Clinical Trials Register

Summary
EudraCT Number:	2013-005483-25
Sponsor's Protocol Code Number:	SMT19969/C003
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-07-10
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

UK - MHRA

A.2

EudraCT number

2013-005483-25

A.3

Full title of the trial

A Phase II, Randomized, Open-Label, Active-Controlled Clinical Study to Investigate the Safety and Efficacy of SMT19969 (200 mg BID) for 10 days Compared with Fidaxomicin (200 mg BID) for 10 days for the Treatment of Clostridium difficile Infection (CDI)

A.3.1

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

The study will look at how safe and well tolerated SMT19969 is compared to fidaxomcin when given orally for 10 days. It will also study if SMT19969 gets into the blood stream, what effect the body has on the drug, how the drug is removed from the body and how long it takes the body to remove it. It will assess the effect of SMT19969 and fidaxomicin on gut bacteria and compare the ability of SMT19969 and fidaxomicin to treat clostridium difficile infection (CDI) and reduce the recurrence of CDI.

A.4.1

Sponsor's protocol code number

SMT19969/C003

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	Summit (Oxford) Limited
B.1.3.4	Country	United Kingdom
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	Summit (Oxford) Limited
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Summit (Oxford) Limited
B.5.2	Functional name of contact point	Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	85b Park Drive, Milton Park
B.5.3.2	Town/ city	Abingdon
B.5.3.3	Post code	OX14 4RY
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	00441235443939
B.5.6	E-mail	codify@summitplc.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	SMT19969
D.3.2	Product code	SMT19969
D.3.4	Pharmaceutical form	Capsule, hard
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	2,2'-bis(4-Pyridyl)-3H,3'H-5,5'-bibenzimidazole, tetrahydrate
D.3.9.1	CAS number	308362-25-6
D.3.9.2	Current sponsor code	SMT19969
D.3.9.3	Other descriptive name	SMT19969
D.3.9.4	EV Substance Code	SUB85907
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	200
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	Comparator
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.2.5	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.3.4	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	fidaxomicin
D.3.9.1	CAS number	873857-62-6
D.3.9.3	Other descriptive name	FIDAXOMICIN
D.3.9.4	EV Substance Code	SUB31455
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	200
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

Clostridium difficile infection

E.1.1.1

Medical condition in easily understood language

Infection of the gut by the bacterium Clostridium difficile

E.1.1.2

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	PT
E.1.2	Classification code	10054236
E.1.2	Term	Clostridium difficile infection
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the safety and tolerability of 10 days dosing with SMT19969 (200mg BID) compared to fidaxomicin (200mg BID) in the treatment of subjects with CDI

E.2.2

Secondary objectives of the trial

• To assess the plasma pharmacokinetics of SMT19969 in patients with CDI.
• To assess the qualitative and quantitative effect of SMT19969 and fidaxomicin on the bowel flora of subjects.
• To evaluate the efficacy of 10 days dosing with SMT19969 (200mg BID) compared to fidaxomicin (200mg BID) in the treatment of subjects with CDI.
• Additional microbiological assessments: C. difficile spore counts and the culture, isolation and quantification of C. difficile. Antibiotic susceptibility testing will be performed on these isolates using a panel to include but not limited to fidaxomicin, vancomycin and metronidazole. C. difficile strains isolated from subjects will undergo characterisation by molecular typing by ribotyping. The presence of vancomycin resistant enterococci (VRE) will be assessed by culture.
• To assess the plasma, urine and faecal concentrations of SMT19969 and its metabolites in patients with CDI receiving SMT19969.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

To be eligible to participate in this study, candidates must meet the following eligibility criteria at the time of screening.
1. Willingness to comply with all study activities and procedures and to provide signed, written informed consent prior to any study procedures. If a subject is unable to provide informed consent due to their medical condition, the subject’s legal representative will be provided with study information in order for consent to be obtained. Where required and agreed by the subject a designated family member/next of kin/carer “caregiver” may support an individual in their participation in the study. These individuals must be fully informed of the study requirements and the limits/requirements of their participation.
2. Male or female subjects who are in-patients or out-patients at time of consent, 18 years of age or older, and satisfy the diagnosis of CDI by clinical and laboratory criteria.
a. Diarrhoea defined as a change in bowel habits, with >3 unformed
bowel movements (UBMs) or >200 mL unformed stool for subjects
having rectal collection devices in the 24 hours prior to randomization;
b. Presence of either toxin A and/or B of C. difficile in the stool
determined by any locally available FDA cleared test (US Only) for
C. difficile toxin, including the Alere C.DIFF QUIK CHEK COMPLETE® rapid test, Enzyme Immunoassays (EIA) for C. difficile Toxin (A [TcdA], B [TcdB], or both A and B [TcdA/B]) or Cell Cytotoxicity Neutralization Assay (CCNA) within 72 hours prior to randomization.
AND/OR
Presence of a toxigenic strain of C. difficile determined by a locally
available FDA cleared Nucleic Acid Amplification Test (NAAT) to
detect the presence of either toxin genes or the pathogenicity locus
(PaLoc) or Non-FDA cleared tests* within 72 hours prior to randomization.
3. No prior antimicrobial treatment > 30 hours for current episode of CDI.
4. Female subjects of childbearing potential and who are sexually active must be using at least two adequate and reliable methods of contraception (e.g., barrier with additional spermicide foam or jelly, intrauterine device, hormonal contraception). Females who are postmenopausal (at least one year without menses) will be considered not of childbearing potential.
5. Subjects (both male and female) must agree to avoid conception during the treatment phase and until the end of their participation in the study

E.4

Principal exclusion criteria

Candidates will be excluded from study entry if any of the following exclusion criteria exist at the time of screening.
1. Life-threatening or fulminant CDI with evidence of hypotension [systolic blood pressure less than 90 mmHg], septic shock, peritoneal signs or ileus, or toxic megacolon.
2. Subjects with history of inflammatory bowel disease (Crohn’s disease or ulcerative colitis).
3. Subjects with 2 or more episodes of CDI in the previous year.
4. Females who are pregnant or breastfeeding.
5. Concurrent use of any product which may have a significant affect upon bowel motility (e.g., metoclopramide, narcotics, loperamide) anti-diarrhoeals, anti-peristalics or any product which may slow bowel movement. Chronic and continued use of such products may be allowed during the study if bowel motility has stablised.
6. Participation in other clinical research studies using an investigational product within one month prior to screening or within 5 half-lives of the investigational agent, whichever is longer
7. Co-administration of potent P-glycoprotein inhibitors such as cyclosporine, ketoconazole, erythromycin, clarithromycin, verapamil, dronedarone and amiodarone.
8. Subjects that the Investigator feels are inappropriate for the study will not be included, e.g. subjects with known hypersensitivity or intolerance to SMT19969, fidaxomicin (and the macrolide antibacterial class of compounds) and their excipients; recent use of pro or prebiotics; prior history of faecal microbiota transplant (FMT) or bowel/stomach surgery

E.5 End points

E.5.1

Primary end point(s)

Number of AEs and SAEs reported within the study

E.5.1.1

Timepoint(s) of evaluation of this end point

Monitored throughout the study

E.5.2

Secondary end point(s)

• Plasma, urine and faecal concentrations of SMT19969 and its metabolites
• The use of 16S ribosomal RNA sequencing, metagenomic and bioinformatic techniques to investigate the bacterial flora of each subject beyond the cultivable species and thus determine deeper effects on bowel flora during therapy.
• Investigator assessed clinical response at the Test Of Cure (TOC) visit - with clinical cure defined as the resolution of diarrhoea (≤ 3 Unformed Bowel Movements (UBMs) per day) while on treatment that is maintained until the TOC visit.
• Sustained Clinical Response - defined as clinical cure at TOC and no recurrence of CDI within 30 days post EOT. Recurrence defined as a new episode of diarrhoea between TOC and end of study with a positive C.difficile diagnostic result and the subject requiring antimicrobial treatment active against C. difficile that is started
between TOC and End of Study (Day 40).
• Time to resolution of diarrhoea (TTROD)
• Time to hospital discharge for in-patients
• Recurrence rate of CDI

E.5.2.1

Timepoint(s) of evaluation of this end point

Monitored throughout the 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

Yes

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

Yes

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

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)

Yes

E.8.2.2

Placebo

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

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

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

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

Yes

F.3.3.7.1

Details of other specific vulnerable populations

persons in nursing homes

F.4 Planned number of subjects to be included

F.4.1

In the member state

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)

None

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	National Institute for Health Research, Clinical Research Network
G.4.3.4	Network Country	United Kingdom

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-08-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-10-08

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-08-09

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