Safety and Pharmacokinetics (PK) in Multidrug-Resistant (MDR) Refractive Tuberculosis
Condition: Tuberculosis
MeSH terms: Tuberculosis; Tuberculosis, Multidrug-Resistant
Intervention: Delamanid; Optimized Background Regimen (OBR)
Intervention description: OPC-67683 film-coated tablets; OBR was selected at the discretion of the study investigator and included at least 2 anti-TB medications based on World Health Organization (WHO's) guidelines for the programmatic management of drug-resistant TB. Study investigator could change OBR for a participant based on his/her tolerability and drug susceptibility testing (DST) results.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 10.0
Sex: All
Minimum age: 18 Years
Maximum age: 64 Years
Healthy volunteers: No
Keywords: MDR-TB; Dose Escalation; Phase II; Open Label; Non Controlled; Pulmonary Multidrug-Resistant Tuberculosis (MDR TB)

Summary:

      The purpose of this study is:

        -  To evaluate the safety and tolerability of orally administered OPC-67683 when
           administered two times daily to MDR tuberculosis (TB) participants refractory to
           treatment with an optimized background regimen of anti-TB medications (OBR).

        -  To evaluate the pharmacokinetics (PK) of OPC-67683 and metabolites.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Provide written, informed consent prior to all trial-related procedures

          2. Male or female participants aged between 18 and 64 years, inclusive.

          3. Able to produce sputum for mycobacterium culture or able to obtain sputum produced
             through Induction.

          4. At least three sputum mycobacterium cultures positive for MTB with in-vitro resistance
             to isoniazid and rifampicin during the previous 270 days (9 months) despite treatment
             with first and second line anti-TB drugs, including one positive culture within the
             previous 60 days from the time of sputum collection, prior to date of screening
             initiation [defined as the date the informed consent form (ICF) is signed and
             screening begins].

          5. Sputum mycobacterial culture positive for MTB with in-vitro susceptibility to at least
             one anti-TB medication within the previous 60 days prior to the date of screening
             initiation.

          6. Participant judged by the investigator to have potential for clinical benefit from
             OPC-67683 exposure.

          7. 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).

          8. Male participant 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:

          1. A history of allergy to any nitro-imidazoles or nitro-imidazole derivatives at any
             time.

          2. Use of the medications in Section 4.1 including: use of amiodarone at any time during
             the previous 12 months, use of other antiarrhythmics for the previous 30 days, as well
             as use of certain antidepressants, anti-histamines, any macrolides, for the previous
             14 days.

          3. Any current serious concomitant conditions or renal impairment characterized by serum
             creatinine levels ~265 micromoles (μmol)/L or hepatic impairment characterized by
             alanine aminotransferase (ALT) and/or aspartate transferase (AST) levels 3 times the
             upper limit of the laboratory reference range.

          4. Current clinically relevant changes in the Screening electrocardiogram (ECG) such as
             any atrioventricular (AV) block, prolongation of the QRS complex over 120 msec (in
             both male and female participants), or of the QT interval with Fridericia's correction
             (QTcF) interval over 450 msec in male participants and over 470 msec in female
             participants.

          5. Current clinically relevant cardiovascular disorder such as heart failure, coronary
             heart disease, uncontrolled or poorly controlled hypertension, arrhythmia,
             tachyarrhythmia or status after myocardial infarction.

          6. For participants with human immunodeficiency virus (HIV) infection, helper/inducer
             T-lymphocyte (CD4 cell) count < 350/mm^3 or on treatment with anti-retroviral
             medication for HIV infection.

          7. Karnofsky score < 50%.

          8. Any current diseases or conditions in which the use of nitro-imidazoles or
             nitro-imidazole derivates is contra-indicated.