Shorter and Safer Treatment Regimens for Latent TB

NCT06498414 | Recruiting Phase 2 DMC

• 1 other identifier: OCT-194228
• Study Type: interventional
• Target: 1,800
• Locations: 5 countries
• Sites: 13

Brief Summary

Our study rationale is based on:

1. 1.Tuberculosis Preventive Treatment (TPT) is given to healthy people and needs to be safe;
2. 2.Tuberculosis Preventive Treatment (TPT) with shorter regimens are superior with respect to acceptance, completion, and costs;
3. 3.4 months of Rifampin 10mg/kg (4R10) is the safest regimen, but is completed by \<80% of patients;
4. 4.The safety of 2 months of Rifampin 20mg/kg (2R20) is similar to that of 4 months of Rifampin 10mg/kg (4R10), but completion is a concern;
5. 5.1-month regimens have promising efficacy;
6. 6.Safety and tolerability must be carefully assessed with comparisons to 4 months of Rifampin 10mg/kg (4R10), and head-to-head with each other.

Conditions

Tuberculosis Infection, Latent

Keywords

Tuberculosis infection; Rifampin; Short treatment for latent tuberculosis; High dose rifampin

Outcome Measures

Primary Outcomes (1)

• Severe treatment-related Adverse Events (AE)

  The investigators wish to capture all clinically relevant Adverse Event (AEs) defined as events that are possibly or probably treatment-related and result in death, hospitalization, or investigators' decision to discontinue study drug. These are defined as Grade 3-5 Adverse Event (AEs) of any type, plus Grade 1-2 rash/allergy. Because allergic reactions that are often detected by participants at an early stage carry the risk of progressing to more advanced manifestations if therapy is continued, stopping study drug is mandated with any Grade allergic reaction. If a suspected treatment-related Adverse Event (AE), or any hospitalization or death occurs during treatment phase (up to 2 weeks after the last dose of study drug taken), the site will file initial and final Adverse Event (AE) reports that will be sent for adjudication by the Adverse Event (AE) panel who will be blinded to study arm.

  From the start of the treatment until 2 weeks after the treatment completion

Secondary Outcomes (6)

• Completion

  at the end of the treatment (1 month, 2 months or 4 months)

• Tuberculosis Preventive Treatment (TPT)-related symptoms - Tolerability

  2 weeks after the treatment has started in all arms

• Patient preferences and acceptability of Tuberculosis Preventive Treatment (TPT)

  2 weeks after the treatment has started in all arms

• Plasma drug exposures

  2 weeks after the treatment has started in all arms

• Assess both health system and patient/family costs

  2 weeks after the treatment has started in all arms

Study Arms (3)

4 months standard dose rifampin (4R10)

ACTIVE COMPARATOR

120 doses daily self-administered rifampin at 10 mg/kg/day (max. 600 mg/day)

Drug: rifampin standard arm

2 months high dose rifampin (2R20)

EXPERIMENTAL

60 doses daily self-administered rifampin at 20 mg/kg/day (max.1200 mg/day)

Drug: rifampin double dose

1 month levofloxacin and rifapentine (1LP)

EXPERIMENTAL

30 doses daily self-administered levofloxacin (15 mg/kg/day, max. 750 mg/day and rifapentine (10mg/kg/day, max. 600mg)

Drug: levofloxacin and rifapentine

Interventions

rifampin standard arm DRUG

120 doses daily self-administered rifampin at 10mg/kg/day (max 600mg/day)

Also known as: 4R10

4 months standard dose rifampin (4R10)

rifampin double dose DRUG

60 doses daily self-administered rifampin at 20 mg/kg (max. 1200 mg/day)

Also known as: 2R20

2 months high dose rifampin (2R20)

levofloxacin and rifapentine DRUG

30 doses daily self-administered levofloxacin (15 mg/kg, max 750mg/day and rifapentine (10mg/kg, max: 600mg)

Also known as: 1LP

1 month levofloxacin and rifapentine (1LP)

Eligibility Criteria

• Age: 5 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults, and children aged ≥5 years with weight of \> 15Kg.
• Positive test for TB infection: either Tuberculin test (\>5mm, or \>10mm, based on epidemiologic and clinical factors and interpreted following local guidelines) or interferon gamma release assay based on Manufacturer's criteria; and,
• Recommended for Tuberculosis Preventive Treatment (TPT), following Canadian guidelines (for Canadian sites), and World Health Organization (WHO) guidelines (for international sites).

