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

Phase 2TerminatedNCT01131351

Otsuka Pharmaceutical Development & Commercialization, Inc.10 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Tuberculosis

Interventions

DelamanidDRUG

OPC-67683 film-coated tablets

Optimized Background Regimen (OBR)DRUG

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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 64 Years

Medical Language ↔ Plain English

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.

Locations (3)

Infectology Center of Latvia - Clinic of Tuberculosis and Lung Diseases

Ogre, Latvia

Hospital for Tuberculosis and Lung Diseases

Šiauliai, Lithuania

National Tuberculosis and Infectious Diseases University Hospital

Vilnius, Lithuania

Outcomes

Primary Outcomes

Percentage of Participants With Potentially Clinically Significant Abnormalities in Vital Signs

Vital signs included body weight \[kilogram (kg)\], body temperature \[degree Celsius (°C)\], heart rate \[beats per minute (BPM)\], respiratory rate (breaths/minute), systolic and diastolic blood pressure \[millimeter of mercury (mmHg)\]. The criteria for clinically significant abnormal value were: body weight (kg): increase \>=5% or decrease \>=5%; body temperature (°C): \>=38.5°C and increase of \>=1.1°C; heart rate (BPM): \>=120 bpm and increase of \>=15 bpm, or \<=60 bpm and decrease of \>=15 bpm; systolic blood pressure (mmHg): \>=160 mmHg and increase of \>=20 mmHg, or \<=90 mmHg and decrease of \>=20 mmHg; diastolic blood pressure (mmHg): \>=105 mmHg and increase of \>=15 mmHg, or \<=50 mmHg and decrease of \>=15 mmHg; respiration rate (breaths per minute) \>30 breaths per minute. Only categories with data for potentially clinically significant abnormal vital sign parameter values are reported.

Time frame: Up to approximately 40 weeks

Percentage of Participants With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Results

The criteria for clinically significant abnormal ECG values were- ventricular rate outlier (\<50 bpm and decrease of \>=25%, \>100 bpm and increase of \>=25%), PR outlier \[increase of \>=25% when PR \>200 milliseconds (ms)\], QRS outlier (increase of \>=25% when QRS \>100 ms), QT (new onset (in treatment period but not at Baseline) \[\>500 ms\]), QT interval corrected by Bazett's formula (QTcB) (new onset \[\>450, \>480, \>500 ms\], increase of \>=30 ms and \<= 60 ms or increase of \>60 ms), QT interval corrected by Fridericia's formula (QTcF) (new onset \[\>450, \>480, \>500 ms\], increase of \>=30 ms and \<= 60 ms or increase of \>60 ms), new abnormal U waves, new ST segment changes, new T wave changes, new abnormal rhythm, new conduction abnormality were reported as categories. Baseline was defined as the average of the ECGs taken at Day -1. Only categories with data for potentially clinically significant abnormal ECG values are reported.

Time frame: Up to approximately 40 weeks

Percentage of Participants With Potentially Clinically Significant Laboratory Values

Clinical laboratory tests included hematology, coagulation, chemistry, and urinalysis. The participants were categorized based on the clinically significant laboratory values as per protocol predefined criteria. The categories with at least one participant with clinically significant value outside the normal range for laboratory assessments are reported.

Data from ClinicalTrials.gov

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