Clinical trial NCT03678688: A Phase 1/2 Trial of Multiple Oral Doses of OPC-167832 for Uncomplicated Pulmonary Tuberculosis
Official title: A Phase 1/2, Active-controlled, Randomized, Open-label Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of Multiple Oral Doses of OPC-167832 Tablets in Subjects With Uncomplicated, Smear-positive, Drug-susceptible Pulmonary Tuberculosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Pulmonary TB
Lead sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Bill and Melinda Gates Foundation
First posted: 2018-09-20
Enrollment: 122
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: This will be a multiple-dose trial of OPC-167832 with 2 stages.

Stage 1 is a multiple ascending dose trial planned to be conducted in 4 sequential cohorts of 18 participants each. There will be 2 arms (OPC-167832, combination of rifampicin, isoniazid, ethambutol, and pyrazinamide (RHEZ)) in each cohort.

Stage 2 will be a parallel group comparison of 4 treatment regimens: 1) OPC-167832 plus Delamanid 2) OPC-167832 plus Bedaquiline 3) OPC-167832 plus Delamanid plus Bedaquiline 4) RHEZ.
Primary purpose: TREATMENT

Brief summary: This trial will evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of multiple oral doses of OPC-167832 in participants with uncomplicated, smear-positive, drug-susceptible pulmonary tuberculosis (TB).


Eligibility criteria: Inclusion Criteria:

* Able to provide written, informed consent prior to initiation of any trial-related procedures, and able, in the opinion of the investigator, to comply with all the requirements of the trial.
* Male or female participants between 18 and 64 years of age (inclusive) at the screening visit.
* Body mass index ≥ 16.0 and ≤ 32.0 kilograms per meters squared (kg/m\^2) (inclusive) at the screening visit.
* Newly diagnosed, uncomplicated, drug-susceptible pulmonary TB.
* Microscopy performed on a sputum smear at screening indicates presence of acid-fast bacilli (at least 1+).
* Able to produce an adequate volume of sputum (approximately 10 millilitres (mL) or more estimated overnight production).
* Female participants of childbearing potential must agree to use 2 different approved methods of birth control or remain abstinent throughout the participation in the trial and for 12 weeks after the last dose of trial treatment (investigational medicinal product (IMP) or RHEZ).
* Male participants must agree to use 2 different approved methods of birth control or remain abstinent throughout the participation in the trial and for 12 weeks after the last dose of trial treatment (IMP or RHEZ).

Exclusion Criteria:

