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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)

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ClinicalTrials.gov Identifier: NCT04630145
Recruitment Status : Recruiting
First Posted : November 16, 2020
Last Update Posted : August 3, 2022
Sponsor:
Information provided by (Responsible Party):
Janssen Pharmaceutical K.K.

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

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Study Type : Interventional  (Clinical Trial)
Estimated 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 : January 8, 2021
Estimated Primary Completion Date : June 1, 2023
Estimated Study Completion Date : October 18, 2024


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.




Primary Outcome Measures :
  1. Percentage of Participants with Sputum Culture Conversion in Mycobacteria Growth Indicator Tube (MGIT) at Week 24 [ Time Frame: 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 :
  1. Percentage of Participants with Sputum Culture Conversion in 7H10 or 7H11 agar media at Week 24 [ Time Frame: 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.

  2. Change from Baseline in Patient-reported Health Status on Total Score of St. George's Respiratory Questionnaire (SGRQ) at Week 24 [ Time Frame: 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).

  3. Percentage of Participants with Sputum Culture Conversion in MGIT and 7H10 or 7H11 agar media at Week 48 and Week 60 [ Time Frame: 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.

  4. Percentage of Participants with Sputum Culture Negativity in MGIT and 7H10 or 7H11 at each visit after Week 2 [ Time Frame: 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.

  5. Time to Sputum Culture Conversion in MGIT up to Week 48 [ Time Frame: 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.

  6. Time to Positivity in MGIT up to Week 48 [ Time Frame: Up to Week 48 ]
    Time to positivity in MGIT up to week 48 will be assessed.

  7. Change From Baseline in Patient Reported Health Status on Total Score of SGRQ at Weeks 48 and 60 [ Time Frame: 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.

  8. Change From Baseline in Lung Function Parameters (Forced Vital Capacity) at Weeks 24, 48, and 60 [ Time Frame: At Weeks 24, 48, and 60 ]
    The lung function parameters including forced expiration volume will be assessed.

  9. Change From Baseline in Lung Function Parameters (Inspiratory Capacity) at Weeks 24, 48, and 60 [ Time Frame: At Weeks 24, 48, and 60 ]
    The lung function parameters including Inspiratory Capacity will be assessed.

  10. Change From Baseline in Lung Function Parameters (Functional Residual Capacity and Total Lung Capacity) at Weeks 24, 48, and 60 [ Time Frame: At Weeks 24, 48, and 60 ]
    The lung function parameters including functional residual capacity and total lung capacity will be assessed.

  11. 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 [ Time Frame: 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.

  12. Number of Participants with Adverse Events (AE) [ Time Frame: 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.

  13. Number of Participants with Clinical Laboratory Abnormalities [ Time Frame: Up to Week 60 ]
    Number of participants with clinical laboratory abnormalities (Hematology, Clinical chemistry, and Urinalysis) will be assessed.

  14. Number of Participants with 12-Lead Electrocardiogram (ECG) Abnormalities [ Time Frame: Up to Week 60 ]
    Number of participants with 12-Lead ECG Abnormalities will be assessed.

  15. Number of Participants with Vital Signs Abnormalities [ Time Frame: 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.

  16. Number of Participants with Physical Examination Abnormalities [ Time Frame: 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.

  17. Number of Participants with Visual Examination Abnormalities [ Time Frame: 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.

  18. Maximum Plasma Concentration (Cmax) of Bedaquiline and its Metabolite M2 [ Time Frame: Day 1, Weeks 2, 8, 12, 24 and Week 48 ]
    Cmax is defined as maximum observed analyte concentration.

  19. Minimum Plasma Concentration Between 0 Hour and the Dosing Interval (tau) (Ctrough) of Bedaquiline and its Metabolite M2 [ Time Frame: Day 1, Weeks 2, 8, 12, 24 and Week 48 ]
    Ctrough is the minimum plasma concentration between 0 hour and dosing interval (tau).

  20. 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 [ Time Frame: 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).

  21. Cmax of Clarithromycin and its Metabolite 4-OH CAM [ Time Frame: Day 1, Weeks 2, 8, 12 and 24 ]
    Cmax is defined as maximum observed analyte concentration.

  22. C (0-trough) of Clarithromycin and its Metabolite 4-OH CAM [ Time Frame: Day 1, Weeks 2, 8, 12 and 24 ]
    Ctrough is the minimum plasma concentration between 0 hour and dosing interval (tau).

  23. AUC (0-tau) of Clarithromycin and its Metabolite 4-OH CAM [ Time Frame: 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).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   20 Years to 79 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04630145


Contacts
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Contact: Study Contact 844-434-4210 Participate-In-This-Study@its.jnj.com

Locations
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Sponsors and Collaborators
Janssen Pharmaceutical K.K.
Investigators
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Study Director: Janssen Pharmaceutical K.K., Japan clinical Trials Janssen Pharmaceutical K.K.
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Responsible Party: Janssen Pharmaceutical K.K.
ClinicalTrials.gov Identifier: NCT04630145    
Other Study ID Numbers: CR108897
TMC207NTM3002 ( Other Identifier: Janssen Pharmaceutical K.K., Japan )
First Posted: November 16, 2020    Key Record Dates
Last Update Posted: August 3, 2022
Last Verified: August 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu
URL: https://www.janssen.com/clinical-trials/transparency

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Mycobacterium Infections
Mycobacterium avium-intracellulare Infection
Lung Diseases
Respiratory Tract Diseases
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Bacterial Infections and Mycoses
Infections
Mycobacterium Infections, Nontuberculous
Clarithromycin
Rifampin
Ethambutol
Rifabutin
Bedaquiline
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Antibiotics, Antitubercular
Antitubercular Agents
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP2C8 Inducers
Cytochrome P-450 CYP2C19 Inducers