Clinical Trials Register

Summary
EudraCT Number:	2011-002754-31
Sponsor's Protocol Code Number:	NUC-3/PSC
National Competent Authority:	Lithuania - SMCA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-06-21
Trial results	View 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

Lithuania - SMCA

A.2

EudraCT number

2011-002754-31

A.3

Full title of the trial

Double-blind, randomized, placebo-controlled, phase II dose-finding study comparing different doses of norursodeoxycholic acid capsules with placebo in the treatment of primary sclerosing cholangitis

Dvigubai koduotas, atsitiktinių imčių, placebu kontroliuojamas, II fazės tyrimas dozei parinkti, lyginant skirtingomis dozėmis skiriamų norursodeoksicholio rūgšties kapsulių ir placebo poveikį pirminiam sklerozuojančiam cholangitui

A.3.1

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

Double-blind (neither physician nor patient knows of the actual treatment which can be with or without active substance), randomized (patient will be allocated to a certain treatment group by chance), placebo-controlled (tested against capsules without active substance), phase II dose-finding study comparing different doses of norursodeoxycholic acid capsules with placebo (without active substance) in the treatment of PSC (inflammation of the bile ducts with scar formation)

Dvigubai koduotas (nei gydytojas, nei pacientas nežinos, ar skiriamos kapsulės yra su veikliąja medžiaga ar be jos), atsitiktinių imčių (pacientas bus paskirtas į vieną iš tyrimo grupių atsitiktine tvarka), placebu kontroliuojamas (lyginamas su kapsulėmis be veikliosios medžiagos), II fazės tyrimas dozei parinkti, lyginant skirtingomis dozėmis skiriamų norursodeoksicholio rūgšties kapsulių ir placebo poveikį pirminiam sklerozuojančiam cholangitui (lėtiniam tulžies latakų uždegimui ir randėjimui)

A.3.2

Name or abbreviated title of the trial where available

Norursodeoxycholic acid vs. Placebo in PSC

Norursodeoksicholio rūgšties palyginimas su placebu, skiriant sergantiesiems PSC

A.4.1

Sponsor's protocol code number

NUC-3/PSC

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	Dr. Falk Pharma GmbH
B.1.3.4	Country	Germany
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	Dr. Falk Pharma GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Dr. Falk Pharma GmbH
B.5.2	Functional name of contact point	Dept. of Clin. Res. & Development
B.5.3	Address:
B.5.3.1	Street Address	Leinenweberstr. 5
B.5.3.2	Town/ city	Freiburg
B.5.3.3	Post code	79108
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4976115140
B.5.5	Fax number	+497611514377
B.5.6	E-mail	zentrale@drfalkpharma.de

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	norursodeoxycholic acid
D.3.4	Pharmaceutical form	Capsule
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	norursodeoxycholic acid
D.3.9.1	CAS number	99697-24-2
D.3.9.3	Other descriptive name	NorUDCA
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	250
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	Capsule
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

primary sclerosing cholangitis

Pirminis sklerozuojantis cholangitas

E.1.1.1

Medical condition in easily understood language

Orphan chronic liver disease with inflammation of the bile ducts.

Reta lėtinė kepenų liga, pasireiškianti tulžes latakų uždegimu.

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	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10036732
E.1.2	Term	Primary sclerosing cholangitis
E.1.2	System Organ Class	100000004871

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 three doses of norUDCA vs. placebo for the treatment of PSC;

To identify efficacious norUDCA dose(s) for the treatment of PSC for further evaluation in phase III

Įvertinti ir palyginti trijų norUDCR dozių ir placebo veiksmingumą sergantiesiems PSC;

Nustatyti sergantiesiems PSC veiksmingą/veiksmingas norUDCR dozę/dozes tolesniam vertinimui III fazės tyrimuose.

E.2.2

Secondary objectives of the trial

To study safety and tolerability (adverse events, laboratory parameters) of norUDCA;

To assess quality of life

Tirti norUDCR saugumą ir toleravimą (nepageidaujamus reiškinius, laboratorinius parametrus);

Įvertinti gyvenimo kokybę

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed informed consent,
2. Male or female patients ≥ 18 and < 80 years,
4. Alkaline Phosphatase ≥ 1.5 x ULN at baseline,
6. Women of child-bearing potential have to apply during the entire duration of the study a highly effective method of birth control, which is defined as one which results in a low failure rate (i.e., less than 1% per year) when used constantly and correctly such as implants, injectables, combined oral contraceptive method, or some IUDs. Women of non-childbearing potential may be included if surgically sterile or post-menopausal for at least 2 years. The investigator is responsible for determining whether the subject has this adequate birth control for study participation.

