Pulmonary Tuberculosis
Conditions
Keywords
Delamanid, Bedaquiline, OPC-167832, and Sutezolid (DBOS), Pretomanid, Bedaquiline, OPC-167832, and Sutezolid (PBOS), Drug sensitive tuberculosis, Rifampicin-resistant tuberculosis (RR-TB), Multi-drug resistant tuberculosis (MDR-TB)
Brief summary
This multicenter, two-stage, open-label, randomized trial will aim to assess the efficacy, safety, optimal duration, and pharmacokinetics (PK) of Delamanid, Bedaquiline, OPC-167832, and Sutezolid (DBOS) and Pretomanid, Bedaquiline, OPC-167832, and Sutezolid (PBOS) in adult participants with drug sensitive tuberculosis (DS-TB) and rifampicin or multi-drug resistant TB (RR/MDR-TB).
Interventions
DRUGDelamanid, Bedaquiline, OPC-167832, and Sutezolid (DBOS)
D- 300 milligram (mg) once daily (QD) for treatment duration; B- 400 mg QD for 2 weeks, 200 mg thrice weekly for remaining treatment weeks; O- 30 mg QD for treatment duration and S- 1200 mg QD for treatment duration
DRUGPretomanid, Bedaquiline, OPC-167832, and Sutezolid (PBOS)
P- 200 mg QD for treatment duration; B- 400 mg QD for 2 weeks, 200 mg thrice weekly for remaining treatment weeks; O- 30 mg QD for treatment duration and S- 1200 mg QD for treatment duration
DRUGIsoniazid, Rifampicin, Pyrazinamide, Ethambutol (HRZE)
Fixed dose combination (FDC) of 75 mg of isoniazid, 150 mg of rifampicin, 400 mg of pyrazinamide, and 275 mg of ethambutol (HRZE) (Standard of Care \[SOC\]). All the doses administered will be weight-based.
DRUGPretomanid or Delamanid, Bedaquiline, OPC-167832, and Sutezolid (XBOS)
X - Pretomanid 200 mg QD for treatment duration OR Delamanid 300 mg QD for treatment duration; B - 400 mg QD for 2 weeks, 200 mg thrice weekly for remaining treatment weeks; O- 30 mg QD for treatment duration and S-1200 mg QD for treatment duration
DRUGIsoniazid and Rifampicin (HR)
Fixed dose combination (FDC) of 75 mg of isoniazid and 150 mg of rifampicin (HR) (Standard of Care \[SOC\]). All the doses administered will be weight-based.
Sponsors
Gates Medical Research Institute
Global Alliance for TB Drug Development
Janssen Pharmaceuticals
Otsuka Pharmaceutical Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
For Stage 1: * Able to provide written, informed consent prior to initiation of any trial-related procedures or treatments, and able, in the opinion of the Investigator, to comply with all the requirements of the trial. * Male or female participants between 18 and 65 years of age (inclusive) at the screening visit. * Body weight ≥35.0 kilograms (kg) and body mass index (BMI) ≥16.0 at the screening visit. * Newly diagnosed within the past 8 weeks prior to informed consent, untreated (≤4 days of treatment), drug-susceptible pulmonary TB, as defined by all of the following: 1. Confirmation of Mtb infection: Mtb positivity on a molecular test (eg, Xpert Ultra, Hain Line probe assay \[LPA\]) conducted on a sputum specimen for trial screening. 2. Evidence of non-paucibacillary disease: ≥1+ sputum smear positivity for acid-fast bacilli using fluorescent microscopy, as defined by the International Union Against Tuberculosis and Lung Disease (IUATLD)/World Health Organization (WHO) scale, OR a Xpert Ultra semi-quantitative result of 'medium' or 'high' on the sputum specimen for trial screening. 3. Drug-susceptible TB: Isoniazid and rifampicin resistance not detected, as determined by a molecular test (eg, Hain LPA, Xpert Ultra, Xpert MTB/Extensively Drug Resistant \[XDR\]) conducted on a sputum specimen for trial screening. 4. Clinical signs and/or symptoms consistent with active TB in the opinion of the Investigator. 5. Chest radiograph consistent with active TB in the opinion of the Investigator. Note, the Investigator is permitted, but not required, to incorporate a radiologist's interpretation into their assessment of a participant's chest radiograph. * Able to spontaneously produce sputum. * Female participants of childbearing potential (FOCBP) must agree to use 2 approved methods of contraception with their male sexual partners or abstain from heterosexual intercourse throughout their participation in the trial. * Male participants must agree to use an approved method of contraception with their female sexual partners of childbearing potential or abstain from heterosexual intercourse throughout their participation in the trial. For Stage 2: • Newly diagnosed within the past 8 weeks of informed consent, untreated (≤4 days of treatment), drug-susceptible or rifampicin-/multi-drug resistant pulmonary TB, as defined by all of the following: 1. Confirmation of Mtb infection: Mtb positivity on a molecular test (eg, Xpert Ultra, Hain LPA) conducted on a screening sputum specimen. 2. Evidence of non-paucibacillary disease: ≥1+ sputum smear positivity for acid-fast bacilli using fluorescent microscopy, as defined on the IUATLD/WHO scale, OR Xpert Ultra semi-quantitative result of 'medium' or 'high' on the sputum specimen for trial screening. 3. Resistance pattern: i. For DS TB arm, isoniazid and rifampicin resistance not detected on a molecular test (eg, Hain LPA, Xpert Ultra, Xpert MTB/XDR) conducted on a screening sputum specimen, OR ii. For RR/MDR TB arm, either rifampicin resistance (RR TB) OR rifampicin and isoniazid resistance (MDR TB) detected on a molecular test (eg, Hain LPA, Xpert Ultra, Xpert MTB/XDR) conducted on a screening sputum specimen. • Participants with RR or MDR TB must also have fluoroquinolone resistance not detected, as determined by a molecular test (eg, Hain LPA second line, Xpert MTB/XDR) performed on the sputum specimen for trial screening. d) Clinical signs and/or symptoms consistent with active TB in the opinion of the Investigator. e) Chest radiograph consistent with active TB in the opinion of the Investigator. The other inclusion criteria remain the same for Stage 2.
Exclusion criteria
* Suspected or documented extra-thoracic TB. Confirmed or suspected lymph node TB is not considered exclusionary. The presence of a pleural effusion considered not clinically significant together with pulmonary TB is not exclusionary. * Known, or suspected of having, resistance to a rifamycin, isoniazid, ethambutol, pyrazinamide, delamanid, pretomanid, bedaquiline, linezolid, tedizolid, or sutezolid either confirmed by the laboratory, or based on epidemiological history, such as a known source case with said resistance. * Received any prior treatment for active Mtb disease (\>4 days) within the past 1 year of informed consent. * Received any treatment with a fluoroquinolone active against Mtb (ie, levofloxacin, moxifloxacin, ciprofloxacin) or an aminoglycoside for more than 14 days within the 3 months prior to informed consent even if the medication was given for a different indication than TB treatment. * Any known prior exposure to delamanid, pretomanid, bedaquiline, OPC-167832, or any oxazolidinone (linezolid, tedizolid, delpazolid, or sutezolid). * Evidence of an active clinically significant/uncontrolled metabolic, gastrointestinal, neurological (including peripheral neuropathy), psychiatric, endocrine (including uncontrolled diabetes), hematologic, ophthalmologic (particularly optic neuritis), or liver disease; active malignancy; or other medical co-morbidity considered significant enough by the Investigator that the participant should not enter the trial. * Significant history of, or current clinically relevant cardiovascular disorder, such as heart failure, coronary artery disease, uncontrolled hypertension, arrhythmia, tachyarrhythmia, prolonged QT syndrome, or presence of symptom(s) strongly suggestive of such a problem, such as exertional chest pressure/pain or unexplained syncope. * Significant history of, or current evidence of an active clinically significant/poorly controlled pulmonary disease, such as asthma, Chronic obstructive Pulmonary disease (COPD), silicosis, or lung fibrosis (other than TB), considered as severe by the Investigator. In particular, any underlying pulmonary condition that could significantly interfere with the assessment of X-ray images, interpretation of sputum findings, or otherwise compromise the participant's participation in the trial is exclusionary based on the Investigator's judgement. Clinically significant post-Coronavirus disease-2019 (COVID-19) pulmonary sequelae should be considered exclusionary. * If HIV-infected, having any of the following present: 1. Not on antiretroviral treatment at time of screening or taking antiretroviral treatment for \<3 months prior to screening, OR 2. Cluster of differentiation (CD)4+ T-cell count \<200 cells/microliter (μL) during the screening period, OR 3. HIV viral load \>200 copies/milliliter (mL) during the screening period, OR 4. Evidence of a currently active opportunistic malignancy or infection related to HIV other than TB that requires treatment with a prohibited concomitant medication (oral candidiasis is not exclusionary) OR 5. HIV-infected participants enrolling at a trial site in Peru will not be eligible due to the requirement for longer TB treatment courses than the standard 6-month HRZE regimen for patients with HIV/TB co-infection as per the Peruvian national TB treatment guidelines. * If female, currently pregnant or breastfeeding, OR having a positive serum or urine pregnancy test during the screening period, OR planning to become pregnant within the 12-month period after the screening period. * Current significant drug and/or alcohol abuse that is likely to result in poor adherence to trial requirements or that would pose a risk to the participant's wellbeing during the trial. * Karnofsky Performance Status scale score at screening of \<60. * Having a disease or condition where the use of delamanid, pretomanid, bedaquiline, OPC-167832, sutezolid, rifampicin, isoniazid, pyrazinamide, or ethambutol is