Evaluation of Early Bactericidal Activity in Pulmonary Tuberculosis (TMC207-CL001)

• Register: ClinicalTrials.gov
• Last refreshed on: 16 December 2017
• Main ID: NCT01215110
• Date of registration: 30/09/2010
• Prospective Registration: No
• Primary sponsor: Global Alliance for TB Drug Development
• Public title: Evaluation of Early Bactericidal Activity in Pulmonary Tuberculosis (TMC207-CL001)
• Scientific title: A Phase II Dose Ranging Trial to Evaluate the Extended Early Bactericidal Activity, Safety, Tolerability, and Pharmacokinetics of TMC207 in Adult Patients With Newly Diagnosed, Uncomplicated, Smear-Positive, Pulmonary Tuberculosis.
• Date of first enrolment: April 2010
• Target sample size: 68
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT01215110
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Double (Participant, Investigator).
• Phase: Phase 2

Countries of recruitment

South Africa

Contacts

• Name: Andreas Diacon
• Affiliation: TASK APPLIED SCIENCE, Karl Bremer Hospital

Key inclusion & exclusion criteria

Inclusion Criteria:

- Provide written, informed consent prior to all trial-related procedures including HIV
testing.

- Male or female, aged between 18 and 65 years inclusive.

- Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive.

- Newly diagnosed, previously untreated, uncomplicated, sputum smear-positive, pulmonary
TB.

- A chest X-ray picture which in the opinion of the Investigator is compatible with TB.

- Sputum positive on direct microscopy for acid-fast bacilli …(at least 1+ on the
International Union Against Tuberculosis and Lung Disease (IUATLD)/World Health
Organization (WHO) scale).

- Ability to produce an adequate volume of sputum as estimated from a spot assessment
(estimated 10 ml or more overnight production).

- Females may participate if they are of non-childbearing potential, if they are using
effective birth control methods and are willing to continue practicing birth control
methods throughout treatment or if they are non-heterosexually active or willing to
practice sexual abstinence throughout the treatment period or have a vasectomized
partner (confirmed sterile). Therefore to be eligible for this study women of
childbearing potential should either:1) use a double barrier method to prevent
pregnancy (i.e. use a condom with either diaphragm or cervical cap) or 2) use hormonal
based contraceptives in combination with a barrier contraceptive, or 3) use an
intrauterine device in combination with a barrier contraceptive. They must also be
willing to continue these contraception until 6 months after last study drug or 6
months after discontinuation from study medication in case of premature
discontinuation. (Note: Hormone-based contraception may not be reliable when taking
TMC207; therefore, hormone-based contraceptives cannot be used by female patients to
prevent pregnancy).

- Male patients must be willing to use a condom with spermicide when having heterosexual
intercourse throughout treatment and until 1 month after last study drug
administration or 1 month after discontinuation from study medication in case of
premature discontinuation.

Exclusion Criteria:

1. Evidence of clinically significant metabolic, gastrointestinal neurological,
psychiatric or endocrine diseases, malignancy, or other abnormalities (other than the
indication being studied).

2. Known or suspected hypersensitivity to study medications (including any rifamycin
antibiotics)

3. Rifampicin-resistant and/or isoniazid-resistant bacteria detected with a sputum
specimen collected within the pre-treatment period and tested at the study laboratory.

4. Clinically significant evidence of extrathoracic TB (miliary TB, abdominal TB,
urogenital TB, osteoarthritic TB, TB meningitis), as judged by the investigator.

5. Current or past history of alcohol and/or drug use that, in the investigator's
opinion, would compromise the participant's safety or compliance to the study protocol
procedures.

6. HIV infected patients:

1. having a cluster of differentiation 4 (CD4)+ count <300 cells/µL;

2. or having received antiretroviral therapy medication within the last 90 days:

3. or having received oral or intravenous antifungal medication within the last 90
days;

4. or with an AIDS-defining opportunistic infection or malignancies (except
pulmonary TB).

7. Significant cardiac arrhythmia requiring medication

8. Having participated in other clinical studies with investigational agents within 8
weeks prior to trial start.

9. Patients with the following QT/corrected QT(QTc) interval characteristics at
screening:

1. Marked prolongation of QT/QTc interval, e.g., confirmed demonstration of QT
corrected for heart rate using Fridericia's method (QTcF) interval >450 ms at
screening;

2. History of additional risk factors for Torsade de Pointes, e.g., heart failure,
hypokalemia, family history of Long QT Syndrome;

3. Use of concomitant medications that prolong the QT/QTc interval listed as
disallowed medication in Section 2.10.2;

4. Pathological Q waves (defined as >40ms or depth >0.4-0.5mV);

5. Evidence of ventricular pre-excitation;

6. ECG evidence of complete or incomplete left bundle branch block or right bundle
branch block;

7. Evidence of second or third degree heart block;

8. Intraventricular conduction delay with QRS duration >120ms;

9. Bradycardia as defined by sinus rate <50bpm

10. Women who are pregnant or breastfeeding

11. History and/or presence (or evidence) of neuropathy or epilepsy.

12. Diabetics using insulin

13. Poor general condition where any delay in treatment cannot be tolerated per discretion
of Investigator.

14. Previously received treatment with TMC207 as part of a clinical trial.

15. Treatment received with any drug active against Mycobacterium tuberculosis within 3
months prior to Visit 1.

16. Any disease or conditions in which any of the medicinal products listed in the section
pertaining to prohibited medications is used.

17. Patients with the following toxicities at screening as defined by the enhanced
Division of Microbiology and Infectious Disease (DMID) adult toxicity table (November
2007):

1. creatinine grade 2 or greater (>1.5 times upper limit of normal [ULN]);

2. lipase grade 3 or greater (>2.0 x ULN);

3. hemoglobin grade 4 (<6.5 g/dL) except after discussion with the Medical Monitor;

4. aspartate aminotransferase (AST) grade 4 (>8.0 x ULN) to be excluded, grade 3
(=3.0 x ULN) must be discussed with Medical Monitor;

5. alanine aminotransferase (ALT) grade 4 (>8.0 x ULN) to be excluded, grade 3 (=3.0
x ULN) must be discussed with Medical Monitor;

6. alkaline phosphatase (ALP) grade 4 (>8.0 x ULN) to be excluded, grade 3 (=3.0 x
ULN) must be discussed with Medical Monitor;

7. 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 Monitor



Age minimum: 18 Years
Age maximum: 65 Years
Gender: All

Health Condition(s) or Problem(s) studied

Pulmonary Tuberculosis

Intervention(s)

Drug: Rifafour e-275 mg

Drug: TMC207

Primary Outcome(s)

Early Bactericidal Activity (EBA) Measured as the Mean Rate of Change of log10 Colony Forming Units (CFU) of M. Tuberculosis Per ml Sputum on Solid Medium Over Time (Days 0-14). [Time Frame: Fourteen consecutive days of treatment]

Secondary Outcome(s)

Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-2) [Time Frame: Two consecutive days of treatment]

Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 7-14) [Time Frame: Days 7-14 of fourteen consecutive days of treatment]

Summary of Statistical Analysis of TMC207 Time of Maximum Plasma Concentration (T(Max)) on Days 1 and 14 [Time Frame: Day 1 (0, 1, 3, 5, 6, 8, 12, and 24 hour post-dose) or Day 14 (0, 1, 3, 5, 6, 8, 12, 24, and 30 hour post-dose)]

Early Bactericidal Activity (EBA) Measured as the Mean Rate of Change of log10 Colony Forming Units (CFU) of M. Tuberculosis Per ml Sputum on Solid Medium Over Time (Days 0-2). [Time Frame: Two consecutive days of treatment]

Early Bactericidal Activity (EBA) Measured as the Mean Rate of Change of log10 Colony Forming Units (CFU) of M. Tuberculosis Per ml Sputum on Solid Medium Over Time (Days 2-14). [Time Frame: Days 2-14 of fourteen consecutive days of treatment]

Early Bactericidal Activity (EBA) Measured as the Mean Rate of Change of log10 Colony Forming Units (CFU) of M. Tuberculosis Per ml Sputum on Solid Medium Over Time (Days 7-14). [Time Frame: Days 7-14 of fourteen consecutive days of treatment]

Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 2-14) [Time Frame: Days 2-14 of fourteen consecutive days of treatment]

Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-14) [Time Frame: Fourteen consecutive days of treatment]

Summary of Statistical Analysis of TMC207 Maximum Plasma Concentration Following Dosing (C(Max)) on Days 1 and 14 [Time Frame: Day 1 (0, 1, 3, 5, 6, 8, 12, and 24 hour post-dose) or Day 14 (0, 1, 3, 5, 6, 8, 12, 24, and 30 hour post-dose)]

Summary of Statistical Analysis of TMC207 Area Under the Concentration-time Curve Over the Dose Interval of 0 to 24 h (AUC(0-24)) on Day 1 and Day 14 [Time Frame: Day 1 (0, 1, 3, 5, 6, 8, 12, and 24 hour post-dose) or Day 14 (0, 1, 3, 5, 6, 8, 12, and 24 hour post-dose)]

Secondary ID(s)

TMC207-CL001

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 26/04/2017
• URL: https://clinicaltrials.gov/ct2/show/results/NCT01215110