Tuberculosis, Pulmonary
Conditions
Keywords
Drug-Sensitive Tuberculosis, Sputum-Positive Tuberculosis
Brief summary
A phase 2, two-part, multicentre, open label, controlled, randomised clinical trial in adult participants with newly diagnosed, sputum-positive pulmonary drug-sensitive tuberculosis (DSTB). Assessing the Safety and Efficacy of TBAJ-587 as Part of a Combination Regimen in Newly Diagnosed, Drug-Sensitive, Sputum-Positive Pulmonary Tuberculosis
Detailed description
This is a phase 2, two-part, multicentre, open label, controlled, randomised clinical trial in adult participants with newly diagnosed, sputum-positive pulmonary DS-TB. The trial will be performed in two sequential parts, each part containing parallel treatment arms. Part A: Participants will be randomly assigned to one of two TBAJ-587 experimental regimens (TBA-587PaL, 100 mg or 200mg dose) or the active SOC control arm (HRZE:). Data from Part A will inform dose selection for Part B. Part B: Participants will be randomly assigned to one of three experimental regimens. The sequential design allows for an interim analysis (section 10.5) between Parts A and B to evaluate the safety and efficacy of lower and higher TBAJ-587 doses before progressing to Part B, where the selected dose will be used. TBAJ-587 may be replaced by a similar diarylquinolone compound if, based on the interim analysis - for scientific and/or safety reasons - determines that TBAJ-587 should not proceed into Part B. Should this occur, the protocol will be updated via submission of a formal protocol amendment. The active control arm included in Part A provides an internal benchmark to confirm that study procedures, microbiological methods, and clinical conduct perform as expected. Data generated from the Part A control arm will therefore serve as the primary internal reference for interpretation of Part B results. Therefore, there is no control arm in Part B. In addition, the bacteriological endpoints used in this study, including time to positivity (TTP) and related measures of early bactericidal activity, are well characterised for HRZE in the published literature. These established external data provide a robust contextual framework against which Part B outcomes can be interpreted, without the need for an additional concurrent control arm. This approach limits unnecessary exposure of participants to standard therapy beyond what is required to establish study validity, while allowing efficient evaluation of the selected investigational regimen in Part B.
Interventions
DRUGTBAJ-587 50 mg
TBAJ-587LD Tablet 50 mg 100 mg OD TBAJ-587HD Tablet 50 mg 200 mg OD TBAJ-587SD Tablet 50 mg Dose selected from Part A daily
DRUGPretomanid 200mg
Pretomanid Tablet 200 mg 200 mg OD
600 mg OD
DRUGBTZ-043 250 mg or 500 mg
1 000 mg OD
H 75 mg, R 150 mg, Z 400 mg, E 275 mg fixed dose combination
DRUGQuabodepistat (Q) 30 mg
30 mg OD
DRUGGanfeborole 20 mg
20 mg OD
Sponsors
TASK Applied Science
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The two parts will be performed sequentially, each part containing parallel treatment arms, with an interim analysis between the two parts: * Part A: Participants will be randomly assigned to one of two TBAJ-587 experimental treatment regimens (100 mg or 200mg dose) combined with pretomanid (Pa) and linezolid (L), or to the control standard-of-care (SOC) (isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE)). * Interim Analysis: Data from Part A will be reviewed and inform dose selection for Part B. * Part B: Participants will be randomly assigned to an experimental regimen containing the selected TBAJ-587 dose and pretomanid (Pa) plus either BTZ-043 (T), quabodepistat (Q) or ganfeborole (G) and linezolid (L).
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* To be eligible to participate in this trial, an individual must meet all the following criteria: 1. Provide written informed consent. 2. Male or female aged 18-65 (inclusive) 3. Clinical evidence of active TB disease, meeting either or both of the following criteria: 1. Symptoms consistent with pulmonary TB at screening AND/OR 2. Imaging findings consistent with active pulmonary TB on chest X-ray performed at screening or within 15 days prior to screening. 4. At least one sputum specimen produced at screening tested on either of the following: Xpert MTB/XDR and Ultra with: * positive for M. tb * a semi-quantitative result of 'medium' (cycle threshold value of \>16-22) or 'high' (cycle threshold value of \>16-22) AND * does not show rifampicin and/or isoniazid resistance. OR a. Sputum smear * Sputum positive for tubercle bacilli (at least 1+ on the IUATLD/WHO scale on smear microscopy) AND o Sensitive to rifampicin and isoniazid by rapid sputum-based test. 5. Able to produce a spot sputum with a volume of at least 4 ml. 6. Body weight within the range of 30 to 100 kgs and body mass index within the range of 15 to 40 kg/m2. 7. Newly diagnosed and untreated for this episode of TB. 8. Individuals with a history of TB may be enrolled in this trial if they meet the following criteria: 1. had a good treatment response in the opinion of the investigator (previous TB symptoms improved sufficiently or resolved) AND 2. completed their previous TB treatment AND 3. received their last dose of treatment more than 6 months before trial treatment AND • remained clinically well after completing treatment for their previous TB. 9. Willing to abstain from alcohol and tyramine containing foods for the treatment duration. 10. Willing to comply with study visits, all study procedures and treatment observation.
Exclusion criteria
* An individual who meets any of the following criteria will be excluded from participation in this trial: 1. Taken more than 1 daily dose of medication with anti-tuberculous activity during the 14 days prior to randomisation (isoniazid, rifampicin, pyrazinamide, ethambutol, linezolid, moxifloxacin, levofloxacin or amikacin). 2. Known or suspected extra-thoracic TB, miliary TB or disseminated TB (in the judgement of the investigator; note uncomplicated pleural effusion occupying \<50% of hemithorax or concomitant intra- or extra-thoracic lymphadenopathy are not exclusions). 3. Severe clinical pulmonary TB e.g. respiratory failure or complications, likely to require hospital admission in the opinion of the investigator. 4. Poor general condition (Karnofsky score ≤50) OR where any delay in treatment cannot be tolerated in the opinion of the investigator. 5. Active malignancy requiring systemic therapy, radiotherapy or palliative therapy. 6. History of myocardial infarction, coronary heart disease or congestive cardiac failure; long QT syndrome or clinically significant arrhythmias; pulmonary hypertension; any known congenital cardiac problems; family history of long QT syndrome or sudden death from unknown or cardiac related cause; uncontrolled arterial hypertension (not excluded if this is corrected prior to randomisation). 7. Cardiac valve abnormalities identified on echocardiogram. 8. History of vitiligo. 9. History of, or ongoing, inflammatory skin disorder such as leprosy, eczema, psoriasis, lichen planus, or other skin rash that would, in the opinion of the investigator, compromise the participant's safety or outcome in the trial. 10. History of seizure(s). 11. History of vascular aneurysm. 12. Symptomatic peripheral neuropathy causing greater than minimal interference with usual social and functional activities. 13. History of optic neuritis. 14. Current alcohol or illicit drug use sufficient to compromise the safety of the participant or research staff or compromise adherence to study procedures, in the opinion of the investigator. 15. Any current or recent use of amphetamines or methamphetamines evident on toxicity screen. 16. Any other medically or socially significant condition (e.g. psychiatric illness, chronic diarrhoeal disease, metabolic condition, other cardiovascular disease not listed under criterion 6), that would, in the opinion of the investigator, compromise the participant's safety or outcome in the trial; or lead to poor compliance with study visits and protocol requirements; or compromise the interpretation of trial safety and efficacy endpoints. 17. Women who are currently pregnant or breast-feeding. 18. Women of childbearing potential (WOCBP) who have had sexual intercourse without contraception after last menses or within the last 3 weeks (whichever is later); or, if unwilling to disclose this information, unable to provide two negative pregnancy tests 8 days apart during the screening period and on day 1 prior to randomisation . 19. WOCBP unwilling or unable to use appropriate non-user dependent contraception during the study intervention period and for at least 6 months after the last dose of study intervention; and unwilling to commit to refrain from donating eggs (ova, oocytes) for the purpose of reproduction during this period 20. Men who are unwilling to use a condom during the study period and for at least 90 days after the last dose of study drug to prevent pregnancy, unless they have had a vasectomy; and are unwilling to commit to refrain from donating fresh unwashed semen. 21. Known allergy to one or more of the study drugs. 22. Taking a concomitant medication that has a known or predicted interaction with any of the study drugs to which the participant might be randomised The participant need not be excluded if: 1. the concomitant medication can be stopped or replaced with an alternative non-interacting medication, if needed AND 2. the investigator judges there to be no residual clinical risk to the participant after stopping the concomitant medication (taking into account the washout period of 5x the half-life of the concomitant medication and the duration of the effect of the interaction on levels of study medication). 23. Taking a concomitant medication that is known to prolong the QTc interval. The participant need not be excluded if the concomitant medication can be stopped or replaced with an alternative medication, if needed, and the duration of the QTc prolongation is expected to resolve prior to dosing of study medication (taking into account the washout period of 5x the half-life of the concomitant medication). 