A Placebo-controlled, Phase 2 Trial to Evaluate OPC 67683 in Patients With Pulmonary Sputum Culture-positive, Multidrug-resistant Tuberculosis (TB)

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withdrawn as ineligible if they are confirmed to not have sputum culture positive MDR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.