Clinical Trials Register

Summary
EudraCT Number:	2011-003130-14
Sponsor's Protocol Code Number:	CSUC-01/10
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:	2012-03-05
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

2011-003130-14

A.3

Full title of the trial

“A placebo-controlled, double-blind, randomised study to assess the efficacy and safety of Kappaproct as an add-on to current practice in chronic active treatment refractory ulcerative colitis patients”

Studio randomizzato, in doppio cieco, controllato verso placebo teso a valutare l'efficacia e la sicurezza di kappaproct in aggiunta alla pratica clinica corrente nei pazienti affetti da colite ulcerosa attiva cronica refrattaria al trattamento

A.3.1

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

Clinical Trial to assess the efficacy and safety of Kappaproct

Studio clinico volto a valutare l'efficacia e la sicurezza di Kappaproct

A.3.2

Name or abbreviated title of the trial where available

CSUC-01/10

A.4.1

Sponsor's protocol code number

CSUC-01/10

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	INDEX PHARMACEUTICALS
B.1.3.4	Country	Sweden
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	Index Pharmaceuticals AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Index Pharmaceuticals AB
B.5.2	Functional name of contact point	Index Pharmaceuticals AB
B.5.3	Address:
B.5.3.1	Street Address	Scheeles vag 2
B.5.3.2	Town/ city	Stockholm
B.5.3.3	Post code	17177
B.5.3.4	Country	Sweden
B.5.4	Telephone number	0046 0 850884730
B.5.5	Fax number	0046 0 850884739
B.5.6	E-mail	info@indexpharmab.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	Yes
D.2.5.1	Orphan drug designation number	EU/3/02/106
D.3 Description of the IMP
D.3.1	Product name	Kappaproct
D.3.2	Product code	DIMS0150
D.3.4	Pharmaceutical form	Rectal solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Rectal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NA
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	DIMS0150
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	15
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	Rectal solution
D.8.4	Route of administration of the placebo	Rectal use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Chronic active treatment refractory ulcerative colitis

Colite ulcerosa cronica attiva refrattaria al trattamento

E.1.1.1

Medical condition in easily understood language

Ulcerative Colitis

Colite ulcerosa

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	14.1
E.1.2	Level	PT
E.1.2	Classification code	10009900
E.1.2	Term	Colitis ulcerative
E.1.2	System Organ Class	10017947 - Gastrointestinal 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 evaluate the induction of clinical remission with Kappaproct given as an add-on treatment in two doses of 30 mg each compared to placebo.

Valutare l'induzione della remissione clinica con kappaproct somministrato come trattamento aggiuntivo in due dosi di 30 mg ciascuna, rispetto al placebo.

E.2.2

Secondary objectives of the trial

• To evaluate the rate of colectomy with Kappaproct given as an add-on treatment in two doses of 30 mg each compared to placebo. • To evaluate the induction and maintenance of steroid-free remission. • To evaluate safety and tolerability

•Valutare l'incidenza di colectomia con kappaproct somministrato come trattamento aggiuntivo in due dosi di 30 mg ciascuna, rispetto al placebo. •Valutare l'induzione e il mantenimento della remissione senza steroidi. •Valutare la sicurezza e la tollerabilità.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female ≥ 18 years of age. 2. Well established diagnosis of moderate to moderately severe chronic active UC with a CAI score ≥9, an endoscopic score ≥2, not responding adequately to currently available therapies and potential candidates for colectomy. Previously tried therapies should include: • At least one treatment course with mesalazine; at least 2.4 g/day for at least 4 weeks, or at least one treatment course with similar drugs in this class. • At least one treatment course of corticosteroids; at least 0.75 mg/kg as starting dose. • At least one treatment course of azathioprine or mercaptopurine of at least 3 months duration and/or at least one adequate treatment course of an anti-TNF alpha. • Any unsuccessful combination treatment of the above. • May have tried treatment with cyclosporine and/or tacrolimus or any otherimmunosuppressant/immunomodulating agent. • Intolerance to any of the above medications is judged as inadequate response. 3. Patients shall at study enrolment be on an accumulated stable tolerable GCS dose equivalent to at least 140 mg of prednisolone/prednisone (by any route of administration) for the last two weeks. Patients may also be on concomitant therapies such as, but not restricted to, 5-ASA, azathioprine and sulphasalazine. 4. Ability to understand the treatment, willingness to comply with all study requirements, and ability to provide informed consent.

