Clinical Trials Register

Summary
EudraCT Number:	2014-003372-23
Sponsor's Protocol Code Number:	TMC207-C211
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2015-05-28
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
H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED

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A. Protocol Information

A.2

EudraCT number

2014-003372-23

A.3

Full title of the trial

A Phase 2, Open-label, Multicenter, Single-arm Study to Evaluate the Pharmacokinetics, Safety, Tolerability and Antimycobacterial Activity of TMC207 in Combination With a Background Regimen (BR) of Multidrug Resistant Tuberculosis
(MDR-TB) Medications for the Treatment of Children and Adolescents 0 Months to <18 Years of Age Who Have Confirmed or Probable Pulmonary MDR-TB

A.3.1

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

Pharmacokinetic Study to Evaluate Anti-mycobacterial Activity of TMC207 in Combination With Background Regimen (BR) of Multidrug Resistant Tuberculosis (MDR-TB) Medications for Treatment of Children/Adolescents Pulmonary MDR-TB

A.4.1

Sponsor's protocol code number

TMC207-C211

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/65/2015

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Janssen-Cilag International NV
B.1.3.4	Country	Belgium
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	Janssen R&D Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Janssen-Cilag International NV
B.5.2	Functional name of contact point	Clinical Registry Group
B.5.3	Address:
B.5.3.1	Street Address	Archimedesweg 29
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333 CM
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31 (0)71 524 2166
B.5.5	Fax number	+31 (0)71 524 2110
B.5.6	E-mail	clinicaltrialsEU@its.jnj.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	Yes
D.2.1.1.1	Trade name	SIRTURO
D.2.1.1.2	Name of the Marketing Authorisation holder	Janssen-Cilag International NV
D.2.1.2	Country which granted the Marketing Authorisation	Belgium
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/3/05/314
D.3 Description of the IMP
D.3.1	Product name	TMC207 (as fumarate salt), R403323
D.3.2	Product code	F001
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	Sirturo
D.3.9.1	CAS number	843663-66-1
D.3.9.2	Current sponsor code	TMC207
D.3.9.3	Other descriptive name	BEDAQUILINE
D.3.9.4	EV Substance Code	SUB32824
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	100
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	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/3/05/314
D.3 Description of the IMP
D.3.1	Product name	TMC207 (as fumarate salt), R403323
D.3.2	Product code	G008
D.3.4	Pharmaceutical form	Dispersible tablet
D.3.4.1	Specific paediatric formulation	Yes
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	Sirturo
D.3.9.1	CAS number	843663-66-1
D.3.9.2	Current sponsor code	TMC207
D.3.9.3	Other descriptive name	BEDAQUILINE
D.3.9.4	EV Substance Code	SUB32824
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	20
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

Multi-drug resistant tuberculosis

E.1.1.1

Medical condition in easily understood language

Tuberculosis

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	19.0
E.1.2	Level	PT
E.1.2	Classification code	10044755
E.1.2	Term	Tuberculosis
E.1.2	System Organ Class	10021881 - Infections and infestations

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 safety and tolerability of TMC207 over a 24-week treatment period in each age cohort.
- to evaluate the pharmacokinetics of TMC207 over a 24-week treatment period in the different age cohorts and to provide guidance on dose selection for each of the age cohorts evaluated in this study.

E.2.2

Secondary objectives of the trial

- to evaluate treatment outcome, including anti-mycobacterial activity of TMC207 in confirmed or probable pulmonary MDR-TB over a 24-week treatment period in each age cohort.
- to evaluate pharmacokinetic-pharmacodynamic relationships for safety and efficacy of TMC207 over a 24-week treatment period in each age cohort.
- to evaluate adherence and palatability of dispersible tablets.
- to evaluate the long-term safety, tolerability, and efficacy of TMC207 in combination with a BR of MDR-TB medications in confirmed or probable pulmonary MDR-TB over 120 weeks post-baseline (including survival follow-up in subjects who prematurely discontinue from study drug and study procedures)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Participant must be a boy or girl, aged from birth (0 months) to less than (<) 18 years at screening. Infants must be greater than or equal to (>=) 37 weeks gestation at baseline - Participant must weigh >4 kilogram (kg) at entry and be within the 5th and 95th percentiles (inclusive) for the participant’s age, based on the World Health Organization (WHO) child growth
standards
- Heterosexually active girls may participate if they are of non-childbearing potential, or if they are using effective birth
control methods and are willing to continue practicing birth control methods throughout Multidrug Resistant Tuberculosis (MDR-TB) treatment and for 6 months after stopping TMC207 treatment, or if they are non-heterosexually active or willing to practice sexual abstinence throughout MDR-TB treatment
- Participants must be starting the initial MDR-TB regimen at baseline or have started an MDR-TB regimen within 8 weeks of baseline and are willing to modify it if necessary to an acceptable MDR-TB regimen for use with TMC207
- Participant must be willing to permanently discontinue RMP from at least 7 days before the baseline

