A Study of Bedaquiline Administered as Part of a Treatment Regimen With Clarithromycin and Ethambutol in Adult Patients With Treatment-refractory Mycobacterium Avium Complex-lung Disease (MAC-LD)

Study Overview
=================
Brief Summary
-----------------
The purpose of the study is to evaluate the efficacy of bedaquiline (BDQ) compared with rifamycin when administered as part of a treatment regimen with clarithromycin (CAM) and ethambutol (EB) in adult participants with treatment-refractory Mycobacterium avium complex-lung disease (MAC-LD) at Week 24 for microbiological assessment in mycobacteria growth indicator tube (MGIT).

Official Title
-----------------
A Phase 2/3, Multicenter, Randomized, Open-label, Active-controlled Study to Evaluate the Efficacy and Safety of Bedaquiline Administered as Part of a Treatment Regimen With Clarithromycin and Ethambutol in Adult Patients With Treatment-refractory Mycobacterium Avium Complex-lung Disease (MAC-LD)

Conditions
-----------------
Treatment-refractory Mycobacterium Avium Complex-lung Disease (MAC-LD)

Intervention / Treatment
-----------------
* Drug: Bedaquiline
* Drug: Clarithromycin
* Drug: Ethambutol
* Drug: Rifampicin
* Drug: Rifabutin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Has body weight greater than or equal to (>=) 40 kilograms (kg) at screening and on Day 1 Has radiological evidence consistent with nontuberculous mycobacterial lung disease (NTM-LD) based on a chest Computed Tomography (CT) scan taken within 6 months prior to screening or at screening Has at least 2 positive sputum cultures of Mycobacterium avium complex (MAC) (sputum cultures to be taken at least 4 weeks apart): one obtained within 12 months prior to screening, which was documented while being treated for Mycobacterium avium complex lung disease (MAC-LD) for a total of at least 6 months; and one at screening (by central microbiology laboratory) Received at least 6 months of consecutive MAC-LD treatment (at least 2 antibiotics for MAC, including a macrolide), that is either ongoing or has stopped within 12 months prior to screening No presence of cognitive dysfunction that would impact the completion of the patient reported outcome (PRO) assessments Exclusion Criteria: Had previous exposure to bedaquiline (BDQ) Has active Tuberculosis (TB) disease Has cystic fibrosis, medically unstable respiratory disease (for example, chronic obstructive pulmonary disease, bronchiectasis, asthma) Has one or more cavities >=2 centimeter (cm) in diameter on a chest CT scan taken within 6 months prior to screening or at screening Treatment already includes an injectable/inhaled aminoglycoside within 3 months prior to screening or the investigator deems the participant to be a candidate for an injectable/inhaled aminoglycoside during screening period or at Day 1

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 79 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: Bedaquiline (BDQ) + Clarithromycin (CAM) + Ethambutol (EB)<br>Participants will receive BDQ 400 milligrams (mg) (4*100 mg tablets) once daily (qd) from Week 1-2 (loading phase), BDQ 200 mg (2*100mg tablets) bi-weekly (biw) from Week 3 to 48 (maintenance phase) and CAM 400 mg or 500 mg twice daily (2*200 mg tablets) along with EB 500-750 mg or 15 mg/kg once a day or maximum daily dose of 1.0 gram for up to Week 48. | Drug: Bedaquiline<br>* Participants will receive BDQ tablets only/<br>Drug: Clarithromycin<br>* Participants will receive CAM 400 or 500 mg twice a day.<br>Drug: Ethambutol<br>* Participants will receive 500 to 750 mg daily (maximum daily dose of 1.0 gram [g]) or 15 mg/kg once a day.<br>|
| Active Comparator: Group B: Rifampicin (RFP) or Rifabutin (RBT) + CAM + EB<br>Participants will receive maximum of 4 capsules of RFP 450 mg daily (or maximum daily dose of 600 mg), CAM 400 mg or 500 mg (2*200 mg tablets) twice a day along with EB 500-750 mg daily or 15 mg/kg once a day or maximum daily dose of 1.0 gram for up to Week 48, followed by 2 capsules of RBT 300 mg or 150 mg once a day. | Drug: Clarithromycin<br>* Participants will receive CAM 400 or 500 mg twice a day.<br>Drug: Ethambutol<br>* Participants will receive 500 to 750 mg daily (maximum daily dose of 1.0 gram [g]) or 15 mg/kg once a day.<br>Drug: Rifampicin<br>* Participants will receive daily dose is 450 mg (maximum 600 mg) RFP capsule once a day.<br>Drug: Rifabutin<br>* Participants will receive daily dose of RBT 300 mg or 150 mg capsules once a day.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Sputum Culture Conversion in Mycobacteria Growth Indicator Tube (MGIT) at Week 24 | Percentage of participant with sputum culture conversion (defined as 3 consecutive negative sputum cultures taken at least 25 days apart) in MGIT at Week 24 will be assessed. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Sputum Culture Conversion in 7H10 or 7H11 agar media at Week 24 | Percentage of participants with sputum culture conversion (defined as 3 consecutive negative sputum cultures taken at least 25 days apart) in 7H10 or 7H11 agar media at Week 24 will be assessed. | Up to Week 24 | 
| Change from Baseline in Patient-reported Health Status on Total Score of St. George's Respiratory Questionnaire (SGRQ) at Week 24 | The SGRQ is a self-administered questionnaire that has been validated in participants with airways disease, specifically in participants with bronchiectasis. The SGRQ assesses health-related quality of life in participants with chronic pulmonary disease by evaluating 3 health domains: symptoms (distress caused by respiratory symptoms); activity (effects of disturbances on mobility and physical activity); and impacts (the effect of disease on factors such as employment, personal control of one's health, and need for medication). A composite total score is derived as the sum of domain scores for symptoms, activity, and impact (0 = best possible score and 100 = worst possible score). | Baseline and Week 24 | 
| Percentage of Participants with Sputum Culture Conversion in MGIT and 7H10 or 7H11 agar media at Week 48 and Week 60 | Percentage of participants with sputum culture conversion (defined as 3 consecutive negative sputum cultures taken at least 25 days apart) in MGIT and 7H10 or 7H11 agar media at Week 48 and Week 60 will be assessed. | Up to Week 48 and Week 60 | 
| Percentage of Participants with Sputum Culture Negativity in MGIT and 7H10 or 7H11 at each visit after Week 2 | Percentage of participants with sputum culture negativity in MGIT and 7H10 or 7H11 at each visit after Week 2 will be assessed. | From Week 2 to Week 60 | 
| Time to Sputum Culture Conversion in MGIT up to Week 48 | Sputum culture conversion is defined as 3 consecutive negative sputum cultures taken at least 25 days apart. Percentage of participants with sputum culture in 7H10 or 7H11 agar media at Week 24 will be assessed. Time to sputum culture conversion in MGIT up to Week 48 will be assessed. | Up to Week 48 | 
| Time to Positivity in MGIT up to Week 48 | Time to positivity in MGIT up to week 48 will be assessed. | Up to Week 48 | 
| Change From Baseline in Patient Reported Health Status on Total Score of SGRQ at Weeks 48 and 60 | The SGRQ is a self-administered questionnaire that has been validated in participants with airways disease, specifically in participants with bronchiectasis. The SGRQ assesses health-related quality of life in participants with chronic pulmonary disease by evaluating 3 health domains: symptoms (distress caused by respiratory symptoms); activity (effects of disturbances on mobility and physical activity); and impacts (the effect of disease on factors such as employment, personal control of one's health, and need for medication). A composite total score is derived as the sum of domain scores for symptoms, activity, and impact (0 = best possible score and 100 = worst possible score). A within patient reduction from baseline in score of 4 units is generally recognized as a clinically meaningful improvement in quality of life. | From baseline to Week 48 and Week 60 | 
| Change From Baseline in Lung Function Parameters (Forced Vital Capacity) at Weeks 24, 48, and 60 | The lung function parameters including forced expiration volume will be assessed. | At Weeks 24, 48, and 60 | 
| Change From Baseline in Lung Function Parameters (Inspiratory Capacity) at Weeks 24, 48, and 60 | The lung function parameters including Inspiratory Capacity will be assessed. | At Weeks 24, 48, and 60 | 
| Change From Baseline in Lung Function Parameters (Functional Residual Capacity and Total Lung Capacity) at Weeks 24, 48, and 60 | The lung function parameters including functional residual capacity and total lung capacity will be assessed. | At Weeks 24, 48, and 60 | 
| Percentage of Participants who Undergo a Change in Their Mycobacterium Avium Complex-lung Disease (MAC-LD) Treatment Regimen by Week 24 and by Week 48 in Group A and by Week 60 in Group B | Percentage of participants who undergo a change in their MAC-LD treatment regimen will be assessed. | Week 24 and Week 48 (Group A) and by week 60 (Group B) | 
| Number of Participants with Adverse Events (AE) | An AE is any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal (investigational or non-investigational) product, whether or not related to that medicinal (investigational or non-investigational) product. | Up to Week 60 | 
| Number of Participants with Clinical Laboratory Abnormalities | Number of participants with clinical laboratory abnormalities (Hematology, Clinical chemistry, and Urinalysis) will be assessed. | Up to Week 60 | 
| Number of Participants with 12-Lead Electrocardiogram (ECG) Abnormalities | Number of participants with 12-Lead ECG Abnormalities will be assessed. | Up to Week 60 | 
| Number of Participants with Vital Signs Abnormalities | Number of participants with vital signs abnormalities (body temperature [axillary], heart rate, respiratory rate, oxygen saturation, blood pressure [systolic and diastolic]) will be assessed. | Up to Week 60 | 
| Number of Participants with Physical Examination Abnormalities | Number of Participants with physical examination abnormalities (all body systems [including height and body weight measurement] and observation for skin events/reactions) will be assessed. | Up to Week 60 | 
| Number of Participants with Visual Examination Abnormalities | Number of participants with visual examination abnormalities (visual acuity testing, color discrimination, visual field testing, and fundoscopy and audiology) will be assessed. | Up to Week 60 | 
| Maximum Plasma Concentration (Cmax) of Bedaquiline and its Metabolite M2 | Cmax is defined as maximum observed analyte concentration. | Day 1, Weeks 2, 8, 12, 24 and Week 48 | 
| Minimum Plasma Concentration Between 0 Hour and the Dosing Interval (tau) (Ctrough) of Bedaquiline and its Metabolite M2 | Ctrough is the minimum plasma concentration between 0 hour and dosing interval (tau). | Day 1, Weeks 2, 8, 12, 24 and Week 48 | 
| Area Under the Plasma Concentration-time Curve From Time Zero to End of Dosing Interval (tau) (AUC [0-tau]) of Bedaquiline and its Metabolite M2 | AUC (0-tau) is area under the plasma concentration-time curve from time zero to end of dosing interval (tau). | Day 1, Weeks 2, 8, 12, 24 and Week 48 | 
| Cmax of Clarithromycin and its Metabolite 4-OH CAM | Cmax is defined as maximum observed analyte concentration. | Day 1, Weeks 2, 8, 12 and 24 | 
| C (0-trough) of Clarithromycin and its Metabolite 4-OH CAM | Ctrough is the minimum plasma concentration between 0 hour and dosing interval (tau). | Day 1, Weeks 2, 8, 12 and 24 | 
| AUC (0-tau) of Clarithromycin and its Metabolite 4-OH CAM | AUC (0-tau) is area under the plasma concentration-time curve from time zero to end of dosing interval (tau). | Day 1, Weeks 2, 8, 12 and 24 |