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Evaluating the Safety, Tolerability, and Pharmacokinetics of Bedaquiline and Delamanid, Alone and in Combination, For Drug-Resistant Pulmonary Tuberculosis

Sponsor
National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
Overall Status
Completed
CT.gov ID
NCT02583048
Collaborator
(none)
84
Enrollment
3
Locations
3
Arms
53.7
Actual Duration (Months)
28
Patients Per Site
0.5
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study evaluated the safety, tolerability, and pharmacokinetics of the anti-tuberculosis (TB) drugs bedaquiline (BDQ) and delamanid (DLM), alone and in combination, among participants (with or without HIV co-infection) taking multidrug treatment for multidrug-resistant tuberculosis (MDR-TB) or rifampin-monoresistant TB (RR-TB).

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

Bedaquiline (BDQ) and delamanid (DLM) are two newly approved anti-TB drugs and are both well tolerated. However, the combined effect of these two drugs has not been studied. Combining these two drugs, together with other anti-TB drugs, may improve outcomes for people with MDR-TB or RR-TB. The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics of BDQ and DLM, alone and in combination, among participants (with or without HIV co-infection) taking multidrug treatment for MDR-TB or RR-TB, and specifically to evaluate the effect of these drugs on the heart.

Participants were randomly assigned to one of three arms: participants in Arm 1 received BDQ, participants in Arm 2 received DLM, and participants in Arm 3 received BDQ and DLM. All participants received their assigned study drugs for 24 weeks together with multidrug background treatment (MBT) for MDR-TB or RR-TB (not provided by the study). HIV-infected participants also received dolutegravir, to be used in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) until study completion. NRTIs were not provided by the study. At study entry participants were initially required to be hospitalized for 2 months, however after an interim analysis, the period of hospitalization was shortened to 2 weeks.

Study visits occurred at entry, each week for 8 weeks after study entry, every other week until week 24, and at weeks 28, 36, 48, 60, 72, 84, 96 and 128. Visits included physical examinations, blood collection, urine collection, sputum sample collection, hair sample collection, chest x-rays, pregnancy testing, electrocardiograms (ECGs), and adherence questionnaires.

Participants were also asked to take part in an optional cerebrospinal fluid sampling study that entailed a lumbar puncture, to be done at weeks 8 or 24.

Study Design

Study Type:
Interventional
Actual Enrollment :
84 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Trial of the Safety, Tolerability, and Pharmacokinetics of Bedaquiline and Delamanid, Alone and in Combination, Among Participants Taking Multidrug Treatment for Drug-Resistant Pulmonary Tuberculosis
Actual Study Start Date :
Aug 15, 2016
Actual Primary Completion Date :
Jan 7, 2019
Actual Study Completion Date :
Feb 4, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: Arm 1: Bedaquiline

Participants received 400 mg of bedaquiline once a day for 2 weeks followed by 200 mg of bedaquiline three times a week for 22 weeks. Participants also received Multidrug Background Treatment (MBT) for TB. For HIV-positive participants only, one 50 mg tablet of Dolutegravir was taken in combination with two NRTIs until study completion.

Drug: Bedaquiline
Four 100 mg tablets (400 mg) orally once a day for 2 weeks, followed by two 100 mg tablets (200 mg) orally three times a week for 22 weeks.
Other Names:
  • Sirturo

    • Drug: Dolutegravir
    For HIV-positive participants only: one 50 mg tablet orally once daily, to be used in combination with two NRTIs until study completion. (NRTIs were not provided by the study.)
    Other Names:
  • Tivicay

    • Drug: Multidrug Background Treatment (MBT) for TB
    A standardized MBT regimen for MDR- or RR-TB except in cases where a participant had known resistance to one of the components of local standard treatment. MBT was provided by the local program.
    Experimental: Arm 2: Delamanid

    Participants received 100 mg of delamanid twice a day for 24 weeks. Participants also received Multidrug Background Treatment (MBT) for TB. For HIV-positive participants only, one 50 mg tablet of Dolutegravir was taken in combination with two NRTIs until study completion.

    Drug: Delamanid
    Two 50 mg tablets (100 mg) orally with food twice a day for 24 weeks.
    Other Names:
  • Deltyba

    • Drug: Dolutegravir
    For HIV-positive participants only: one 50 mg tablet orally once daily, to be used in combination with two NRTIs until study completion. (NRTIs were not provided by the study.)
    Other Names:
  • Tivicay

    • Drug: Multidrug Background Treatment (MBT) for TB
    A standardized MBT regimen for MDR- or RR-TB except in cases where a participant had known resistance to one of the components of local standard treatment. MBT was provided by the local program.
    Experimental: Arm 3: Bedaquiline and Delamanid

    Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. Participants also received Multidrug Background Treatment (MBT) for TB. For HIV-positive participants only, one 50 mg tablet of Dolutegravir was taken in combination with two NRTIs until study completion.

    Drug: Bedaquiline
    Four 100 mg tablets (400 mg) orally once a day for 2 weeks, followed by two 100 mg tablets (200 mg) orally three times a week for 22 weeks.
    Other Names:
  • Sirturo

    • Drug: Delamanid
    Two 50 mg tablets (100 mg) orally with food twice a day for 24 weeks.
    Other Names:
  • Deltyba

    • Drug: Dolutegravir
    For HIV-positive participants only: one 50 mg tablet orally once daily, to be used in combination with two NRTIs until study completion. (NRTIs were not provided by the study.)
    Other Names:
  • Tivicay

    • Drug: Multidrug Background Treatment (MBT) for TB
    A standardized MBT regimen for MDR- or RR-TB except in cases where a participant had known resistance to one of the components of local standard treatment. MBT was provided by the local program.

    Outcome Measures

    Primary Outcome Measures

    1. Mean Change From Baseline in QTcF [Baseline and at weeks 8, 10, 12, 14, 16, 18, 20, 22 and 24]

      Mean change from baseline in QTcF (ie, QTcF prolongation) in milliseconds (ms), where baseline QTcF was represented by QTcF durations measured at week 0, and post-baseline QTcF was represented by QTcF durations measured at weeks 8 through 24 (pooled). QTcF calculated as average of 1-3 available QTcF values per visit.

    2. Post-Baseline QTcF [Baseline and at weeks 8, 10, 12, 14, 16, 18, 20, 22, and 24.]

      Baseline and post-baseline absolute QTcF in milliseconds (ms) estimated using an ANOVA model, where baseline QTcF was represented by QTcF durations measured at week 0, and post-baseline QTcF was represented by QTcF durations measured at weeks 8 through 24 (pooled). QTcF calculated as average of 1-3 available QTcF values per visit. Interim analysis conducted when week 24 QT data was available for ≥12 participants stipulated 99.9% confidence interval; original coverage of 95% was widened to 95.1%.

    Secondary Outcome Measures

    1. Percentage of Participants With an Occurrence of QTcF Greater Than 500 Milliseconds (ms) [At weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24]

      Participants who experienced QTcF greater than 500 ms at least once at any time from week 2 to 24. QTcF calculated as average of 1-3 available QTcF values per visit.

    2. Percentage of Participants With an Increase in QTcF From Baseline of Greater Than 60 Milliseconds (ms) [Baseline and at weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24]

      Participants who experienced QTcF increase from baseline greater than 60 ms at least once at any time from week 2 to 24. QTcF calculated as average of 1-3 available QTcF values per visit.

    3. Changes in QTcF From Baseline [Baseline and at weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 and 28.]

      Change from baseline in QTcF, calculated as the difference between each post-baseline week and week 0. (QTcF calculated as average of 1-3 available QTcF values per visit.)

    4. Percentage of Participants With an Occurrence of QTcF >480 and ≤500 Milliseconds (ms) [At weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24]

      Participants who experienced QTcF >480 and ≤500 ms at least once at any time from week 2 to 24. QTcF calculated as average of 1-3 available QTcF values per visit.

    5. Percentage of Participants With an Occurrence of QTcF Increase From Baseline of >30 and ≤60 Milliseconds (ms) [Baseline and at weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24]

      Participants who experienced QTcF increase from baseline of >30 and ≤60 ms at least once at any time from week 2 to 24. QTcF calculated as average of 1-3 available QTcF values per visit.

