Clinical Trials Register

Summary
EudraCT Number:	2016-005199-90
Sponsor's Protocol Code Number:	RHB-104-04
National Competent Authority:	Slovakia - SIDC (Slovak)
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-02-14
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

Slovakia - SIDC (Slovak)

A.2

EudraCT number

2016-005199-90

A.3

Full title of the trial

An Open Label Study to Assess the Efficacy and Safety of Fixed-Dose
Combination RHB-104 in Subjects with Active Crohn’s Disease Despite 26
Weeks of Participation in the MAP US RHB-104-01 Study

Otvorené klinické skúšanie hodnotiace účinnosť a bezpečnosť fixnej kombinácie liečiv RHB-104 u pacientov s aktívnou Crohnovou chorobou napriek 26 týždňoch účasti v klinickej štúdii MAP US RHB-104-01

A.3.1

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

Open Label Study to evaluate whether a fixed-dose of RHB-104 is safe and effective in subjects suffering from moderate to Severely Crohn’s disease.

A.3.2

Name or abbreviated title of the trial where available

RHB-104-04 and MAP (US2)

A.4.1

Sponsor's protocol code number

RHB-104-04

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	RedHill Biopharma Ltd.
B.1.3.4	Country	Israel
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	RedHill Biopharma Ltd.
B.4.2	Country	Israel
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	RedHill Biopharma Ltd.
B.5.2	Functional name of contact point	Medical Director - Ira Kalfus
B.5.3	Address:
B.5.3.1	Street Address	251 Central Park West, Suite 3A
B.5.3.2	Town/ city	New York, NY
B.5.3.3	Post code	10024
B.5.3.4	Country	United States
B.5.4	Telephone number	+1917817 7517
B.5.5	Fax number	+1888685 5218
B.5.6	E-mail	ira@redhillbio.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.3.2	Product code	RHB-104
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	Clarithromycin
D.3.9.1	CAS number	81103-11-9
D.3.9.3	Other descriptive name	CLARITHROMYCIN
D.3.9.4	EV Substance Code	SUB06641MIG
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	95
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Rifabutin
D.3.9.1	CAS number	72559-06-9
D.3.9.3	Other descriptive name	RIFABUTIN
D.3.9.4	EV Substance Code	SUB10304MIG
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	45
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Clofazimine
D.3.9.1	CAS number	2030-63-9
D.3.9.3	Other descriptive name	CLOFAZIMINE
D.3.9.4	EV Substance Code	SUB06694MIG
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	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
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

Moderately to Severely Active Crohn's Disease

E.1.1.1

Medical condition in easily understood language

Crohn's Disease

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10011401
E.1.2	Term	Crohn's disease
E.1.2	System Organ Class	10017947 - Gastrointestinal disorders

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 estimate the remission rate, defined as a CDAI score of less than 150, at 16 weeks after the initiation of the open-label phase.

E.2.2

Secondary objectives of the trial

To estimate the
-response rate of patients, defined by a reduction of CDAI score of ≥100 points at week 16 after the initiation of the open-label phase
- average duration of remission among participants
- average time to first response among participants
- average duration of response among participants
- the proportion of participants who maintain a state of remission from
week 16 through week 52.

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

Title: Colonoscopy for evaluation of mucosal healing via Crohn’s Disease Endoscopic Index of Severity (CDEIS) and Simple Endoscopic Score for Crohn’s Disease (SES-CD).

Objectives:
- To estimate the change from baseline in the mean Crohn’s Disease Endoscopic Index of Severity (CDEIS) after 16 and 52 weeks of treatment
- To estimate the change from baseline in the mean Simple Endoscopic Activity Score (SES-CD) after 16 and 52 weeks of treatment
- To make a comparison of success rates of (ΔCDEIS and SES-CD) defined by 25% and 50% improvements
- To estimate the correlation between the change from baseline in the endoscopic index (ΔCDEIS) and the clinical index (ΔCDAI) after 16 and 52 weeks of treatment
- To make a comparison of success rates of (ΔCDEIS) defined by 25% and 50% improvements and CDAI defined remission
- To make a comparison of success rates of (ΔCDEIS) defined by 25% and 50% improvements and CDAI defined response
- To make a comparison of success rates of (ΔSES-CD) defined by 25% and 50% improvements and CDAI defined remission
- To make a comparison of success rates of (ΔSES-CD) defined by 25% and 50% improvements and CDAI defined response