* Participants are known or suspected of having resistance to rifampicin, isoniazid, ethambutol, or pyrazinamide using any combination of Xpert Mycobacterium tuberculosis/Rifampin (MTB/RIF), line probe assay, culture, and/or epidemiologic history at screening.
* Poor general condition where no delay in treatment can be tolerated or where immediate hospital admission is warranted.
* Evidence of clinically significant metabolic (including ongoing or current hypokalemia), gastrointestinal, neurological, psychiatric, endocrine or liver (e.g., hepatitis B and C) disease; malignancy; or other abnormalities (other than the indication being studied).
* History of or current clinically relevant cardiovascular disorder such as heart failure, coronary heart disease, hypertension, arrhythmia or symptom strongly suggestive of such a problem (for example, syncope or palpitations), tachyarrhythmia or status after myocardial infarction.
* Known bleeding disorders or family history of bleeding disorders.
* Any diseases or conditions in which the use of delamanid, rifampicin, isoniazid, pyrazinamide, ethambutol, or Bedaquiline is contraindicated.
* Any prior treatment for M. tuberculosis within the past 3 years.
* Any treatment with a drug active against M. tuberculosis (e.g., quinolones) within the 3 months prior to screening.
* Clinical evidence of severe extrapulmonary TB (e.g., miliary TB, abdominal TB, urogenital TB, osteoarthritic TB, TB meningitis).
* Evidence of pulmonary silicosis, lung fibrosis, or other lung condition considered as severe by the investigator (other than TB). In particular any underlying condition that could interfere with the assessment of x-ray images, sputum collection, or interpretation of sputum findings, or otherwise compromise the subject's participation in the trial.
* Any renal impairment characterized by serum creatinine clearance of \<60 millilitres per minute (mL/min), or hepatic impairment characterized by alanine transaminase, aspartate transaminase, or total bilirubin \>1.5 x upper limit of normal (ULN) of the clinical laboratory reference range at screening.
* For Stage 1, participants who are human immunodeficiency virus (HIV) positive are excluded. For Stage 2, participants with HIV co-infection who are on antiretroviral drugs during screening or with CD4 cell count \<500/ millimeters cubed (mm\^3) are excluded.
* Changes in the electrocardiogram (ECG) such as QTcF \>450 milliseconds (msec), atrioventricular block II or III, bi-fasicular block, at screening or current history of clinically significant ventricular arrhythmias. Other ECG changes if considered clinically significant by the investigator.
* Participants receiving any of the prohibited medications within the specified periods or who would be likely to require prohibited concomitant therapy during the trial.
* Female participants who are breast-feeding or who have a positive pregnancy test result prior to receiving the first dose of IMP or RHEZ on Day 1.
* History of significant drug and/or alcohol abuse within 2 years prior to screening.
* History of or current hepatitis or carriers of HBsAg and/or anti-HCV.
* Positive urine or blood alcohol test and/or urine drug screen for substance abuse at screening (not including cannabinoids).
* History of having taken an investigational drug within 30 days preceding trial entry (ie, prior to screening).
* A history of difficulty in donating blood.
* Donation of blood or plasma within 30 days prior to dosing.
* Consumption of alcohol and/or grapefruit, grapefruit juice, Seville oranges, or Seville orange juice and related products within 72 hours prior to the first dose of IMP or RHEZ on Day 1.
* History of serious mental disorders that, in the opinion of the investigator, would exclude the subject from participating in this trial.
* Any known prior exposure to OPC-167832, delamanid or Bedaquiline.
* Participants with significant medical comorbidities that in the opinion of the investigator, should not participate in the trial.

