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CompletedNCT02583048Updated Jan 27, 2022Results posted

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

A Phase 2 interventional study of Bedaquiline and Delamanid in Tuberculosis and HIV Infections, sponsored by National Institute of Allergy and Infectious Diseases (NIAID). Completed at 3 sites in 2 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-01-27.

Sponsored by National Institute of Allergy and Infectious Diseases (NIAID) · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
84
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study 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).

Read the 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.

02

Conditions studied

  • Tuberculosis
  • HIV Infections
03

In context

Tuberculosis

1,417 studies on the registry are indexed under Tuberculosis; 208 are open to participants now.

This study's enrollment of 84 is below the median of 150 across 952 interventional studies indexed under Tuberculosis.

Browse Tuberculosis studies →

Lead sponsor

National Institute of Allergy and Infectious Diseases (NIAID) is the lead sponsor of 2,401 studies on the registry; 179 are open to participants now.

Of its 396 completed or terminated interventional studies of FDA-regulated products, 294 (74%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
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

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 28)
  • 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
05

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
84 participants (actual)

Study arms

  • 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 · Drug: Dolutegravir · Drug: Multidrug Background Treatment (MBT) for TB

  • 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 · Drug: Dolutegravir · Drug: Multidrug Background Treatment (MBT) for TB

  • 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 · Drug: Delamanid · Drug: Dolutegravir · Drug: Multidrug Background Treatment (MBT) for TB

Interventions

  • DrugBedaquiline

    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.

    Also known as: Sirturo

  • DrugDelamanid

    Two 50 mg tablets (100 mg) orally with food twice a day for 24 weeks.

    Also known as: Deltyba

  • DrugDolutegravir

    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.)

    Also known as: Tivicay

  • DrugMultidrug 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.

06

What researchers measure

Primary outcomes

  1. Mean Change From Baseline in QTcF

    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

  2. Post-Baseline QTcF

    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.

Secondary outcomes

  1. Percentage of Participants With an Occurrence of QTcF Greater Than 500 Milliseconds (ms)

    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

  2. Percentage of Participants With an Increase in QTcF From Baseline of Greater Than 60 Milliseconds (ms)

    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

  3. Changes in QTcF From Baseline

    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.

  4. Percentage of Participants With an Occurrence of QTcF >480 and ≤500 Milliseconds (ms)

    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

  5. Percentage of Participants With an Occurrence of QTcF Increase From Baseline of >30 and ≤60 Milliseconds (ms)

    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

  6. BDQ PK Parameter Minimum Plasma Concentration (Cmin) Determined Based on BDQ Levels From Individual Participants Enrolled in Arms 1 and 3

    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

  7. BDQ PK Parameter Maxmum Plasma Concentration (Cmax) Determined Based on BDQ Levels From Individual Participants Enrolled in Arms 1 and 3

    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

  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

    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

  9. N-monodesmethyl Metabolite of BDQ PK Parameter Cmin Determined Based on BDQ Metabolite Levels From Individual Participants Enrolled in Arms 1 and 3

    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

  10. N-monodesmethyl Metabolite of BDQ PK Parameter Cmax Determined Based on BDQ Metabolite Levels From Individual Participants Enrolled in Arms 1 and 3

    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

  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

    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

  12. DLM PK Parameter Cmin Determined Based on DLM Levels From Individual Participants Enrolled in Arms 2 and 3

    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

  13. DLM PK Parameter Cmax Determined Based on DLM Levels From Individual Participants Enrolled in Arms 2 and 3

    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

  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

    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

  15. DLM Metabolite DM6705 PK Parameter Cmin Determined Based on DLM Metabolite Levels From Individual Participants Enrolled in Arms 2 and 3

    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

  16. DLM Metabolite DM6705 PK Parameter Cmax Determined Based on DLM Metabolite Levels From Individual Participants Enrolled in Arms 2 and 3

    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

  17. DLM Metabolite DM6705 PK AUC 0-11h Determined Based on Intensive PK Samples Obtained From Individual Participants Enrolled in Arms 2 and 3

    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

  18. Percentage of Participants With an Occurrence of Grade 3 or Higher Adverse Event

    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

  19. Percentage of Participants Who Discontinued Study TB Drug(s) For Any Reason

    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

  20. Percentage of Participants Who Died

    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

07

Results

Posted Jan 29, 2020

Participant flow

Participants were enrolled from August 2016 to July 2018 at 3 non-US clinical research sites.

Participant flow — Overall Study
MilestoneArm 1: BedaquilineArm 2: DelamanidArm 3: Bedaquiline and Delamanid
Started282828
Completed282727
Not completed011
Withdrew: Withdrawal by subject010
Withdrew: Failed to meet eligibility criterion001

Outcome measures

PrimaryMean Change From Baseline in QTcF

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
Reported as:
Mean · milliseconds (ms)
Mean Change From Baseline in QTcF
milliseconds (ms)Arm 1: BedaquilineArm 2: DelamanidArm 3: Bedaquiline and Delamanid
Mean Change From Baseline in QTcF12.3 (7.8 to 16.7)8.6 (4.0 to 13.1)20.7 (16.1 to 25.3)
Statistical analysis
  • Arm 1: Bedaquiline vs Arm 3: Bedaquiline and Delamanid · Mean difference (net): 8.4 · 95.1% CI 2.0 to 14.8Arm 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%.
  • Arm 2: Delamanid vs Arm 3: Bedaquiline and Delamanid · Mean difference (net): 12.1 · 95.1% CI 5.7 to 18.6Arm 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%.
PrimaryPost-Baseline QTcF

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.
Reported as:
Least squares mean · milliseconds (ms)
Post-Baseline QTcF
milliseconds (ms)Arm 1: BedaquilineArm 2: DelamanidArm 3: Bedaquiline and Delamanid
Baseline397.4 (389.3 to 405.6)404.9 (396.6 to 413.2)391.7 (383.2 to 400.2)
Post-baseline409.7 (402.5 to 416.8)413.4 (406.1 to 420.8)412.4 (405.0 to 419.9)
SecondaryPercentage of Participants With an Occurrence of QTcF Greater Than 500 Milliseconds (ms)

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
Reported as:
Number · Percentage of participants
Percentage of Participants With an Occurrence of QTcF Greater Than 500 Milliseconds (ms)
Percentage of participantsArm 1: BedaquilineArm 2: DelamanidArm 3: Bedaquiline and Delamanid
Percentage of Participants With an Occurrence of QTcF Greater Than 500 Milliseconds (ms)0 (0 to 12)0 (0 to 13)0 (0 to 13)
SecondaryPercentage of Participants With an Increase in QTcF From Baseline of Greater Than 60 Milliseconds (ms)

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
Reported as:
Number · Percentage of participants
Percentage of Participants With an Increase in QTcF From Baseline of Greater Than 60 Milliseconds (ms)
Percentage of participantsArm 1: BedaquilineArm 2: DelamanidArm 3: Bedaquiline and Delamanid
Percentage of Participants With an Increase in QTcF From Baseline of Greater Than 60 Milliseconds (ms)4 (0 to 18)0 (0 to 13)7 (1 to 24)
SecondaryChanges in QTcF From Baseline

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.
Reported as:
Median · milliseconds (ms)
Changes in QTcF From Baseline
milliseconds (ms)Arm 1: BedaquilineArm 2: DelamanidArm 3: Bedaquiline and Delamanid
Change from baseline to Week 216.70 (-25.70 to 57.00)4.15 (-25.70 to 24.30)13.15 (-6.70 to 55.70)
Change from baseline to Week 415.00 (-21.00 to 40.70)8.70 (-15.70 to 24.70)14.30 (-8.70 to 50.30)
Change from baseline to Week 615.30 (-25.30 to 40.00)9.30 (-19.00 to 37.70)15.30 (-11.00 to 33.70)
Change from baseline to Week 812.00 (-40.30 to 47.30)7.00 (-30.30 to 39.00)20.30 (-14.00 to 47.30)
Change from baseline to Week 1010.30 (-30.30 to 51.00)7.80 (-25.30 to 37.70)18.30 (-15.00 to 58.30)
Change from baseline to Week 129.30 (-11.70 to 46.30)10.30 (-21.00 to 38.70)20.30 (-20.30 to 50.30)
Change from baseline to Week 1412.70 (-16.00 to 53.00)5.30 (-18.00 to 49.00)21.30 (-19.00 to 51.00)
Change from baseline to Week 1615.35 (-34.30 to 55.30)7.35 (-46.00 to 38.70)21.00 (-22.70 to 62.70)
Change from baseline to Week 1817.65 (-17.30 to 72.30)11.70 (-28.30 to 39.30)12.70 (-26.70 to 66.30)
Change from baseline to Week 209.30 (-24.30 to 46.70)13.65 (-21.30 to 29.30)21.00 (-18.30 to 70.00)
Change from baseline to Week 2212.00 (-16.00 to 56.70)9.00 (-15.70 to 34.30)20.85 (-19.30 to 75.00)
Change from baseline to Week 2411.70 (-26.00 to 46.00)13.00 (-19.30 to 40.30)24.00 (-19.00 to 46.30)
Change from baseline to Week 2813.30 (-20.30 to 43.00)6.00 (-25.30 to 38.30)17.65 (-16.00 to 55.70)
SecondaryPercentage of Participants With an Occurrence of QTcF >480 and ≤500 Milliseconds (ms)

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
Reported as:
Number · Percentage of participants
Percentage of Participants With an Occurrence of QTcF >480 and ≤500 Milliseconds (ms)
Percentage of participantsArm 1: BedaquilineArm 2: DelamanidArm 3: Bedaquiline and Delamanid
Percentage of Participants With an Occurrence of QTcF >480 and ≤500 Milliseconds (ms)0 (0 to 12)0 (0 to 13)0 (0 to 13)
SecondaryPercentage of Participants With an Occurrence of QTcF Increase From Baseline of >30 and ≤60 Milliseconds (ms)

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
Reported as:
Number · Percentage of participants
Percentage of Participants With an Occurrence of QTcF Increase From Baseline of >30 and ≤60 Milliseconds (ms)
Percentage of participantsArm 1: BedaquilineArm 2: DelamanidArm 3: Bedaquiline and Delamanid
Percentage of Participants With an Occurrence of QTcF Increase From Baseline of >30 and ≤60 Milliseconds (ms)32 (16 to 52)41 (22 to 61)37 (19 to 58)
SecondaryBDQ PK Parameter Minimum Plasma Concentration (Cmin) Determined Based on BDQ Levels From Individual Participants Enrolled in Arms 1 and 3

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
Reported as:
Mean · ng/mL
BDQ PK Parameter Minimum Plasma Concentration (Cmin) Determined Based on BDQ Levels From Individual Participants Enrolled in Arms 1 and 3
ng/mLArm 1: BedaquilineArm 3: Bedaquiline and Delamanid
Week 2796.8 ± 406.1850.9 ± 343.8
Week 8505.9 ± 218.6601.9 ± 212.6
Week 24653.4 ± 271.3629.4 ± 247.0
Statistical analysis
  • Arm 1: Bedaquiline vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 1.117 · 90% CI 0.884 to 1.411The numerator represents Arm 3 and the denominator represents Arm 1.
  • Arm 1: Bedaquiline vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 1.202 · 90% CI 0.989 to 1.461The numerator represents Arm 3 and the denominator represents Arm 1.
  • Arm 1: Bedaquiline vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 0.958 · 90% CI 0.774 to 1.187The numerator represents Arm 3 and the denominator represents Arm 1.
SecondaryBDQ PK Parameter Maxmum Plasma Concentration (Cmax) Determined Based on BDQ Levels From Individual Participants Enrolled in Arms 1 and 3

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
Reported as:
Mean · ng/mL
BDQ PK Parameter Maxmum Plasma Concentration (Cmax) Determined Based on BDQ Levels From Individual Participants Enrolled in Arms 1 and 3
ng/mLArm 1: BedaquilineArm 3: Bedaquiline and Delamanid
Week 22434.3 ± 1148.42405.2 ± 1128.2
Week 81455.6 ± 670.61477.2 ± 704.7
Week 241507.3 ± 495.81368.2 ± 518.6
Statistical analysis
  • Arm 1: Bedaquiline vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 0.986 · 90% CI 0.801 to 1.215The numerator represents Arm 3 and the denominator represents Arm 1.
  • Arm 1: Bedaquiline vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 0.978 · 90% CI 0.764 to 1.251The numerator represents Arm 3 and the denominator represents Arm 1.
  • Arm 1: Bedaquiline vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 0.859 · 90% CI 0.667 to 1.108The numerator represents Arm 3 and the denominator represents Arm 1.
SecondaryBDQ 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