E.4

Principal exclusion criteria

- Participant has a clinically significant active medical condition or the presence of any concomitant severe illness or
rapidly deteriorating health condition, including immune deficiency, which in the opinion of the investigator would prevent
appropriate participation in the study, or that would make implementation of the protocol or interpretation of the study results difficult, or otherwise make the subject a poor candidate for a clinical study
- Participant is a girl who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 6 months after stopping TMC207 treatment
- Participant (or the mother if the potential subject is a child aged <6 months) has a test positive for Human Immunodeficiency Virus (HIV) at screening or within 1 month before screening
- Participant has known or presumed complicated or severe extrapulmonary manifestations of TB, including TB meningitis. Participants with adenopathy or adenitis are allowed to enter the study
- Participant has a significant cardiac arrhythmia that requires medication or a history of risk factors for Torsade de Pointes, example heart failure, hypokalemia, known personal or family history of Long QT Syndrome, and untreated hypothyroidism

E.5 End points

E.5.1

Primary end point(s)

1- Number of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs)
2- Maximum Plasma Concentration (Cmax)
3- Time to Reach Maximum Plasma Concentration (Tmax)
4- Minimum Plasma Concentration (Cmin)
5- Area Under the Plasma Concentration-time Curve From the Time of Dose Administration up to X Hours (AUCtime-h)
6- Elimination Half-life (t1/2)
7- Area Under the Plasma Concentration-time Curve From the Time of Dose Administration up to 168 Hours [AUC168h]
8- Volume of Distribution (Vd)
9- Apparent Clearance (CL)

E.5.1.1

Timepoint(s) of evaluation of this end point

1- 120 Weeks
2- Pre-dose (time 0) at Day 1 and at Week 4, 6, 8, 16, 20; Pre-dose, and at 2 and 24 hours post-dose at Week 24
3- Pre-dose (time 0) at Day 1 and at Week 4, 6, 8, 16, 20; Pre-dose, and at 2 and 24 hours post-dose at Week 24
4- Pre-dose (time 0) at Day 1 and at Week 4, 6, 8, 16, 20; Pre-dose, and at 2 and 24 hours post-dose at Week 24; Pre-dose at Week 28, 32, 40, 48, 60, 72, 84, 96, 108, and 120
5/6/8/9- Pre-dose (time 0) at Day 1 and at Week 4, 6, 8, 16, 20; Pre-dose, and at 2 and 24 hours post-dose at Week 24; Pre or Post-dose at Week 28, 32, 40, 48, 60, 72, 84, 96, 108, and 120
7- Pre-dose (time 0) at Day 1 up to 168 hour

E.5.2

Secondary end point(s)

1- Percentage of Participants with Favorable Treatment outcome (Sustained Positive Clinical Cure)
2- Time to First Confirmed Smear and Sputum Culture Conversion

E.5.2.1

Timepoint(s) of evaluation of this end point

1- Week 24, Week 120 (end of study)
2- Baseline (Day 1) up to Week 120

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

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

Yes

E.6.13.1

Other scope of the trial description

tolerability

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

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)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

Will this trial be conducted at a single site globally?

E.8.4

Will this trial be conducted at multiple sites globally?

Yes

E.8.6 Trial involving sites outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Yes

E.8.6.3

Specify the countries outside of the EEA in which trial sites are planned

India

Philippines

Russian Federation

South Africa

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.8.9.2

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

Yes

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

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

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Subjects under age incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

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)

LPLV

G. Investigator Networks to be involved in the Trial

H.4 Third Country in which the Trial was first authorised
H.4.1	Third Country in which the trial was first authorised:	South Africa

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