1. Pazienti di sesso maschile o femminile di età pari o superiore a 18 anni. 2. Diagnosi ben definita di CU attiva cronica da moderata a moderatamente grave con un punteggio CAI ≥9, un punteggio endoscopico ≥2, con una risposta inadeguata alle terapie attualmente disponibili e potenziali candidati per colectomia. Le terapie tentate in precedenza devono includere: • Almeno un corso di trattamento con mesalazina; almeno 2,4 g/die per almeno 4 settimane, o almeno un corso di trattamento con farmaci simili di questa classe. • Almeno un corso di trattamento con corticosteroidi; almeno 0,75 mg/kg come dose iniziale. • Almeno un corso di trattamento con azatioprina o mercaptopurina di almeno 3 mesi di durata e/o almeno un adeguato corso di trattamento con un anti-TNF alfa. • Una qualsiasi combinazione dei trattamenti summenzionati senza esito positivo. • Eventuale trattamento con ciclosporina e/o tacrolimus o qualsiasi altro agente immunosoppressivo/immunomodulante. • L'intolleranza a qualsiasi farmaco tra quelli summenzionati è giudicata una risposta inadeguata. 3. Al momento dell'arruolamento nello studio, i pazienti devono avere accumulato una dose tollerabile stabile di GCS equivalente ad almeno 140 mg di prednisolone/prednisone (tramite qualsiasi via di somministrazione) per le ultime due settimane. I pazienti potranno altresì essere in terapia con farmaci concomitanti quali, a titolo esemplificativo ma non esaustivo, 5-ASA, azatioprina e sulfasalazina. 4. Capacità di comprendere il trattamento, disponibilità a rispettare tutti i requisiti dello studio e capacità di fornire il consenso informato.

E.4

Principal exclusion criteria

1. Patients with suspicion of Crohn’s enterocolitis, ischaemic colitis, radiation colitis, diverticular disease associated colitis, as well as microscopic colitis should be excluded. Patients with disease limited to the rectum (ulcerative proctitis) should also be excluded. 2. History or presence of a clinically significant cardiovascular, hepatic, renal, haematological, endocrine, neurological, psychiatric disease, or immune compromised state as judged relevant by the investigator. 3. Patients with acute fulminant UC and/or signs of systemic toxicity to an extent that requires immediate surgical action. 4. History or presence of any colonic malignancy and/or dysplasia. 5. Concomitant treatment with cyclosporine, tacrolimus, anti-TNFs or similar immunosuppressants/immunomodulators is not allowed and should have been discontinued 4 weeks before enrolment. Patients who fail the wash-out criteria can undergo wash-out and be re-screened at a later time point. 6. Treatment with antibiotics or Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) within two weeks before enrolment. 7. An active ongoing infection 8. Positive Clostridium difficile stool assay. 9. Currently receiving parenteral nutrition or blood transfusions. 10. Pregnancy or breast-feeding. 11. Women of childbearing potential not using reliable contraceptive methods (reliable methods are barrier protection, hormonal contraception, intra-uterine device or abstinence). 12. Concurrent participation in another clinical study with investigational therapy or previous use of investigational therapy within 30 days before enrolment. Patients who fail the wash-out criteria can undergo wash-out and be re-screened at a later time point.

1. Pazienti con sospetto di enterocolite di Crohn, colite ischemica, colite da radiazioni, colite associata a malattia diverticolare e colite microscopica devono essere esclusi. 2. Anamnesi o presenza di una patologia cardiovascolare, epatica, renale, ematologica, endocrina, neurologica, psichiatrica clinicamente significativa o stato immunocompromesso se giudicato tale dallo sperimentatore. 3. Pazienti con CU fulminante acuta e/o segni di tossicità sistemica ad un livello che richiede l'intervento chirurgico immediato. 4. Anamnesi o presenza di neoplasia e/o displasia del colon. 5. Il trattamento concomitante con ciclosporina, tacrolimus, anti-TNF o immunosoppressivi/immunomodulatori simili non è consentito e deve essere interrotto 4 settimane prima dell'arruolamento. I pazienti che non soddisfano i criteri di wash-out potranno essere sottoposti a wash-out e a nuovo screening in un momento successivo. 6. Trattamento con antibiotici o farmaci antinfiammatori non steroidei (FANS) entro due settimane prima dell'arruolamento. 7. Infezione attiva in corso. 8. Esame delle feci positivo a Clostridium difficile. 9. Pazienti attualmente sottoposti a nutrizione parenterale o trasfusioni di sangue. 10. Gravidanza o allattamento. 11. Donne in età fertile che non utilizzano metodi contraccettivi affidabili (ovvero protezione a barriera, contraccezione ormonale, dispositivo intrauterino o astinenza). 12. Partecipazione concomitante ad un altro studio clinico con terapia sperimentale o precedente utilizzo di una terapia sperimentale nei 30 giorni prima dell'arruolamento. I pazienti che non soddisfano i criteri di wash-out potranno essere sottoposti a wash-out e a nuovo screening in un momento successivo.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the induction of clinical remission at week 12, defined as a CAI score of <= 4, with subscores of stools weekly not exceeding 0 and 0 or 1 respectively