E.3

Principal inclusion criteria

1) Participation in RHB-104-01 for:
- 26 weeks, and a Crohn’s Disease Activity Index (CDAI) score of ≥ 150 at Visit Week 26 OR
- More than 26 weeks, with a CDAI ≥150 at Visit Week 26 and all subsequent visits, and subject is between Week 26 and 52 within 4 weeks (28 days) of site activation
2) White blood cell count ≥ 3.5x109 at screening
3) Subject agrees to use the following effective contraceptive methods
- diaphragm, cervical cap, contraceptive sponge or condom with spermicidal foam
- IUD/IUS
- progestogen injection (Depo-Provera®)
throughout the study and for at least 6 weeks after last study drug administration, unless subject or partner of subject is post-menopausal or otherwise incapable of becoming pregnant by reason of surgery or tubal ligation, or has had a vasectomy. In regions where local regulatory contraceptive requirements differ, the ICF will reflect local policies

E.4

Principal exclusion criteria

1) Treatment with any medication that causes QT prolongation or Torsades de Pointes, including but not limited to: amiodarone, amitriptyline, astemizole, cisapride, citalopram dose greater than 20 mg/day, dihydroergotamine, disopyramide, dofetilide, dronedarone, ergotamine, ibutilde, ondansetron or other 5-HT3 receptor antagonists, pimozide, procainamide, quinidine, quinine, quinolones, ranolazine, risperidone, sotalol, terfenadine and tolteridine. QT prolonging drugs may be referenced at the CredibleMeds® web site:
https://crediblemeds.org/index.php/drugsearch
2) Treatment with the following CYP3A4 interactive medications: alfentanyl,alprazolam, amlodipine, anti-retroviral agents, apixabin, aprepitant, aripiprazole, atorvastatin, boceprevir, buspirone, carbamazepine, carvedilol, colchicine, cyclosporine, digoxin, diltiazem, estrogens, felodipine, fluconazole, fluvoxamine, grapefruit juice, haloperidol, ketoconazole, lovastatin, lurasidone, metoprolol, nefazodone, nifedipine, nisoldipine, nitrendipine, propranol, roflumilast, simvastatin, St. John’s wort, and voriconazole.
3) Positive stool results for C. difficile.
4) Currently diagnosed or history of uveitis confirmed by either an ophthalmologist or optometrist.
5) Evidence of any significant hematological, hepatic, renal, cardiac, pulmonary,
metabolic, neurological, psychiatric or other disease (e.g. porphyria) that might interfere with subject’s ability to safely enter and or complete the study requirements.
6) Clinically significant abnormalities of hematology or biochemistry as confirmed by repeat testing based on investigator’s discretion, including but not limited to,
elevations greater than 2 times the upper limit of normal of Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), or creatinine clearance
less than 60 ml/min at screening via estimated Cockcroft-Gault formula:
Creatinine Clearance = [140 - age in years] * weight (kg) / 72 * Serum Creatinine
(mg/dl) [multiply estimated rate by 0.85 for women], using actual body weight.
7) QTcF>450ms in males and QTcF>460ms in females, bundle branch block, or major ST or T wave abnormalities that make the assessment of the QT impossible.
8) Females who have a positive pregnancy test or are lactating.

E.5 End points

E.5.1

Primary end point(s)

Remission (primary outcome measure) – Remission in a subject is defined as a CDAI score of <150 at 16 weeks.

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 16

E.5.2

Secondary end point(s)

Response – A response in the individual subject is defined as reduction in CDAI score of ≥100 from baseline where baseline is the measure taken at Screening of this trial (Visit Week 26 of RHB-104-01.)

E.5.2.1

Timepoint(s) of evaluation of this end point

Visit Week 26 of RHB-104-01 study

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

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

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)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

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

Australia

Canada

Czech Republic

Israel

New Zealand

Poland

Serbia

Slovakia

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

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:

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

100

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)

Subject will return to the physician for follow-up and treatment if necessary after ending the participation in the trial.

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

2018-02-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-02-14

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2019-08-19

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