Safety, tolerability and effectiveness of TMC207 in combination with an individualized background regimen in MDR-TB (Multi-drug Resistant Tuberculosis).

• Register: EUCTR
• Last refreshed on: 18 November 2013
• Main ID: EUCTR2008-008444-25-EE
• Date of registration: 29/07/2009
• Prospective Registration: Yes
• Primary sponsor: Janssen Infectious Diseases BVBA
• Public title: Safety, tolerability and effectiveness of TMC207 in combination with an individualized background regimen in MDR-TB (Multi-drug Resistant Tuberculosis).
• Scientific title: A Phase II, open-label trial with TMC207 as part of a multi-drug resistant tuberculosis (MDR-TB) treatment regimen in subjects with sputum smear-positive pulmonary infection with MDR-TB.
• Date of first enrolment: 19/11/2009
• Target sample size: 225
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2008-008444-25
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: no Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no

Countries of recruitment

Argentina, Brazil, China, Estonia, Hong Kong, India, Korea, Democratic People's Republic of, Latvia, Mexico, Peru, Philippines, Russian Federation, South Africa, Thailand, Turkey, Ukraine, Vietnam

Contacts

• Name: Janssen Biologics BV
• Affiliation: Janssen-Cilag International NV - Clinical Registry Group

• Name: Janssen Biologics BV
• Affiliation: Janssen-Cilag International NV - Clinical Registry Group

Key inclusion & exclusion criteria

Inclusion criteria:
1. Male or female subjects aged 18 years or older. Females may participate if they are of nonchildbearing potential, if they are using effective birth control methods and are willing to continue practicing birth control methods as outlined in Protocol Section 5.2.4 throughout MDR-TB treatment, or if they are nonheterosexually active or willing to practice sexual abstinence throughout MDR-TB treatment.
2. Confirmed pulmonary MDR-TB infection, which is defined as infection by a strain of M. tuberculosis resistant to at least both RMP and INH by previous screening from a TB treatment facility or by use of a rapid screen test within the preceding 6 months. Subjects infected with XDR-TB are also allowed to enter the trial if they have at least 3 TB drugs in their BR to which they are likely to be susceptible.
3. Positive for acid-fast bacilli (AFB) on direct smear examination of expectorated sputum specimen (= 1+ smear-positive) or sputum culture positive for Mycobacterium tuberculosis within the preceding 6 months.
4. Documented HIV-negative or -positive status at screening or within 1 month prior to trial start (via enzyme-linked immunosorbent assay [ELISA] and/or Western Blot). Note: HIV-positive subjects are eligible, provided they meet the requirements and are willing to follow the ARV treatment procedures as outlined in Section 5.2.4 and they are not using disallowed (ARV) medication as described in Section 5.3.11.
5. Subjects having signed the ICF voluntarily before the first trial-related activity.
6. Subjects who can comply with protocol requirements.
7. Subjects who agree to comply with the NTP treatment guidelines.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 10
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 2

Exclusion criteria:
1. Subjects having a known or suspected hypersensitivity or serious adverse reaction to TMC207.
2. Subjects using disallowed concomitant therapy as specified in Protocol Section 5.3.11.
3. Subjects having a current or past history of alcohol and/or drug use that, in the investigator's opinion, would compromise the subject's safety or compliance to the study protocol procedures.
4. HIV infected subjects having a CD4+ count < 250 cells/µL.
5. Subjects with significant cardiac arrhythmia requiring medication.
6. Subjects with complicated or severe extrapulmonary manifestations of TB, including central nervous system infection.
7. Having participated in other clinical studies with investigational agents, within 8 weeks prior to trial start.
8. Presence of any concomitant severe illness or rapidly deteriorating health condition, including immune deficiency 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 trial.
9. Subjects with the following QT/QTc interval characteristics at screening:
a. A marked prolongation of QT/QTc interval, e.g., confirmed demonstration of QTcF (Fridericia correction) interval > 450 ms at screening;
b. A history of additional risk factors for Torsade de Pointes, e.g., heart failure, hypokalemia, family history of Long QT Syndrome;
c. The use of concomitant medications that prolong the QT/QTc interval listed as disallowed medication in Protocol Section 5.3.11;
d. Pathological Q-waves (defined as > 40 ms or depth > 0.4-0.5 mV);
e. Evidence of ventricular pre-excitation;
f. ECG evidence of complete or incomplete left bundle branch block or right bundle branch block;
g. Evidence of second or third degree heart block;
h. Intraventricular conduction delay with QRS duration > 120 ms;
i. Bradycardia as defined by sinus rate < 50 bpm.
10. Subjects with the following toxicities at screening as defined by the enhanced Division of Microbiology and Infectious Diseases (DMID) adult toxicity table (November 2007):
- Creatinine grade 2 or greater (> 1.5 times upper limit of normal [ULN]);
- Lipase grade 3 or greater (> 2.0 x ULN);
- Hemoglobin grade 4 (< 6.5 g/dL) except after discussion with the Medical Leader;
- Aspartate aminotransferase (AST) grade 4 (> 8.0 x ULN) to be excluded, grade 3 (= 3.0 x ULN) must be discussed with Medical Leader;
- Alanine aminotransferase (ALT) grade 4 (> 8.0 x ULN) to be excluded, grade 3 (= 3.0 x ULN) must be discussed with Medical Leader;
- Alkaline phosphatase (ALP) grade 4 (> 8.0 x ULN) to be excluded, grade 3 (= 3.0 x ULN) must be discussed with Medical Leader;
- Total bilirubin grade 3 or greater (> 2.00 x ULN, or > 1.50 x ULN when accompanied by any increase in other liver function test) to be excluded, grade 2 (> 1.50 x ULN, or > 1.25 x ULN when accompanied by any increase in other liver function test) must be discussed with the Medical Leader;
11. Women who are pregnant or breastfeeding.
12. Subjects who have previously received treatment with TMC207 as part of a clinical trial.
13. Subjects having AIDS defining illnesses other than TB, or showing severe symptoms of HIV infection that would make the subject a poor candidate for participation in the trial.
14. Subjects who, upon the evaluation of their pulmonary disease, will require surgical procedure for management of their TB infection within the 24-week treatment period with TMC207.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Sputum smear-positive pulmonary multi-drug resistant tuberculosis
MedDRA version: 14.1 Level: PT Classification code 10044755 Term: Tuberculosis System Organ Class: 10021881 - Infections and infestations

Therapeutic area: Diseases [C] - Bacterial Infections and Mycoses [C01]

Intervention(s)

Product Name: TMC207 (as fumarate salt), R403323
Product Code: F001
Pharmaceutical Form: Tablet
INN or Proposed INN: N/A
CAS Number: 845533-86-0
Current Sponsor code: TMC207
Other descriptive name: R403323
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Primary Outcome(s)

Primary end point(s): The median time to sputum conversion will be assessed using a Cox regression model.

Main Objective: - To evaluate safety, tolerability, and efficacy of TMC207 as part of a multi-drug regimen in the treatment of subjects with MDR-TB;
- To evaluate the pharmacokinetics of TMC207 and its primary metabolite M2, and pharmacokinetic/pharmacodynamic relationships for safety and efficacy.
- To explore the effect of TMC207 on the experience of TB symptoms as measured by the Tuberculosis Symptoms Profile (TSP), and to explore the measurement properties of the TSP.

Secondary Objective: N/A

Timepoint(s) of evaluation of this end point: N/A

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: N/A

Secondary end point(s): N/A

Secondary ID(s)

2008-008444-25-LV

TMC207-TiDP13-C209

Source(s) of Monetary Support

Janssen Infectious Diseases BVBA