1

Timepoint(s) of evaluation of this end point

52 weeks

52 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

Yes

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

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

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

baseline gut microbiome-based randomization

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

Yes

E.8.2.3.1

Comparator description

Crohn's Disease Exclusion Diet (CDED)

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

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

Canada

Israel

United States

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

The end of the study is defined as completion of the last visit or procedure shown in the SoA in the trial globally.

Eind van de studie wordt gedefinieerd als het afronden van het laatste bezoek of procedure van de laatst geincludeerde zoals beschreven in het protocol.

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

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

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)

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2020-02-04.

Yes

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)

Treatment or care after the trial is conform standard of care.

Behandeling en/of zorg na de trial is gelijk aan de reguliere zorg.

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

2020-02-04

Ethics Committee Opinion of the trial application

Not-Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-04-21

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-02-27

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