Evaluating the Safety, Tolerability, and Pharmacokinetics of Bedaquiline and Delamanid, Alone and in Combination, For Drug-Resistant Pulmonary Tuberculosis
Condition: Tuberculosis; HIV Infections
MeSH terms: Tuberculosis; Tuberculosis, Pulmonary
Intervention: Bedaquiline; Delamanid; Dolutegravir; Multidrug Background Treatment (MBT) for TB
Intervention description: 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.; Two 50 mg tablets (100 mg) orally with food twice a day for 24 weeks.; 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.); 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 MeSH terms: Dolutegravir; Bedaquiline
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 84.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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).
    

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