Clinical Trials Register

Summary
EudraCT Number:	2019-004469-41
Sponsor's Protocol Code Number:	PN-943-03
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:	2021-06-15
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

2019-004469-41

A.3

Full title of the trial

A Phase 2 Randomized, Double-blind, Placebo-controlled, Parallel-group, Multi-center Study to Evaluate the Safety and Efficacy of Oral PN-943 in Subjects with Moderate to Severe Active Ulcerative Colitis

Studio di Fase 2, randomizzato, in doppio cieco, controllato verso placebo, a gruppi paralleli, multicentrico per valutare la sicurezza e l’efficacia di PN-943 orale in soggetti con colite ulcerosa attiva da moderata a grave

A.3.1

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

A trial to investigate the safety and efficacy of PN-943 in patients with
moderate or severe Ulcerative Colitis (a long-term condition where the
colon and rectum become inflamed)

Uno studio per indagare la sicurezza e l'efficacia di PN-943 in pazienti con Colite ulcerosa moderata o grave (una condizione a lungo termine in cui il colon e il retto si infiammano)

A.3.2

Name or abbreviated title of the trial where available

PN-943-03

A.4.1

Sponsor's protocol code number

PN-943-03

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	Protagonist Therapeutics, Inc.
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	Protagonist Therapeutics, Inc
B.4.2	Country	European Union
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Protagonist Therapeutics, Inc.
B.5.2	Functional name of contact point	Clinical-Regulatory Info Group
B.5.3	Address:
B.5.3.1	Street Address	7707, Gateway Blvd, ste 140
B.5.3.2	Town/ city	Newark
B.5.3.3	Post code	CA 94560-1160
B.5.3.4	Country	United States
B.5.4	Telephone number	0015104740170
B.5.5	Fax number	0015103283232
B.5.6	E-mail	clinregpn943@ptgx-inc.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	No
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	PN-943
D.3.2	Product code	[PN-943]
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	ACETATO DI AMMONIO
D.3.9.2	Current sponsor code	PN-943
D.3.9.3	Other descriptive name	PN-943
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	150
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	No
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	PN-943
D.3.2	Product code	[PN-943]
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	ACETATO DI AMMONIO
D.3.9.2	Current sponsor code	PN-943
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	300
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	Tablet
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

Ulcerative colitis (US) is a chronic relapsing inflammatory bowel disease of the large intestine characterized by bloody diarrhoea, abdominal cramps and fatigue. UC is characterized by inflammation and ulceration of mainly the mucosal and occasionally submucosal intestinal layers.

La colite ulcerosa (US) è ¿¿una malattia infiammatoria cronica recidivante dell'intestino crasso caratterizzata da diarrea sanguinolenta, crampi addominali e affaticamento. L'UC è caratterizzata da infiammazione e ulcerazione principalmente degli strati intestinali della mucosa e occasionalmente sottomucosi.

E.1.1.1

Medical condition in easily understood language

English Ulcerative colitis is a long-term condition where the large intestine
(colon) and rectum become inflamed. Small ulcers can develop on the
colon's lining, and can bleed and produce pus.

La colite ulcerosa è una condizione a lungo termine in cui l'intestino crasso,colon e retto si infiammano.Piccole ulcere possono svilupparsi sul rivestimento del colon e può sanguinare e produrre pus.

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10045365
E.1.2	Term	Ulcerative colitis
E.1.2	System Organ Class	100000004856

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Evaluate safety, tolerability and efficacy of PN-943 treatment in subjects with moderate to severe active ulcerative colitis compared to placebo.

valutare la sicurezza, la tollerabilità e l’efficacia del trattamento con PN-943 in soggetti con colite ulcerosa attiva da moderata a grave rispetto al placebo.

