Clinical trial NCT04694586: Drug Exposure and Safety of a Shorter Tuberculosis Treatment Based on High-Dose Rifampicin and Pyrazinamide
Official title: A Prospective Multicenter Phase II-study: Pharmacokinetics and Safety of High-Dose Rifampicin and Pyrazinamide in a Shorter Tuberculosis Treatment Compared With Standardized Treatment in Patients With Mild to Moderate Pulmonary TB
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE2
Conditions: Tuberculosis, Pulmonary
Keywords: Drug-susceptible pulmonary tuberculosis
Rifampicin
Pyrazinamide
Shorter tuberculosis treatment
Pharmacokinetics/Pharmacodynamics
PK/PD
TB
Adverse event
Lead sponsor: University Hospital, Linkoeping
Sponsor class: OTHER
Collaborators: name: Linkoeping University
First posted: 2021-01-05
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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 term Actual Study Start Date (stated 23rd of November 2020) refers to when the study opened for recruitment and this date will be updated once the first patient is enrolled in the trial.

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.

Eligibility criteria: 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
* TB in the central nervous system
* Extrapulmonary TB (outside central nervous system) 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

Primary outcomes:
measure: Area under the plasma concentration-time curve (AUC) of 40 mg/kg PZA in a high-dose RIF regimen compared with standard-of-care
timeFrame: At treatment Day 14
Secondary outcomes:
measure: Safety of 35 mg/kg RIF and 40 mg/kg PZA compared with standard-of-care: AE and SAE
timeFrame: 4 months in the intervention arm, 6 months in the control arm
measure: Peak Plasma Concentration (Cmax) of 40 mg/kg PZA in a high-dose RIF regimen compared with standard-of-care
timeFrame: At treatment Day 14
measure: Area under the plasma concentration-time curve (AUC) of high-dose RIF in combination with PZA 40 mg/kg compared with standard-of-care
timeFrame: At treatment Day 14
measure: Peak Plasma Concentration (Cmax) of high-dose RIF in combination with PZA 40 mg/kg compared with standard-of-care
timeFrame: At treatment Day 14
measure: Drug exposure of PZA 40 mg/kg in relation to Mtb drug-susceptibility level (MIC) compared with standard-of-care and literature-derived suggested PK/PD targets
timeFrame: Day 0 (MIC) and Day 14 (AUC)
measure: Drug exposure of RIF 35 mg/kg in relation to Mtb drug-susceptibility level (MIC) compared with standard-of-care and literature-derived suggested PK/PD targets
timeFrame: Day 0 (MIC) and Day 14 (AUC)
measure: Prediction of PZA pharmacokinetics at steady state (Day 14) based on drug concentration measurement at treatment Day 1
timeFrame: At treatment Day 1 (first dose) and Day 14
measure: Prediction of RIF pharmacokinetics at steady state (Day 14) based on drug concentration measurement at treatment Day 1
timeFrame: At treatment Day 1 (first dose) and Day 14
Other outcomes:
Locations:
city: Linköping
country: Sweden
facility: Linköping University Hospital
Study officials:
affiliation: Linkoeping University
name: Katarina Niward, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ekqvist D, Bornefall A, Augustinsson D, Sonnerbrandt M, Nordvall MJ, Fredrikson M, Carlsson B, Sandstedt M, Simonsson USH, Alffenaar JC, Paues J, Niward K. Safety and pharmacokinetics-pharmacodynamics of a shorter tuberculosis treatment with high-dose pyrazinamide and rifampicin: a study protocol of a phase II clinical trial (HighShort-RP). BMJ Open. 2022 Mar 10;12(3):e054788. doi: 10.1136/bmjopen-2021-054788.