A Trial to Evaluate OPC 67683 in Participants With Pulmonary Sputum Culture-positive, Multidrug-resistant Tuberculosis (TB)

A Multi Center, Randomized, Double-blind, Placebo-controlled Phase 2 Trial to Evaluate the Safety, Efficacy and Pharmacokinetics of Multiple Doses of OPC 67683 in Patients With Pulmonary Sputum Culture-Positive, Multidrug-resistant Tuberculosis

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), participants will be randomized to receive:

• 100 mg OPC-67683 twice daily (BID)
• 200 mg OPC-67683 BID
• Placebo BID

After 56 days participants will complete their optimized background regimen (OBR).

This is a multi center, randomized, double-blinded, stratified, placebo-controlled clinical trial in three parallel groups. Participants will be randomized to one of the following three treatment groups:

• OBR plus 100 mg OPC-67683 BID
• OBR plus 200 mg OPC-67683 BID
• OBR plus placebo BID

The three treatment groups will comprise approximately 140 participants 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 participants (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 participants with and without cavities visible in the lung fields on baseline chest radiograph will be allocated to each treatment group. A total of approximately 430 male or female participants 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. Participants 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AFB smears and a positive rapid rifampicin resistance test will be enrolled as presumptively culture positive and withdrawn as ineligible if they are confirmed to not have sputum culture positive MDR TB.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 participants aged between 18 and 64 years, inclusive.
• Either mycobacterial culture of sputum positive for growth of Mycobacterium tuberculosis or sputum smear positive for acid fast bacilli within 60 days prior to the expected date of enrollment.
• Participant with TB caused by isolates of Mycobacterium 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 participants 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 participants must agree to use an adequate method of contraception (double barrier) throughout the participation in the trial and for 30 weeks 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 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 alanine transaminase (ALT) and/or aspartate transferase (AST) levels 3 times the upper limit of the laboratory reference range.
• Current clinically relevant changes in the electrocardiogram (ECG) such as any atrioventricular (AV) block, prolongation of the QRS complex over 120 milliseconds (in both male and female participants), or of either the QT interval corrected by Fridericia's formula (QTcF) or QT interval corrected by Bazett's formula (QTcB) interval over 430 milliseconds in male participants and 450 milliseconds in female participants.
• Current clinically relevant cardiovascular disorder such as heart failure, coronary heart disease, hypertension, arrhythmia, tachyarrhythmia or status after myocardial infarction.
• For participants with human immunodeficiency virus (HIV) infection, cluster of differentiation 4 helper/inducer T cell[s] (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 participant in the opinion of the investigator.
• Administered an investigational medicinal product (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 participant not a good candidate for the trial or may prevent the participant from reliably participating in the entire course of the trial.