    6. BDQ PK Parameter Minimum Plasma Concentration (Cmin) Determined Based on BDQ Levels From Individual Participants Enrolled in Arms 1 and 3 [Intensive BDQ PK samples at pre-dose, 5h, 7h, 10h and 22h post-dose at weeks 2, 8 and 24]

      This evaluates the effect of DLM on the BDQ PK parameter Cmin obtained from participants enrolled in Arms 1 and 3 (without and with co-administration of DLM). Cmin defines minimum concentration observed over the first 22 hours of the BDQ dosing interval.

    7. BDQ PK Parameter Maxmum Plasma Concentration (Cmax) Determined Based on BDQ Levels From Individual Participants Enrolled in Arms 1 and 3 [Intensive BDQ PK samples at pre-dose, 5h, 7h, 10h and 22h post-dose at weeks 2, 8 and 24]

      This evaluates the effect of DLM on the BDQ PK parameter Cmax obtained from participants enrolled in Arms 1 and 3 (without and with co-administration of DLM). Cmax defines maximum concentration observed over the first 22 hours of the BDQ dosing interval.

    8. BDQ PK Parameter Area Under the Concentration Time Curve (AUC 0-22h) Calculated Based on Intensive PK Samples Obtained From Individual Participants Enrolled in Arms 1 and 3 [Intensive BDQ PK samples at pre-dose, 5h, 7h, 10h and 22h post-dose at Weeks 2, 8 and 24]

      This evaluates the effect of DLM on the BDQ PK parameter AUC 0-22h obtained from participants enrolled in Arms 1 and 3 (without and with co-administration of DLM). AUC 0-22h defines area under the concentration-time curve over the period of 22 hours post-dose.

    9. N-monodesmethyl Metabolite of BDQ PK Parameter Cmin Determined Based on BDQ Metabolite Levels From Individual Participants Enrolled in Arms 1 and 3 [Intensive BDQ Metabolite PK samples at pre-dose, 5h, 7h, 10h and 22h post-dose at weeks 2, 8 and 24]

      This evaluates the effect of DLM on the N-monodesmethyl Metabolite of BDQ PK parameter Cmin obtained from participants enrolled in Arms 1 and 3 (without and with co-administration of DLM). Cmin defines minimum concentration observed over the first 22 hours of the BDQ dosing interval.

    10. N-monodesmethyl Metabolite of BDQ PK Parameter Cmax Determined Based on BDQ Metabolite Levels From Individual Participants Enrolled in Arms 1 and 3 [Intensive BDQ Metabolite PK samples at pre-dose, 5h, 7h, 10h and 22h post-dose at weeks 2, 8 and 24]

      This evaluates the effect of DLM on the BDQ Metabolite N-monodesmethyl BDQ PK parameter Cmax obtained from participants enrolled in Arms 1 and 3 (without and with co-administration of DLM). Cmax defines maximum concentration observed over the first 22 hours of the BDQ dosing interval.

    11. N-monodesmethyl Metabolite of BDQ PK Parameter AUC 0-22h Calculated Based on Intensive PK Samples Obtained From Individual Participants Enrolled in Arms 1 and 3 [Intensive BDQ PK samples at pre-dose, 5h, 7h, 10h and 22h post-dose at Weeks 2, 8 and 24]

      This evaluates the effect of DLM on the N-monodesmethyl Metabolite of BDQ PK parameter AUC 0-22h obtained from participants enrolled in Arms 1 and 3 (without and with co-administration of DLM). AUC 0-22h defines area under the concentration-time curve over the period of 22 hours post-dose.

    12. DLM PK Parameter Cmin Determined Based on DLM Levels From Individual Participants Enrolled in Arms 2 and 3 [Intensive DLM PK samples at pre-dose, 4h, 8h, and 11h post-dose at weeks 2, 8 and 24]

      This evaluates the effect of BDQ on the DLM PK parameter Cmin obtained from participants enrolled in Arms 2 and 3 (without and with co-administration of BDQ). Cmin defines minimum concentration observed over the first 11 hours of the DLM dosing interval.

    13. DLM PK Parameter Cmax Determined Based on DLM Levels From Individual Participants Enrolled in Arms 2 and 3 [Intensive DLM PK samples at pre-dose, 4h, 8h, and 11h post-dose at weeks 2, 8 and 24]

      This evaluates the effect of BDQ on the DLM PK parameter Cmax obtained from participants enrolled in Arms 2 and 3 (without and with co-administration of BDQ). Cmax defines maximum concentration observed over the first 11 hours of the DLM dosing interval.

    14. DLM PK Area Under the Concentration Time Curve (AUC 0-11h) Determined Based on Intensive PK Samples Obtained From Individual Participants Enrolled in Arms 2 and 3 [Intensive DLM PK samples at pre-dose, 4h, 8h, and 11h post-dose at weeks 2, 8 and 24]

      This evaluates the effect of BDQ on the DLM PK parameter AUC 0-11h obtained from participants enrolled in Arms 2 and 3 (without and with co-administration of BDQ). AUC 0-11h defines area under the concentration-time curve over the first 11 hours of the DLM dosing interval.

    15. DLM Metabolite DM6705 PK Parameter Cmin Determined Based on DLM Metabolite Levels From Individual Participants Enrolled in Arms 2 and 3 [Intensive DLM PK samples at pre-dose, 4h, 8h, and 11h post-dose at weeks 2, 8 and 24]

      This evaluates the effect of BDQ on the DLM Metabolite DM6705 PK parameter Cmin obtained from participants enrolled in Arms 2 and 3 (without and with co-administration of BDQ). Cmin defines minimum concentration observed over the first 11 hours of the DLM dosing interval.

    16. DLM Metabolite DM6705 PK Parameter Cmax Determined Based on DLM Metabolite Levels From Individual Participants Enrolled in Arms 2 and 3 [Intensive DLM PK samples at pre-dose, 4h, 8h, and 11h post-dose at weeks 2, 8 and 24]

      This evaluates the effect of BDQ on the DLM Metabolite DM6705 PK parameter Cmax obtained from participants enrolled in Arms 2 and 3 (without and with co-administration of BDQ). Cmax defines maximum concentration observed over the first 11 hours of the DLM dosing interval.

    17. DLM Metabolite DM6705 PK AUC 0-11h Determined Based on Intensive PK Samples Obtained From Individual Participants Enrolled in Arms 2 and 3 [Intensive DLM PK samples at pre-dose, 4h, 8h, and 11h post-dose at weeks 2, 8 and 24]

      This evaluates the effect of BDQ on the DLM Metabolite DM6705 PK parameter AUC 0-11h obtained from participants enrolled in Arms 2 and 3 (without and with co-administration of BDQ). AUC 0-11h defines area under the concentration-time curve over the first 11 hours of the DLM dosing interval.

    18. Percentage of Participants With an Occurrence of Grade 3 or Higher Adverse Event [From initiation of study TB treatment (week 0) to week 24]

      Participants with an occurrence of an adverse event (laboratory value, sign/symptom, diagnosis) of grade 3 or 4. Severity grading based on DAIDS AE Grading Table Version 2.0. Participants were counted once at the highest grade (grade 3 or grade 4).

    19. Percentage of Participants Who Discontinued Study TB Drug(s) For Any Reason [From initiation of study TB treatment (week 0) to week 24]

      Percentage of participants who discontinued study TB drug(s) for any reason

    20. Percentage of Participants Who Died [From initiation of study TB treatment (week 0) to week 24]

      Among participants who took at least one dose of study TB treatment, percentage of participants who died on or before week 24. Note that the all-cause mortality includes deaths that occurred at any time during treatment or follow-up through week 128.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Documented pulmonary infection due to strains of MTB with (a) resistance to isoniazid (INH) and rifampin (RIF) (MDR-TB) or (b) resistance to RIF but not INH (RR-TB) from a sputum sample collected within 60 days prior to entry.

    • Laboratory confirmation of infection with an MTB strain that is susceptible to fluoroquinolones and aminoglycosides within 60 days prior to entry.

    • HIV-1 infection status documented as either absent or present, as defined below:

    • Absence of HIV-1 infection, within 60 days prior to entry. OR

    • HIV-1 infection

    • For HIV-positive participants only: CD4+ count greater than or equal to 100 cells/mm^3 within 60 days prior to entry.

