Clinical trial NCT01131351: Safety and Pharmacokinetics (PK) in Multidrug-Resistant (MDR) Refractive Tuberculosis
Official title: A Phase 2, Multi-center, Non-controlled, Open-label Dose Escalation Trial to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of Orally Administered OPC-67683 Two Times Daily to Patients With Pulmonary Multidrug-Resistant Tuberculosis Refractory to Conventional Treatment
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Tuberculosis
Keywords: MDR-TB
Dose Escalation
Phase II
Open Label
Non Controlled
Pulmonary Multidrug-Resistant Tuberculosis (MDR TB)
Lead sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Sponsor class: INDUSTRY
First posted: 2010-05-26
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief 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.

Primary outcomes:
measure: Percentage of Participants With Potentially Clinically Significant Abnormalities in Vital Signs
timeFrame: Up to approximately 40 weeks
measure: Percentage of Participants With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Results
timeFrame: Up to approximately 40 weeks
measure: Percentage of Participants With Potentially Clinically Significant Laboratory Values
timeFrame: Up to approximately 40 weeks
measure: Percentage of Participants With Abnormal Audiometry Assessment Values
timeFrame: Up to approximately 40 weeks
measure: Percentage of Participants With Abnormal Visual Acuity Assessment Values
timeFrame: Up to approximately 40 weeks
measure: Percentage of Participants Taking Concomitant Anti-Tuberculosis (TB) Medication During the Trial
timeFrame: Up to approximately 40 weeks
measure: Percentage of Participants Taking Concomitant (Excluding Anti-TB) Medication During the Trial
timeFrame: Up to approximately 40 weeks
measure: Percentage of Participants With Adverse Events (AEs)
timeFrame: Up to approximately 40 weeks
measure: Percentage of Participants With Immediately Reportable Events (IREs)
timeFrame: Up to approximately 40 weeks
measure: Cmax: Maximal Peak Plasma Concentration for Delamanid
timeFrame: At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196
measure: Tmax: Time to Reach Maximal Peak Plasma Concentration for Delamanid
timeFrame: At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196
measure: AUC0-24h: Area Under the Plasma Concentration-Time Curve From 0 To 24 Hours for Delamanid
timeFrame: At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196
measure: Rac (Cmax): Ratio of Accumulation for Cmax of Delamanid
timeFrame: At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196
measure: Rac (AUC): Ratio of Accumulation for AUC of Delamanid
timeFrame: At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196
Secondary outcomes:
measure: Cmax: Maximal Peak Plasma Concentration for Delamanid Metabolites
timeFrame: At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196
measure: Tmax: Time to Reach Maximal Peak Plasma Concentration for Delamanid Metabolites
timeFrame: At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196
measure: AUC0-24h: Area Under the Plasma Concentration-Time Curve From 0 To 24 Hours for Delamanid Metabolites
timeFrame: At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196
measure: Rac (Cmax): Ratios of Accumulation for Cmax for Delamanid Metabolites
timeFrame: At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196
measure: Rac (AUC): Ratios of Accumulation for AUC for Delamanid Metabolites
timeFrame: At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196
measure: Percentage of Participants With Sputum Culture Conversion by Mycobacteria Growth Indicator Tube (MGIT) at Day 168
timeFrame: Day 168 (Week 24)
measure: Percentage of Participants With Sputum Culture Conversion on Solid Mycobacterial Culture Media at Day 168
timeFrame: Day 168 (Week 24)
measure: Mean Change From Baseline in Time to Culture Positivity Using MGIT
timeFrame: Baseline and Days 7, 14, 21, 28, 35, 42, 49, 56, 70, 84, 98, 112, 126, 140, 154, 168, 182, 196, 224, 252, and 280
Other outcomes:
Locations:
city: Ogre
country: Latvia
facility: Infectology Center of Latvia - Clinic of Tuberculosis and Lung Diseases
city: Siauliai
country: Lithuania
facility: Hospital for Tuberculosis and Lung Diseases
city: Vilnius
country: Lithuania
facility: National Tuberculosis and Infectious Diseases University Hospital
Study officials:
References: