A Placebo-controlled, Phase 2 Trial to Evaluate OPC 67683 in Patients With Pulmonary Sputum Culture-positive, Multidrug-resistant Tuberculosis (TB)
A Placebo-controlled, Phase 2 Trial to Evaluate OPC 67683 in Patients With Pulmonary Sputum Culture-positive, Multidrug-resistant Tuberculosis (TB)
This is a clinical trial to evaluate the safety and efficacy of OPC-67683 in the treatment of
 multidrug resistant tuberculosis (MDR TB) for 56 days. In addition to an optimized background
 regimen (OBR).patients will receive will be randomized to:

 -  100 mg OPC-67683 BID

 -  200 mg OPC-67683 BID

 -  placebo BID After 56 days subjects will complete their OBR.
This is a multi center, randomized, double-blinded, stratified, placebo-controlled clinical
 trial in three parallel groups. Patients will be randomized to one of the following three
 treatment groups:

 -  Optimized Background Regimen (OBR) plus 100 mg OPC-67683 twice daily

 -  OBR plus 200 mg OPC-67683 twice daily

 -  OBR plus placebo twice daily

 The three treatment groups will comprise approximately 140 patients each (male or female).
 The trial will consist of the following periods:

 -  Pre-treatment Period (Visits 1 to 3 [Day -9 to Day -1])

 -  Treatment Period (Visits 4 to 59 [Days 1 to 56])

 -  Post-treatment Period (Visits 60 to 64 [Days 57 to 84]) Enrolled patients (those
 accepted into the screening period of the trial who signed an informed consent form)
 will be stratified at randomization by extent of pulmonary TB; an equal number of
 patients with and without cavities visible in the lung fields on baseline chest
 radiograph will be allocated to each treatment group. A total of 430 male or female
 patients aged 18 to 64 years, inclusive, with pulmonary, sputum culture-positive MDR TB
 (TB caused by Mycobacterium tuberculosis strains resistant to at least isoniazid and
 rifampicin) or with sputum smears positive for acid fast bacilli (AFB) and a positive
 rapid test for rifampicin resistance on direct sputum within 60 days prior to the
 expected date of enrollment. Patients with positive AFB smears and a positive rapid
 rifampicin resistance test will be enrolled as presumptively culture positive and
 withdrawn as ineligible if they are confirmed to not have sputum culture positive MDR
 TB.
Inclusion Criteria:

 -  Provide written, informed consent prior to all trial-related procedures

 -  Male and female patients aged between 18 and 64 years, inclusive.

 -  Either mycobacterial culture of sputum positive for growth of M. tuberculosis or
 sputum smear positive for acid fast bacilli within 60 days prior to the expected date
 of enrollment.

 -  Patient with TB caused by isolates of M. tuberculosis complex confirmed to be
 resistant to treatment with isoniazid and rifampicin, or with positive rapid test for
 rifampicin resistance on direct sputum positive for acid fast bacilli within 60 days
 prior to the expected date of enrollment.

 -  Findings on chest radiograph consistent with TB.

 -  Able to produce sputum for mycobacterial culture.

 -  Female patients of childbearing potential must have a negative urine pregnancy test
 and agree to use a highly effective method of birth control (for example, two of the
 following precautions: tubal ligation, vaginal diaphragm, intrauterine device, oral
 contraceptives, contraceptive implant, combined hormonal patch, combined injectable
 contraceptive or depot-medroxyprogesterone acetate) throughout the participation in
 the trial and for 22 weeks after last dose (to cover duration of ovulation).

 -  Male patients must agree to use an adequate method of contraception (double barrier)
 throughout the participation in the trial and for 30weeks after last dose (to cover
 duration of spermatogenesis).

 Exclusion Criteria:

 -  A history of allergy to any nitro-imidazoles or nitro-imidazole derivates at any time.

 -  Use of the medications in Section 4.1 of the protocol including: use of amiodarone at
 any time during the previous 12 months, use of other anti-arrhythmics for the previous
 30 days, and use of certain other medications, including certain anti-depressants,
 anti-histamines, and macrolides, for the previous 14 days.

 -  Any current serious concomitant conditions or renal impairment characterized by serum
 creatinine levels ≥265 micromol/L or hepatic impairment characterized by ALT and/or
 aspartate transferase (AST) levels 3 times the upper limit of the laboratory reference
 range.

 -  Current clinically relevant changes in the ECG such as any atrioventricular (AV)
 block, prolongation of the QRS complex over 120 milliseconds (in both male and female
 patients), or of either the QTcF or QTcB interval over 430 milliseconds in male
 patients and 450 milliseconds in female patients.

 -  Current clinically relevant cardiovascular disorder such as heart failure, coronary
 heart disease, hypertension, arrhythmia, tachyarrhythmia or status after myocardial
 infarction.

 -  For patients with HIV infection, CD4 cell count < 350/mm3 or on treatment with
 anti-retroviral medication for HIV infection.

 -  Karnofsky score < 60%.

 -  Any diseases or conditions in which the use of nitro-imidazoles or nitro-imidazole
 derivates is contra-indicated.

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

 -  Known or suspected alcohol abuse, that is, abuse sufficient enough to compromise the
 safety or cooperation of the patient in the opinion of the investigator.

 -  Administered an IMP within 1 month prior to Visit 1 (Screening [Days -9 to -3]).

 -  Pregnant, breast-feeding, or planning to conceive or father a child within the
 timeframe described in the informed consent form.

 -  Recent use of methadone, benzodiazepines, cocaine, amphetamine/metamphetamine,
 tetrahydrocannabinol, barbiturates, tricyclic antidepressants, and opiates as
 determined by a urine drug screen unless evidence is provided that the positive drug
 screen is the result of authorized medications products prescribed by a physician for
 a non abuse related indication.

 -  Any disorder that in the judgment of the investigator makes the subject not a good
 candidate for the trial or may prevent the patient from reliably participating in the
 entire course of the trial.