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
Reported as:
Mean · ng*h/mL
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
ng*h/mLArm 1: BedaquilineArm 3: Bedaquiline and Delamanid
Week 231570.9 ± 14612.832399.4 ± 13625.2
Week 819234.6 ± 7785.720176.1 ± 8175.5
Week 2421048.5 ± 8329.719522.6 ± 7545.7
Statistical analysis
  • Arm 1: Bedaquiline vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 1.036 · 90% CI 0.847 to 1.267The numerator represents Arm 3 and the denominator represents Arm 1.
  • Arm 1: Bedaquiline vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 1.037 · 90% CI 0.843 to 1.276The numerator represents Arm 3 and the denominator represents Arm 1.
  • Arm 1: Bedaquiline vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 0.915 · 90% CI 0.727 to 1.151The numerator represents Arm 3 and the denominator represents Arm 1.
SecondaryN-monodesmethyl Metabolite of BDQ PK Parameter Cmin Determined Based on BDQ Metabolite Levels From Individual Participants Enrolled in Arms 1 and 3

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
Reported as:
Mean · ng/mL
N-monodesmethyl Metabolite of BDQ PK Parameter Cmin Determined Based on BDQ Metabolite Levels From Individual Participants Enrolled in Arms 1 and 3
ng/mLArm 1: BedaquilineArm 3: Bedaquiline and Delamanid
Week 2353.3 ± 137.8361.6 ± 122.8
Week 8200.0 ± 81.1204.7 ± 76.3
Week 24204.0 ± 62.8174.0 ± 82.1
Statistical analysis
  • Arm 1: Bedaquiline vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 1.043 · 90% CI 0.864 to 1.258The numerator represents Arm 3 and the denominator represents Arm 1.
  • Arm 1: Bedaquiline vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 1.029 · 90% CI 0.858 to 1.235The numerator represents Arm 3 and the denominator represents Arm 1.
  • Arm 1: Bedaquiline vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 0.808 · 90% CI 0.657 to 0.993The numerator represents Arm 3 and the denominator represents Arm 1.
SecondaryN-monodesmethyl Metabolite of BDQ PK Parameter Cmax Determined Based on BDQ Metabolite Levels From Individual Participants Enrolled in Arms 1 and 3

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
Reported as:
Mean · ng/mL
N-monodesmethyl Metabolite of BDQ PK Parameter Cmax Determined Based on BDQ Metabolite Levels From Individual Participants Enrolled in Arms 1 and 3
ng/mLArm 1: BedaquilineArm 3: Bedaquiline and Delamanid
Week 2404.8 ± 143.7429.8 ± 139.8
Week 8248.5 ± 95.4241.5 ± 87.2
Week 24232.9 ± 68.6196.8 ± 92.5
Statistical analysis
  • Arm 1: Bedaquiline vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 1.068 · 90% CI 0.903 to 1.263The numerator represents Arm 3 and the denominator represents Arm 1.
  • Arm 1: Bedaquiline vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 0.973 · 90% CI 0.820 to 1.155The numerator represents Arm 3 and the denominator represents Arm 1.
  • Arm 1: Bedaquiline vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 0.803 · 90% CI 0.656 to 0.983The numerator represents Arm 3 and the denominator represents Arm 1.
SecondaryN-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

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
Reported as:
Mean · ng*h/mL
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
ng*h/mLArm 1: BedaquilineArm 3: Bedaquiline and Delamanid
Week 28435.5 ± 3220.18713.4 ± 2858.9
Week 85067.5 ± 2017.64963.4 ± 1847.6
Week 244771.4 ± 1577.94033.5 ± 1978.7
Statistical analysis
  • Arm 1: Bedaquiline vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 1.049 · 90% CI 0.881 to 1.248The numerator represents Arm 3 and the denominator represents Arm 1.
  • Arm 1: Bedaquiline vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 0.979 · 90% CI 0.823 to 1.165The numerator represents Arm 3 and the denominator represents Arm 1.
  • Arm 1: Bedaquiline vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 0.808 · 90% CI 0.638 to 1.025The numerator represents Arm 3 and the denominator represents Arm 1.
SecondaryDLM PK Parameter Cmin Determined Based on DLM Levels From Individual Participants Enrolled in Arms 2 and 3