Primary outcomes:
measure: Stage 1: Change From Baseline in TB Bacterial Load in Sputum as a Measure of Early Bactericidal Activity (EBA)
timeFrame: Baseline to Day 14
measure: Stage 1 and Stage 2: Maximum (Peak) Plasma Concentration (Cmax) of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
measure: Stage 1 and Stage 2: Cmax at Steady-state (Cmax,ss) of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 1 and Stage 2: Time to Cmax (Tmax) of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
measure: Stage 1 and Stage 2: Tmax of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 1 and Stage 2: Area Under the Concentration-Time Curve (AUC) From Time Zero to Time t (the Last Observable Concentration, Here t=24) (AUC0-24), for OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
measure: Stage 1 and Stage 2: AUC Calculated Over the Dosing Interval at Steady-state (AUCτ) for OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 1 and Stage 2: Terminal-phase Elimination Half-life (t1/2,z) of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 1 and Stage 2: Apparent Clearance From Plasma at Steady-state (CLss/F) of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 1 and Stage 2: Accumulation Ratio of Cmax (RCmax) for OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 1 and Stage 2: Accumulation Ratio of AUC (RAUC) for OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 1 and Stage 2: Cmax Normalized to Dose (Cmax/Dose) of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 2: AUCτ Normalized to Dose (AUCτ/Dose) of OPC-167832 When Administered Alone (Stage 1) and in Combination With Delamanid, and BDQ (Stage 2)
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 2: Cmax of Delamanid
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
measure: Stage 2: Cmax,ss of Delamanid
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 2: Tmax of Delamanid
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
measure: Stage 2: Tmax of Delamanid
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 2: AUC0-24 of Delamanid
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
measure: Stage 2: AUCτ of Delamanid
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 2: T1/2,z of Delamanid
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 2: CLss/F of Delamanid From Plasma
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 2: RCmax of Delamanid
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 2: RAUC of Delamanid
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 2: Cmax/Dose of Delamanid
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 2: AUCτ/Dose of Delamanid
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 2: Cmax of Bedaquiline
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
measure: Stage 2: Cmax,ss of Bedaquiline
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 2: Tmax of Bedaquiline
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
measure: Stage 2: Tmax of Bedaquiline
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 2: AUC0-24 of Bedaquiline
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
measure: Stage 2: AUCτ of Bedaquiline
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 2: T1/2,z of Bedaquiline
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 2: CLss/F of BDQ From Plasma
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 2: Cmax/Dose of Bedaquiline
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 2: AUCτ/Dose of Bedaquiline
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 1 and Stage 2: Number of Participants With Treatment-emergent Adverse Events (AEs)
timeFrame: From first dose of study drug to end of follow up period (up to 34 days)
measure: Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Vital Sign Values
timeFrame: From first dose of study drug to end of follow up period (up to 34 days)
measure: Stage 1 and Stage 2: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters
timeFrame: From first dose of study drug to end of follow up period (up to 34 days)
Secondary outcomes:
measure: Stage 1 and Stage 2: Change From Baseline in Lipoarabinomannan (LAM) in the Mycobacteria Growth Indicator Tube® (MGIT) System
timeFrame: Baseline to Day 14
measure: Stage 1 and Stage 2: Change From Baseline in Time to Detection (TTD) in the MGIT System
timeFrame: Day 1 to Day 14 of treatment period + 42 days of inoculation period (up to 56 days)
measure: Stage 2: Change From Baseline in TB Bacterial Load in Sputum as a Measure of EBA
timeFrame: Baseline to Day 14
measure: Stage 2: Plasma Concentration of Rifampin
timeFrame: 2 hours and 6 hours post-dose on Day 14
measure: Stage 1: Plasma Concentration of Isoniazid
timeFrame: 2 hours and 6 hours post-dose on Day 14
measure: Stage 2: Cmax of DM-6705
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
measure: Stage 2: Cmax,ss of DM-6705
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 2: Tmax of DM-6705
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1; Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 2: AUC0-24 for DM-6705
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1; Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 2: T1/2,z of DM-6705
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 2: Cmax of N-Desmethyl Bedaquiline
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1
measure: Stage 2: Cmax,ss of N-Desmethyl Bedaquiline
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 2: Tmax of N-Desmethyl Bedaquiline
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours (±15 minutes) postdose on Day 1; Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 2: AUC0-24 for N-Desmethyl Bedaquiline
timeFrame: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose on Day 1; Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 14
measure: Stage 2: Number of Participants With TEAEs on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline
timeFrame: From first dose of study drug to end of follow up period (up to 34 days)
measure: Stage 2: Number of Participants With Clinically Significant Vital Sign Changes on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline
timeFrame: From first dose of study drug to end of follow up period (up to 34 days)
measure: Stage 2: Number of Participants With Clinically Significant Changes in ECG Evaluations on Administration of OPC-167832 in Combination With Delamanid and/or Bedaquiline
timeFrame: From first dose of study drug to end of follow up period (up to 34 days)
Other outcomes:
measure: Correlation of QT Interval and Plasma Concentrations of OPC-167832 and/or Delamanid and/or Bedaquiline
timeFrame: Day 1 and Day 14
Locations:
city: Cape Town
country: South Africa
facility: University of Cape Town (Pty) Ltd.
state: Mowbray
city: Cape Town
country: South Africa
facility: Satellite Site: Task at Brooklyn Chest Hospital
city: Cape Town
country: South Africa
facility: TASK Clinical Research Centre
Study officials:
affiliation: TASK Clinical Research Centre
name: Veronique R de Jager, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Cape Town (Pty) Ltd.
name: Prof. Rodney Dawson, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: TASK Clinical Research Centre (TCRC)
name: Prof. Andreas Diacon
role: PRINCIPAL_INVESTIGATOR
References: