A15 Respiratory tuberculosis, bacteriologically and histologically confirmed Respiratory tuberculosis, bacteriologically and histologically confirmed
Conditions
Interventions
Combination regimens of DBOS and PBOS, administered for 4 months, in participants with pulmonary DS-TB in comparison with the 2HRZE/4HR regimen as assessed by unfavorable outcome status through end of
Sponsors
Gates Medical Research Institute
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: For Stage 1, participants are required to meet all of the following inclusion criteria when assessed: 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. 2) Male or female participants between 18 and 65 years of age (inclusive) at the screening visit. 3) Body weight =35.0 kg and body mass index (BMI) =16.0 at the screening visit. 4) Newly diagnosed within the past 3 weeks prior to informed consent, untreated (=4 days of treatment), drug-susceptible pulmonary TB, as defined by all of the following: a) Confirmation of Mtb infection: Mtb positivity on a molecular test (eg, Xpert Ultra, Hain LPA) conducted on a sputum specimen for trial screening b) 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)/WHO scale, OR a Xpert Ultra semi-quantitative result of ‘medium’ or ‘high’ on the sputum specimen for trial screening c) Drug-susceptible TB: Isoniazid and rifampicin resistance not detected, as determined by a molecular test (eg, Hain LPA, Xpert Ultra, Xpert MTB/XDR) conducted on a 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. Note, the Investigator is permitted, but not required, to incorporate a radiologist’s interpretation into their assessment of a participant’s chest radiograph 5) Able to spontaneously produce sputum. 6) 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 (see Section 13.3). 7) 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 (see Section 13.3). For Stage 2, inclusion criteria #4 will be changed to the following: 4) Newly diagnosed within the past 3 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: a) Confirmation of Mtb infection: Mtb positivity on a molecular test (eg, Xpert Ultra, Hain LPA) conducted on a screening sputum specimen b) 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 c) 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 s
Exclusion criteria
Exclusion criteria: Participants are excluded from the trial if any of the following criteria apply. 1) 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. 2) 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. 3) Received any prior treatment for active Mtb disease (>4 days) within the past 1 year of informed consent. 4) 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. 5) Any known prior exposure to delamanid, pretomanid, bedaquiline, OPC-167832, or any oxazolidinone (linezolid, tedizolid, delpazolid, or sutezolid). 6) 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. 7) 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. 8) Significant history of, or current evidence of an active clinically significant/poorly controlled pulmonary disease, such as asthma, 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-COVID-19 pulmonary sequelae should be considered exclusionary. 9) If HIV-infected, having any of the following present: a) Not on antiretroviral treatment at time of screening or taking antiretroviral treatment for 200 copies/mL during the screening period, OR d) 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). 10) 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. Refer to Section 13.3 (Appendix 3, Section 13.3) for more information. 11) 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 duri
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| In participants receiving at least 1 dose of any trial intervention, the percentage of participants reporting o Severe AEs (= Grade 3) and/or SAEs through two weeks after the end of treatment in each arm In the Per Protocol population (Section 1.8.1), the proportion of participants with unfavorable status at Week 17 for DBOS and Week 26 for 2HRZE/4HR NAME OF THE RESULT: Stage 1: • Severe AEs (= Grade 3) and SAEs through two weeks after the end of treatment Unfavorable outcome status (defined in Section 11.3.1) PERIOD OF TIME WHERE TE MEASUREMENT WILL BE CONDUCTED AND WHICH WILL ALLOW OBTAINING THE PRIMARY RESULT: 19 weeks for DBOS and PBOS and 28 weeks for 2HRZE/4HR Through end of treatment for each arm;In participants receiving at least 1 dose of trial intervention, the percentage of participants reporting o Severe AEs (= Grade 3) and/or SAEs through two weeks after the end of treatment in each arm In the mITT population, difference in the proportion of participants with unfavorable status at 12 months post-randomization (XBOS minus 2HRZE/4HR) as a function of XBOS treatment duration NAME OF THE RESULT: Stage 2: • Severe AEs (= Grade 3) and SAEs through two weeks after the end of treatment Unfavorable outcome status at end of the post treatment follow-up period PERIOD OF TIME WHERE TE MEASUREMENT WILL BE CONDUCTED AND WHICH WILL ALLOW OBTAINING THE PRIMARY RESULT: Through 11 to 19 weeks for XBOS arms and through 28 weeks for 2HRZE/4HR arm 12 months post randomization | — |
Secondary
| Measure | Time frame |
|---|---|
| In participants receiving at least 1 dose of any trial intervention, the percentage of participants reporting o Severe AEs (= Grade 3) and/or SAEs through two weeks after the end of treatment in each arm In the Per Protocol population (Section 1.8.1), the proportion of participants with unfavorable status at Week 17 for DBOS and Week 26 for 2HRZE/4HR NAME OF THE RESULT: Stage 1: • Severe AEs (= Grade 3) and SAEs through two weeks after the end of treatment Unfavorable outcome status (defined in Section 11.3.1) PERIOD OF TIME WHERE TE MEASUREMENT WILL BE CONDUCTED AND WHICH WILL ALLOW OBTAINING THE PRIMARY RESULT: 19 weeks for DBOS and PBOS and 28 weeks for 2HRZE/4HR Through end of treatment for each arm;In participants receiving at least 1 dose of trial intervention, the percentage of participants reporting o Severe AEs (= Grade 3) and/or SAEs through two weeks after the end of treatment in each arm In the mITT population, difference in the proportion of participants with unfavorable status at 12 months post-randomization (XBOS minus 2HRZE/4HR) as a function of XBOS treatment duration NAME OF THE RESULT: Stage 2: • Severe AEs (= Grade 3) and SAEs through two weeks after the end of treatment Unfavorable outcome status at end of the post treatment follow-up period PERIOD OF TIME WHERE TE MEASUREMENT WILL BE CONDUCTED AND WHICH WILL ALLOW OBTAINING THE PRIMARY RESULT: Through 11 to 19 weeks for XBOS arms and through 28 weeks for 2HRZE/4HR arm 12 months post randomization;• In participants receiving at least 1 dose of any trial intervention, the percentage of participants reporting o All-cause trial treatment discontinuation in each arm o Severe AEs (= Grade 3) and/or SAEs through 12 months post randomization • In participants with HIV co-infection receiving at least 1 dose of trial intervention, the percentage of participants reporting o Severe AEs (= Grade 3) and/or SAEs in each arm through 12 months post randomization o Severe AEs (= Grade 3) and/or SAEs through two | — |
Countries
Peru, Philippines, South Africa
Contacts
Public ContactMiriam Luz Vargas
IQVIA RDS PERU S.R.L.
Outcome results
None listed