TuberculosisPhase 2NCT02583048
Evaluating the Safety, Tolerability, and Pharmacokinetics of Bedaquiline and Delamanid, Alone and in Combination, For Drug-Resistant Pulmonary Tuberculosis
A Phase 2 study testing Bedaquiline, Delamanid and Dolutegravir in people with Tuberculosis and HIV Infections, run by National Institute of Allergy and Infectious Diseases (NIAID) at 3 sites in 2 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Tuberculosis, HIV Infections
- What is being tested?
- Bedaquiline, Delamanid and Dolutegravir
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 84 participants
- Where
- 3 sitesin 2 countries
- Study dates
- 15 Aug 2016to 4 Feb 2021
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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
Who cannot join
- 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
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- 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:
- Serum creatinine greater than 1.4 x upper limit of normal (ULN)
- Lipase greater than 1.6 x ULN
- Alanine aminotransferase (ALT) greater than 2.5 x ULN
- Total bilirubin greater than 1.6 x ULN
- 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:
- 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)
- History or presence of allergy to DTG or its components
- Severe hepatic impairment (Class C) as determined by Child-Pugh classification
- 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
Trial locations and contacts
3 sites in 2 countries.
3 sites in 2 countries
South Africa2 sites
Task Applied Science (TASK) CRS
Cape Town, Western Cape, 7530
South African Tuberculosis Vaccine Initiative (SATVI) CRS
Cape Town, Western Cape, 7705
About this study
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
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.
- Conditions
- Tuberculosis, HIV Infections
- Being tested
- Bedaquiline, Delamanid, Dolutegravir, Multidrug Background Treatment (MBT) for TB
- Medical subject headings
- Tuberculosis, HIV Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BedaquilineDrug
Also called Sirturo
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.
DelamanidDrug
Also called Deltyba
Two 50 mg tablets (100 mg) orally with food twice a day for 24 weeks.
DolutegravirDrug
Also called Tivicay
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.)
Multidrug Background Treatment (MBT) for TBDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Arm 1: Bedaquiline | Experimental | 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. Receives: Drug: Bedaquiline; Drug: Dolutegravir; Drug: Multidrug Background Treatment (MBT) for TB |
| Arm 2: Delamanid | Experimental | 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. Receives: Drug: Delamanid; Drug: Dolutegravir; Drug: Multidrug Background Treatment (MBT) for TB |
| Arm 3: Bedaquiline and Delamanid | Experimental | 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. Receives: Drug: Bedaquiline; Drug: Delamanid; Drug: Dolutegravir; Drug: Multidrug Background Treatment (MBT) for TB |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline and at weeks 8, 10, 12, 14, 16, 18, 20, 22 and 24
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%.
Measured: Baseline and at weeks 8, 10, 12, 14, 16, 18, 20, 22, and 24.
Secondary outcomes (20)
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.
Measured: At weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24
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.
Measured: Baseline and at weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24
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.)
Measured: Baseline and at weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 and 28.
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.
Measured: At weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24
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.
Measured: Baseline and at weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24
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.
Measured: Intensive BDQ PK samples at pre-dose, 5h, 7h, 10h and 22h post-dose at weeks 2, 8 and 24
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.
Measured: Intensive BDQ PK samples at pre-dose, 5h, 7h, 10h and 22h post-dose at weeks 2, 8 and 24
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.
Measured: Intensive BDQ PK samples at pre-dose, 5h, 7h, 10h and 22h post-dose at Weeks 2, 8 and 24
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.
Measured: Intensive BDQ Metabolite PK samples at pre-dose, 5h, 7h, 10h and 22h post-dose at weeks 2, 8 and 24
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.
Measured: Intensive BDQ Metabolite PK samples at pre-dose, 5h, 7h, 10h and 22h post-dose at weeks 2, 8 and 24
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.
Measured: Intensive BDQ PK samples at pre-dose, 5h, 7h, 10h and 22h post-dose at Weeks 2, 8 and 24
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.
Measured: Intensive DLM PK samples at pre-dose, 4h, 8h, and 11h post-dose at weeks 2, 8 and 24
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.
Measured: Intensive DLM PK samples at pre-dose, 4h, 8h, and 11h post-dose at weeks 2, 8 and 24
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.