    • For HIV-positive participants only: For participants on ART for greater than or equal to 6 months and have an HIV-1 viral load greater than 500 copies/mL within 60 days prior to entry, a HIV-1 genotype within 60 days prior to entry must have shown that at least one fully active NRTI was available to the participant within the country program.

    • For females of reproductive potential, a negative serum pregnancy test within 48 hours prior to entry

    • All participants of reproductive potential who are participating in sexual activity that could lead to pregnancy must have agreed to use one method of birth control while receiving TB study medications and for 6 months after stopping TB study medications.

    • Participants who were not of reproductive potential were eligible without requiring the use of contraceptives.

    • For HIV-positive female participants of reproductive potential, the use of contraceptives was required for the full duration of time the participant was taking dolutegravir (ie, through study completion at week 128).

    • Chest x-ray performed within 60 days prior to entry to classify participant as having cavitary or non-cavitary disease

    • Documentation of Karnofsky performance score greater than or equal to 50 within 14 days prior to study entry

    • Ability and willingness of participant or legally authorized representative to provide informed consent

    • Willingness to be hospitalized for the required inpatient component of the study

    • Taking MBT for a minimum of 7 days within the 10 days prior to entry

    Exclusion Criteria:

    • History of clinically relevant, currently active or underlying gastrointestinal, hepatic, cardiovascular, nervous system, psychiatric, metabolic (e.g., untreated hypothyroidism), renal, respiratory (other than due to TB), inflammatory, neoplastic, skin, immunological or infectious disease, which is not stable and controlled, that in the opinion of the investigator would preclude safe participation in the trial

    • Current clinically relevant extrapulmonary TB, in the opinion of the site investigator, including but not limited to central nervous system (CNS) TB or TB osteoarthritis

    • Previous treatment for MDR- or RR-TB, other than for the qualifying episode, at any time in the past

    • Receipt of BDQ or DLM at any time in the past

    • Breastfeeding

    • QTcF interval greater than 450 ms within 72 hours prior to entry

    • Clinically significant ECG abnormality in the opinion of the site investigator within 60 days prior to entry, including but not limited to second or third degree atrioventricular (AV) block, prolongation of the QRS complex over 120 ms (in both male and female participants), or clinically important arrhythmia

    • Current clinically relevant cardiovascular disorder in the opinion of the site investigator, including but not limited to heart failure, coronary heart disease, arrhythmia, or tachyarrhythmia

    • Known family history of Long QT Syndrome in a first-degree relative (i.e., parent, offspring, or sibling)

    • Requirement or expected requirement for protease inhibitors (PIs), efavirenz (EFV), or any other medication that is a moderate to strong inhibitor or inducer of CYP3A and CYP3A4 over the 24 weeks of study treatment. NOTE: Participants taking a PI or EFV can be switched to a treatment that is allowed in the study, but the PI must be stopped at least 2 days prior to starting study MDR- or RR-TB drugs and EFV must be stopped at least 7 days prior to starting study MDR- or RR-TB drugs.

    • Requirement or expected requirement for a medication that significantly prolongs QTc, including but not limited to moxifloxacin (levofloxacin is acceptable), from 72 hours prior to study entry through 4 weeks after discontinuation of study treatment (week

    • Requirement or expected requirement of clofazimine, from 7 days prior to study entry through week 24 (discontinuation of study treatment).

    • For individuals receiving the WHO short course regimen that contains clofazimine, receipt of more than 21 cumulative days of clofazimine at any time prior to, or at the time of, study entry.

    • Known allergy/sensitivity or any hypersensitivity to components of study TB drugs or their formulation or to the nitroimidazole class of antibiotics

    • Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements

    • Any of the following laboratory abnormalities within 14 days prior to entry:

    1. Serum creatinine greater than 1.4 x upper limit of normal (ULN)

    2. Lipase greater than 1.6 x ULN

    3. Alanine aminotransferase (ALT) greater than 2.5 x ULN

    4. Total bilirubin greater than 1.6 x ULN

    5. Potassium less than 3.4 or greater than 5.6 mmol/L; magnesium less than 0.59 mmol/L; calcium less than 1.75 mmol/L

    • Known current hepatitis B or C infection, current treatment for hepatitis B or hepatitis C infection, or positive for hepatitis B surface antigen or hepatitis C antibodies within 60 days prior to entry

    • Among participants with HIV infection, in whom use of dolutegravir (DTG) is anticipated, any of the following:

    1. Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, esophageal varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)

    2. History or presence of allergy to DTG or its components

    3. Severe hepatic impairment (Class C) as determined by Child-Pugh classification

    4. Previous use of raltegravir

    • Documentation of any new and/or unstable AIDS-defining illness (other than TB) as defined by the CDC within 60 days prior to entry

    • Acute or serious illness (other than TB) requiring systemic treatment and/or hospitalization within 60 days prior to entry

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Barranco CRS Lima Peru 15063
    2 Task Applied Science (TASK) CRS Cape Town Western Cape Province South Africa 7530
    3 South African Tuberculosis Vaccine Initiative (SATVI) CRS Cape Town Western Cape Province South Africa 7705

    Sponsors and Collaborators

    • National Institute of Allergy and Infectious Diseases (NIAID)

    Investigators

    • Study Chair: Kelly Dooley, MD, PhD, Johns Hopkins Adult AIDS CRS
    • Study Chair: Gary Maartens, MBChB, MMed, University of Cape Town

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    National Institute of Allergy and Infectious Diseases (NIAID)
    ClinicalTrials.gov Identifier:
    NCT02583048
    Other Study ID Numbers:
    • A5343
    • 12005
    First Posted:
    Oct 21, 2015
    Last Update Posted:
    Jan 27, 2022
    Last Verified:
    Jan 1, 2022
    Additional relevant MeSH terms:
    Tuberculosis
    Tuberculosis, Pulmonary
    Dolutegravir
    Bedaquiline

    Study Results

    Participant Flow

    Recruitment Details Participants were enrolled from August 2016 to July 2018 at 3 non-US clinical research sites.
    Pre-assignment Detail Participants were randomized with equal probability to each of the 3 experimental arms.
    Arm/Group Title Arm 1: Bedaquiline Arm 2: Delamanid Arm 3: Bedaquiline and Delamanid
    Arm/Group Description Participants received 400 mg of bedaquiline once a day for 2 weeks followed by 200 mg of bedaquiline three times a week for 22 weeks. For HIV-positive participants only: One 50 mg tablet of Dolutegravir was taken orally once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 100 mg of delamanid twice a day for 24 weeks. For HIV-positive participants only: One 50 mg tablet of Dolutegravir was taken orally once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. For HIV-positive participants only: One 50 mg tablet of Dolutegravir was taken orally once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study).
    Period Title: Overall Study
    STARTED 28 28 28
    COMPLETED 28 27 27
    NOT COMPLETED 0 1 1

    Baseline Characteristics

    Arm/Group Title Arm 1: Bedaquiline Arm 2: Delamanid Arm 3: Bedaquiline and Delamanid Total
    Arm/Group Description Participants received 400 mg of bedaquiline once a day for 2 weeks followed by 200 mg of bedaquiline three times a week for 22 weeks. For HIV-positive participants only: One 50 mg tablet of Dolutegravir was taken orally once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 100 mg of delamanid twice a day for 24 weeks. For HIV-positive participants only: One 50 mg tablet of Dolutegravir was taken orally once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. For HIV-positive participants only: One 50 mg tablet of Dolutegravir was taken orally once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Total of all reporting groups
    Overall Participants 28 28 28 84
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    34.5
    32
    34
    34
    Sex: Female, Male (Count of Participants)
    Female
    6
    21.4%
    7
    25%
    8
    28.6%
    21
    25%
    Male
    22
    78.6%
    21
    75%
    20
    71.4%
    63
    75%
    Race/Ethnicity, Customized (Count of Participants)
    White
    0
    0%
    1
    3.6%
    0
    0%
    1
    1.2%
    Black African
    16
    57.1%
    11
    39.3%
    11
    39.3%
    38
    45.2%
    Mestizo
    1
    3.6%
    2
    7.1%
    3
    10.7%
    6
    7.1%
    Coloured
    11
    39.3%
    13
    46.4%
    14
    50%
    38
    45.2%
    Other
    0
    0%
    1
    3.6%
    0
    0%
    1
    1.2%
    Region of Enrollment (Count of Participants)
    South Africa
    27
    96.4%
    26
    92.9%
    25
    89.3%
    78
    92.9%
    Peru
    1
    3.6%
    2
    7.1%
    3
    10.7%
    6
    7.1%
    Baseline QTcF (milliseconds) [Median (Full Range) ]
    Median (Full Range) [milliseconds]
    394.3
    406.2
    387.3
    395.5
    HIV-1 Positive (Count of Participants)
    Count of Participants [Participants]
    10
    35.7%
    11
    39.3%
    10
    35.7%
    31
    36.9%