You may not qualify if:

• Current tuberculosis (TB) disease - detected pre-enrolment with symptom screen, chest x-ray, and confirmatory microbiological (culture or genotypic) testing as needed; Prior to referral to research staff (research clinic) for consideration as potential participants, all persons must undergo symptoms screen and a chest Xray. If chest Xray is not available, then a negative results from a GeneXpert MTb RIF Ultra of spontaneous (expectorated) sputum will be considered sufficient to exclude TB disease pre-referral. If Chest Xray is abnormal or symptoms consistent with TB disease are present then at least two AFB smears and mycobacterial cultures must be done, and must be negative, or one GeneXpert MTb Rif Ultra must be negative before enrolment
• Children aged 0-4 years;
• Persons weighing \<15 kg.
• Women who are pregnant or breast-feeding;
• Women of child-bearing potential and not willing to take an effective form of contraception (non-hormonal) during the treatment phase;
• Documented prior treatment for tuberculosis (TB) infection or disease;
• Pre-enrolment - alanine transaminase (ALT), White Blood Cells, platelets or hemoglobin that correspond to a Grade 3 adverse event (AE);
• Rifampin or rifapentine contra-indicated - due to allergy/hypersensitivity to any rifamycin (rifampin, rifabutin or rifapentine), or, drug interactions too difficult to manage;
• Have a prolonged QT interval on routine ECG pre-enrolment or take any medications that may prolong the QT interval and that are not recommended to take with a fluroquinolone. (See APPENDIX 5 in supplement for list of medications contra-indicated to take with Levofloxacin);
• Household contacts (HHC) of index TB patients with phenotypic or genotypic resistance to Rifampin or Levofloxacin. HHC may be enrolled, then excluded post-randomization, if resistance is identified later. Note that all sites routinely test Rifampin resistance in all people newly diagnosed to have TB disease, but do not test routinely for susceptibility to Levofloxacin unless Rifampin resistance is detected. Hence HHCs may be enrolled if their Index TB patient is Rifampin susceptible, even if Drug Susceptibility Testing to Levofloxacin is not done and/or not available.

Sponsors & Collaborators

• McGill University Health Centre/Research Institute of the McGill University Health Centre: lead
• Canadian Institutes of Health Research (CIHR): collaborator

Study Sites (13)

Centre National Hospitalier Universitaire de Pneumo Phtisiologie de Cotonou (CNHU-PPC)

Cotonou, Benin

NOT YET RECRUITING

Manaus

Manaus, Brazil

RECRUITING

Unviversity of Calgary

Calgary, Alberta, Canada

RECRUITING

The Governors of the University of Alberta

Edmonton, Alberta, T6G 2C8, Canada

RECRUITING

BCCDC TB clinic

Vancouver, British Columbia, Canada

RECRUITING

University of Manitoba

Winnipeg, Manitoba, Canada

RECRUITING

University of Ottawa

Ottawa, Ontario, Canada

RECRUITING

St. Michael's Hospital

Toronto, Ontario, M5B1W8, Canada

RECRUITING

University Health Network

Toronto, Ontario, M6M2J5, Canada

RECRUITING

MUHC

Montreal, Quebec, H4A 3J1, Canada

RECRUITING

Hopital du Sacré-Coeur de Montreal

Montreal, Quebec, H4J 1C5, Canada

NOT YET RECRUITING

Universitas Padjadjaran, Klinik Penelitian Tuberculosis (TB research clinic)

Bandung, Indonesia

RECRUITING

Vietnam

Ho Chi Minh City, Vietnam

NOT YET RECRUITING

Related Publications (2)

• Gafar F, Yunivita V, Fregonese F, Apriani L, Aarnoutse RE, Ruslami R, Menzies D. Pharmacokinetics of standard versus high-dose rifampin for tuberculosis preventive treatment: A sub-study of the 2R2 randomized controlled trial. Int J Antimicrob Agents. 2024 Jul;64(1):107197. doi: 10.1016/j.ijantimicag.2024.107197. Epub 2024 May 14.

  PMID: 38750674 BACKGROUND

• Fregonese F, Apriani L, Barss L, Benedetti A, Cook V, Fisher D, Fox GJ, Johnston J, Long R, Nguyen TA, Nguyen VN, Ruslami R, Menzies D. High dose rifampin for 2 months vs standard dose rifampin for 4 months, to treat TB infection: Protocol of a 3-arm randomized trial (2R2). PLoS One. 2023 Feb 2;18(2):e0278087. doi: 10.1371/journal.pone.0278087. eCollection 2023.

  PMID: 36730240 RESULT

MeSH Terms

Conditions

Latent Tuberculosis

Interventions

Levofloxacin; rifapentine

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Latent Infection

Intervention Hierarchy (Ancestors)

Ofloxacin; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Dick Menzies, MD

  RI-MUHC

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Dick Menzies, MD

CONTACT

514-934-1934; dick.menzies@mcgill.ca

Chantal Valiquette

CONTACT

514-934-1934; chantal.valiquette@affiliate.mcgill.ca

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Outcomes (Adverse event and tuberculosis (TB) disease) judge by independent blinded panel
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Senior Investigator at Research Institute of McGill University Health Center

Model Details: We plan an initial randomization ratio of 1:2:2 for 4 months of rifampin 10mg/kg (4R10), 2 months of rifampin 20mg/kg (2R20), and one month levofloxacin and rifapentine (1LP).

Study Record Dates

• First Submitted: April 29, 2024
• First Posted: July 12, 2024
• Study Start: June 10, 2025
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): June 1, 2029
• Last Updated: April 30, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: Protocol and consent form will be available once approval is received from the research ethical board and will remain available.
• Access Criteria: Access criteria will be specified in the plan for data sharing, once available.

Locations

CA (9); VN (1); BR (1); ID (1); BE (1)