Patient case: 19-year-old female with long QT syndrome; genetic feature: KCNH2

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

Summary: 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).

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, pregnancy testing, electrocardiograms (ECGs), and adherence questionnaires.
  Participants may also be asked to take part in an optional cerebrospinal fluid sampling study that will entail a lumbar puncture, to be done at weeks 8 or 24.

Eligibility: 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.
  -  NOTE C: For HIV-positive female participants of reproductive potential, the use of contraceptives is required for the full duration of time the participant is taking dolutegravir (ie, through study completion at week 128). Contraceptive options for women of reproductive potential while taking dolutegravir include the following:
  -  Contraceptive subdermal implant
  -  Intrauterine device or intrauterine system
  -  Combined estrogen and progestogen oral contraceptive
  -  Injectable progestogen
  -  Contraceptive vaginal ring
  -  Percutaneous contraceptive patches
  -  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

Relevance to patient case: not relevant