Evaluating Newly Approved Drugs for Multidrug-resistant TB

Study Overview
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Brief Summary
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endTB Clinical Trial a Phase III, randomized, controlled, open-label, non-inferiority, multi-country trial evaluating the efficacy and safety of five new, all-oral, shortened regimens for multidrug-resistant tuberculosis (MDR-TB).

Detailed Description
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This is a Phase III, randomized, controlled, open-label, non-inferiority, multi-country trial evaluating the efficacy and safety of new combination regimens for MDR-TB treatment. Regimens examined combine newly approved drugs bedaquiline and/or delamanid with existing drugs known to be active against Mycobacterium tuberculosis (linezolid, clofazimine, moxifloxacin or levofloxacin, and pyrazinamide). The study will enroll in parallel across 5 experimental and 1 standard-of-care control arms. Randomization will be outcome adapted using Bayesian interim analysis of efficacy endpoints. Experimental regimens will contain bedaquiline and/or delamanid and up to 4 companion drugs. Control-arm treatment may contain one of the following (bedaquiline or delamanid) and companion drugs, constructed and delivered according to local standard of care and consistent with WHO guidelines. Trial participation in all arms will last at least until Week 73, and up to Week 104. In the experimental arms, treatment will be for 39 weeks (participants in the experimental arms will be allowed up to 47 weeks to complete the 39-week treatment course) and post-treatment follow up for up to 65 additional weeks. In the control arm, treatment will be delivered according to local standard of care (in consistence with WHO guidance); duration may vary and will be approximately 86 weeks for the conventional regimen and 39-52 weeks for the standardized shorter regimen. Non-inferiority will be established for any experimental arm if the lower bound of the one-sided 97.5% confidence interval around the difference in favorable outcome between the control and experimental arms is greater than or equal to -12%.

Official Title
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Evaluating Newly Approved Drugs for Multidrug-resistant TB (endTB): A Clinical Trial

Conditions
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Tuberculosis, Multidrug-Resistant, Infection, Bacterial, Pulmonary Tuberculoses

Intervention / Treatment
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* Drug: Bedaquiline
* Drug: Delamanid
* Drug: Clofazimine
* Drug: Levofloxacin
* Drug: Moxifloxacin
* Drug: Linezolid
* Drug: Pyrazinamide
* Drug: Control arm MDR-TB regimen, consistent with WHO guidelines


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A patient will be eligible for randomization if s/he: Has documented pulmonary tuberculosis due to strains of M. tuberculosis resistant to rifampin (RIF) and susceptible to fluoroquinolones, diagnosed by validated rapid molecular test; Is ≥ 15 years of age; Is willing to use contraception: pre-menopausal women or women whose last menstrual period was within the preceding year, who have not been sterilized must agree to use contraception unless their partner has had a vasectomy; men who have not had a vasectomy must agree to use condoms; Provides informed consent for study participation; additionally a legal representative of patients considered minor per local laws should also provide consent; Lives in a dwelling that can be located by study staff and expects to remain in the area for the duration of the study. Exclusion Criteria: A patient will not be eligible for randomization if s/he: Has known allergies or hypersensitivity to any of the investigational drugs; Is known to be pregnant or is unwilling or unable to stop breast-feeding an infant; Is unable to comply with treatment or follow-up schedule; Any condition (social or medical) which, in the opinion of the site principal investigator, would make study participant unsafe; a. Has had exposure (intake of the drug for 30 days or more) in the past five years to bedaquiline, delamanid, linezolid, or clofazimine, or has proven or likely resistance to bedaquiline, delamanid, linezolid, or clofazimine (e.g., household contact of a DR-TB index case who died or experienced treatment failure after treatment containing bedaquiline, delamanid, linezolid, or clofazimine or had resistance to one of the listed drugs); exposure to other anti-TB drugs is not a reason for exclusion. b. Has received second-line drugs for 15 days or more prior to screening visit date in the current MDR/RR-TB treatment episode. Exceptions include: (1) patients whose treatment has failed according to the WHO definition151 and who are being considered for a new treatment regimen; (2) patients starting a new treatment regimen after having been lost to follow-up according to the WHO definition149 and, (3) patients in whom treatment failure is suspected (but not confirmed according to WHO definition), who are being considered for a new treatment regimen, and for whom the Clinical Advisory Committee (CAC) consultation establishes eligibility. Has one or more of the following: Hemoglobin ≤ 7.9 g/dL; Uncorrectable electrolytes disorders: Calcium < 7.0 mg/dL; Potassium < 3.0 or ≥6.0 mEq/L; Magnesium < 0.9 mEq/L; Serum creatinine > 3 x ULN; Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3 x ULN; Total bilirubin ≥ 1.5 x ULN if accompanied by AST or ALT > ULN or total bilirubin ≥ 2 x ULN when other liver function results are in the normal range; Grade 4 result on any of the specified laboratory tests as defined by the MSF Severity Scale. Has cardiac risk factors defined as: A confirmed QTc interval of greater than or equal to 450 ms. Retesting to reassess eligibility will be allowed once using an unscheduled visit during the screening phase; Evidence of ventricular pre-excitation (e.g., Wolff Parkinson White syndrome); Electrocardiographic evidence of either: Complete left bundle branch block or right bundle branch block; OR Incomplete left bundle branch block or right bundle branch block and QRS complex duration greater or equal to 120 msec on at least one ECG; Having a pacemaker implant; Congestive heart failure; Evidence of second or third degree heart block; Bradycardia as defined by sinus rate less than 50 bpm; Personal or family history of Long QT Syndrome; Personal history of arrhythmic cardiac disease, with the exception of sinus arrhythmia; Personal history of syncope (i.e. cardiac syncope not including syncope due to vasovagal or epileptic causes). Concurrent participation in another trial of any medication used or being studied for TB treatment, as defined in cited documents. Is taking any medication that is contraindicated with the medicines in the trial regimen which cannot be stopped (with or without replacement) or requires a wash-out period longer than 2 weeks.

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: endTB regimen 1 (BeLiMoZ)<br>Subjects who are randomized to this arm will receive treatment for 39 weeks and post-treatment followup for 65 weeks. Participants may take as long as 47 weeks to complete all doses of a 39-week treatment regimen. Dosing of experimental regimens will be oral and weight based. Subjects will undergo a linezoilid dose reduction randomization to either 300mg daily or 600mg three times a week after 16 weeks of treatment or after a linezolid-related AE requiring dose reduction, whichever is earlier. | Drug: Bedaquiline<br> <br> * Other names: Sirturo;Drug: Moxifloxacin<br> <br> Drug: Linezolid<br> <br> Drug: Pyrazinamide<br> <br> |
| Experimental: endTB regimen 2 (BeLiCLeZ)<br>Subjects who are randomized to this arm will receive treatment for 39 weeks and post-treatment followup for 65 weeks. Participants may take as long as 47 weeks to complete all doses of a 39-week treatment regimen. Dosing of experimental regimens will be oral and weight based. Subjects will undergo a linezoilid dose reduction randomization to either 300mg daily or 600mg three times a week after 16 weeks of treatment or after a linezolid-related AE requiring dose reduction, whichever is earlier. | Drug: Bedaquiline<br> <br> * Other names: Sirturo;Drug: Clofazimine<br> <br> * Other names: Lamprene;Drug: Levofloxacin<br> <br> Drug: Linezolid<br> <br> Drug: Pyrazinamide<br> <br> |
| Experimental: endTB regimen 3 (BeDeLiLeZ)<br>Subjects who are randomized to this arm will receive treatment for 39 weeks and post-treatment followup for 65 weeks. Participants may take as long as 47 weeks to complete all doses of a 39-week treatment regimen. Dosing of experimental regimens will be oral and weight based. Subjects will undergo a linezoilid dose reduction randomization to either 300mg daily or 600mg three times a week after 16 weeks of treatment or after a linezolid-related AE requiring dose reduction, whichever is earlier. | Drug: Bedaquiline<br> <br> * Other names: Sirturo;Drug: Delamanid<br> <br> * Other names: OPC-67683;Drug: Levofloxacin<br> <br> Drug: Linezolid<br> <br> Drug: Pyrazinamide<br> <br> |
| Experimental: endTB regimen 4 (DeLiCLeZ)<br>Subjects who are randomized to this arm will receive treatment for 39 weeks and post-treatment followup for 65 weeks. Participants may take as long as 47 weeks to complete all doses of a 39-week treatment regimen. Dosing of experimental regimens will be oral and weight based. Subjects will undergo a linezoilid dose reduction randomization to either 300mg daily or 600mg three times a week after 16 weeks of treatment or after a linezolid-related AE requiring dose reduction, whichever is earlier. | Drug: Delamanid<br> <br> * Other names: OPC-67683;Drug: Clofazimine<br> <br> * Other names: Lamprene;Drug: Levofloxacin<br> <br> Drug: Linezolid<br> <br> Drug: Pyrazinamide<br> <br> |
| Experimental: endTB regimen 5 (DeCMoZ)<br>Subjects who are randomized to this arm will receive treatment for 39 weeks and post-treatment followup for 65 weeks. Participants may take as long as 47 weeks to complete all doses of a 39-week treatment regimen. Dosing of experimental regimens will be oral and weight based. | Drug: Delamanid<br> <br> * Other names: OPC-67683;Drug: Clofazimine<br> <br> * Other names: Lamprene;Drug: Moxifloxacin<br> <br> Drug: Pyrazinamide<br> <br> |
| Active Comparator: endTB regimen 6 (Control)<br>endTB regimen 6 is the control regimen. | Drug: Control arm MDR-TB regimen, consistent with WHO guidelines<br>* Control arm MDR-TB regimen, consistent WHO guidelines<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Week 73 Efficacy | Proportion of participants with favorable outcome at week 73. A participant's outcome will be classified as favorable at week 73 if the outcome is not classified as unfavorable, and one of the following is true: The last two culture results are negative. These two cultures must be taken from sputum samples collected on separate visits, the latest between weeks 65 and 73; The last culture result (from a sputum sample