contraindicated. * Positive Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Polymerase chain reaction (PCR) result on nasopharyngeal sample taken during screening. Prior history of COVID-19/SARS-CoV-2 infection is not exclusionary if SARS-CoV-2 PCR performed on screening sample is negative. * Any of the following laboratory results during screening: 1. Estimated creatinine clearance \<60 mL/minute 2. Alanine transaminase (ALT) or aspartate transaminase (AST) \>2.5 × upper limit of normal of the clinical laboratory reference range 3. Total bilirubin \>2x upper limit of normal of the clinical laboratory reference range, at screening 4. Hemoglobin \<8.0 grams per deciliter (g/dL) 5. Platelet count \<100 x 10\^9/liter (L) 6. White blood cell count \<2.0 x 10\^9/L 7. Screening glycosylated hemoglobin (HbA1c) ≥10.0% 8. Positive hepatitis B surface antigen 9. Positive hepatitis C antibody. * Moderate to severe substance use disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria (substances of concern may include cocaine, amphetamines, opiates, barbiturates, benzodiazepines, or alcohol). * A clinically significant Electrocardiogram (ECG) abnormality at screening as confirmed by a central ECG reading service. Examples of such include, but are not limited to, second- or third-degree atrioventricular block, complete right bundle branch block, left bundle branch block, QRS duration ≥120 millisecond (msec), QT interval corrected using Fridericia's formula (QTcF) interval \>450 msec in males or \>470 msec in females, atrial fibrillation or flutter, supraventricular tachycardia, and ventricular tachycardia or multiple multifocal premature ventricular complexes. The following ECG findings are not considered clinically significant: sinus tachycardia, mild first-degree atrioventricular block (P-R interval \<0.23 sec), right or left axis deviation, incomplete right bundle branch block, and isolated left anterior fascicular block (left anterior hemiblock) in young otherwise healthy participants. * Participants receiving any of the prohibited medications within the specified periods or who would be likely to require prohibited concomitant therapy during the trial. * History of having taken another investigational drug within 30 days preceding trial entry or participates in another clinical study during the duration of this trial. * Prospective approvals of protocol deviations to enrollment criteria, also known as protocol waivers or exemptions, are not permitted. * Participants with baseline culture results (defined as collected during screening period through up to Week 1) that are all negative for growth of Mtb will not be included in efficacy analyses. DS-TB participants whose baseline phenotypic DST results demonstrate resistance to isoniazid and/or rifampicin will not be included in efficacy analyses. Their treatment will be modified accordingly based on their resistance profile, relevant local/national guidelines, and the participant's interest to continue in the trial after discussion with the Investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With DS-TB Reporting ≥ Grade 3 Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Two weeks after the end of treatment [19 weeks for Arm 1 (DBOS) and Arm 2 (PBOS), and 28 weeks for Arm 3 (HRZE)] | An Adverse Event is any untoward medical occurrence in a patient or clinical trial participant, temporally associated with the use of trial intervention, whether or not it is considered related to trial intervention. TEAEs are new or worsening AEs that occur on or after first dose of treatment and no later than two weeks after last dose of treatment. Intensity for each TEAE was graded using Division of Allergy and Infectious Diseases (DAIDS) grading as Grade 1 (Mild), Grade 2 (Moderate), Grade 3 (Severe), Grade 4 (Potentially Life-threatening), or Grade 5 (Death), as determined by Investigator. A serious adverse event (SAE) is defined as any untoward medical occurrence that, at any dose that resulted in death, was immediately life-threatening, required inpatient hospitalization or prolongation of an existing hospitalization, significant disability or incapacity, had a congenital anomaly or birth defect, or was determined to be a medically significant or important event or reaction. |