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
Reported as:
Mean · ng/mL
DLM PK Parameter Cmin Determined Based on DLM Levels From Individual Participants Enrolled in Arms 2 and 3
ng/mLArm 2: DelamanidArm 3: Bedaquiline and Delamanid
Week 2224.8 ± 59.0206.8 ± 64.8
Week 8198.2 ± 64.3217.2 ± 64.6
Week 24220.9 ± 78.9182.2 ± 78.5
Statistical analysis
  • Arm 2: Delamanid vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 0.903 · 90% CI 0.778 to 1.049The numerator represents Arm 3 and the denominator represents Arm 2.
  • Arm 2: Delamanid vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 1.114 · 90% CI 0.944 to 1.315The numerator represents Arm 3 and the denominator represents Arm 2.
  • Arm 2: Delamanid vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 0.804 · 90% CI 0.639 to 1.012The numerator represents Arm 3 and the denominator represents Arm 2.
SecondaryDLM PK Parameter Cmax Determined Based on DLM Levels From Individual Participants Enrolled in Arms 2 and 3

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
Reported as:
Mean · ng/mL
DLM PK Parameter Cmax Determined Based on DLM Levels From Individual Participants Enrolled in Arms 2 and 3
ng/mLArm 2: DelamanidArm 3: Bedaquiline and Delamanid
Week 2317.8 ± 88.7298.3 ± 84.2
Week 8294.1 ± 100.0320.9 ± 98.4
Week 24290.3 ± 81.6259.0 ± 102.8
Statistical analysis
  • Arm 2: Delamanid vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 0.937 · 90% CI 0.810 to 1.084The numerator represents Arm 3 and the denominator represents Arm 2.
  • Arm 2: Delamanid vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 1.107 · 90% CI 0.929 to 1.318The numerator represents Arm 3 and the denominator represents Arm 2.
  • Arm 2: Delamanid vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 0.856 · 90% CI 0.703 to 1.043The numerator represents Arm 3 and the denominator represents Arm 2.
SecondaryDLM 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

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
Reported as:
Mean · ng*h/mL
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
ng*h/mLArm 2: DelamanidArm 3: Bedaquiline and Delamanid
Week 22789.6 ± 761.92654.9 ± 724.3
Week 82547.6 ± 838.42823.2 ± 792.7
Week 242473.0 ± 778.22324.9 ± 987.3
Statistical analysis
  • Arm 2: Delamanid vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 0.951 · 90% CI 0.825 to 1.096The numerator represents Arm 3 and the denominator represents Arm 2.
  • Arm 2: Delamanid vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 1.136 · 90% CI 0.948 to 1.362The numerator represents Arm 3 and the denominator represents Arm 2.
  • Arm 2: Delamanid vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 0.898 · 90% CI 0.727 to 1.109The numerator represents Arm 3 and the denominator represents Arm 2.
SecondaryDLM Metabolite DM6705 PK Parameter Cmin Determined Based on DLM Metabolite Levels From Individual Participants Enrolled in Arms 2 and 3

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
Reported as:
Mean · ng/mL
DLM Metabolite DM6705 PK Parameter Cmin Determined Based on DLM Metabolite Levels From Individual Participants Enrolled in Arms 2 and 3
ng/mLArm 2: DelamanidArm 3: Bedaquiline and Delamanid
Week 261.9 ± 19.358.5 ± 17.0
Week 890.6 ± 38.294.4 ± 37.8
Week 2475.7 ± 41.671.0 ± 46.6
Statistical analysis
  • Arm 2: Delamanid vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 0.939 · 90% CI 0.806 to 1.094The numerator represents Arm 3 and the denominator represents Arm 2.
  • Arm 2: Delamanid vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 1.081 · 90% CI 0.864 to 1.352The numerator represents Arm 3 and the denominator represents Arm 2.
  • Arm 2: Delamanid vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 0.865 · 90% CI 0.597 to 1.253The numerator represents Arm 3 and the denominator represents Arm 2.
SecondaryDLM Metabolite DM6705 PK Parameter Cmax Determined Based on DLM Metabolite Levels From Individual Participants Enrolled in Arms 2 and 3

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
Reported as:
Mean · ng/mL
DLM Metabolite DM6705 PK Parameter Cmax Determined Based on DLM Metabolite Levels From Individual Participants Enrolled in Arms 2 and 3
ng/mLArm 2: DelamanidArm 3: Bedaquiline and Delamanid
Week 266.6 ± 18.164.3 ± 19.8
Week 899.7 ± 41.0105.4 ± 46.2
Week 2482.1 ± 46.175.6 ± 47.9
Statistical analysis
  • Arm 2: Delamanid vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 0.950 · 90% CI 0.825 to 1.095The numerator represents Arm 3 and the denominator represents Arm 2.
  • Arm 2: Delamanid vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 1.080 · 90% CI 0.862 to 1.354The numerator represents Arm 3 and the denominator represents Arm 2.
  • Arm 2: Delamanid vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 0.865 · 90% CI 0.605 to 1.239The numerator represents Arm 3 and the denominator represents Arm 2.
SecondaryDLM Metabolite DM6705 PK AUC 0-11h Determined Based on Intensive PK Samples Obtained From Individual Participants Enrolled in Arms 2 and 3

