Evaluation of Early Bactericidal Activity in Pulmonary Tuberculosis (TMC207-CL001)
Condition: Pulmonary Tuberculosis
MeSH terms: Tuberculosis; Tuberculosis, Pulmonary
Intervention: TMC207; Rifafour e-275 mg
Intervention MeSH terms: Bedaquiline
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 68.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Bedaquiline; Sirturo; Early Bactericidal Activity; EBA; Pulmonary Tuberculosis; TMC207

Summary:

      The trial will evaluate the extended bactericidal activity of 14 consecutive days of oral
      administration of TMC207 at multiple doses as determined by the rate of change of log10
      colony forming units (CFU) per ml sputum over the time period Day 7-14 in participants with
      smear positive pulmonary tuberculosis (TB). A control group will receive standard treatment.
    

Eligibility 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