    Outcome Measures

    1. Primary Outcome
    Title Mean Change From Baseline in QTcF
    Description Mean change from baseline in QTcF (ie, QTcF prolongation) in milliseconds (ms), where baseline QTcF was represented by QTcF durations measured at week 0, and post-baseline QTcF was represented by QTcF durations measured at weeks 8 through 24 (pooled). QTcF calculated as average of 1-3 available QTcF values per visit.
    Time Frame Baseline and at weeks 8, 10, 12, 14, 16, 18, 20, 22 and 24

    Outcome Measure Data

    Analysis Population Description
    Participants with a baseline QTcF measurement, and at least one post-baseline QTcF measurement from a visit conducted at week 8 through 24, prior to permanent discontinuation of study Tuberculosis (TB) drug and without a temporary discontinuation of study TB drug of 7 or more days immediately preceding the measurement.
    Arm/Group Title Arm 1: Bedaquiline Arm 2: Delamanid Arm 3: Bedaquiline and Delamanid
    Arm/Group Description Participants received 400 mg of bedaquiline once a day for 2 weeks followed by 200 mg of bedaquiline three times a week for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 100 mg of delamanid twice a day for 24 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study).
    Measure Participants 26 25 24
    Mean (95.1% Confidence Interval) [milliseconds (ms)]
    12.3
    8.6
    20.7
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 3: Bedaquiline and Delamanid
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Net)
    Estimated Value 8.4
    Confidence Interval (2-Sided) 95.1%
    2.0 to 14.8
    Parameter Dispersion Type:
    Value:
    Estimation Comments Arm 3 minus Arm 1 difference in change from baseline estimated from ANOVA model. Interim analysis conducted when week 24 QT data was available for ≥12 participants stipulated 99.9% confidence interval; original coverage of 95% was widened to 95.1%.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm 2: Delamanid, Arm 3: Bedaquiline and Delamanid
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Net)
    Estimated Value 12.1
    Confidence Interval (2-Sided) 95.1%
    5.7 to 18.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments Arm 3 minus Arm 2 difference in change from baseline estimated from ANOVA model. Interim analysis conducted when week 24 QT data was available for ≥12 participants stipulated 99.9% confidence interval; original coverage of 95% was widened to 95.1%.
    2. Primary Outcome
    Title Post-Baseline QTcF
    Description Baseline and post-baseline absolute QTcF in milliseconds (ms) estimated using an ANOVA model, where baseline QTcF was represented by QTcF durations measured at week 0, and post-baseline QTcF was represented by QTcF durations measured at weeks 8 through 24 (pooled). QTcF calculated as average of 1-3 available QTcF values per visit. Interim analysis conducted when week 24 QT data was available for ≥12 participants stipulated 99.9% confidence interval; original coverage of 95% was widened to 95.1%.
    Time Frame Baseline and at weeks 8, 10, 12, 14, 16, 18, 20, 22, and 24.

    Outcome Measure Data

    Analysis Population Description
    Participants with a baseline QTcF measurement, and at least one post-baseline QTcF measurement from a visit conducted at week 8 through 24, prior to permanent discontinuation of study Tuberculosis (TB) drug and without a temporary discontinuation of study TB drug of 7 or more days immediately preceding the measurement.
    Arm/Group Title Arm 1: Bedaquiline Arm 2: Delamanid Arm 3: Bedaquiline and Delamanid
    Arm/Group Description Participants received 400 mg of bedaquiline once a day for 2 weeks followed by 200 mg of bedaquiline three times a week for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 100 mg of delamanid twice a day for 24 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study).
    Measure Participants 26 25 24
    Baseline
    397.4
    404.9
    391.7
    Post-baseline
    409.7
    413.4
    412.4
    3. Secondary Outcome
    Title Percentage of Participants With an Occurrence of QTcF Greater Than 500 Milliseconds (ms)
    Description Participants who experienced QTcF greater than 500 ms at least once at any time from week 2 to 24. QTcF calculated as average of 1-3 available QTcF values per visit.
    Time Frame At weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24

    Outcome Measure Data

    Analysis Population Description
    Participants who took at least one dose of study TB treatment.
    Arm/Group Title Arm 1: Bedaquiline Arm 2: Delamanid Arm 3: Bedaquiline and Delamanid
    Arm/Group Description Participants received 400 mg of bedaquiline once a day for 2 weeks followed by 200 mg of bedaquiline three times a week for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 100 mg of delamanid twice a day for 24 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study).
    Measure Participants 28 27 27
    Number (95% Confidence Interval) [Percentage of participants]
    0
    0%
    0
    0%
    0
    0%
    4. Secondary Outcome
    Title Percentage of Participants With an Increase in QTcF From Baseline of Greater Than 60 Milliseconds (ms)
    Description Participants who experienced QTcF increase from baseline greater than 60 ms at least once at any time from week 2 to 24. QTcF calculated as average of 1-3 available QTcF values per visit.
    Time Frame Baseline and at weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24

    Outcome Measure Data

    Analysis Population Description
    Participants who took at least one dose of study TB treatment.
    Arm/Group Title Arm 1: Bedaquiline Arm 2: Delamanid Arm 3: Bedaquiline and Delamanid
    Arm/Group Description Participants received 400 mg of bedaquiline once a day for 2 weeks followed by 200 mg of bedaquiline three times a week for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 100 mg of delamanid twice a day for 24 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study).
    Measure Participants 28 27 27
    Number (95% Confidence Interval) [Percentage of participants]
    4
    14.3%
    0
    0%
    7
    25%
    5. Secondary Outcome
    Title Changes in QTcF From Baseline
    Description Change from baseline in QTcF, calculated as the difference between each post-baseline week and week 0. (QTcF calculated as average of 1-3 available QTcF values per visit.)
    Time Frame Baseline and at weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 and 28.

    Outcome Measure Data

    Analysis Population Description
    Participants with baseline and at least one post baseline QTcF collected at a scheduled visit while taking study TB drug(s).
    Arm/Group Title Arm 1: Bedaquiline Arm 2: Delamanid Arm 3: Bedaquiline and Delamanid
    Arm/Group Description Participants received 400 mg of bedaquiline once a day for 2 weeks followed by 200 mg of bedaquiline three times a week for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 100 mg of delamanid twice a day for 24 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study).
    Measure Participants 28 26 26
    Change from baseline to Week 2
    16.70
    4.15
    13.15
    Change from baseline to Week 4
    15.00
    8.70
    14.30
    Change from baseline to Week 6
    15.30
    9.30
    15.30
    Change from baseline to Week 8
    12.00
    7.00
    20.30
    Change from baseline to Week 10
    10.30
    7.80
    18.30
    Change from baseline to Week 12
    9.30
    10.30
    20.30
    Change from baseline to Week 14
    12.70
    5.30
    21.30
    Change from baseline to Week 16
    15.35
    7.35
    21.00
    Change from baseline to Week 18
    17.65
    11.70
    12.70
    Change from baseline to Week 20
    9.30
    13.65
    21.00
    Change from baseline to Week 22
    12.00
    9.00
    20.85
    Change from baseline to Week 24
    11.70
    13.00
    24.00
    Change from baseline to Week 28
    13.30
    6.00
    17.65
    6. Secondary Outcome
    Title Percentage of Participants With an Occurrence of QTcF >480 and ≤500 Milliseconds (ms)
    Description Participants who experienced QTcF >480 and ≤500 ms at least once at any time from week 2 to 24. QTcF calculated as average of 1-3 available QTcF values per visit.
    Time Frame At weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24