Measured: Intensive DLM PK samples at pre-dose, 4h, 8h, and 11h post-dose at weeks 2, 8 and 24
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.
Measured: Intensive DLM PK samples at pre-dose, 4h, 8h, and 11h post-dose at weeks 2, 8 and 24
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.
Measured: Intensive DLM PK samples at pre-dose, 4h, 8h, and 11h post-dose at weeks 2, 8 and 24
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.
Measured: Intensive DLM PK samples at pre-dose, 4h, 8h, and 11h post-dose at weeks 2, 8 and 24
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).
Measured: From initiation of study TB treatment (week 0) to week 24
Percentage of Participants Who Discontinued Study TB Drug(s) For Any Reason
Percentage of participants who discontinued study TB drug(s) for any reason
Measured: From initiation of study TB treatment (week 0) to week 24
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.
Measured: From initiation of study TB treatment (week 0) to week 24
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Oct 2015 (estimated)
- Study start15 Aug 2016
- Primary completion7 Jan 2019
- Study completion4 Feb 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for TuberculosisStudies of the same condition, open and under way.
- More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 84 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Kelly Dooley, MD, PhD, Study chair, Johns Hopkins Adult AIDS CRSGary Maartens, MBChB, MMed, Study chair, University of Cape Town
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02583048
- Sponsor's protocol ID
- A5343
- Other IDs
- 12005
- Status last verified
- Jan 2022
- First submitted
- 20 Oct 2015
- Last updated
- 27 Jan 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
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 35668346Dooley 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 at a glance
From the registry record, last updated by the sponsor on 27 Jan 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02583048
- Acronym / sponsor ID
- A5343
- Conditions
- Tuberculosis, HIV Infections
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 84 participants (actual)
- Lead sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)US National Institutes of Health
- Study start
- 15 Aug 2016 (actual)
- Primary completion
- 7 Jan 2019 (actual)
- Study completion
- 4 Feb 2021 (actual)
- First posted
- 21 Oct 2015 (estimated)
- Results
- Posted 29 Jan 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Arm 1: Bedaquiline | Experimental | Drug: Bedaquiline, Drug: Dolutegravir, Drug: Multidrug Background Treatment (MBT) for TBParticipants 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. |
| Arm 2: Delamanid | Experimental | Drug: Delamanid, Drug: Dolutegravir, Drug: Multidrug Background Treatment (MBT) for TBParticipants 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. |
| Arm 3: Bedaquiline and Delamanid | Experimental | Drug: Bedaquiline, Drug: Delamanid, Drug: Dolutegravir, Drug: Multidrug Background Treatment (MBT) for TBParticipants 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (16 listed)
- 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:
- 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.
Key exclusion criteria (29 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BedaquilineAlso: SirturoFour 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. | Drug | Arm 1: Bedaquiline, Arm 3: Bedaquiline and Delamanid |
| DelamanidAlso: DeltybaTwo 50 mg tablets (100 mg) orally with food twice a day for 24 weeks. | Drug | Arm 2: Delamanid, Arm 3: Bedaquiline and Delamanid |
| DolutegravirAlso: TivicayFor 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.) | Drug | Arm 1: Bedaquiline, Arm 2: Delamanid, Arm 3: Bedaquiline and Delamanid |
| Multidrug Background Treatment (MBT) for TBA 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. | Drug | Arm 1: Bedaquiline, Arm 2: Delamanid, Arm 3: Bedaquiline and Delamanid |
Primary outcome
Mean Change From Baseline in QTcF
Time frame: 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.
Post-Baseline QTcF
Time frame: 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%.
20 secondary outcomes
Percentage of Participants With an Occurrence of QTcF Greater Than 500 Milliseconds (ms)
Time frame: At weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24
Percentage of Participants With an Increase in QTcF From Baseline of Greater Than 60 Milliseconds (ms)
Time frame: Baseline and at weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24
Changes in QTcF From Baseline
Time frame: Baseline and at weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 and 28.
