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

This study is currently recruiting participants.
Verified December 2017 by National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor:
ClinicalTrials.gov Identifier:
NCT02583048
First Posted: October 21, 2015
Last Update Posted: December 7, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
  Purpose
This study will evaluate the safety, tolerability, and pharmacokinetics of the anti-tuberculosis (TB) drugs bedaquiline (BDQ) and delamanid (DLM), alone and in combination, among participants (with or without HIV co-infection) taking multidrug treatment for multidrug-resistant tuberculosis (MDR-TB) or rifampin-monoresistant TB (RR-TB).

Condition Intervention Phase
Tuberculosis HIV Infections Drug: Bedaquiline Drug: Delamanid Drug: Dolutegravir Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Trial of the Safety, Tolerability, and Pharmacokinetics of Bedaquiline and Delamanid, Alone and in Combination, Among Participants Taking Multidrug Treatment for Drug-Resistant Pulmonary Tuberculosis

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Arm-specific mean change from baseline in QTcF [ Time Frame: Weeks 0, 8, 10, 12, 14, 16, 18, 20, 22 and 24 ]
  • Differences in arm-specific mean change from baseline in QTcF, Arm 3 minus Arm 1, and Arm 3 minus Arm 2 [ Time Frame: Weeks 0, 8, 10, 12, 14, 16, 18, 20, 22 and 24 ]

Secondary Outcome Measures:
  • Arm-specific proportions of participants exhibiting QTcF above 500 ms at any time during study treatment [ Time Frame: Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24 ]
  • Arm-specific proportions of participants exhibiting QTcF increase from baseline of more than 60 ms at any time during study treatment [ Time Frame: Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24 ]
  • Arm- and visit-specific QTcF changes from baseline during study treatment, and at week 28 [ Time Frame: Weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 and 28 ]
  • Arm-specific proportions of participants exhibiting each of the following, at any time during study treatment: (a) absolute QTcF >480 and ≤500 ms and (b) QTcF increase from baseline of >30 and ≤60 ms [ Time Frame: Weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 and 28 ]
  • In Arms 1 and 3, arm- and visit-specific means of PK parameters for BDQ and its metabolite, estimated using noncompartmental methods applied to concentrations from intensive PK sampling, and visit-specific geometric mean ratios (Arm 3 relative to Arm 1) [ Time Frame: Weeks 2, 8 and 24 ]
  • In Arms 2 and 3, arm- and visit-specific means of PK parameters for DLM and its metabolite, estimated using noncompartmental methods applied to concentrations from intensive PK sampling, and visit-specific geometric mean ratios (Arm 3 relative to Arm 2) [ Time Frame: Weeks 2, 8 and 24 ]
  • Arm-specific proportions of participants exhibiting: (1) grade 3 or higher adverse events of any type at any time while on study TB drug (safety); (2) discontinuation of study TB drug(s) for any reason (tolerability); (3) death [ Time Frame: Weeks 0-24 ]

Estimated Enrollment: 84
Study Start Date: August 2016
Estimated Study Completion Date: July 2020
Estimated Primary Completion Date: July 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1: Bedaquiline
Participants will receive 400 mg of bedaquiline once a day for 2 weeks followed by 200 mg of bedaquiline three times a week for 22 weeks.
Drug: Bedaquiline
Bedaquiline will be administered as four 100 mg tablets (400 mg) by mouth once a day for 2 weeks, followed by two 100 mg tablets (200 mg) by mouth three times a week for 22 weeks, for all study arms involving the use of this drug.
Drug: Dolutegravir
For HIV-positive participants only: dolutegravir will be administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs will not be provided by the study.)
Experimental: Arm 2: Delamanid
Participants will receive 100 mg of delamanid twice a day for 24 weeks.
Drug: Delamanid
Delamanid will be administered with food as two 50 mg tablets (100 mg) by mouth twice a day for 24 weeks, for all study arms involving the use of this drug.
Drug: Dolutegravir
For HIV-positive participants only: dolutegravir will be administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs will not be provided by the study.)
Experimental: Arm 3: Bedaquiline and Delamanid
Participants will receive 400 mg of bedaquiline once a day and 100 mg of delamanid twice a day for 2 weeks. They will then receive 200 mg of bedaquiline three times a week and 100 mg of delamanid twice a day for 22 weeks.
Drug: Bedaquiline
Bedaquiline will be administered as four 100 mg tablets (400 mg) by mouth once a day for 2 weeks, followed by two 100 mg tablets (200 mg) by mouth three times a week for 22 weeks, for all study arms involving the use of this drug.
Drug: Delamanid
Delamanid will be administered with food as two 50 mg tablets (100 mg) by mouth twice a day for 24 weeks, for all study arms involving the use of this drug.
Drug: Dolutegravir
For HIV-positive participants only: dolutegravir will be administered at a dose of one 50 mg tablet once daily, to be used in combination with two NRTIs until study completion. (NRTIs will not be provided by the study.)