1. Pasirašytas informuoto asmens sutikimas.
2. Vyrai arba moterys nuo ≥ 18 iki < 80 metų.
4. Šarminės fosfatazės kiekis, ≥ 1,5 karto viršijantis VNR pradinio vertinimo metu.
6. Pastoti galinčios moterys turės visu tyrimo laikotarpiu naudoti labai veiksmingą kontracepcijos metodą, apibrėžiamą kaip metodas, kurį, naudojant pastoviai ir tinkamai, pastojama retai (tai yra, pastojimo dažnis yra mažiau kaip 1% per metus). Labai veiksmingos kontracepcijos metodo pavyzdžiai gali būti implantai, švirkščiamieji kontraceptikai, kombinuoti geriamieji kontraceptikai arba kai kurie gimdos vidaus prietaisai. Į tyrimą galės būti įtraukiamos ir pastoti negalinčios moterys, jei joms atlikta chirurginė sterilizacija arba yra praėję ne mažiau kaip 2 metai po menopauzės. Tyrėjas nustatys, ar moterų naudojama kontracepcija yra pakankama dalyvavimui tyrime.

E.4

Principal exclusion criteria

1. History or presence of other concomitant liver diseases including:
• Positive hepatitis B or C serology (Hbs Ag+, anti-HBc+, anti-HCV;
Note: Patients who present with anti-HBc+ only, may be included if they are HBV-DNA negative)
• Primary Biliary Cirrhosis, (AMA-positive)
• Wilson’s Disease
• Haemochromatosis
• Autoimmune Hepatitis
• Chronic alcoholic consumption (daily consumption >30g/d)
• Biopsy proven NASH
• Cholangiocarcinoma,
2. Treatment with any of the following drugs within the last 3 months prior to baseline: any glucocorticosteroids (including budesonide), azathioprine or other immunosuppressive drugs (e.g. cyclophosphamide, cyclosporine, methotrexate, tacrolimus, 6-mercaptopurine), chlorambucil, pentoxyfylline, penicillamine, pirfenidone, fibrates, biologics (e.g., anti-tumor necrosis factor-alpha therapy), or rifampicin,
5. Child B/C liver cirrhosis,
12. Total bilirubin > 3.0 mg/dl (> 51.3 μmol/L), at screening or baseline,
13. Both total bilirubin levels > ULN within the last 6 months prior to baseline and a rise of this level by more than 50% within the last 6 months prior to baseline,
14. Albumin < 36 g/L, at screening or baseline,
16. Any relevant systemic disease (e.g., AIDS),
17. Abnormal renal function (Cystatin C > 1,15 ULN) at screening and/or at baseline visit,
18. TSH > ULN at screening,
20. Any active malignant disease,
21. Known intolerance/hypersensitivity to study drug, or drugs of similar chemical structure or pharmacological profile

