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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Tuberculosis

Intervention / Treatment
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* Drug: Delamanid
* Drug: Optimized Background Regimen (OBR)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide written, informed consent prior to all trial-related procedures Male or female participants aged between 18 and 64 years, inclusive. Able to produce sputum for mycobacterium culture or able to obtain sputum produced through Induction. 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]. 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. Participant judged by the investigator to have potential for clinical benefit from OPC-67683 exposure. 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 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: A history of allergy to any nitro-imidazoles or nitro-imidazole derivatives at any time. 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. 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. 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. Current clinically relevant cardiovascular disorder such as heart failure, coronary heart disease, uncontrolled or poorly controlled hypertension, arrhythmia, tachyarrhythmia or status after myocardial infarction. 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. Karnofsky score < 50%. Any current diseases or conditions in which the use of nitro-imidazoles or nitro-imidazole derivates is contra-indicated.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Delamanid 250 mg BID+ OBR<br>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. | Drug: Delamanid<br>* OPC-67683 film-coated tablets<br>* Other names: OPC-67683;Drug: Optimized Background Regimen (OBR)<br>* 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.<br>|
| Experimental: Delamanid 300 mg BID+ OBR<br>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. | Drug: Delamanid<br>* OPC-67683 film-coated tablets<br>* Other names: OPC-67683;Drug: Optimized Background Regimen (OBR)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | Up to approximately 40 weeks | 
| Percentage of Participants With Abnormal Audiometry Assessment Values |  | Up to approximately 40 weeks | 
| Percentage of Participants With Abnormal Visual Acuity Assessment Values |  | Up to approximately 40 weeks | 
| Percentage of Participants Taking Concomitant Anti-Tuberculosis (TB) Medication During the Trial |  | Up to approximately 40 weeks | 
| Percentage of Participants Taking Concomitant (Excluding Anti-TB) Medication During the Trial |  | Up to approximately 40 weeks | 
| Percentage of Participants With Adverse Events (AEs) | An AE was defined as any new medical problem, or exacerbation of an existing problem, experienced by a participant while enrolled in the trial, whether or not it was considered drug-related by the investigator. | Up to approximately 40 weeks | 
| Percentage of Participants With Immediately Reportable Events (IREs) | An AE was considered serious if it was fatal; life-threatening; persistently or significantly disabling or incapacitating; required in-participant hospitalization or prolonged hospitalization; a congenital anomaly/birth defect; or other medically significant event that, based upon appropriate medical judgment, may have jeopardized the participant and may have required medical or surgical intervention to prevent one of the outcomes listed above. The following were considered as IREs- serious adverse events (SAEs), pregnancies in trial participants or their partners, and all events involving overdose, misuse and abuse. | Up to approximately 40 weeks | 
| Cmax: Maximal Peak Plasma Concentration for Delamanid |  | At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196 | 
| Tmax: Time to Reach Maximal Peak Plasma Concentration for Delamanid |  | At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196 | 
| AUC0-24h: Area Under the Plasma Concentration-Time Curve From 0 To 24 Hours for Delamanid | AUC0-24h was calculated as 2×AUC0-12h. | At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196 | 
| Rac (Cmax): Ratio of Accumulation for Cmax of Delamanid | Ratio of accumulation for Cmax was assessed on Days 14, 28, 56, 112 and 196 with respect to Day 1. | At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196 | 
| Rac (AUC): Ratio of Accumulation for AUC of Delamanid | Ratio of accumulation for AUC was assessed on Days 14, 28, 56, 112 and 196 with respect to Day 1. | At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax: Maximal Peak Plasma Concentration for Delamanid Metabolites | The primary metabolites of delamanid are DM-6704, DM-6705 and DM-6706. | At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196 | 
| Tmax: Time to Reach Maximal Peak Plasma Concentration for Delamanid Metabolites | The primary metabolites of delamanid are DM-6704, DM-6705 and DM-6706. | At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196 | 
| AUC0-24h: Area Under the Plasma Concentration-Time Curve From 0 To 24 Hours for Delamanid Metabolites | The primary metabolites of delamanid are DM-6704, DM-6705 and DM-6706. | At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196 | 
| Rac (Cmax): Ratios of Accumulation for Cmax for Delamanid Metabolites | The primary metabolites of delamanid are DM-6704, DM-6705 and DM-6706. Ratio of accumulation for Cmax was planned to be assessed on Days 14, 28, 56, 112 and 196 with respect to Day 1. | At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196 | 
| Rac (AUC): Ratios of Accumulation for AUC for Delamanid Metabolites | The primary metabolites of delamanid are DM-6704, DM-6705 and DM-6706. Ratio of accumulation for AUC was planned to be assessed on Days 14, 28, 56, 112 and 196 with respect to Day 1. Limited metabolite exposure on Day 1 did not allow for estimation of Rac for metabolites. | At 24 hours post dose on Days 1, 14, 28, 56, 112 and 196 | 
| Percentage of Participants With Sputum Culture Conversion by Mycobacteria Growth Indicator Tube (MGIT) at Day 168 | Sputum culture conversion was evaluated using the MGIT culture system. A participant was classified as demonstrating a sputum culture conversion if he/she achieved two consecutive sputum cultures negative for growth of Mycobacterium tuberculosis at least 28 days apart after his/her last sputum culture positive for growth and not followed by any sputum specimens positive for growth. | Day 168 (Week 24) | 
| Percentage of Participants With Sputum Culture Conversion on Solid Mycobacterial Culture Media at Day 168 | Sputum culture status was determined using solid mycobacterial culture media and measuring colony counts per milliliter of sputum. The unit for colony counts: log10 colony-forming unit (CFU)/mL. A participant was classified as demonstrating a sputum culture conversion if he/she achieved two consecutive sputum cultures negative for growth of Mycobacterium tuberculosis at least 28 days apart after his/her last sputum culture positive for growth and not followed by any sputum specimens positive for growth. | Day 168 (Week 24) | 
| Mean Change From Baseline in Time to Culture Positivity Using MGIT | The value for time to positivity was defined (in days) as the time interval from inoculation until a positive signal was detected for MTB on sputum culture in the MGIT system during the routine 42 day incubation period. Time to positivity analysis was based on the corresponding qualitative sputum results of positive and negative sputum cultures in days of the initial positive signal for a culture from the MGIT system. Mean is reported for Baseline and mean change from baseline is reported for Days 7, 14, 21, 28, 35, 42, 49, 56, 70, 84, 98, 112, 126, 140, 154, 168, 182, 196, 224, 252, and 280. Baseline is Day -2 and -1. Mean time to culture positivity at Baseline was defined as the average of Day -2 and Day -1 values, if the cultures on both days were positive; and if only one culture was positive, the value for the positive culture was used as baseline. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MDR-TB, Dose Escalation, Phase II, Open Label, Non Controlled, Pulmonary Multidrug-Resistant Tuberculosis (MDR TB)