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

NCT04694586 | Suspended Phase 2

• 1 other identifier: 2019-003721-25
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

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.

Conditions

Tuberculosis, Pulmonary

Keywords

Drug-susceptible pulmonary tuberculosis; Rifampicin; Pyrazinamide; Shorter tuberculosis treatment; Pharmacokinetics/Pharmacodynamics; PK/PD; TB; Adverse event

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (8)

• Safety of 35 mg/kg RIF and 40 mg/kg PZA compared with standard-of-care: AE and SAE

  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

  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

  At treatment Day 14

• Peak Plasma Concentration (Cmax) of high-dose RIF in combination with PZA 40 mg/kg compared with standard-of-care

  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

  Day 0 (MIC) and Day 14 (AUC)

Study Arms (2)

High-dose rifampicin and pyrazinamide

EXPERIMENTAL

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; Drug: pyrazinamide; Drug: HRZE; Drug: HR

Standardized TB treatment

NO INTERVENTION

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)

Interventions

rifampicin DRUG

rifampicin 35 mg/kg

Also known as: rifampin, rimactan, R

High-dose rifampicin and pyrazinamide

pyrazinamide DRUG

pyrazinamide 40 mg/kg

Also known as: Z

High-dose rifampicin and pyrazinamide

HRZE DRUG

isoniazid 75 mg + rifampicin 150 mg + pyrazinamide 400 mg + ethambutol 275 mg combination tablets

Also known as: isoniazid, H, rifampicin, R, pyrazinamide, Z, ethambutol, E

High-dose rifampicin and pyrazinamide

HR DRUG

isoniazid 75 mg + rifampicin 150 mg combination tablets

Also known as: isoniazid, H, rifampicin, R

High-dose rifampicin and pyrazinamide

Eligibility Criteria

• Age: 18 Years+
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University Hospital, Linkoeping: lead
• Linkoeping University: collaborator

Study Sites (1)

Linköping University Hospital

Linköping, S-581 85, Sweden

Location

Related Publications (1)

• 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.

  PMID: 35273049 DERIVED

MeSH Terms

Conditions

Tuberculosis, Pulmonary

Interventions

Rifampin; Pyrazinamide; Isoniazid; Protons; Ethambutol

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Pyrazines; Heterocyclic Compounds, 1-Ring; Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Pyridines; Cations, Monovalent; Cations; Ions; Electrolytes; Inorganic Chemicals; Hydrogen; Elements; Gases; Nucleons; Elementary Particles; Physical Phenomena; Ethylenediamines; Diamines; Polyamines; Amines

Study Officials

• Katarina Niward, MD, PhD

  Linkoeping University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Prospective

Study Record Dates

• First Submitted: November 23, 2020
• First Posted: January 5, 2021
• Study Start: November 30, 2022
• Primary Completion: May 31, 2024
• Study Completion (Estimated): May 31, 2026
• Last Updated: January 5, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will not share

Locations

SE (1)