24. Treatment with any immunosuppressive drugs within the 2 weeks prior to screening (taking systemic corticosteroids for less than 5 consecutive days and stopped at or prior to screening is not an exclusion; topical or inhaled steroids that are taken at a dose below the threshold considered to have systemic immunosuppressive effects are not excluded). 25. Participation in other clinical intervention trials with an investigational agent within 8 weeks prior to the first dosing day in this trial. 26. 12-lead ECGs at screening or at baseline shows QTcF \>450 ms (men) or \>460 ms (women) calculated by Fridericia's formula; and/or any other clinically significant abnormality such as arrhythmia or ischaemia. 27. Any of the following laboratory parameters at screening: 1. Hemoglobin \< 9 g/dl 2. Platelet count \< 100 x 109 cells/L 3. Absolute neutrophil count \<1 000 cells/μL 4. eGFR \<75 ml/min, calculated using race free CKD EPI 2021 eGFR normalised by body surface area through additional inclusion of weight AND height parameters (not excluded if corrected to above this level) 5. Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) \> 3 times the upper limit of normal (ULN) 6. Total bilirubin \> 1.5 times the ULN 7. Serum potassium \<3.5 mmol/L (not excluded if corrected to above this level) 8. Serum magnesium \< 0.50mmol/L (not excluded if corrected to above this level) 9. Serum calcium (corrected for albumin level) \< 2.10 mmol/L (not excluded if corrected to above this level). 10. HbA1C \>8.0% 28. Hepatitis B surface antigen positive (known, or on a test performed at screening), hepatitis A IgM and hepatitis C antibodies. (Participants with positive hepatitis C antibodies but negative PCR can be allowed in the trial) 29. Human Immunodeficiency Virus (HIV) antibody positive (known, or on test performed at screening) unless ALL of the following conditions are met: 1. Viral load (HIV-RNA) below 200 copies/mL on the last test, done within the previous 90 days (or at screening if no test performed in the previous 90 days). 2. CD4 count \> 200 cells/mm3 on the last test, done within the previous 90 days (or at screening if no test performed in the previous 90 days). 3. The participant has been taking a regimen of dolutegravir (DTG), tenofovir (TFV) and lamivudine(3TC)/emtricitabine for at least 6 months prior to screening with good adherence. 30. For Part B only: Participants unwilling or unable to disclose information regarding their last unprotected sexual intercourse (UPSI), or whose responses are considered unreliable or non-compliant by the Investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Change in Log10-Transformed Sputum Culture Time to Positivity From Baseline Through Week 8 | From baseline to the end of treatment at 8 weeks | Time to positivity is the time, measured in hours, required for a sputum culture to produce a positive result indicating detectable growth of Mycobacterium tuberculosis. The rate of change in log10-transformed time to positivity will be estimated for each treatment arm. Increasing time to positivity indicates a reduction in the viable mycobacterial load in sputum. Measured as change in log10(days). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Adverse Events of Special Interest | From enrollment through the final follow-up visit at Week 12 | Adverse events of special interest are protocol-defined events that require specific monitoring because of their potential clinical importance in relation to the study drugs. Participants experiencing one or more adverse events of special interest will be counted once. Measured as a percentage of participants. |
| Time to Sustained Sputum Culture Conversion From Baseline Through Week 8 | From baseline to the end of treatment at 8 weeks | Sustained sputum culture conversion is defined as the first of two consecutive negative sputum cultures, with no subsequent positive culture. Time to conversion will be calculated from baseline to the date of the first negative culture that meets this definition. Measured in days. |
| Percentage of Participants With Sustained Sputum Culture Conversion at Week 8 | At the end of treatment at 8 weeks | Sustained sputum culture conversion is defined as the first of two consecutive negative sputum cultures, with no subsequent positive culture. Participants who meet this definition by Week 8 will be included in the percentage. Measured as percentage of participants. |
| Percentage of Participants With Treatment-Emergent Adverse Events | From enrollment through the final follow-up visit at Week 12 | A treatment-emergent adverse event (TEAE) is an adverse event that begins or worsens after the participant receives the first dose of study treatment. Participants experiencing one or more TEAEs will be counted once. Measured as percentage of participants. |
