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)

Sponsor

Janssen Pharmaceutical K.K. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04630145

Collaborator

(none)

180

Enrollment

Locations

Arms

45.3

Anticipated Duration (Months)

4.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Treatment-refractory Mycobacterium Avium Complex-lung Disease (MAC-LD)	Drug: Bedaquiline Drug: Clarithromycin Drug: Ethambutol Drug: Rifampicin Drug: Rifabutin	Phase 2/Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

180 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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)

Actual Study Start Date :

Jan 8, 2021

Anticipated Primary Completion Date :

Jun 1, 2023

Anticipated Study Completion Date :

Oct 18, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group A: Bedaquiline (BDQ) + Clarithromycin (CAM) + Ethambutol (EB) Participants will receive BDQ 400 milligrams (mg) (4100 mg tablets) once daily (qd) from Week 1-2 (loading phase), BDQ 200 mg (2100mg tablets) bi-weekly (biw) from Week 3 to 48 (maintenance phase) and CAM 400 mg twice daily (2*200 mg tablets) along with EB 500-750 mg qd or maximum daily dose of 1.0 gram for up to Week 48.	Drug: Bedaquiline Participants will receive BDQ tablets only/ Drug: Clarithromycin Participants will receive CAM 400 mg twice a day. Drug: Ethambutol Participants will receive 500 to 750 mg daily (maximum daily dose of 1.0 gram [g]) daily.
Active Comparator: Group B: Rifampicin (RFP) or Rifabutin (RBT) + CAM + EB Participants will receive maximum of 4 capsules of RFP 450 mg daily (or maximum daily dose of 600 mg), CAM 400 mg (2*200 mg tablets) twice a day along with EB 500-750 mg daily followed by 2 capsules of RBT 150 mg once a day (qd) or maximum daily dose of 1.0 gram for up to Week 48.	Drug: Clarithromycin Participants will receive CAM 400 mg twice a day. Drug: Ethambutol Participants will receive 500 to 750 mg daily (maximum daily dose of 1.0 gram [g]) daily. Drug: Rifampicin Participants will receive daily dose is 450 mg (maximum 600 mg) RFP capsule once a day. Drug: Rifabutin Participants will receive daily dose of RBT 300 mg capsules once a day.

Arm

Intervention/Treatment

Experimental: Group A: Bedaquiline (BDQ) + Clarithromycin (CAM) + Ethambutol (EB)

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 twice daily (2*200 mg tablets) along with EB 500-750 mg qd or maximum daily dose of 1.0 gram for up to Week 48.

Drug: Bedaquiline

Participants will receive BDQ tablets only/

Drug: Clarithromycin

Participants will receive CAM 400 mg twice a day.

Drug: Ethambutol

Participants will receive 500 to 750 mg daily (maximum daily dose of 1.0 gram [g]) daily.

Active Comparator: Group B: Rifampicin (RFP) or Rifabutin (RBT) + CAM + EB

Participants will receive maximum of 4 capsules of RFP 450 mg daily (or maximum daily dose of 600 mg), CAM 400 mg (2*200 mg tablets) twice a day along with EB 500-750 mg daily followed by 2 capsules of RBT 150 mg once a day (qd) or maximum daily dose of 1.0 gram for up to Week 48.

Drug: Clarithromycin

Participants will receive CAM 400 mg twice a day.

Drug: Ethambutol

Participants will receive 500 to 750 mg daily (maximum daily dose of 1.0 gram [g]) daily.

Drug: Rifampicin

Participants will receive daily dose is 450 mg (maximum 600 mg) RFP capsule once a day.

Drug: Rifabutin

Participants will receive daily dose of RBT 300 mg capsules once a day.

Outcome Measures

Primary Outcome Measures

Percentage of Participants with Sputum Culture Conversion in Mycobacteria Growth Indicator Tube (MGIT) at Week 24 [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.

Secondary Outcome Measures

Percentage of Participants with Sputum Culture Conversion in 7H10 or 7H11 agar media at Week 24 [Up to 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.
Change from Baseline in Patient-reported Health Status on Total Score of St. George's Respiratory Questionnaire (SGRQ) at Week 24 [Baseline and 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).
Percentage of Participants with Sputum Culture Conversion in MGIT and 7H10 or 7H11 agar media at Week 48 and Week 60 [Up to 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.
Percentage of Participants with Sputum Culture Negativity in MGIT and 7H10 or 7H11 at each visit after Week 2 [From Week 2 to Week 60]
Percentage of participants with sputum culture negativity in MGIT and 7H10 or 7H11 at each visit after Week 2 will be assessed.
Time to Sputum Culture Conversion in MGIT up to Week 48 [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.
Time to Positivity in MGIT up to Week 48 [Up to Week 48]
Time to positivity in MGIT up to week 48 will be assessed.
Change From Baseline in Patient Reported Health Status on Total Score of SGRQ at Weeks 48 and 60 [From baseline to Week 48 and Week 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.
Change From Baseline in Lung Function Parameters (Forced Vital Capacity) at Weeks 24, 48, and 60 [At Weeks 24, 48, and 60]
The lung function parameters including forced expiration volume will be assessed.
Change From Baseline in Lung Function Parameters (Inspiratory Capacity) at Weeks 24, 48, and 60 [At Weeks 24, 48, and 60]
The lung function parameters including Inspiratory Capacity will be assessed.
Change From Baseline in Lung Function Parameters (Functional Residual Capacity and Total Lung Capacity) at Weeks 24, 48, and 60 [At Weeks 24, 48, and 60]
The lung function parameters including functional residual capacity and total lung capacity will be assessed.
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 [Week 24 and Week 48 (Group 1) and by week 60 (Group 2)]
Percentage of participants who undergo a change in their MAC-LD treatment regimen will be assessed.
Number of Participants with Adverse Events (AE) [Up to Week 60]
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.
Number of Participants with Clinical Laboratory Abnormalities [Up to Week 60]
Number of participants with clinical laboratory abnormalities (Hematology, Clinical chemistry, and Urinalysis) will be assessed.
Number of Participants with 12-Lead Electrocardiogram (ECG) Abnormalities [Up to Week 60]
Number of participants with 12-Lead ECG Abnormalities will be assessed.
Number of Participants with Vital Signs Abnormalities [Up to Week 60]
Number of participants with vital signs abnormalities (body temperature [axillary], heart rate, respiratory rate, oxygen saturation, blood pressure [systolic and diastolic]) will be assessed.
Number of Participants with Physical Examination Abnormalities [Up to Week 60]
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.
Number of Participants with Visual Examination Abnormalities [Up to Week 60]
Number of participants with visual examination abnormalities (visual acuity testing, color discrimination, visual field testing, and fundoscopy and audiology) will be assessed.
Maximum Plasma Concentration (Cmax) of Bedaquiline and its Metabolite M2 [Day 1, Weeks 2, 8, 12, 24 and Week 48]
Cmax is defined as maximum observed analyte concentration.
Minimum Plasma Concentration Between 0 Hour and the Dosing Interval (tau) (Ctrough) of Bedaquiline and its Metabolite M2 [Day 1, Weeks 2, 8, 12, 24 and Week 48]
Ctrough is the minimum plasma concentration between 0 hour and dosing interval (tau).
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 [Day 1, Weeks 2, 8, 12, 24 and Week 48]
AUC (0-tau) is area under the plasma concentration-time curve from time zero to end of dosing interval (tau).
Cmax of Clarithromycin and its Metabolite 4-OH CAM [Day 1, Weeks 2, 8, 12 and 24]
Cmax is defined as maximum observed analyte concentration.
C (0-trough) of Clarithromycin and its Metabolite 4-OH CAM [Day 1, Weeks 2, 8, 12 and 24]
Ctrough is the minimum plasma concentration between 0 hour and dosing interval (tau).
AUC (0-tau) of Clarithromycin and its Metabolite 4-OH CAM [Day 1, Weeks 2, 8, 12 and 24]
AUC (0-tau) is area under the plasma concentration-time curve from time zero to end of dosing interval (tau).