| Percentage of Participants With Pulmonary DS-TB With Unfavorable Outcome Status | Through Week 17 post-randomization for Arm 1 (DBOS) and Arm 2 (PBOS), and Week 26 post-randomization for Arm 3 (HRZE) | Participants that experienced one or more of the following events after randomization were categorized as having an unfavorable outcome status: absence of microbiological cure (positive sputum culture, excluding documented TB re-infection with a different Mtb strain than baseline, at Week 17 \[DBOS and PBOS arms\] or Week 17-26 \[HRZE arm\]); death from any cause; permanent discontinuation of trial treatment before the end of the assigned treatment duration; extension of TB treatment by the Investigator more than 5 days beyond the end of the assigned treatment duration for any reason such as re-start of TB treatment by the Investigator during the post-treatment follow-up period excluding documented TB re-infection with a different Mycobacteria tuberculosis (Mtb) strain than baseline; positive culture for Mtb at last visit excluding documented TB re-infection with a different Mtb strain than baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Reporting All-cause Permanent Trial Treatment Discontinuation | Through 12 months post-randomization | Trial treatment of participants was discontinued due to various reasons such as, pregnancy, AE, SAE, death, laboratory abnormality, intercurrent medical condition or illness, new requirement for a concomitant medication on the excluded medication list, or other situation where an Investigator determined that continued administration of trial treatment is not in the best interest of the participant and study terminated by sponsor and treatment failure. |
| Percentage of Participants With DS-TB Reporting ≥ Grade 3 Severe AEs and Serious Adverse Events (SAEs) | Through 12 months post-randomization | An AE is any untoward medical occurrence in a patient or clinical trial participant, temporally associated with the use of trial intervention, whether or not it is considered related to the trial intervention. Intensity for each AE was graded using Division of Allergy and Infectious Diseases (DAIDS) grading as Grade 1 (Mild), Grade 2 (Moderate), Grade 3 (Severe), Grade 4 (Potentially Life-threatening), or Grade 5 (Death), as determined by the Investigator. A SAE is defined as any untoward medical occurrence that, at any dose that resulted in death, was immediately life-threatening, required inpatient hospitalization or prolongation of an existing hospitalization, significant disability or incapacity, had a congenital anomaly or birth defect and was medically significant or important event or reaction. |
| Percentage of Participants With Pulmonary DS-TB Reporting Unfavorable Outcome Status | 12 months post-randomization | Participants that experienced one or more of the following events following randomization were categorized as having an unfavorable outcome status: absence of microbiological cure (positive sputum culture from Week 17 or later, excluding documented TB re-infection with a different Mtb strain than baseline); death from any cause; permanent discontinuation of trial treatment before the end of the assigned treatment duration; extension of TB treatment by the Investigator more than 5 days beyond the end of the assigned treatment duration for any reason such as re-start of TB treatment by the Investigator during the post-treatment follow-up period excluding documented TB re-infection with a different Mtb strain than baseline; positive culture for Mtb at last visit excluding documented TB re-infection with a different Mtb strain than baseline. |
| Percentage of Participants With Sputum Culture Conversion (SCC) in Mycobacteria Growth Indicator Tube (MGIT) Culture | Week 9, Week 15, and Week 19 for DBOS/PBOS or Week 28 for HRZE | Sputum culture conversion (SCC) was assessed using MGIT liquid culture and was defined as two successive Mtb culture negative results collected at least 5 days apart up to and including the assessment timepoint (Week 28) without any intervening or subsequent Mtb culture positive results through Week 28, ignoring contaminated and unevaluable cultures. A higher percentage reflects more participants achieving and maintaining sputum culture conversion to negative for Mtb. |
| Median Time to Sustained SCC to Negative for Mtb Growth in MGIT | Through Month 12 post-randomization | Time to sustained SCC (SSCC) is defined as the time from first dose to the first of two successive Mtb culture negative results, collected at least 5 days apart, without any intervening or subsequent Mtb culture positive result for the duration of a participant's follow-up. For positive Mtb culture results at or after Week 17, the strain must have been indistinguishable from baseline based on whole genome sequencing results to lose SSCC status. Participants in the who never achieved SSCC were censored at the date of sputum collection that yielded their last negative or positive culture result |
| Change From Baseline in Sputum MGIT Culture Time to Detection (TTD) | Baseline (Day 1) and at Weeks 4, 9, 13, and 17 | TTD is measured as the length of time in days from the beginning of culture incubation to the detection of pure Mtb growth. At each study visit, up to two MGIT sputum cultures were performed. The shorter TTD value from the (up to) two cultures resulted as pure Mtb-positive without contamination, was used for analysis at that timepoint. If culture was negative for Mtb, TTD was set to 43 days. Culture results of "Positive for MTB Complex with contamination", "Positive for MTB and NTM", "Contaminated", or "No result", were excluded from the analysis. Mean change from Baseline in sputum MGIT culture TTD was calculated as change in the TTD at week T minus baseline TTD. Higher TTD indicates slower bacterial growth. |