collected between weeks 65 and 73) is negative; and either there is no other post-baseline culture result or the penultimate culture result is positive due to laboratory cross contamination; and bacteriological, radiological and clinical evolution is favorable; There is no culture result from a sputum sample collected between weeks 65 and 73 or the result of that culture is positive due to laboratory cross contamination; and the most recent culture result is negative; and bacteriological, radiological and clinical evolution is favorable. | Week 73 after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Week 104 Efficacy | Proportion of participants with favorable outcome at week 104. • A participant's outcome will be classified as favorable at week 104 if the outcome is not classified as unfavorable, and one of the following is true: The last two cultures are negative. These two cultures must be from sputum samples collected on separate visits, the latest between weeks 97 and 104; The last culture result (from a sputum sample collected between weeks 97 and 104) is negative; and either there is no other post-baseline culture result or the penultimate culture result is positive due to laboratory cross contamination; and bacteriological, radiological and clinical evolution is favorable; There is no culture result from a sputum sample collected between weeks 97 and 104 or the result of that culture is positive due to laboratory cross contamination; and the most recent culture result is negative; and bacteriological, radiological and clinical evolution is favorable. | Week 104 after randomization | 
| Early Treatment Response (culture conversion) | Proportion of patients with culture conversion assessed in MGIT system (and LJ where possible): 2 consecutive negative cultures from specimens collected at 2 different visits; if there is a missing or contaminated culture between 2 negatives, the definition of conversion is still met; Time to culture conversion: assessed in MGIT system (and LJ where possible): time from treatment initiation to first of 2 consecutive negative cultures; if there is a missing or contaminated culture between 2 negatives, the definition of conversion is still met; Change in time to positivity (TTP) in MGIT over 8 weeks. | Week 8 after randomization | 
| Week 39 Efficacy | Proportion of participants with favorable outcome at week 39: • A participant's outcome will be classified as favorable at week 39 if the last culture result (from a sample collected between weeks 36 and 39) is negative; and the outcome is not classified as unfavorable. A participant's outcome will be classified as unfavorable at week 39 in case of: In the experimental arm, addition or replacement of one or more drugs; In the control arm, addition or replacement of two or more drugs; Death from any cause; At least one culture result (from a sample collected between weeks 36 and 39) is positive; The patient is not assessable because the last available culture result is from a sample collected before week 36. | Week 39 after randomization | 
| Week 73 Survival | At 73 weeks, the proportion of patients who died of any cause | Week 73 after randomization | 
| Week 104 Survival | At 104 weeks, the proportion of patients who died of any cause | Week 104 after randomization | 
| Week 73 Safety | The proportion of participants with grade 3 or greater AEs and serious adverse events (SAEs) of any grade by 73 weeks | Week 73 after randomization | 
| Week 104 Safety | The proportion of participants with grade 3 or greater AEs and serious adverse events (SAEs) of any grade by 104 weeks | Week 104 after randomization | 
| Week 73 Safety: proportion of patients with AESIs | The proportion of patients with AESIs by 73 weeks | Week 73 after randomization | 
| Week 104 Safety: proportion of patients with AESIs | The proportion of patients with AESIs by 104 weeks | Week 104 after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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bedaquiline, delamanid, linezolid, clofazimine, tuberculosis, MDR-TB XDR-TB