L'induzione della remissione clinica alla settimana 12, definita come punteggio CAI ≤4, con sottopunteggi di sangue nelle feci e numero di feci settimanali non superiore, rispettivamente, a 0 e 0 o 1.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 WEEKS

12 SETTIMANE

E.5.2

Secondary end point(s)

• The time to colectomy. • The rate of colectomy at 3, 5 and 12 months. • Steroid free remission at 5 and 12 months. • The induction of registration remission at week 4 and 12, and the maintenance of this remission at 5 and 12 months, defined as a CAI score of ≤4 and an endoscopic score of 0 or 1. • The induction of clinical remission at week 1, 4, 8 and the maintenance of this remission at 5 and 12 months, defined as a CAI score of ≤4. • The induction of clinical response at week 1, 4, 8 and 12, defined as a decrease in CAI score of ≥5 from baseline. Health related quality of life evaluation using an inflammatory bowel disease questionnaire (IBDQ) and a short-form health survey with 36 questions (SF-36) at week 12 and at 12 months, compared to baseline. • The induction of mucosal healing defined as an endoscopic score of 0 or 1 at week 4 and 12. • The histopathological response/remission at week 4 and 12. Histopathological response is defined as an improvement in the histopathological score of ≥3 from baseline, i.e. a histopathological response could go from 5 to 2 or from 4 to 1. Histopathological remission is defined as an improvement from baseline to a histopathological score of 0. • Frequency of and time to UC relapses, defined as an increase of CAI ≥5 from the previous study visit. • Safety and tolerability.

•L'intervallo di tempo fino alla colectomia. •Il tasso di colectomia ai mesi 3, 5 e 12. •Remissione senza steroidi ai mesi 5 e 12. •L'induzione di remissione documentata alle settimane 4 e 12, e il mantenimento di questa remissione ai mesi 5 e 12, definita come punteggio CAI ≤4 e punteggio endoscopico di 0 o 1. •L'induzione della remissione clinica alle settimane 1, 4, 8 e il mantenimento di questa remissione ai mesi 5 e 12, definita come punteggio CAI ≤4. •L'induzione della risposta clinica alle settimane 1, 4, 8 e 12, definita come riduzione del punteggio CAI ≥5 dal basale. •Valutazione della qualità della vita in relazione allo stato di salute utilizzando un questionario sulle malattie infiammatorie dell'intestino (IBDQ, Inflammatory Bowel Disease Questionnaire) e un sondaggio breve con 36 voci sullo stato di salute (SF-36) alle settimane 12 e a 12 mesi, rispetto al basale. •L'induzione della guarigione mucosale definita come punteggio endoscopico di 0 o 1 alle settimane 4 e 12. •La risposta/remissione istopatologica alle settimane 4 e 12. La risposta istopatologica è definita come miglioramento del punteggio istopatologico ≥3 rispetto al basale, ovvero la risposta istopatologica potrebbe essere compresa tra 5 e 2 o tra 4 e 1. La remissione istopatologica è definita come miglioramento dal basale a un punteggio istopatologico di 0. •La frequenza e la durata delle ricadute di CU, definite come aumento del punteggio CAI ≥5 rispetto alla precedente visita dello studio. •Sicurezza e tollerabilità.

E.5.2.1

Timepoint(s) of evaluation of this end point

Please refer to the previous section

Si faccia riferimento alla sezione precedente

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

Yes

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

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

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

when the patient has completed the 12 month follow up visit

Quando il paziente ha completato la visita di follow up a 12 mesi

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:

100

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

132

F.4.2.2

In the whole clinical trial

132

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)

At the end of the Study the patients will be treated according to the standard of care

al termine dello studio i pazienti saranno trattatti secondo la pratica clinica comune

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

2012-03-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-02-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-04-30

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