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

NCT ID: NCT02583048

Last Updated: 2022-01-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 84 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-08-15
• Study Completion Date: 2021-02-04

Brief Summary

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

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Bedaquiline

Intervention Type: DRUG

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.

Dolutegravir

Intervention Type: DRUG

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 TB

Intervention Type: DRUG

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.

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.

Group Type: EXPERIMENTAL

Delamanid

Intervention Type: DRUG

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

Dolutegravir

Intervention Type: DRUG

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 TB

Intervention Type: DRUG

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.

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.

Group Type: EXPERIMENTAL

Bedaquiline

Intervention Type: DRUG

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.

Delamanid

Intervention Type: DRUG

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

Dolutegravir

Intervention Type: DRUG

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 TB

Intervention Type: DRUG

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.

Interventions

Bedaquiline

Four 100 mg tablets (400 mg) orally once a day for 2 weeks, followed by two 100 mg tablets (200 mg) orally three times a week for 22 weeks.

Intervention Type: DRUG

Delamanid

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

Intervention Type: DRUG

Dolutegravir

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

Intervention Type: DRUG

Multidrug Background Treatment (MBT) for TB

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

Intervention Type: DRUG

Other Intervention Names

Sirturo; Deltyba; Tivicay

Eligibility Criteria

Inclusion Criteria

• Documented pulmonary infection due to strains of MTB with (a) resistance to isoniazid (INH) and rifampin (RIF) (MDR-TB) or (b) resistance to RIF but not INH (RR-TB) from a sputum sample collected within 60 days prior to entry.
• Laboratory confirmation of infection with an MTB strain that is susceptible to fluoroquinolones and aminoglycosides within 60 days prior to entry.
• HIV-1 infection status documented as either absent or present, as defined below:

• Absence of HIV-1 infection, within 60 days prior to entry. OR
• HIV-1 infection
• For HIV-positive participants only: CD4+ count greater than or equal to 100 cells/mm^3 within 60 days prior to entry.
• For HIV-positive participants only: For participants on ART for greater than or equal to 6 months and have an HIV-1 viral load greater than 500 copies/mL within 60 days prior to entry, a HIV-1 genotype within 60 days prior to entry must have shown that at least one fully active NRTI was available to the participant within the country program.
• For females of reproductive potential, a negative serum pregnancy test within 48 hours prior to entry
• All participants of reproductive potential who are participating in sexual activity that could lead to pregnancy must have agreed to use one method of birth control while receiving TB study medications and for 6 months after stopping TB study medications.
• Participants who were not of reproductive potential were eligible without requiring the use of contraceptives.
• For HIV-positive female participants of reproductive potential, the use of contraceptives was required for the full duration of time the participant was taking dolutegravir (ie, through study completion at week 128).
• Chest x-ray performed within 60 days prior to entry to classify participant as having cavitary or non-cavitary disease
• Documentation of Karnofsky performance score greater than or equal to 50 within 14 days prior to study entry
• Ability and willingness of participant or legally authorized representative to provide informed consent
• Willingness to be hospitalized for the required inpatient component of the study
• Taking MBT for a minimum of 7 days within the 10 days prior to entry

Exclusion Criteria

• History of clinically relevant, currently active or underlying gastrointestinal, hepatic, cardiovascular, nervous system, psychiatric, metabolic (e.g., untreated hypothyroidism), renal, respiratory (other than due to TB), inflammatory, neoplastic, skin, immunological or infectious disease, which is not stable and controlled, that in the opinion of the investigator would preclude safe participation in the trial
• Current clinically relevant extrapulmonary TB, in the opinion of the site investigator, including but not limited to central nervous system (CNS) TB or TB osteoarthritis
• Previous treatment for MDR- or RR-TB, other than for the qualifying episode, at any time in the past
• Receipt of BDQ or DLM at any time in the past
• Breastfeeding
• QTcF interval greater than 450 ms within 72 hours prior to entry
• Clinically significant ECG abnormality in the opinion of the site investigator within 60 days prior to entry, including but not limited to second or third degree atrioventricular (AV) block, prolongation of the QRS complex over 120 ms (in both male and female participants), or clinically important arrhythmia
• Current clinically relevant cardiovascular disorder in the opinion of the site investigator, including but not limited to heart failure, coronary heart disease, arrhythmia, or tachyarrhythmia
• Known family history of Long QT Syndrome in a first-degree relative (i.e., parent, offspring, or sibling)
• Requirement or expected requirement for protease inhibitors (PIs), efavirenz (EFV), or any other medication that is a moderate to strong inhibitor or inducer of CYP3A and CYP3A4 over the 24 weeks of study treatment. NOTE: Participants taking a PI or EFV can be switched to a treatment that is allowed in the study, but the PI must be stopped at least 2 days prior to starting study MDR- or RR-TB drugs and EFV must be stopped at least 7 days prior to starting study MDR- or RR-TB drugs.
• Requirement or expected requirement for a medication that significantly prolongs QTc, including but not limited to moxifloxacin (levofloxacin is acceptable), from 72 hours prior to study entry through 4 weeks after discontinuation of study treatment (week 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Kelly Dooley, MD, PhD

Role: STUDY_CHAIR

Johns Hopkins Adult AIDS CRS

Gary Maartens, MBChB, MMed

Role: STUDY_CHAIR

University of Cape Town

Locations

Barranco CRS

Lima, , Peru

Task Applied Science (TASK) CRS

Cape Town, Western Cape, South Africa

South African Tuberculosis Vaccine Initiative (SATVI) CRS

Cape Town, Western Cape, South Africa

Countries

Peru; South Africa

References

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.

Reference Type: DERIVED

PMID: 35668346 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33587897 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-tables

Location of DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0, November 2014

http://rsc.tech-res.com/clinical-research-sites/safety-reporting/manual

Location of Version 2.0 the DAIDS EAE Manual for Expedited AE Reporting

Other Identifiers

12005

Identifier Type: REGISTRY

Identifier Source: secondary_id

A5343

Identifier Type: -

Identifier Source: org_study_id