| Percentage of Participants With SCC in Solid Culture | Week 9, Week 15, and Week 19 for DBOS/PBOS or Week 28 for HRZE | Löwenstein Jensen (LJ) medium was used as an additional solid culture medium for isolation of Mtb. SCC in LJ was defined as two negative solid sputum cultures obtained at least 5 days apart up to and including the assessment timepoint (Week X) without any intervening or subsequent Mtb culture positive result through Week X ignoring contaminated and unevaluable cultures. A higher percentage reflects more participants achieving and maintaining sputum culture conversion to negative for Mtb. |
| Median Time to Sustained SCC to Negative in Solid Culture | Through Month 12 post-randomization | Time to sustained SCC (SSCC) using LJ medium is defined as the time from first dose to the first of two successive Mtb culture negative results, collected at least 5 days apart, without any intervening or subsequent Mtb culture positive result for the duration of a participant's follow-up. For positive Mtb culture results at or after Week 17, the strain must have been indistinguishable from baseline based on whole genome sequencing results to lose SSCC status. Participants who never achieved SSCC were censored at the date of sputum collection that yielded their last negative or positive culture result. |
| Percentage of Participants Developing Resistance Against Each Drug | Up to 12 months post-randomization | Phenotypic drug susceptibility testing (DST) was performed on Mtb-positive cultures in the MGIT system to assess if any resistance had developed during and after treatment. DST was performed on the baseline visit or Week 1 sputum culture depending on suitability of culture growth for DST performance, and again on the first culture positive for Mtb at Week 13 or afterwards in all arms. WHO-recommended critical concentrations were used to test for susceptibility to Bedaquiline (1.0 microgram \[ug\]/mL), Delamanid (0.6 ug/mL), Isoniazid (0.1 ug/mL), Rifampicin (1.0 ug/mL), Pyrazinamide (100 ug/mL), and Ethambutol (5 ug/mL). |
| Median Minimum Inhibitory Concentration (MIC) Values at Baseline and Post-Baseline for Delamanid, Pretomanid, Bedaquiline, OPC-167832, and Sutezolid | Up to 12 months post-randomization | MIC testing determined the lowest drug concentration for Mtb susceptibility in the DBOS and PBOS groups, following the same schedule as DST. Bedaquiline, Delamanid, and Pretomanid were tested via the MGIT system, while OPC-167832 and Sutezolid used EUCAST-recommended broth microdilution. Baseline is defined as last assessment made prior to first administered dose of trial medication. In measured values table below, baseline and post-baseline median MIC values are presented for each drug. |
Countries
Philippines, South Africa
Contacts
STUDY_DIRECTORGates MRI
Gates Medical Research Institute
Participant flow
Recruitment details
This multicenter, two-stage, open-label, randomized trial evaluated the efficacy, safety, and pharmacokinetics (PK) of two novel regimens: DBOS: Delamanid (D), Bedaquiline (B), OPC-167832 (O), and Sutezolid (S) and PBOS: Pretomanid (P), Bedaquiline, OPC-167832, and Sutezolid in adult participants with drug sensitive tuberculosis (DS-TB) against the standard 2HRZE/4HR regimen (Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), Ethambutol (E), referred to as HRZE hereafter).
Pre-assignment details
Total of 93 participants were enrolled and started on study treatment (DBOS, n=30; PBOS, n=32; HRZE, n=31). One randomized participant from PBOS arm withdrew from the trial before starting study treatment. The study was terminated early based on preliminary results showing inadequate efficacy to support either investigational regimen's ability to meet the core trial objective of identifying a ≤3-month regimen after review with the Independent Data Monitoring Committee. Stage 2 was not conducted.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 31.3 years STANDARD_DEVIATION 10.13 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 15 Participants |
| Race/Ethnicity, Customized Asian | 12 Participants |
| Race/Ethnicity, Customized Black | 6 Participants |
| Race/Ethnicity, Customized Black or African American | 9 Participants |
| Race/Ethnicity, Customized Multiple | 2 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized Southern African Colored | 32 Participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 32 | 1 / 31 |
| other Total, other adverse events | 27 / 30 | 24 / 32 | 25 / 31 |
| serious Total, serious adverse events | 4 / 30 | 1 / 32 | 2 / 31 |
Outcome results
None listed