    Outcome Measure Data

    Analysis Population Description
    Participants who took at least one dose of study TB drug(s).
    Arm/Group Title Arm 1: Bedaquiline Arm 2: Delamanid Arm 3: Bedaquiline and Delamanid
    Arm/Group Description Participants received 400 mg of bedaquiline once a day for 2 weeks followed by 200 mg of bedaquiline three times a week for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 100 mg of delamanid twice a day for 24 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study).
    Measure Participants 28 27 27
    Number (95% Confidence Interval) [Percentage of participants]
    0
    0%
    0
    0%
    0
    0%
    7. Secondary Outcome
    Title Percentage of Participants With an Occurrence of QTcF Increase From Baseline of >30 and ≤60 Milliseconds (ms)
    Description Participants who experienced QTcF increase from baseline of >30 and ≤60 ms at least once at any time from week 2 to 24. QTcF calculated as average of 1-3 available QTcF values per visit.
    Time Frame Baseline and at weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24

    Outcome Measure Data

    Analysis Population Description
    Participants who took at least one dose of study treatment.
    Arm/Group Title Arm 1: Bedaquiline Arm 2: Delamanid Arm 3: Bedaquiline and Delamanid
    Arm/Group Description Participants received 400 mg of bedaquiline once a day for 2 weeks followed by 200 mg of bedaquiline three times a week for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 100 mg of delamanid twice a day for 24 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study).
    Measure Participants 28 27 27
    Number (95% Confidence Interval) [Percentage of participants]
    32
    114.3%
    41
    146.4%
    37
    132.1%
    8. Secondary Outcome
    Title BDQ PK Parameter Minimum Plasma Concentration (Cmin) Determined Based on BDQ Levels From Individual Participants Enrolled in Arms 1 and 3
    Description This evaluates the effect of DLM on the BDQ PK parameter Cmin obtained from participants enrolled in Arms 1 and 3 (without and with co-administration of DLM). Cmin defines minimum concentration observed over the first 22 hours of the BDQ dosing interval.
    Time Frame Intensive BDQ PK samples at pre-dose, 5h, 7h, 10h and 22h post-dose at weeks 2, 8 and 24

    Outcome Measure Data

    Analysis Population Description
    Participants who took at least one dose of study treatment, and were taking study drug at the time of the PK visit.
    Arm/Group Title Arm 1: Bedaquiline Arm 3: Bedaquiline and Delamanid
    Arm/Group Description Participants received 400 mg of bedaquiline once a day for 2 weeks followed by 200 mg of bedaquiline three times a week for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study).
    Measure Participants 28 24
    Week 2
    796.8
    (406.1)
    850.9
    (343.8)
    Week 8
    505.9
    (218.6)
    601.9
    (212.6)
    Week 24
    653.4
    (271.3)
    629.4
    (247.0)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 2.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 1.117
    Confidence Interval (2-Sided) 90%
    0.884 to 1.411
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 1.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 8.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 1.202
    Confidence Interval (2-Sided) 90%
    0.989 to 1.461
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 1.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 24.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 0.958
    Confidence Interval (2-Sided) 90%
    0.774 to 1.187
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 1.
    9. Secondary Outcome
    Title BDQ PK Parameter Maxmum Plasma Concentration (Cmax) Determined Based on BDQ Levels From Individual Participants Enrolled in Arms 1 and 3
    Description This evaluates the effect of DLM on the BDQ PK parameter Cmax obtained from participants enrolled in Arms 1 and 3 (without and with co-administration of DLM). Cmax defines maximum concentration observed over the first 22 hours of the BDQ dosing interval.
    Time Frame Intensive BDQ PK samples at pre-dose, 5h, 7h, 10h and 22h post-dose at weeks 2, 8 and 24

    Outcome Measure Data

    Analysis Population Description
    Participants who took at least one dose of study treatment, and were taking study drug at the time of the PK visit.
    Arm/Group Title Arm 1: Bedaquiline Arm 3: Bedaquiline and Delamanid
    Arm/Group Description Participants received 400 mg of bedaquiline once a day for 2 weeks followed by 200 mg of bedaquiline three times a week for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study).
    Measure Participants 28 24
    Week 2
    2434.3
    (1148.4)
    2405.2
    (1128.2)
    Week 8
    1455.6
    (670.6)
    1477.2
    (704.7)
    Week 24
    1507.3
    (495.8)
    1368.2
    (518.6)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 2.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 0.986
    Confidence Interval (2-Sided) 90%
    0.801 to 1.215
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 1.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 8.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 0.978
    Confidence Interval (2-Sided) 90%
    0.764 to 1.251
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 1.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 24.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 0.859
    Confidence Interval (2-Sided) 90%
    0.667 to 1.108
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 1.
    10. Secondary Outcome
    Title BDQ PK Parameter Area Under the Concentration Time Curve (AUC 0-22h) Calculated Based on Intensive PK Samples Obtained From Individual Participants Enrolled in Arms 1 and 3
    Description This evaluates the effect of DLM on the BDQ PK parameter AUC 0-22h obtained from participants enrolled in Arms 1 and 3 (without and with co-administration of DLM). AUC 0-22h defines area under the concentration-time curve over the period of 22 hours post-dose.
    Time Frame Intensive BDQ PK samples at pre-dose, 5h, 7h, 10h and 22h post-dose at Weeks 2, 8 and 24

    Outcome Measure Data

    Analysis Population Description
    Participants who took at least one dose of study treatment, and were taking study drug at the time of the PK visit.
    Arm/Group Title Arm 1: Bedaquiline Arm 3: Bedaquiline and Delamanid
    Arm/Group Description Participants received 400 mg of bedaquiline once a day for 2 weeks followed by 200 mg of bedaquiline three times a week for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study).
    Measure Participants 28 24
    Week 2
    31570.9
    (14612.8)
    32399.4
    (13625.2)
    Week 8
    19234.6
    (7785.7)
    20176.1
    (8175.5)
    Week 24
    21048.5
    (8329.7)
    19522.6
    (7545.7)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 2.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 1.036
    Confidence Interval (2-Sided) 90%
    0.847 to 1.267
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 1.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 8.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 1.037
    Confidence Interval (2-Sided) 90%
    0.843 to 1.276
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 1.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 24.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 0.915
    Confidence Interval (2-Sided) 90%
    0.727 to 1.151
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 1.
    11. Secondary Outcome
    Title N-monodesmethyl Metabolite of BDQ PK Parameter Cmin Determined Based on BDQ Metabolite Levels From Individual Participants Enrolled in Arms 1 and 3
    Description This evaluates the effect of DLM on the N-monodesmethyl Metabolite of BDQ PK parameter Cmin obtained from participants enrolled in Arms 1 and 3 (without and with co-administration of DLM). Cmin defines minimum concentration observed over the first 22 hours of the BDQ dosing interval.
    Time Frame Intensive BDQ Metabolite PK samples at pre-dose, 5h, 7h, 10h and 22h post-dose at weeks 2, 8 and 24

    Outcome Measure Data

    Analysis Population Description
    Participants who took at least one dose of study treatment, and were taking study drug at the time of the PK visit.
    Arm/Group Title Arm 1: Bedaquiline Arm 3: Bedaquiline and Delamanid
    Arm/Group Description Participants received 400 mg of bedaquiline once a day for 2 weeks followed by 200 mg of bedaquiline three times a week for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study).
    Measure Participants 28 26
    Week 2
    353.3
    (137.8)
    361.6
    (122.8)
    Week 8
    200.0
    (81.1)
    204.7
    (76.3)
    Week 24
    204.0
    (62.8)
    174.0
    (82.1)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 2.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 1.043
    Confidence Interval (2-Sided) 90%
    0.864 to 1.258
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 1.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 8.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 1.029
    Confidence Interval (2-Sided) 90%
    0.858 to 1.235
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 1.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 24.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 0.808
    Confidence Interval (2-Sided) 90%
    0.657 to 0.993
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 1.
    12. Secondary Outcome
    Title N-monodesmethyl Metabolite of BDQ PK Parameter Cmax Determined Based on BDQ Metabolite Levels From Individual Participants Enrolled in Arms 1 and 3
    Description This evaluates the effect of DLM on the BDQ Metabolite N-monodesmethyl BDQ PK parameter Cmax obtained from participants enrolled in Arms 1 and 3 (without and with co-administration of DLM). Cmax defines maximum concentration observed over the first 22 hours of the BDQ dosing interval.
    Time Frame Intensive BDQ Metabolite PK samples at pre-dose, 5h, 7h, 10h and 22h post-dose at weeks 2, 8 and 24