E.2.2

Secondary objectives of the trial

Evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and biomarker responses to PN-943 in subjects with moderate to severe active ulcerative colitis.

valutare la farmacocinetica (PK), la farmacodinamica (PD) e la risposta dei biomarcatori a PN-943 in soggetti con colite ulcerosa attiva da moderata a grave.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Part 1 Inclusion Criteria:
1. Male and female subjects age 18 (or the minimum country specific age of consent if >18) to 75 years.
2. Subject understands the study procedures and agrees to participate in the study by giving written informed consent.
3. Diagnosis of UC for = 8 weeks prior to screening supported by appropriate documentation of biopsy results consistent with UC, in the opinion of the investigator; if UC has been present for > 10 years, a total colonoscopy with biopsy must have been performed within 2 years of screening to rule out dysplasia. Subjects must be up-to-date on colorectal cancer surveillance per local standards and guidelines. The colorectal cancer screening may be performed during screening colonoscopy.
4. Moderate to severe active UC with an Adapted Mayo Score of 5 to 9, rectal bleeding subscore (RBS) =1, stool frequency subscore (SFS) =1, and endoscopic subscore (ESS) =2 at baseline (pre-randomization) as determined by blinded central read. ESS of =2 must be observed at =15 cm from the anal verge.
5. Demonstrated inadequate response, loss of response, or intolerance of at least 1 of the following treatments including oral corticosteroids, immunomodulators, IL-12/23 antagonists, and/or TNFa antagonists as defined in the protocol at inclusion criterias section
6. A female participant must be:
a) Not of childbearing potential OR
b) Of childbearing potential and practicing a highly effective method of contraception (failure rate of <1% when used consistently and correctly) and agrees to remain on a highly effective method while receiving study medication and until 30 days after receiving the last dose of study medication. (Appendix 6).
7. A female participant must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for a period of 30 days after receiving the last dose of study medication.
8. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at screening and a negative urine pregnancy test at Day 1 prior to the first dose of study medication.
9. Men with partners of child bearing potential must agree to use a highly effective method of contraception (failure rate of <1% when used consistently and correctly) and agree to remain on a highly effective method while receiving study medication and until 90 days after receiving last dose of study medication (Appendix 6).
10. A male participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 90 days after receiving the last dose.
11. Subject is eligible according to the tuberculosis (TB) screening criteria as stated in the protocol (Appendix 3).
For Inclusion criteria of Part 2, please refer to Study protocol.

Criteri di inclusione Parte 1:
1. Soggetti di sesso maschile e femminile di età compresa tra 18 (o l’età minima specifica per il paese per dare il consenso se > 18 anni) e 75 anni.
2. Il soggetto comprende le procedure dello studio e acconsente a partecipare allo studio dando il proprio consenso informato scritto.
3. Diagnosi di CU per =8 settimane prima dello screening supportata da documentazione appropriata di risultati bioptici compatibili con CU, secondo l’opinione dello sperimentatore; se la CU è presente da >10 anni, una colonscopia totale con biopsia deve essere stata effettuata entro 2 anni dallo screening per escludere displasia. I soggetti devono essere in regola con gli standard e le linee guida locali in merito alla prevenzione del tumore del colon-retto. Lo screening per il tumore del colon-retto può essere eseguito durante la colonscopia di screening.
4. CU da moderata a grave con punteggio Mayo adattato da 5 a 9, parametro del sanguinamento rettale (RBS) =1, parametro di frequenza dell’evacuazione (SFS) =1 e parametro endoscopico (ESS) =2 al basale (prima della randomizzazione), come determinato mediante una lettura centralizzata in cieco. ESS =2 deve essere osservato a =15 cm dal margine anale.
5. Risposta inadeguata comprovata, perdita della risposta o intolleranza ad almeno 1 dei seguenti trattamenti, compresi corticosteroidi, farmaci immunomodulanti, anti-IL-12/23 e/o anti-TNFa come definiti nel protocollo nella sezione dei criteri di inclusione.
6. Le partecipanti di sesso femminile devono essere:
a) Non in età fertile OPPURE
b) In età fertile e adottare un metodo contraccettivo altamente efficace (tasso di fallimento <1% quando usato in modo costante e corretto) e accettare di continuare a usare un metodo contraccettivo altamente efficace mentre ricevono il farmaco dello studio e fino a 30 giorni dopo aver ricevuto l’ultima dose di farmaco dello studio. (Appendice 6).
7. Le partecipanti di sesso femminile devono accettare di non donare ovuli (cellule uovo, ovociti) a scopo di riproduzione assistita durante lo studio e per un periodo di 30 giorni dopo aver ricevuto l’ultima dose di farmaco dello studio.
8. Le donne in età fertile devono avere un test di gravidanza sierico negativo allo screening e un test di gravidanza urinario negativo al Giorno 1 prima della prima dose di farmaco dello studio.
9. I soggetti di sesso maschile con partner in età fertile devono accettare di usare un metodo contraccettivo altamente efficace (tasso di fallimento <1% quando usato in modo costante e corretto) e accettare di continuare a usare un metodo contraccettivo altamente efficace mentre ricevono il farmaco dello studio e fino a 90 giorni dopo aver ricevuto l’ultima dose di farmaco dello studio (Appendice 6).
10. I partecipanti di sesso maschile devono accettare di non donare sperma a scopo di riproduzione durante lo studio e per un periodo di 90 giorni dopo aver ricevuto l’ultima dose.
11. Il soggetto è idoneo secondo i criteri di screening della tubercolosi (TB) specificati nel protocollo (Appendice 3).
Per i criteri di inclusione relativi alla PArte 2 si prega di fare riferimento al protocollo di studio.