Detailed Description:

Bedaquiline (BDQ) and delamanid (DLM) are two newly approved anti-TB drugs and are both well tolerated. However, the combined effects of these two drugs have 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 is 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. Researchers will specifically evaluate the effect of these drugs on the heart.

Participants will be randomly assigned to one of three arms: participants in Arm 1 will receive BDQ, participants in Arm 2 will receive DLM, and participants in Arm 3 will receive BDQ and DLM. All participants will receive 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 will also receive dolutegravir, to be used in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) until study completion. NRTIs will not be provided by the study. All participants are expected to be hospitalized for 2 weeks starting at study entry. Participants may also be hospitalized for longer than 2 weeks.

Study visits will occur at entry, each week for 8 weeks after study entry, every other week until week 24, and 8 additional visits between weeks 25 and 128. Visits may include physical examinations, blood collection, urine collection, sputum sample collection, hair sample collection, chest x-rays, electrocardiograms (ECGs), and adherence questionnaires.

  Eligibility

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Men and women 18 years of age and older
  • 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. Must be lab confirmed by either genotypic (eg, Hain GenoType MTBDRplus) or phenotypic (susceptibility testing on liquid or solid culture) methods. NOTE: MDR- or RR-TB diagnosis for purposes of meeting the inclusion criterion can be from a study testing laboratory or from an outside laboratory, as long as it is 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 by either genotypic testing (such as Hain GenoType MTBDRsl) or phenotypic testing (susceptibility testing on liquid or solid culture) within 60 days prior to entry. NOTE: Fluoroquinolone and aminoglycoside susceptibility testing for purposes of meeting the inclusion criterion can be from a study testing laboratory or from an outside laboratory, as long as it is from a sputum sample collected within 60 days prior to entry.
  • HIV-1 infection status must be documented as either absent or present, as defined below:

    • Absence of HIV-1 infection, as documented by any licensed rapid HIV test or HIV-1 enzyme or chemiluminescence immunoassay (E/CIA) test kit, within 60 days prior to entry. OR
    • HIV-1 infection, documented by any licensed rapid HIV test or HIV-1 E/CIA test kit at any time prior to entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen or plasma HIV-1 RNA viral load.
    • NOTE: The term "licensed" refers to a U.S. FDA-approved kit, which is recommended. For sites that are unable to obtain an FDA-approved kit, a kit that has been certified or licensed by an oversight body within the country and validated internally is acceptable.
    • World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment. A reactive initial rapid test should be confirmed by either another type of rapid assay or an E/CIA that is based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load.
  • For HIV-positive participants only: CD4+ count greater than or equal to 100 cells/mm^3 within 60 days prior to entry. CD4+ count must be obtained from a laboratory certified for protocol testing by the Division of AIDS (DAIDS) Immunology Quality Assurance (IQA) Program
  • For HIV-positive participants only: for those who have been 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, an HIV-1 genotype within 60 days prior to entry must show that at least one fully active NRTI is available to the participant within the country program.
  • For females of reproductive potential, negative serum pregnancy test within 48 hours prior to entry
  • Female and male participants of reproductive potential who are participating in sexual activity that could lead to pregnancy must agree to use one of the following forms of birth control while receiving TB study medications and for 6 months after stopping TB study medications:

    • male or female condoms
    • diaphragm or cervical cap with spermicide, if available
    • intrauterine device (IUD)
    • oral contraceptives or Depo-Provera
    • NOTE A: Female participants who are not of reproductive potential are eligible without requiring the use of contraceptives. Participant-reported history is acceptable documentation of menopause (i.e., at least one year amenorrheic), hysterectomy, or bilateral oophorectomy or bilateral tubal ligation; these participants are all considered not of reproductive potential.
    • NOTE B: Male participants who are not of reproductive potential (i.e., documented azoospermia) or whose female partner/s are not of reproductive potential (as defined above) are eligible without requiring the use of contraceptives.
  • 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. Drug information may be found on the AIDS Clinical Trials Group (ACTG) Drug Interactions Database, located at: http://tprc.pharm.buffalo.edu/home/di_search/. 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, a drug that might cause QT prolongation at current treatment doses on its own and can potentiate QT prolongation when given together with BDQ for prolonged periods, 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 at any network-approved non-U.S. laboratory that operates in accordance with Good Clinical Laboratory Practices (GCLP) and participates in appropriate external quality assurance programs.

    1. Serum creatinine greater than 1.4 x upper limit of normal (ULN)
    2. Lipase greater than 1.6 x ULN
    3. Alanine aminotransferase (ALT) greater than 2.5 x ULN
    4. Total bilirubin greater than 1.6 x ULN
    5. Potassium less than 3.4 or greater than 5.6 mmol/L; magnesium less than 0.59 mmol/L; calcium less than 1.75 mmol/L
  • Known current hepatitis B or C infection, current treatment for hepatitis B or hepatitis C infection, or positive for hepatitis B surface antigen or hepatitis C antibodies within 60 days prior to entry
  • Among participants with HIV infection, in whom use of dolutegravir (DTG) is anticipated, any of the following:

    1. Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, esophageal varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
    2. History or presence of allergy to DTG or its components
    3. Severe hepatic impairment (Class C) as determined by Child-Pugh classification
    4. Previous use of raltegravir
  • Documentation of any new and/or unstable AIDS-defining illness (other than TB) as defined by the CDC within 60 days prior to entry
  • Acute or serious illness (other than TB) requiring systemic treatment and/or hospitalization within 60 days prior to entry
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02583048


Locations
Peru
Barranco CRS Recruiting
Lima, Peru, 04
Contact: Fanny Rosas, R.N.    51-1-2067800 ext 401    frosas@impactaperu.org   
South Africa
Task Applied Science (TASK) CRS Recruiting
Cape Town, Western Cape Province, South Africa, 7530
Contact: Christelle v. Niekerk    27-21-9171044    christelle@task.org.za   
South African Tuberculosis Vaccine Initiative (SATVI) CRS Recruiting
Cape Town, Western Cape Province, South Africa, 7705
Contact: Chris Hikuam    27-21-4066228    chris.hikuam@uct.ac.za   
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
Study Chair: Kelly Dooley, MD, PhD Johns Hopkins Adult AIDS CRS
Study Chair: Gary Maartens, MBChB, MMed University of Cape Town
  More Information

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT02583048     History of Changes
Other Study ID Numbers: A5343
12005 ( Registry Identifier: DAIDS-ES Registry )
First Submitted: October 20, 2015
First Posted: October 21, 2015
Last Update Posted: December 7, 2017
Last Verified: December 2017

Additional relevant MeSH terms:
HIV Infections
Tuberculosis
Tuberculosis, Pulmonary
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Dolutegravir
Bedaquiline
Diarylquinolines
HIV Integrase Inhibitors
Integrase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Antitubercular Agents