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years to 79 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 no longer than 36 months; and one at screening (by central microbiology laboratory)
Received at least 6 months and no more than 36 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 aminoglycoside at screening

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Toyota Memorial Hospital	Aichi	Japan	471-8513
2	Fukuoka University Chikushi Hospital	Chikushino-shi	Japan	818-8502
3	Fukui Prefectural Hospital	Fukui-shi	Japan	910-0846
4	Gifu Prefectural General Medical Center	Gifu	Japan	500-8717
5	Hamamatsu Rosai Hospital	Hamamatsu-shi	Japan	430-8525
6	Seirei Hamamatsu General Hospital	Hamamatsu	Japan	430-8558
7	NHO Tenryu Hospital	Hamamatue	Japan	434-8511
8	Matsunami Health Promotion Clinic	Hashimagun Kasamatsucho	Japan	501-6062
9	National Hospital Organization Himeji Medical Center	Himeji	Japan	670-8520
10	National Hospital Organization Minami Kyoto Hospital	Joyo	Japan	610-0113
11	Fukujuji Hospital	Kiyose	Japan	204-0022
12	Kobe City Hospital Organization Kobe City Medical Center West Hospital	Kobe Nagata-Ku	Japan	653-0013
13	National Hospital Organization Kochi National Hospital	Kochi	Japan	780-8077
14	National Hospital Organization Fukuoka Higashi Medical Center	Koga	Japan	811-3195
15	Saitama Prefectural Cardiovascular and Respiratory Center	Kumagaya	Japan	360-0197
16	Rakuwakai Otowa Hospital	Kyoto	Japan	607-8062
17	Matsusaka Municipal Hospital	Matsusaka	Japan	515-8544
18	Musashino Red Cross Hospital	Musashino	Japan	180-8610
19	Nagaoka Red Cross Hospital	Nagaoka	Japan	940-2085
20	Nagasaki University Hospital	Nagasaki-shi	Japan	852-8501
21	Kojunkai Daido Clinic	Nagoya	Japan	457-8511
22	National Hospital Organization Nishiniigata Chuo Hospital	Niigata	Japan	950-2085
23	National Hospital Organization Omuta National Hospital	Omuta	Japan	837-0911
24	National Hospital Organization Sagamihara National Hospital	Sagamihara	Japan	252-0392
25	Saitama City Hospital	Saitama-shi	Japan	336-8522
26	Kinki-chuo Chest Medical Center	Sakai	Japan	591-8555
27	Hokkaido Medical Center	Sapporo Nishi-Ku	Japan	063-0005
28	Tohoku Medical And Pharmaceutical University Hospital	Sendai	Japan	983-8512
29	Tokyo Shinagawa Hospital	Shinagawa-ku	Japan	140-8522
30	Keio University Hospital	Shinjuku-ku	Japan	160-8582
31	Nagano Prefectural Shinshu Medical Center	Suzaka	Japan	386-8610
32	National Hospital Organization Ibarakihigashi	Tokai-mura	Japan	319-1113
33	National Hospital Organization Tokyo Medical Center	Tokyo	Japan	152-8902
34	National Center for Global Health and Medicine	Tokyo	Japan	162-8655
35	National Hospital Organization Tokyo National Hospital	Tokyo	Japan	204-8585
36	National Hospital Organization Ehime Medical Center	Toon	Japan	791-0281
37	National Hospital Organization Osaka Toneyama Medical Center	Toyonaka-shi	Japan	560-8552
38	Toyota Kosei Hospital	Toyota	Japan	470-0396
39	JRC Wakayama Medical Center	Wakayama	Japan	640-8558
40	Kanagawa Cardiovascular And Respiratory Center	Yokohama	Japan	236-0051