E.4

Principal exclusion criteria

For exclusion criteria related to Part 1 and 2 of study protocol please refer to the study protocol, as the text space in the Appendix is not sufficient.

Per i Criteri di esclusione relativi alla Parte 1 e 2 si prega di fare riferimento al protocollo di studio poichè lo spazio di testo in appendice risulta insufficiente.

E.5 End points

E.5.1

Primary end point(s)

Efficacy
Proportion of subjects achieving clinical remission at Week 12 compared to placebo.

Efficacia
Percentuale di soggetti che raggiungono la remissione clinica alla settimana 12 rispetto al placebo.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 weeks

12 settimane

E.5.2

Secondary end point(s)

• Comparison of PN-943 high dose and low dose individually to placebo:
a) Proportion of subjects with endoscopic improvement at Week 12
b) Proportion of subjects achieving endoscopic remission at Week 12
c) Proportion of subjects with histological improvement at Week 12
d) Proportion of subjects achieving histological remission at Week 12

• Proportion of subjects achieving clinical remission at Week 52. Clinical remission is determined using the Adapted Mayo score (sum of 3 subscores from the Mayo score):
- Stool frequency subscore (SFS)
- Rectal bleeding subscore (RBS)
- Endoscopic subscore (ESS)

Confronto tra PN-943 ad alta dose e dose bassa individualmente al placebo:
a) Percentuale di soggetti con miglioramento endoscopico alla settimana 12
b)Percentuale di soggetti che hanno raggiunto remissione endoscopica alla settimana 12
c)Percentuale di soggetti con miglioramento istologico alla settimana 12
d)Percentuale di soggetti che hanno raggiunto remissione istologicaalla settimana 12

Proporzione di soggetti che raggiungono la remissione clinica alla settimana 52. La remissione clinica è stabilita usando il Punteggio adattato Mayo (somma di 3 sottopunteggi dal punteggio Mayo):
-Sottopunteggio di frequenza di defecazione (SFS)
-Sottopunteggio del sanguinamento rettale (RBS)
-Sottopunteggio endoscopico (ESS)

E.5.2.1

Timepoint(s) of evaluation of this end point

Weeks 12 and 52

setimana 12 e 52

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

Yes

E.6.7

Pharmacodynamic

Yes

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

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

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

Information not present in EudraCT

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

Georgia

Korea, Republic of

Russian Federation

Serbia

Ukraine

United States

Austria

Germany

Hungary

Italy

Netherlands

Poland

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

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:

135

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

150

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)

nessuno

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

2020-07-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-04-02

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

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