Percentage of Participants With an Occurrence of QTcF >480 and ≤500 Milliseconds (ms)
Time frame: At weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24
Percentage of Participants With an Occurrence of QTcF Increase From Baseline of >30 and ≤60 Milliseconds (ms)
Time frame: Baseline and at weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24
BDQ PK Parameter Minimum Plasma Concentration (Cmin) Determined Based on BDQ Levels From Individual Participants Enrolled in Arms 1 and 3
Time frame: Intensive BDQ PK samples at pre-dose, 5h, 7h, 10h and 22h post-dose at weeks 2, 8 and 24
BDQ PK Parameter Maxmum Plasma Concentration (Cmax) Determined Based on BDQ Levels From Individual Participants Enrolled in Arms 1 and 3
Time frame: Intensive BDQ PK samples at pre-dose, 5h, 7h, 10h and 22h post-dose at weeks 2, 8 and 24
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
Time frame: Intensive BDQ PK samples at pre-dose, 5h, 7h, 10h and 22h post-dose at Weeks 2, 8 and 24
N-monodesmethyl Metabolite of BDQ PK Parameter Cmin Determined Based on BDQ Metabolite Levels From Individual Participants Enrolled in Arms 1 and 3
Time frame: Intensive BDQ Metabolite PK samples at pre-dose, 5h, 7h, 10h and 22h post-dose at weeks 2, 8 and 24
N-monodesmethyl Metabolite of BDQ PK Parameter Cmax Determined Based on BDQ Metabolite Levels From Individual Participants Enrolled in Arms 1 and 3
Time frame: Intensive BDQ Metabolite PK samples at pre-dose, 5h, 7h, 10h and 22h post-dose at weeks 2, 8 and 24
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
Time frame: Intensive BDQ PK samples at pre-dose, 5h, 7h, 10h and 22h post-dose at Weeks 2, 8 and 24
DLM PK Parameter Cmin Determined Based on DLM Levels From Individual Participants Enrolled in Arms 2 and 3
Time frame: Intensive DLM PK samples at pre-dose, 4h, 8h, and 11h post-dose at weeks 2, 8 and 24
DLM PK Parameter Cmax Determined Based on DLM Levels From Individual Participants Enrolled in Arms 2 and 3
Time frame: Intensive DLM PK samples at pre-dose, 4h, 8h, and 11h post-dose at weeks 2, 8 and 24
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
Time frame: Intensive DLM PK samples at pre-dose, 4h, 8h, and 11h post-dose at weeks 2, 8 and 24
DLM Metabolite DM6705 PK Parameter Cmin Determined Based on DLM Metabolite Levels From Individual Participants Enrolled in Arms 2 and 3
Time frame: Intensive DLM PK samples at pre-dose, 4h, 8h, and 11h post-dose at weeks 2, 8 and 24
DLM Metabolite DM6705 PK Parameter Cmax Determined Based on DLM Metabolite Levels From Individual Participants Enrolled in Arms 2 and 3
Time frame: Intensive DLM PK samples at pre-dose, 4h, 8h, and 11h post-dose at weeks 2, 8 and 24
DLM Metabolite DM6705 PK AUC 0-11h Determined Based on Intensive PK Samples Obtained From Individual Participants Enrolled in Arms 2 and 3
Time frame: Intensive DLM PK samples at pre-dose, 4h, 8h, and 11h post-dose at weeks 2, 8 and 24
Percentage of Participants With an Occurrence of Grade 3 or Higher Adverse Event
Time frame: From initiation of study TB treatment (week 0) to week 24
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
Percentage of Participants Who Died
Time frame: From initiation of study TB treatment (week 0) to week 24
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Jan 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 35668346Tanneau 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.
- Derived from this study: PubMed 33587897Dooley 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.
- Location of DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0, November 2014Link provided by the sponsor.
- Location of Version 2.0 the DAIDS EAE Manual for Expedited AE ReportingLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Kelly Dooley, MD, PhD study chair
Johns Hopkins Adult AIDS CRS
Gary Maartens, MBChB, MMed study chair
University of Cape Town
3 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Bedaquiline, Delamanid and Dolutegravir in people with Tuberculosis and HIV Infections, run by National Institute of Allergy and Infectious Diseases (NIAID) at 3 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 Jan 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in South Africa, Peru. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 29 Jan 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mean Change From Baseline in QTcF (time frame: Baseline and at weeks 8, 10, 12, 14, 16, 18, 20, 22 and 24). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02583048, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Jan 2022.