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

August 14, 2026 updated by: Katarina Niward, University Hospital, Linkoeping

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

Status

Indicates the current recruitment status or the expanded access status.
Suspended

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
40

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
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
Time Frame: At treatment Day 14
PZA AUC(0-24h) at Day 14 after treatment initiation
At treatment Day 14

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
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
Time Frame: 4 months in the intervention arm, 6 months in the control arm
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
Time Frame: At treatment Day 14
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
Time Frame: At treatment Day 14
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
Time Frame: At treatment Day 14
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
Time Frame: Day 0 (MIC) and Day 14 (AUC)
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
Time Frame: Day 0 (MIC) and Day 14 (AUC)
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
Time Frame: At treatment Day 1 (first dose) and Day 14
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
Time Frame: At treatment Day 1 (first dose) and Day 14
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

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University Hospital, Linkoeping

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Linkoeping University

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Katarina Niward, MD, PhD, Linkoeping University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
November 30, 2022

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
May 31, 2029

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
May 31, 2030

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
November 23, 2020

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 1, 2021

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 5, 2021

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
August 17, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 14, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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