Safety and Pharmacokinetics (PK) in Multidrug-Resistant (MDR) Refractive Tuberculosis

Otsuka

Status and phase: Terminated; Phase 2

Conditions: Tuberculosis

Treatments: Drug: Delamanid; Drug: Optimized Background Regimen (OBR)

Study type: Interventional

Funder types: Industry

Identifiers

NCT01131351

2009-014944-13 (EudraCT Number)

242-08-210

Details and patient eligibility

About

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.

Enrollment: 10 patients

Sex: All

Ages: 18 to 64 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

---

10 participants in 2 patient groups

Delamanid 250 mg BID+ OBR

Experimental group

Description:

Participants received delamanid five 50 milligrams (mg) (250 mg) tablets, twice a day (BID), along with at least 2 additional anti-TB medications per optimized background regimen (OBR) for up to 28 weeks.

Treatment:

Drug: Delamanid

Drug: Optimized Background Regimen (OBR)

Delamanid 300 mg BID+ OBR

Experimental group

Description:

Participants received delamanid six 50 mg (300 mg) tablets, BID, along with at least 2 additional anti-TB medications per OBR for up to 28 weeks.

Treatment:

Drug: Delamanid

Drug: Optimized Background Regimen (OBR)