    Outcome Measure Data

    Analysis Population Description
    Participants who took at least one dose of study treatment, and were taking study drug at the time of the PK visit.
    Arm/Group Title Arm 1: Bedaquiline Arm 3: Bedaquiline and Delamanid
    Arm/Group Description Participants received 400 mg of bedaquiline once a day for 2 weeks followed by 200 mg of bedaquiline three times a week for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study).
    Measure Participants 28 26
    Week 2
    404.8
    (143.7)
    429.8
    (139.8)
    Week 8
    248.5
    (95.4)
    241.5
    (87.2)
    Week 24
    232.9
    (68.6)
    196.8
    (92.5)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 2.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 1.068
    Confidence Interval (2-Sided) 90%
    0.903 to 1.263
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 1.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 8.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 0.973
    Confidence Interval (2-Sided) 90%
    0.820 to 1.155
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 1.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 24.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 0.803
    Confidence Interval (2-Sided) 90%
    0.656 to 0.983
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 1.
    13. Secondary Outcome
    Title N-monodesmethyl Metabolite of BDQ PK Parameter AUC 0-22h Calculated Based on Intensive PK Samples Obtained From Individual Participants Enrolled in Arms 1 and 3
    Description This evaluates the effect of DLM on the N-monodesmethyl Metabolite of BDQ PK parameter AUC 0-22h obtained from participants enrolled in Arms 1 and 3 (without and with co-administration of DLM). AUC 0-22h defines area under the concentration-time curve over the period of 22 hours post-dose.
    Time Frame Intensive BDQ PK samples at pre-dose, 5h, 7h, 10h and 22h post-dose at Weeks 2, 8 and 24

    Outcome Measure Data

    Analysis Population Description
    Participants who took at least one dose of study treatment, and were taking study drug at the time of the PK visit.
    Arm/Group Title Arm 1: Bedaquiline Arm 3: Bedaquiline and Delamanid
    Arm/Group Description Participants received 400 mg of bedaquiline once a day for 2 weeks followed by 200 mg of bedaquiline three times a week for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study).
    Measure Participants 28 26
    Week 2
    8435.5
    (3220.1)
    8713.4
    (2858.9)
    Week 8
    5067.5
    (2017.6)
    4963.4
    (1847.6)
    Week 24
    4771.4
    (1577.9)
    4033.5
    (1978.7)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 2.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 1.049
    Confidence Interval (2-Sided) 90%
    0.881 to 1.248
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 1.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 8.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 0.979
    Confidence Interval (2-Sided) 90%
    0.823 to 1.165
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 1.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 24.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 0.808
    Confidence Interval (2-Sided) 90%
    0.638 to 1.025
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 1.
    14. Secondary Outcome
    Title DLM PK Parameter Cmin Determined Based on DLM Levels From Individual Participants Enrolled in Arms 2 and 3
    Description This evaluates the effect of BDQ on the DLM PK parameter Cmin obtained from participants enrolled in Arms 2 and 3 (without and with co-administration of BDQ). Cmin defines minimum concentration observed over the first 11 hours of the DLM dosing interval.
    Time Frame Intensive DLM PK samples at pre-dose, 4h, 8h, and 11h post-dose at weeks 2, 8 and 24

    Outcome Measure Data

    Analysis Population Description
    Participants who took at least one dose of study treatment, and were taking study drug at the time of the PK visit.
    Arm/Group Title Arm 2: Delamanid Arm 3: Bedaquiline and Delamanid
    Arm/Group Description Participants received 100 mg of delamanid twice a day for 24 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study).
    Measure Participants 25 26
    Week 2
    224.8
    (59.0)
    206.8
    (64.8)
    Week 8
    198.2
    (64.3)
    217.2
    (64.6)
    Week 24
    220.9
    (78.9)
    182.2
    (78.5)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 2.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 0.903
    Confidence Interval (2-Sided) 90%
    0.778 to 1.049
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 2.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 8.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 1.114
    Confidence Interval (2-Sided) 90%
    0.944 to 1.315
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 2.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 24.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 0.804
    Confidence Interval (2-Sided) 90%
    0.639 to 1.012
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 2.
    15. Secondary Outcome
    Title DLM PK Parameter Cmax Determined Based on DLM Levels From Individual Participants Enrolled in Arms 2 and 3
    Description This evaluates the effect of BDQ on the DLM PK parameter Cmax obtained from participants enrolled in Arms 2 and 3 (without and with co-administration of BDQ). Cmax defines maximum concentration observed over the first 11 hours of the DLM dosing interval.
    Time Frame Intensive DLM PK samples at pre-dose, 4h, 8h, and 11h post-dose at weeks 2, 8 and 24

    Outcome Measure Data

    Analysis Population Description
    Participants who took at least one dose of study treatment, and were taking study drug at the time of the PK visit.
    Arm/Group Title Arm 2: Delamanid Arm 3: Bedaquiline and Delamanid
    Arm/Group Description Participants received 100 mg of delamanid twice a day for 24 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study).
    Measure Participants 25 26
    Week 2
    317.8
    (88.7)
    298.3
    (84.2)
    Week 8
    294.1
    (100.0)
    320.9
    (98.4)
    Week 24
    290.3
    (81.6)
    259.0
    (102.8)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 2.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 0.937
    Confidence Interval (2-Sided) 90%
    0.810 to 1.084
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 2.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 8.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 1.107
    Confidence Interval (2-Sided) 90%
    0.929 to 1.318
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 2.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 24.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 0.856
    Confidence Interval (2-Sided) 90%
    0.703 to 1.043
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 2.
    16. Secondary Outcome
    Title DLM PK Area Under the Concentration Time Curve (AUC 0-11h) Determined Based on Intensive PK Samples Obtained From Individual Participants Enrolled in Arms 2 and 3
    Description This evaluates the effect of BDQ on the DLM PK parameter AUC 0-11h obtained from participants enrolled in Arms 2 and 3 (without and with co-administration of BDQ). AUC 0-11h defines area under the concentration-time curve over the first 11 hours of the DLM dosing interval.
    Time Frame Intensive DLM PK samples at pre-dose, 4h, 8h, and 11h post-dose at weeks 2, 8 and 24

    Outcome Measure Data

    Analysis Population Description
    Participants who took at least one dose of study treatment, and were taking study drug at the time of the PK visit.
    Arm/Group Title Arm 2: Delamanid Arm 3: Bedaquiline and Delamanid
    Arm/Group Description Participants received 100 mg of delamanid twice a day for 24 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study).
    Measure Participants 25 26
    Week 2
    2789.6
    (761.9)
    2654.9
    (724.3)
    Week 8
    2547.6
    (838.4)
    2823.2
    (792.7)
    Week 24
    2473.0
    (778.2)
    2324.9
    (987.3)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 2.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 0.951
    Confidence Interval (2-Sided) 90%
    0.825 to 1.096
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 2.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 8.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 1.136
    Confidence Interval (2-Sided) 90%
    0.948 to 1.362
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 2.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 24.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 0.898
    Confidence Interval (2-Sided) 90%
    0.727 to 1.109
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 2.
    17. Secondary Outcome
    Title DLM Metabolite DM6705 PK Parameter Cmin Determined Based on DLM Metabolite Levels From Individual Participants Enrolled in Arms 2 and 3
    Description This evaluates the effect of BDQ on the DLM Metabolite DM6705 PK parameter Cmin obtained from participants enrolled in Arms 2 and 3 (without and with co-administration of BDQ). Cmin defines minimum concentration observed over the first 11 hours of the DLM dosing interval.
    Time Frame Intensive DLM PK samples at pre-dose, 4h, 8h, and 11h post-dose at weeks 2, 8 and 24