| Percentage of Participants With Treatment-Emergent Adverse Events by Maximum Severity Grade as Assessed by CTCAE Version 5.0 | From enrollment through the final follow-up visit at Week 12 | The severity of each TEAE will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Grades range from 1 to 5: Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening and Grade 5 is death. Participants will be summarized according to their maximum recorded severity grade. Measured as percentage of participants. |
| Percentage of Participants With Drug-Related Treatment-Emergent Adverse Events | From enrollment through the final follow-up visit at Week 12 | A drug-related TEAE is a treatment-emergent adverse event assessed by the investigator as having a causal relationship to one or more study drugs. Participants experiencing one or more drug-related TEAEs will be counted once. Measured as percentage of participants. |
| Percentage of Participants With Serious Treatment-Emerent Adverse Events | From enrollment through the final follow-up visit at Week 12 | A serious TEAE is a treatment-emergent adverse event that results in death, is life-threatening, requires or prolongs inpatient hospitalization, results in persistent or significant disability or incapacity, causes a congenital anomaly or birth defect, or is considered another medically important event. Participants experiencing one or more serious TEAEs will be counted once. Measured as percentage of participants. |
| Percentage of Participants With Treatment-Emergent Adverse Events Leading to Treatment Discontinuation | From enrollment through the final follow-up visit at Week 12 | Participants who permanently discontinue one or more study drugs because of a TEAE will be included in this measure. Participants experiencing more than one qualifying event will be counted once. Measured as a percentage of participants. |
| Maximum Observed Plasma Concentration of Study Drugs and Their Metabolites | At Day 15 and Week 8 for participants in Part A and at Day 15 for participants in Part B | The maximum observed plasma concentration (Cmax) will be estimated using non-compartmental analysis for the applicable study drugs and metabolites in each treatment arm. These include TBAJ-587 and its metabolites M2, M3 and M12; pretomanid; linezolid; BTZ-043 and its metabolite M1; quabodepistat; and ganfeborole. No pharmacokinetic measurements will be performed in the HRZE control arm. Measured in ng/mL |
| Minimum Observed Plasma Concentration of Study Drugs and Their Metabolites | At Day 15 and Week 8 for participants in Part A and at Day 15 for participants in Part B | The minimum observed plasma concentration (Cmin) will be estimated using non-compartmental analysis for the applicable study drugs and metabolites in each treatment arm. These include TBAJ-587 and its metabolites M2, M3 and M12; pretomanid; linezolid; BTZ-043 and its metabolite M1; quabodepistat; and ganfeborole. No pharmacokinetic measurements will be performed in the HRZE control arm. Measured as ng/mL. |
| Time to Maximum Observed Plasma Concentration of Study Drugs and Their Metabolites | At Day 15 and Week 8 for participants in Part A and at Day 15 for participants in Part B | The time to maximum observed plasma concentration (Tmax) will be estimated using non-compartmental analysis for the applicable study drugs and metabolites in each treatment arm. These include TBAJ-587 and its metabolites M2, M3 and M12; pretomanid; linezolid; BTZ-043 and its metabolite M1; quabodepistat; and ganfeborole. No pharmacokinetic measurements will be performed in the HRZE control arm. Measured in hours. |
| Percentage of Participants With Treatment-Emergent Adverse Events Leading to Death | From enrollment through the final follow-up visit at Week 12 | Participants who die as a result of a TEAE will be included in this measure. Each participant will be counted once, regardless of the number of TEAEs contributing to the death. Measured as a percentage of participants. |
| Area Under the Plasma Concentration-Time Curve From 0 to 24 Hours for Study Drugs and Their Metabolites | At Day 15 and Week 8 for participants in Part A and at Day 15 for participants in Part B | The area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24) will be estimated using non-compartmental analysis for the applicable study drugs and metabolites in each treatment arm. These include TBAJ-587 and its metabolites M2, M3 and M12; pretomanid; linezolid; BTZ-043 and its metabolite M1; quabodepistat; and ganfeborole. No pharmacokinetic measurements will be performed in the HRZE control arm. Measured as ng-h/mL |
Countries
South Africa
Contacts
CONTACTKim Nieuwenhout
CONTACTVani Govender
PRINCIPAL_INVESTIGATORFairoez Ryklief, MBBChB
TASK Clinical Trials
Outcome results
None listed