1. Kita gretutinė kepenų liga, dabar ar anamnezėje, įskaitant:
• Teigiamus serologinių tyrimų dėl hepatito B arba C rezultatus (hepatito B paviršinio antigeno (HbsAg), antikūnų prieš hepatito B šerdinį antigeną (anti-HBc), hepatito C viruso antikūnų (anti-HCV) nustatymą (Pastaba: pacientai, kuriems bus nustatytas tik anti-HBc, galės būti įtraukiami, jei jiems bus nustatyti neigiami hepatito B viruso DNR (HBV-DNR) tyrimo rezultatai);
• Pirminę biliarinę cirozę (kai yra nustatomi antimitochondriniai antikūnai (AMA));
• Vilsono ligą;
• Hemochromatozę;
• Autoimuninį hepatitą;
• Lėtinį alkoholio vartojimą (kai kasdien suvartojama > 30 g);
• Biopsija patvirtintą nealkoholinį steatohepatitą (NASH);
• Tulžies latakų karcinomą.
2. Gydymas bet kuriuo iš žemiau išvardintų vaistinių preparatų paskutiniuosius 3 mėnesius iki pradinio įvertinimo: bet kokiais gliukokortikosteroidais (įskaitant budezonidą), azatioprinu arba kitais imunosupresantais (pavyzdžiui, ciklofosfamidu, ciklosporinu, metotreksatu, takrolimuzu, 6-merkaptopurinu), chlorambuciliu, pentoksifilinu, penicilaminu, pirfenidonu, fibratais, biologiniais vaistais (pavyzdžiui, navikinį nekrozės faktorių α veikiančia terapija) arba rifampicinu.
5. B/C klasės kepenų cirozė pagal Child klasifikaciją.
12. Bendras bilirubinas > 3,0 mg/dl (> 51.3 µmol/l) atrankos arba pradinio vertinimo metu.
13. VNR viršijantis bendro bilirubino kiekis 6 mėnesių laikotarpiu iki pradinio vertinimo ir bendro bilirubino kiekio pakilimas daugiau kaip 50% per paskutinius 6 mėnesius iki pradinio vertinimo.
14. Albuminas < 36 g/l atrankos arba pradinio vertinimo metu.
16. Bet kokia reikšminga sisteminė liga (pavyzdžiui, AIDS).
17. Nenormali inkstų funkcija (cistatinas C > 1,15 VNR) atrankos ir/arba pradinio vertinimo vizito metu.
18. Skydliaukę stimuliuojantis hormonas (TSH) > VNR atrankos metu.
20. Bet kokia aktyvi navikinė liga.
21. Nustatytas tiriamojo vaistinio preparato arba panašios cheminės struktūros ar farmakologinių charakteristikų vaistinių preparatų netoleravimas/padidėjęs jautrumas tiriamajam vaistiniam preparatui arba panašios cheminės struktūros ar farmakologinių charakteristikų vaistiniams preparatams.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the change in serum alkaline phosphatase.

Pagrindinis tikslinis veiksmingumo vertinimo rodiklis yra šarminės fosfatazės kiekio serume pokyčiai.

E.5.1.1

Timepoint(s) of evaluation of this end point

At the EOT visit.

Tiriamojo vaistinio preparato vartojimo pabaigos vizito metu.

E.5.2

Secondary end point(s)

Secondary efficacy endpoints are:

· s-ALP at each study visit (screening to follow-up)

· γ-GT, AST, ALT and serum bilirubin levels at each study visit (screening to follow-up)

· Course of pruritus (measured by VAS): absolute change in the pruritus score from baseline to EOT, and from EOT to the follow-up visit

Papildomi tiksliniai veiksmingumo vertinimo rodikliai:

• ŠF kiekis serume kiekvieno vizito metu (nuo atrankos iki stebėjimo).
• γ-GT, AST, ALT ir bilirubino kiekis serume kiekvieno vizito metu (nuo atrankos iki stebėjimo).
• Niežėjimo kitimas (vertinant VAS skalėje): absoliutus niežėjimo įverčio pokytis nuo pradinio vertinimo iki TVP vartojimo pabaigos ir nuo TVP vartojimo pabaigos iki stebėjimo vizito.

E.5.2.1

Timepoint(s) of evaluation of this end point

Timepoints of evaluation are included in the description of endpoints in E.5.2.

Rodiklių vertinimo laikas yra nurodytas papildomų tikslinių veiksmingumo vertinimo rodiklių aprašyme E.5.2

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

Yes

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

Yes

E.8.2.3.1

Comparator description

Skirtingos tiriamojo vaistinio preparato dozės

Different dosages of IMP

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

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

last visit of the last subject

Paskutinio paciento paskutinis vizitas

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:

120

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

160

F.4.2.2

In the whole clinical trial

160

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)

Planned Treatment during Follow-up and after Study End
In cases, where a patient still shows clinical symptoms at EOT/withdrawal visit, the patient may receive symptomatic treatment in the choice of the investigator during the follow-up phase. For all patients, treatment after study end (after V9 [follow-up visit]) is left to investigator’s discretion.

Tokiu atveju, jei pacientui tiriamojo preparato vartojimo pabaigos/pasitraukimo iš tyrimo vizito metu vis dar būtų klinikinių simtomų, gydytojas tyrėjas nuspręs, ar stebėjimo fazės metu pacientui bus skiriamas simptominis gydymas. Po tyrimo pabaigos vizito (V9 [stebėjimo vizito]) visi pacientai bus gydomi toliau gydytojo nuožiūra.

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

2012-09-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-08-01

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-10-22

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