    Outcome Measure Data

    Analysis Population Description
    Participants who took at least one dose of study treatment, and were taking study drug at the time of the PK visit.
    Arm/Group Title Arm 2: Delamanid Arm 3: Bedaquiline and Delamanid
    Arm/Group Description Participants received 100 mg of delamanid twice a day for 24 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study).
    Measure Participants 25 26
    Week 2
    61.9
    (19.3)
    58.5
    (17.0)
    Week 8
    90.6
    (38.2)
    94.4
    (37.8)
    Week 24
    75.7
    (41.6)
    71.0
    (46.6)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 2.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 0.939
    Confidence Interval (2-Sided) 90%
    0.806 to 1.094
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 2.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 8.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 1.081
    Confidence Interval (2-Sided) 90%
    0.864 to 1.352
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 2.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 24.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 0.865
    Confidence Interval (2-Sided) 90%
    0.597 to 1.253
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 2.
    18. Secondary Outcome
    Title DLM Metabolite DM6705 PK Parameter Cmax Determined Based on DLM Metabolite Levels From Individual Participants Enrolled in Arms 2 and 3
    Description This evaluates the effect of BDQ on the DLM Metabolite DM6705 PK parameter Cmax obtained from participants enrolled in Arms 2 and 3 (without and with co-administration of BDQ). Cmax defines maximum concentration observed over the first 11 hours of the DLM dosing interval.
    Time Frame Intensive DLM PK samples at pre-dose, 4h, 8h, and 11h post-dose at weeks 2, 8 and 24

    Outcome Measure Data

    Analysis Population Description
    Participants who took at least one dose of study treatment, and were taking study drug at the time of the PK visit.
    Arm/Group Title Arm 2: Delamanid Arm 3: Bedaquiline and Delamanid
    Arm/Group Description Participants received 100 mg of delamanid twice a day for 24 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study).
    Measure Participants 25 26
    Week 2
    66.6
    (18.1)
    64.3
    (19.8)
    Week 8
    99.7
    (41.0)
    105.4
    (46.2)
    Week 24
    82.1
    (46.1)
    75.6
    (47.9)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 2.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 0.950
    Confidence Interval (2-Sided) 90%
    0.825 to 1.095
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 2.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 8.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 1.080
    Confidence Interval (2-Sided) 90%
    0.862 to 1.354
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 2.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 24.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 0.865
    Confidence Interval (2-Sided) 90%
    0.605 to 1.239
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 2.
    19. Secondary Outcome
    Title DLM Metabolite DM6705 PK AUC 0-11h Determined Based on Intensive PK Samples Obtained From Individual Participants Enrolled in Arms 2 and 3
    Description This evaluates the effect of BDQ on the DLM Metabolite DM6705 PK parameter AUC 0-11h obtained from participants enrolled in Arms 2 and 3 (without and with co-administration of BDQ). AUC 0-11h defines area under the concentration-time curve over the first 11 hours of the DLM dosing interval.
    Time Frame Intensive DLM PK samples at pre-dose, 4h, 8h, and 11h post-dose at weeks 2, 8 and 24

    Outcome Measure Data

    Analysis Population Description
    Participants who took at least one dose of study treatment, and were taking study drug at the time of the PK visit.
    Arm/Group Title Arm 2: Delamanid Arm 3: Bedaquiline and Delamanid
    Arm/Group Description Participants received 100 mg of delamanid twice a day for 24 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study).
    Measure Participants 25 26
    Week 2
    628.0
    (188.1)
    621.2
    (178.3)
    Week 8
    953.9
    (395.2)
    990.9
    (378.1)
    Week 24
    749.9
    (420.4)
    742.5
    (479.5)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 2.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 0.984
    Confidence Interval (2-Sided) 90%
    0.851 to 1.138
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 2.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 8.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 1.086
    Confidence Interval (2-Sided) 90%
    0.866 to 1.361
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 2.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Arm 1: Bedaquiline, Arm 2: Delamanid
    Comments Statistical analysis for Week 24.
    Type of Statistical Test Equivalence
    Comments GMRs were compared to no effect boundaries of 0.67 to 1.50.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Geometric Mean Ratio
    Estimated Value 0.927
    Confidence Interval (2-Sided) 90%
    0.650 to 1.322
    Parameter Dispersion Type:
    Value:
    Estimation Comments The numerator represents Arm 3 and the denominator represents Arm 2.
    20. Secondary Outcome
    Title Percentage of Participants With an Occurrence of Grade 3 or Higher Adverse Event
    Description Participants with an occurrence of an adverse event (laboratory value, sign/symptom, diagnosis) of grade 3 or 4. Severity grading based on DAIDS AE Grading Table Version 2.0. Participants were counted once at the highest grade (grade 3 or grade 4).
    Time Frame From initiation of study TB treatment (week 0) to week 24

    Outcome Measure Data

    Analysis Population Description
    Participants who took at least one dose of study TB treatment.
    Arm/Group Title Arm 1: Bedaquiline Arm 2: Delamanid Arm 3: Bedaquiline and Delamanid
    Arm/Group Description Participants received 400 mg of bedaquiline once a day for 2 weeks followed by 200 mg of bedaquiline three times a week for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 100 mg of delamanid twice a day for 24 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study).
    Measure Participants 28 27 27
    Grade 3 adverse event
    36
    128.6%
    11
    39.3%
    19
    67.9%
    Grade 4 adverse event
    4
    14.3%
    11
    39.3%
    19
    67.9%
    21. Secondary Outcome
    Title Percentage of Participants Who Discontinued Study TB Drug(s) For Any Reason
    Description Percentage of participants who discontinued study TB drug(s) for any reason
    Time Frame From initiation of study TB treatment (week 0) to week 24

    Outcome Measure Data

    Analysis Population Description
    Participants who took at least one dose of study TB treatment.
    Arm/Group Title Arm 1: Bedaquiline Arm 2: Delamanid Arm 3: Bedaquiline and Delamanid
    Arm/Group Description Participants received 400 mg of bedaquiline once a day for 2 weeks followed by 200 mg of bedaquiline three times a week for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 100 mg of delamanid twice a day for 24 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study).
    Measure Participants 28 27 27
    Number (95% Confidence Interval) [Percentage of participants]
    11
    39.3%
    19
    67.9%
    22
    78.6%
    22. Secondary Outcome
    Title Percentage of Participants Who Died
    Description Among participants who took at least one dose of study TB treatment, percentage of participants who died on or before week 24. Note that the all-cause mortality includes deaths that occurred at any time during treatment or follow-up through week 128.
    Time Frame From initiation of study TB treatment (week 0) to week 24

    Outcome Measure Data

    Analysis Population Description
    Participants who took at least one dose of study TB treatment.
    Arm/Group Title Arm 1: Bedaquiline Arm 2: Delamanid Arm 3: Bedaquiline and Delamanid
    Arm/Group Description Participants received 400 mg of bedaquiline once a day for 2 weeks followed by 200 mg of bedaquiline three times a week for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 100 mg of delamanid twice a day for 24 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study).
    Measure Participants 28 27 27
    Number (95% Confidence Interval) [Percentage of participants]
    0
    0%
    0
    0%
    0
    0%

