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Tuberculosis, PulmonaryPhase 2HIGHSHORT-RPNCT04694586

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

A Phase 2 study testing rifampicin, pyrazinamide and HRZE in people with Tuberculosis, Pulmonary, run by University Hospital, Linkoeping at 1 site in Sweden.

Suspended

Paused. Enrolment is on hold for now and may resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Tuberculosis, Pulmonary
What is being tested?
rifampicin, pyrazinamide and HRZE
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
40 participants
Where
1 siteSweden
Study dates
30 Nov 2022to 31 May 2030
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 25Show fewer
  • 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

Trial locations and contacts

1 site in 1 country.

Sweden1 site

  • Linköping University Hospital

    Linköping, S-581 85

Other trials in Sweden

About this study

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

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.

Read the 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.

Being tested
rifampicin, pyrazinamide, HRZE, HR
Keywords
Drug-susceptible pulmonary tuberculosis, Rifampicin, Pyrazinamide, Shorter tuberculosis treatment, Pharmacokinetics/Pharmacodynamics, PK/PD, TB, Adverse event
Medical subject headings
Tuberculosis, Pulmonary

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • rifampicinDrug

    Also called rifampin, rimactan, R

    rifampicin 35 mg/kg

  • pyrazinamideDrug

    Also called Z

    pyrazinamide 40 mg/kg

  • HRZEDrug

    Also called isoniazid, H, rifampicin, R

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

  • HRDrug

    Also called isoniazid, H, rifampicin, R

    isoniazid 75 mg + rifampicin 150 mg combination tablets

Study groups in NCT04694586
Study groupRoleWhat they receive
High-dose rifampicin and pyrazinamideExperimentalrifampicin 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)
Receives: Drug: rifampicin; Drug: pyrazinamide; Drug: HRZE; Drug: HR
Standardized TB treatmentNo interventionisoniazid 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 being measured

The primary outcome is the main question the study is designed to answer.

  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

    Measured: At treatment Day 14

Secondary outcomes (8)

  1. 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)

    Measured: 4 months in the intervention arm, 6 months in the control arm

  2. 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

    Measured: At treatment Day 14

  3. 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

    Measured: At treatment Day 14

  4. 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

    Measured: At treatment Day 14

  5. 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

    Measured: Day 0 (MIC) and Day 14 (AUC)

  6. 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

    Measured: Day 0 (MIC) and Day 14 (AUC)

  7. 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

    Measured: At treatment Day 1 (first dose) and Day 14

  8. 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

    Measured: At treatment Day 1 (first dose) and Day 14

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Jan 2021
  2. Study start30 Nov 2022
  3. Primary completion31 May 2029 (estimated)
  4. Study completion31 May 2030 (estimated)

Why it stopped: Suspended 15th of Nov 2023 due to conditions affecting recruitment process.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Prospective
Masking
None (open label)
Enrolment
40 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04694586
Sponsor's protocol ID
2019-003721-25
Other IDs
2019
Acronym
HIGHSHORT-RP
Status last verified
Aug 2026
First submitted
23 Nov 2020
Last updated
17 Aug 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No: Needs additional approval (Amendment) from the Ethical Committee in Sweden.

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.

    PubMed 35273049

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing rifampicin, pyrazinamide and HRZE in people with Tuberculosis, Pulmonary, run by University Hospital, Linkoeping at 1 site in Sweden.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: paused, as of the sponsor's last update on 17 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Sweden. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome 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 (time frame: At treatment Day 14). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04694586, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Aug 2026.

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