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

NCT02583048 | Completed Phase 2 Results DMC

• 2 other identifiers: A534312005
• Study Type: interventional
• Target: 84
• Locations: 2 countries
• Sites: 3

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).

Conditions

Tuberculosis; HIV Infections

Outcome Measures

Primary Outcomes (2)

• 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.

  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%.

  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)

  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)

  Baseline and at weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24

• Changes in QTcF From Baseline

  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)

  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)

  Baseline and at weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24

Study Arms (3)

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.

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.

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.

Drug: Bedaquiline; Drug: Delamanid; Drug: Dolutegravir; Drug: Multidrug Background Treatment (MBT) for TB

Interventions

Bedaquiline 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.

Also known as: Sirturo

Arm 1: Bedaquiline; Arm 3: Bedaquiline and Delamanid

Delamanid DRUG

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

Also known as: Deltyba

Arm 2: Delamanid; Arm 3: Bedaquiline and Delamanid

Dolutegravir 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.)

Also known as: Tivicay

Arm 1: Bedaquiline; Arm 2: Delamanid; Arm 3: Bedaquiline and Delamanid

Multidrug Background Treatment (MBT) for TB 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 1: Bedaquiline; Arm 2: Delamanid; Arm 3: Bedaquiline and Delamanid

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (3)

Barranco CRS

Lima, 15063, Peru

Location

Task Applied Science (TASK) CRS

Cape Town, Western Cape, 7530, South Africa

Location

South African Tuberculosis Vaccine Initiative (SATVI) CRS

Cape Town, Western Cape, 7705, South Africa

Location

Related Publications (2)

• 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.

  PMID: 35668346 DERIVED

• 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.

  PMID: 33587897 DERIVED

Related Links

• Location of DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0, November 2014
• Location of Version 2.0 the DAIDS EAE Manual for Expedited AE Reporting

MeSH Terms

Conditions

Tuberculosis; HIV Infections

Interventions

bedaquiline; OPC-67683; dolutegravir

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Results Point of Contact

• Title: ACTG Clinicaltrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social and Scientific Systems, a DLH Holdings Company.

ACTGCT.gov@fstrf.org

(301) 628-3348

Study Officials

• Kelly Dooley, MD, PhD

  Johns Hopkins Adult AIDS CRS

  STUDY CHAIR

• Gary Maartens, MBChB, MMed

  University of Cape Town

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 20, 2015
• First Posted: October 21, 2015
• Study Start: August 15, 2016
• Primary Completion: January 7, 2019
• Study Completion: February 4, 2021
• Last Updated: January 27, 2022
• Results First Posted: January 29, 2020

Record last verified: 2022-01

Locations

ZA (2); PE (1)