    Adverse Events

    Time Frame From start of study treatment to study completion at Week 128 or premature study discontinuation.
    Adverse Event Reporting Description For participants who took at least one dose of study TB treatment. All diagnoses (per ACTG criteria for clinical events and other diseases); signs/symptoms (S/S) of grade 3 or higher or any S/S that led to a change in BDQ, DLM and/or DTG regardless of grade; hematologies, LFTs and chemistries of grade 3 and higher, or any laboratory finding that led to a change in BDQ, DLM and/or DTG regardless of grade.The DAIDS AE Grading Table Version 2.0, and the DAIDS EAE Manual Version 2.0 were used.
    Arm/Group Title Arm 1: Bedaquiline Arm 2: Delamanid Arm 3: Bedaquiline and Delamanid
    Arm/Group Description Participants received 400 mg of bedaquiline once a day for 2 weeks followed by 200 mg of bedaquiline three times a week for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 100 mg of delamanid twice a day for 24 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study). Participants received 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They then received 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks. For HIV-positive participants only: dolutegravir was administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs not provided by the study.) Participants also took Multidrug Background Treatment (MBT) for TB (not provided by the study).
    All Cause Mortality
    Arm 1: Bedaquiline Arm 2: Delamanid Arm 3: Bedaquiline and Delamanid
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/28 (0%) 1/27 (3.7%) 0/27 (0%)
    Serious Adverse Events
    Arm 1: Bedaquiline Arm 2: Delamanid Arm 3: Bedaquiline and Delamanid
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/28 (7.1%) 3/27 (11.1%) 8/27 (29.6%)
    Gastrointestinal disorders
    Pancreatitis 0/28 (0%) 1/27 (3.7%) 0/27 (0%)
    Hepatobiliary disorders
    Drug-induced liver injury 0/28 (0%) 0/27 (0%) 1/27 (3.7%)
    Immune system disorders
    Hypersensitivity 0/28 (0%) 0/27 (0%) 1/27 (3.7%)
    Injury, poisoning and procedural complications
    Stab wound 0/28 (0%) 0/27 (0%) 1/27 (3.7%)
    Investigations
    Blood creatine phosphokinase increased 0/28 (0%) 1/27 (3.7%) 4/27 (14.8%)
    Electrocardiogram QT prolonged 1/28 (3.6%) 0/27 (0%) 0/27 (0%)
    Musculoskeletal and connective tissue disorders
    Myalgia 1/28 (3.6%) 0/27 (0%) 0/27 (0%)
    Nervous system disorders
    Focal dyscognitive seizures 0/28 (0%) 0/27 (0%) 1/27 (3.7%)
    Generalised tonic-clonic seizure 0/28 (0%) 0/27 (0%) 1/27 (3.7%)
    Seizure 0/28 (0%) 0/27 (0%) 1/27 (3.7%)
    Psychiatric disorders
    Major depression 0/28 (0%) 1/27 (3.7%) 0/27 (0%)
    Substance-induced psychotic disorder 0/28 (0%) 0/27 (0%) 1/27 (3.7%)
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis 0/28 (0%) 0/27 (0%) 1/27 (3.7%)
    Other (Not Including Serious) Adverse Events
    Arm 1: Bedaquiline Arm 2: Delamanid Arm 3: Bedaquiline and Delamanid
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 21/28 (75%) 16/27 (59.3%) 21/27 (77.8%)
    Blood and lymphatic system disorders
    Anaemia 3/28 (10.7%) 0/27 (0%) 1/27 (3.7%)
    Ear and labyrinth disorders
    Deafness 3/28 (10.7%) 2/27 (7.4%) 6/27 (22.2%)
    Deafness neurosensory 8/28 (28.6%) 4/27 (14.8%) 4/27 (14.8%)
    Tinnitus 2/28 (7.1%) 0/27 (0%) 2/27 (7.4%)
    Eye disorders
    Conjunctivitis allergic 0/28 (0%) 2/27 (7.4%) 1/27 (3.7%)
    Optic neuropathy 0/28 (0%) 2/27 (7.4%) 1/27 (3.7%)
    Gastrointestinal disorders
    Abdominal pain 2/28 (7.1%) 2/27 (7.4%) 0/27 (0%)
    Abdominal pain upper 0/28 (0%) 2/27 (7.4%) 0/27 (0%)
    Diarrhoea 0/28 (0%) 1/27 (3.7%) 2/27 (7.4%)
    Gastrooesophageal reflux disease 1/28 (3.6%) 3/27 (11.1%) 1/27 (3.7%)
    Nausea 0/28 (0%) 2/27 (7.4%) 3/27 (11.1%)
    Vomiting 1/28 (3.6%) 2/27 (7.4%) 0/27 (0%)
    General disorders
    Injection site reaction 0/28 (0%) 2/27 (7.4%) 0/27 (0%)
    Infections and infestations
    Acute sinusitis 1/28 (3.6%) 3/27 (11.1%) 1/27 (3.7%)
    Oral candidiasis 0/28 (0%) 6/27 (22.2%) 1/27 (3.7%)
    Oral herpes 1/28 (3.6%) 2/27 (7.4%) 0/27 (0%)
    Pharyngitis 3/28 (10.7%) 5/27 (18.5%) 2/27 (7.4%)
    Investigations
    Alanine aminotransferase increased 0/28 (0%) 0/27 (0%) 2/27 (7.4%)
    Aspartate aminotransferase increased 2/28 (7.1%) 0/27 (0%) 1/27 (3.7%)
    Blood albumin decreased 1/28 (3.6%) 2/27 (7.4%) 0/27 (0%)
    Blood glucose decreased 0/28 (0%) 1/27 (3.7%) 2/27 (7.4%)
    Blood uric acid increased 3/28 (10.7%) 1/27 (3.7%) 0/27 (0%)
    Haemoglobin decreased 3/28 (10.7%) 0/27 (0%) 1/27 (3.7%)
    Weight decreased 3/28 (10.7%) 0/27 (0%) 1/27 (3.7%)
    Metabolism and nutrition disorders
    Decreased appetite 2/28 (7.1%) 0/27 (0%) 1/27 (3.7%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 2/28 (7.1%) 0/27 (0%) 0/27 (0%)
    Costochondritis 1/28 (3.6%) 0/27 (0%) 2/27 (7.4%)
    Pain in extremity 4/28 (14.3%) 0/27 (0%) 1/27 (3.7%)
    Nervous system disorders
    Dizziness 3/28 (10.7%) 0/27 (0%) 2/27 (7.4%)
    Headache 3/28 (10.7%) 2/27 (7.4%) 0/27 (0%)
    Hypoaesthesia 2/28 (7.1%) 1/27 (3.7%) 0/27 (0%)
    Neuropathy peripheral 6/28 (21.4%) 2/27 (7.4%) 3/27 (11.1%)
    Paraesthesia 4/28 (14.3%) 1/27 (3.7%) 2/27 (7.4%)
    Seizure 0/28 (0%) 0/27 (0%) 3/27 (11.1%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease 0/28 (0%) 0/27 (0%) 2/27 (7.4%)
    Cough 2/28 (7.1%) 0/27 (0%) 2/27 (7.4%)
    Dyspnoea 2/28 (7.1%) 0/27 (0%) 2/27 (7.4%)
    Oropharyngeal pain 2/28 (7.1%) 3/27 (11.1%) 2/27 (7.4%)
    Rhinitis allergic 1/28 (3.6%) 0/27 (0%) 2/27 (7.4%)
    Rhinorrhoea 4/28 (14.3%) 2/27 (7.4%) 1/27 (3.7%)
    Skin and subcutaneous tissue disorders
    Acne 8/28 (28.6%) 6/27 (22.2%) 8/27 (29.6%)
    Drug eruption 1/28 (3.6%) 1/27 (3.7%) 2/27 (7.4%)
    Pruritus 3/28 (10.7%) 2/27 (7.4%) 4/27 (14.8%)
    Rash 1/28 (3.6%) 2/27 (7.4%) 1/27 (3.7%)
    Vascular disorders
    Hypertension 2/28 (7.1%) 1/27 (3.7%) 1/27 (3.7%)
    Orthostatic hypotension 2/28 (7.1%) 0/27 (0%) 0/27 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    In accordance with the Clinical Trials Agreement between NIAID (DAIDS) and company collaborators, NIAID (DAIDS) provides companies with a copy of any abstract, press release, or manuscript prior to submission for publication with sufficient time for company review and comment. The publication/other disclosure can be delayed for up to 30 additional business days for manuscripts and five (5) business days for abstracts, to preserve U.S. or foreign patent or other intellectual property rights.

    Results Point of Contact

    Name/Title ACTG Clinicaltrials.gov Coordinator
    Organization ACTG Network Coordinating Center, Social and Scientific Systems, a DLH Holdings Company.
    Phone (301) 628-3348
    Email ACTGCT.gov@fstrf.org
    Responsible Party:
    National Institute of Allergy and Infectious Diseases (NIAID)
    ClinicalTrials.gov Identifier:
    NCT02583048
    Other Study ID Numbers:
    • A5343
    • 12005
    First Posted:
    Oct 21, 2015
    Last Update Posted:
    Jan 27, 2022
    Last Verified:
    Jan 1, 2022