Drug Exposure and Safety of a Shorter Tuberculosis Treatment Based on High-Dose Rifampicin and Pyrazinamide
Drug Exposure and Safety of a Shorter Tuberculosis Treatment Based on High-Dose Rifampicin and Pyrazinamide
Tuberculosis (TB) treatment is long and complex with the risk of poor treatment adherence and
 treatment failure. Several attempts to shorten treatment of drug-susceptible TB have been
 unsuccessful. However, recent data support a shortened regimen for mild and moderate
 pulmonary TB and simultaneous optimization of rifampicin (RIF) and pyrazinamide (PZA).

 This phase II clinical study aim to investigate a strategy to shorten TB treatment by
 exploring safety and drug exposure of a high-dose sterilizing TB regimen.
In five sites in Sweden (Linköping, Norrköping, Jönköping, Kalmar and Stockholm), 40
 consenting adult patients with mild to moderate drug-susceptible pulmonary TB will be
 recruited.

 The study participants are randomized to receive either 6-month standardized TB treatment
 (n=10) or a 4-month regimen (n=30) of rifampicin (RIF) 35 mg/kg and isoniazid (INH) 5 mg/kg
 complemented the first 8 weeks by pyrazinamide (PZA) 40 mg/kg and ethambutol (EMB) 15-20
 mg/kg.

 First-line drug concentration is determined at 0, 1, 2, 4, 6, 8, 12 and 24 h Day 1 and Week 2
 and potential side effects thoroughly monitored throughout the study.

 Early bactericidal activity (EBA) and sputum culture conversion are evaluated by time to
 culture positivity (TTP) in liquid medium system BACTEC MGIT (MGIT, mycobacteria growth
 indicator tube) 960 of induced sputum samples collected at day 0, 5 and at week 1, 2 and 8
 after treatment initiation.

 Clinical symptoms are assessed by a clinical scoring tool (TBscore II). Final treatment
 outcome and occurrence of relapse after the end of treatment are recorded according to World
 Health Organization (WHO) definitions.

 Peak drug concentration (Cmax) and area under the plasma concentration-time curve (AUC) 0-24h
 will be estimated by non-compartmental analysis and conditions for early therapeutic drug
 monitoring (TDM) of high-dose RIF/PZA will be explored by model-based analysis.

 Primary and main secondary outcomes in the study are the distribution of pharmacokinetics
 (Cmax, AUC) of high-dose PZA/RIF regimen, safety in terms of incidence of adverse
 event/severe adverse event (AE/SAE) probably related or related to TB treatment, and drug
 exposure (AUC) of high-dose PZA/RIF in relation to Mycobacterium tuberculosis (Mtb)
 drug-susceptibility level (MIC) compared with standard-of-care and suggested
 literature-derived pharmacokinetic/pharmacodynamic (PK/PD) targets.
Inclusion Criteria:

 -  Patient 18 years and older

 -  Confirmed pulmonary TB (positive Mtb culture or positive polymerase chain reaction
 (PCR) Mtb-complex)

 -  Intended to start on first-line TB treatment

 -  HIV negative

 -  BMI >17

 -  Written Informed Consent

 -  Women of childbearing potential should agree on adequate contraceptives during
 treatment period and have a negative pregnancy test prior to treatment initiation

 Exclusion Criteria:

 -  Not able to provide informed consent/unable to assimilate study information

 -  Concomitant infectious disease that requires treatment

 -  Known allergy to rifamycins, isoniazid, pyrazinamide, ethambutol or history of severe
 sideeffect to any of the drugs

 -  Drug-induced inflammatory liver diseases in medical history

 -  History of acute liver disease

 -  On-going liver disease including hepatitis and elevated transaminase levels >x5 upper
 normal limit

 -  Porphyria

 -  Drug-drug interaction between concomitant drugs and rifampicin that could not be
 bridged by dose-adjustment of the concomitant drug

 -  Jaundice

 -  Acute gout

 -  Treatment of active TB during the last year

 -  Drug resistance to RIF, INH, PZA or EMB

 -  Miliary TB

 -  Pulmonary TB with smear positivity grade 3 and/or chest X-ray grading equal to
 advanced TB

 -  Extrapulmonary TB without pulmonary TB

 -  Pregnancy and breast-feeding

 -  Immunosuppressive condition

 -  Heart failure (NYHA class III and IV)

 -  Renal failure with estimated glomerular filtration rate (eGFR) <50 mL/min

 -  Dysregulated diabetes mellitus

 -  Alcohol and drug abuse

 -  Weight <35 kg or >90 kg

 -  Participation in other clinical trial (investigating a drug) within the last 30 days
 prior to study inclusion

 -  Person who the investigator, after consultation with the central contact persons of
 the study, finds by other reason than the above listed not suitable for study
 participation