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

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.

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:

• 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