Drug Exposure and Safety of a Shorter Tuberculosis Treatment Based on High-Dose Rifampicin and Pyrazinamide

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Tuberculosis, Pulmonary

Intervention / Treatment
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* Drug: rifampicin
* Drug: pyrazinamide
* Drug: HRZE
* Drug: HR


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High-dose rifampicin and pyrazinamide<br>rifampicin 35 mg/kg for 4 months provided as a combination of fixed drug combination tablets (HRZE for 8 weeks and HR Week 9-16) and single drug tablets of rifampicin (R) AND pyrazinamide 40 mg/kg the first 2 months provided as a combination of fixed drug combination tablets (HRZE) and single drug tablets of pyrazinamide (Z) fixed drug combination tablets are: isoniazid 75 mg + rifampicin 150 mg + pyrazinamide 400 mg + ethambutol 275 mg (HRZE) combination tablets for 8 weeks AND isoniazid 75 mg + rifampicin 150 mg (HR) combination tablets for Weeks 9 to 16 (total treatment duration 4 months) | Drug: rifampicin<br>* rifampicin 35 mg/kg<br>* Other names: R;Drug: pyrazinamide<br>* pyrazinamide 40 mg/kg<br>* Other names: Z;Drug: HRZE<br>* isoniazid 75 mg + rifampicin 150 mg + pyrazinamide 400 mg + ethambutol 275 mg combination tablets<br>* Other names: E;Drug: HR<br>* isoniazid 75 mg + rifampicin 150 mg combination tablets<br>* Other names: R;|
| No Intervention: Standardized TB treatment<br>isoniazid 75 mg + rifampicin 150 mg + pyrazinamide 400 mg + ethambutol 275 mg (HRZE) combination tablets for 8 weeks AND isoniazid 75 mg + rifampicin 150 mg (HR) combination tablets for Weeks 9-26 (total treatment duration 6 months) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration-time curve (AUC) of 40 mg/kg PZA in a high-dose RIF regimen compared with standard-of-care | PZA AUC(0-24h) at Day 14 after treatment initiation | At treatment Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of 35 mg/kg RIF and 40 mg/kg PZA compared with standard-of-care: AE and SAE | Registration of AE/SAE (incidence, severity, drug relatedness, leading to early withdrawal, and leading to death) | 4 months in the intervention arm, 6 months in the control arm | 
| Peak Plasma Concentration (Cmax) of 40 mg/kg PZA in a high-dose RIF regimen compared with standard-of-care | PZA Cmax at Day 14 after treatment initiation | At treatment Day 14 | 
| Area under the plasma concentration-time curve (AUC) of high-dose RIF in combination with PZA 40 mg/kg compared with standard-of-care | RIF AUC(0-24h) at Day 14 after treatment initiation | At treatment Day 14 | 
| Peak Plasma Concentration (Cmax) of high-dose RIF in combination with PZA 40 mg/kg compared with standard-of-care | RIF Cmax at Day 14 after treatment initiation | At treatment Day 14 | 
| 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 | PZA AUC/MIC | Day 0 (MIC) and Day 14 (AUC) | 
| 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 | RIF AUC/MIC | Day 0 (MIC) and Day 14 (AUC) | 
| Prediction of PZA pharmacokinetics at steady state (Day 14) based on drug concentration measurement at treatment Day 1 | PZA AUC(0-24h) at Day 1 compared with PZA AUC(0-24h) at Day 14 | At treatment Day 1 (first dose) and Day 14 | 
| Prediction of RIF pharmacokinetics at steady state (Day 14) based on drug concentration measurement at treatment Day 1 | RIF AUC(0-24h) at Day 1 compared with RIF AUC(0-24h) at Day 14 | At treatment Day 1 (first dose) and Day 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug-susceptible pulmonary tuberculosis, Rifampicin, Pyrazinamide, Shorter tuberculosis treatment, Pharmacokinetics/Pharmacodynamics, PK/PD, TB, Adverse event