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

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

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.

Study Overview

• Status: Suspended
• Conditions: Tuberculosis, Pulmonary
• Intervention / Treatment: Drug: rifampicin; Drug: pyrazinamide; Drug: HRZE; Drug: HR

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.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Katarina Niward, MD, PhD; Phone Number: +46101030000; Email: katarina.niward@liu.se
• Study Contact Backup: Name: Jakob Paues, MD, PhD; Phone Number: +46101030000; Email: jakob.paues@liu.se

Study Locations

• Sweden
  • Linköping, Sweden, S-581 85
    • Linköping University hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High-dose rifampicin and pyrazinamide; 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; rifampicin 35 mg/kg; Other Names: rifampin; R; rimactan; Drug: pyrazinamide; pyrazinamide 40 mg/kg; Other Names: Z; Drug: HRZE; isoniazid 75 mg + rifampicin 150 mg + pyrazinamide 400 mg + ethambutol 275 mg combination tablets; Other Names: isoniazid; R; rifampicin; Z; ethambutol; H; pyrazinamide; E; Drug: HR; isoniazid 75 mg + rifampicin 150 mg combination tablets; Other Names: isoniazid; R; rifampicin; H
No Intervention: Standardized TB treatment; 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?

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

Collaborators and Investigators

• Sponsor: University Hospital, Linkoeping
• Collaborators: Linkoeping University
• Investigators: Principal Investigator: Katarina Niward, MD, PhD, Linkoeping University

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2022
• Primary Completion (Estimated): May 31, 2024
• Study Completion (Estimated): May 31, 2026

Study Registration Dates

• First Submitted: November 23, 2020
• First Submitted That Met QC Criteria: January 1, 2021
• First Posted (Actual): January 5, 2021

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 3, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: TB; Adverse event; PK/PD; Rifampicin; Pharmacokinetics/Pharmacodynamics; Drug-susceptible pulmonary tuberculosis; Pyrazinamide; Shorter tuberculosis treatment
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antimetabolites; Hypolipidemic Agents; Lipid Regulating Agents; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Fatty Acid Synthesis Inhibitors; Rifampin; Isoniazid; Pyrazinamide; Ethambutol
• Other Study ID Numbers: 2019-003721-25

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Needs additional approval (Amendment) from the Ethical Committee in Sweden.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No