A Study of the Early Effects, Safety, and Acceptability of Oral Alpibectir in Combination With Ethionamide

Exclusion Criteria36

• Evidence of clinically significant conditions or findings, other than TB, that might compromise safety or the interpretation of trial endpoints, per discretion of the investigator.
• Poor general condition where any delay in treatment cannot be tolerated per discretion of the investigator.
• History of epilepsy, seizures or other neuropsychiatric disorders that might compromise safety or the interpretation of trial endpoints, per discretion of the investigator.
• Cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• History of hypothyroidism
• QTcF of >450 ms at baseline
• Clinically significant evidence of extra-thoracic TB, as judged by the investigator.
• History of allergy to any of the trial IMP as confirmed by the clinical judgement of the investigator.
• Alcohol or drug abuse, that in the opinion of the investigator, is sufficient to compromise the safety or cooperation of the participant.
• HIV positive AND:
• CD4 < 250cells/mm3
• On other ART regimen not listed below or, if not on ART they are not willing to wait to start treatment until completion of study regimen
• Note: ART regimens permitted is limited to the following in line with local guidelines for 1st line ART:
• NRTIs selected from: Emtricitabine, Lamivudine, Tenofovir
• PLUS Dolutegravir 50 mg daily, or 50 mg twice daily if randomized to a rifampicin containing arm.
• Participants established on ART (2 NRTIs and dolutegravir) for more than 30 days at start of screening are eligible for participation.
• As the drug-drug interaction potential of ART has not been fully investigated with the IMP, NNRTIs (efavirenz, nevirapine) and other protease inhibitors will not be permitted in this study.
• Female participant who is pregnant, breast-feeding, or planning to conceive a child within the anticipated period of trial participation and for at least 90 days after the last dose of study intervention. Male participant planning to conceive a child for at least 90 days, after the last dose of study intervention in the trial.
• Treatment History
• Participation in other clinical studies with investigational agents within 8 weeks prior to screening.
• Treatment received for this episode of TB with any drug active against M. tb (including but not limited to isoniazid, ethambutol, cycloserine, fluoroquinolones, rifamycins, aminoglycosides, nitroimidazoles, bedaquiline, oxazolidinones, para-amino salicylic acid, pyrazinamide, thioacetazone, thioamides).
• Treatment with immunosuppressive medications such as TNF-alpha inhibitors within 2 weeks prior to screening, or systemic corticosteroids for more than 7 days within 2 weeks prior to screening.
• Unavoidable treatment with prohibited concomitant medications (see section 5.3.2) anticipated during administration of IMP.
• Laboratory Safety Testing
• Presence of hepatitis B surface antigen (HBsAg+)
• Positive hepatitis C antibody test result (HCV IgG+)
• Participants with the following toxicities at screening as defined by the enhanced CTCAE toxicity table:
• creatinine >1.5 times upper limit of normal (ULN)
• haemoglobin <8.0 g/dL
• platelets <50x109 cells/L
• serum potassium <3.0 mmol/L
• alanine aminotransferase (ALT) ≥5 x ULN
• total bilirubin >1.5 x ULN; Participants with Gilbert's syndrome can be included with total bilirubin >1.5 x ULN as long as direct bilirubin is ≤1.5xULN
• Total white cell count <1.5 cells/L
• Thyroid Stimulating Hormone > ULN
• Glucose < 3.5 mmol/L