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
Reported as:
Mean · ng*h/mL
DLM Metabolite DM6705 PK AUC 0-11h Determined Based on Intensive PK Samples Obtained From Individual Participants Enrolled in Arms 2 and 3
ng*h/mLArm 2: DelamanidArm 3: Bedaquiline and Delamanid
Week 2628.0 ± 188.1621.2 ± 178.3
Week 8953.9 ± 395.2990.9 ± 378.1
Week 24749.9 ± 420.4742.5 ± 479.5
Statistical analysis
  • Arm 2: Delamanid vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 0.984 · 90% CI 0.851 to 1.138The numerator represents Arm 3 and the denominator represents Arm 2.
  • Arm 2: Delamanid vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 1.086 · 90% CI 0.866 to 1.361The numerator represents Arm 3 and the denominator represents Arm 2.
  • Arm 2: Delamanid vs Arm 3: Bedaquiline and Delamanid · Geometric mean ratio: 0.927 · 90% CI 0.650 to 1.322The numerator represents Arm 3 and the denominator represents Arm 2.
SecondaryPercentage of Participants With an Occurrence of Grade 3 or Higher Adverse Event

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
Reported as:
Number · Percentage of participants
Percentage of Participants With an Occurrence of Grade 3 or Higher Adverse Event
Percentage of participantsArm 1: BedaquilineArm 2: DelamanidArm 3: Bedaquiline and Delamanid
Grade 3 adverse event36 (19 to 56)11 (2 to 29)19 (6 to 38)
Grade 4 adverse event4 (0 to 18)11 (2 to 29)19 (6 to 38)
SecondaryPercentage of Participants Who Discontinued Study TB Drug(s) For Any Reason

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
Reported as:
Number · Percentage of participants
Percentage of Participants Who Discontinued Study TB Drug(s) For Any Reason
Percentage of participantsArm 1: BedaquilineArm 2: DelamanidArm 3: Bedaquiline and Delamanid
Percentage of Participants Who Discontinued Study TB Drug(s) For Any Reason11 (2 to 28)19 (6 to 38)22 (9 to 42)
SecondaryPercentage of Participants Who Died

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
Reported as:
Number · Percentage of participants
Percentage of Participants Who Died
Percentage of participantsArm 1: BedaquilineArm 2: DelamanidArm 3: Bedaquiline and Delamanid
Percentage of Participants Who Died0 (0 to 12)0 (0 to 13)0 (0 to 13)

Adverse events

Collected over From start of study treatment to study completion at Week 128 or premature study discontinuation.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Arm 1: Bedaquiline0/28 (0%)2/28 (7.1%)21/28 (75%)
Arm 2: Delamanid1/27 (3.7%)3/27 (11.1%)16/27 (59.3%)
Arm 3: Bedaquiline and Delamanid0/27 (0%)8/27 (29.6%)21/27 (77.8%)
Most frequent serious events
Showing 10 of 13
Most frequent serious events
EventArm 1: BedaquilineArm 2: DelamanidArm 3: Bedaquiline and Delamanid
Blood creatine phosphokinase increasedInvestigations0/281/274/27
PancreatitisGastrointestinal disorders0/281/270/27
Drug-induced liver injuryHepatobiliary disorders0/280/271/27
HypersensitivityImmune system disorders0/280/271/27
Stab woundInjury, poisoning and procedural complications0/280/271/27
Focal dyscognitive seizuresNervous system disorders0/280/271/27
Generalised tonic-clonic seizureNervous system disorders0/280/271/27
SeizureNervous system disorders0/280/271/27
Major depressionPsychiatric disorders0/281/270/27
Substance-induced psychotic disorderPsychiatric disorders0/280/271/27
Most frequent other events
Showing 10 of 46
Most frequent other events
EventArm 1: BedaquilineArm 2: DelamanidArm 3: Bedaquiline and Delamanid
AcneSkin and subcutaneous tissue disorders8/286/278/27
Deafness neurosensoryEar and labyrinth disorders8/284/274/27
DeafnessEar and labyrinth disorders3/282/276/27
Oral candidiasisInfections and infestations0/286/271/27
Neuropathy peripheralNervous system disorders6/282/273/27
PharyngitisInfections and infestations3/285/272/27
PruritusSkin and subcutaneous tissue disorders3/282/274/27
Pain in extremityMusculoskeletal and connective tissue disorders4/280/271/27
ParaesthesiaNervous system disorders4/281/272/27
RhinorrhoeaRespiratory, thoracic and mediastinal disorders4/282/271/27

Baseline characteristics

All randomized participants.

Age, Continuous
Age, Continuous(years)Arm 1: BedaquilineArm 2: DelamanidArm 3: Bedaquiline and DelamanidTotal
Median34.5 (20 to 58)32 (18 to 73)34 (18 to 55)34 (18 to 73)
Sex: Female, Male
Sex: Female, Male(Participants)Arm 1: BedaquilineArm 2: DelamanidArm 3: Bedaquiline and DelamanidTotal
Female67821
Male22212063
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)Arm 1: BedaquilineArm 2: DelamanidArm 3: Bedaquiline and DelamanidTotal
White0101
Black African16111138
Mestizo1236
Coloured11131438
Other0101
Region of Enrollment
Region of Enrollment(Participants)Arm 1: BedaquilineArm 2: DelamanidArm 3: Bedaquiline and DelamanidTotal
South Africa27262578
Peru1236
Baseline QTcF
Baseline QTcF(milliseconds)Arm 1: BedaquilineArm 2: DelamanidArm 3: Bedaquiline and DelamanidTotal
Median394.3 (360.7 to 461.0)406.2 (364.3 to 445.0)387.3 (368.3 to 422.3)395.5 (360.7 to 461.0)
HIV-1 Positive
HIV-1 Positive(Participants)Arm 1: BedaquilineArm 2: DelamanidArm 3: Bedaquiline and DelamanidTotal
Count of participants10111031
08

Study locations

3 sites
  • Barranco CRS
    Lima, 15063, Peru
  • Task Applied Science (TASK) CRS
    Cape Town, Western Cape Province 7530, South Africa
  • South African Tuberculosis Vaccine Initiative (SATVI) CRS
    Cape Town, Western Cape Province 7705, South Africa
09

References and documents

Publications

  • Tanneau L, Karlsson MO, Diacon AH, Shenje J, De Los Rios J, Wiesner L, Upton CM, Dooley KE, Maartens G, Svensson EM. Population Pharmacokinetics of Delamanid and its Main Metabolite DM-6705 in Drug-Resistant Tuberculosis Patients Receiving Delamanid Alone or Coadministered with Bedaquiline. Clin Pharmacokinet. 2022 Aug;61(8):1177-1185. doi: 10.1007/s40262-022-01133-2. Epub 2022 Jun 7. PubMed 35668346 ↗
  • Dooley KE, Rosenkranz SL, Conradie F, Moran L, Hafner R, von Groote-Bidlingmaier F, Lama JR, Shenje J, De Los Rios J, Comins K, Morganroth J, Diacon AH, Cramer YS, Donahue K, Maartens G; AIDS Clinical Trials Group (ACTG) A5343 DELIBERATE Study Team. QT effects of bedaquiline, delamanid, or both in patients with rifampicin-resistant tuberculosis: a phase 2, open-label, randomised, controlled trial. Lancet Infect Dis. 2021 Jul;21(7):975-983. doi: 10.1016/S1473-3099(20)30770-2. Epub 2021 Feb 12. PubMed 33587897 ↗

Study documents

  • Study protocol · Jun 26, 2018
  • Statistical analysis plan · Jul 11, 2018

Documents are hosted by the registry — open the source record to download them.

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Jan 27, 2022, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT02583048
Lead sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Responsible party
Sponsor
First posted
Oct 21, 2015
Start date
Aug 15, 2016
Primary completion
Jan 7, 2019
Completion
Feb 4, 2021
Results posted
Jan 29, 2020
Last update
Jan 27, 2022

Study contacts

Kelly Dooley, MD, PhD
study chair · Johns Hopkins Adult AIDS CRS
Gary Maartens, MBChB, MMed
study chair · University of Cape Town

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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