Short Course Regimen in Low Risk Active Tuberculosis- a Multicenter, Randomized, Active-controlled, Trial

Safety and Efficacy of Four-month Short Course Regimen in Low Risk Active Tuberculosis- a Multicenter Randomized Controlled Trial

Tuberculosis remains an important global health problem, and the world is currently not on track to end the TB epidemic by 2030. With the concerted efforts of the government and medical community, the incidence of TB in Taiwan has gradually decreased, however, Taiwan remains an endemic area for TB. The development of efficacious, safe, and shorter treatment regimens could significantly improve treatment completion rate and reduce transmission of TB. The current treatment guidelines for drug-susceptible TB from the World Health Organization (WHO), American Thoracic Society (ATS), United States Center for Diseases Control (U.S. CDC), Infectious Diseases Society of America (IDSA) and European Respiratory Society (ERS) include 2 months of isoniazid, rifampin, pyrazinamide and ethambutol (HREZ), followed by 4 months of isoniazid, rifampin, and ethambutol(HRE). The current treatment regimen requires 6 months of treatment, despite being highly efficacious, requires long duration of treatment. Adherence to treatment is the major barrier which poses a negative impact to TB control, and increased cost to both the patient and the public health system. Developing an efficacious, safe and short treatment regimen can significantly improve TB management and treatment success rates.

Study Overview

• Status: Recruiting
• Conditions: Pulmonary Tuberculosis
• Intervention / Treatment: Drug: 4-month regimen (2HERZ/2HRE); Drug: 6-month (2HERZ/4HRE)

Detailed Description

This prospective, multicenter, randomized, open-labeled 3-year study, will recruit 270 adult patients with newly diagnosed tuberculosis with low risk of recurrence, and randomized 1:1 to a 4 months 2HREZ/2HRE (n=135) versus standard, 6 months regimen 2HREZ/4HRE (n=135). Expected enrollment will be 90 patients in year 1, 90 in year 2 and 90 in year 3.

This study aims to evaluate the efficacy, safety and long-term recurrence rate of a short-course, 4-months regimen including 2HREZ/2HRE compared with the standard 6-months regimen, 2HREZ/4HRE, and the impact of short regimen on reducing the costs and loading to the public health and medical system

• Study Type: Interventional
• Enrollment (Estimated): 270
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Susan Shin-Jung Lee, M.D., Ph.D.; Phone Number: 72029 +886-7342-2121; Email: ssjlee28@yahoo.com.tw
• Study Contact Backup: Name: Mei-Ling Lin, University; Phone Number: 72062 +886-7342-2121; Email: ed101622@gmail.com

Study Locations

• Taiwan
  • Kaohsiung, Taiwan, 80756
    • Recruiting
    • Kaohsiung Medical University Chung-Ho Memorial Hospital
    • Contact: Chau-Chyun Sheu, M.D. Ph.D.; Phone Number: +886-7312-1101; Email: sheu@kmu.edu.tw
  • Kaohsiung, Taiwan, 813
    • Recruiting
    • Kaohsiung Veterans General Hospital
    • Contact: Susan Shin-Jung Lee, M.D., Ph.D.; Phone Number: 2029 +886-7342-2121; Email: ssjlee28@yahoo.com.tw
    • Contact: Hsin-Wei Tung, R.N.; Phone Number: 2062 +886-73422121
    • Contact: Susan Shin-Jung Lee, M.D., Ph.D.
    • Contact: Yao-Shen Chen, M.D.
    • Contact: Hung-Chin Tsai, M.D., Ph.D.
    • Contact: Jui-Kuang Chen, M.D.
    • Contact: Cheng-Len Sy, M.D., BSMT
    • Contact: Kuan-Sheng Wu, M.D.
    • Contact: Yu-Ting Tseng, M.D.
    • Contact: Ya-Wei Weng, M.D.
    • Contact: Chih-Chen Chou, M.D.
    • Contact: Huan-Yi Wu, M.D.
    • Contact: David-Lin Lee, M.D.
    • Contact: Wei-Hsin Hung, M.D.
    • Contact: Chun-Hsiang Hsu, M.D.
  • Taipei, Taiwan
    • Recruiting
    • National Taiwan University Hospital
    • Contact: Chin-Chung Shu, M.D.; Phone Number: 65132 +886-2312-3456
    • Contact: Chin-Chung Shu, M.D.
  • Taipei, Taiwan, 112
    • Recruiting
    • Taipei Veterans General Hospital
    • Contact: Jia-Yih Feng, M.D.; Phone Number: 7564 +886-2871-2121
    • Contact: Jia-Yih Feng, M.D.
    • Contact: Sheng-Wei Pan, M.D.
  • Taoyuan City, Taiwan, 333
    • Recruiting
    • Linkou Chang Gung Memorial Hospital
    • Contact: Tsai-Yu Wang, M.D.; Phone Number: 8470 +886-3-3281200
    • Contact: Tsai-Yu Wang, M.D.
    • Contact: Chung-Shu Lee, M.D.
    • Contact: Po-Jui Chang, M.D.
    • Contact: Meng-Heng Hsieh, M.D.
  • Bangiao
    • New Taipei, Bangiao, Taiwan, 220
      • Recruiting
      • Far Eastern Memorial Hospital
      • Contact: Wang Ping-Huai PhD, PhD; Phone Number: 02-9866-7000 02-9866-7000; Email: pinghuaiwang@gmail.com
  • West
    • Taichung, West, Taiwan, 199
      • Recruiting
      • Taichung Hospital
      • Contact: Huang Jhong-Ru PhD, PhD; Phone Number: 04-222294411 04-222294411; Email: pcipur@gmail.com
  • Yanchao
    • Kaoshiung, Yanchao, Taiwan, 82445
      • Recruiting
      • E-DA Healthcare Group
      • Contact: Lee Ho-Sheng PhD, PhD; Phone Number: 07-6150011 07-6150011; Email: leehoshn@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Newly diagnosed pulmonary tuberculosis patients combined with any of the following diagnostic conditions:

  • at least one set of sputum specimens is positive for Mycobacterium tuberculosis culture or TB PCR test; or
  • pathological and histological findings of typical tuberculosis manifestations;
  • clinical diagnosis and Physician determines the need for complete anti-tuberculosis treatment
• Those who have had tuberculosis in the past and have been cured for at least three years can be included
• Aged over 20 years old

• Laboratory data at the time of inclusion in the study or within 14 days:

  • Serum or plasma glutamic acid pyruvate transaminase (ALT) value ≦ three times the upper limit of normal
  • Serum or plasma total bilirubin ≦ 2.5 times the upper limit of normal
  • Serum or plasma creatinine ≦ twice the upper limit of normal or creatinine clearance greater than 30 mL/min
  • Heme ≧7.0 g/Dl
  • Platelets ≧100,000/mm3
• Patient signs consent form
• Patients who agree to join and cooperate with the county and city health bureau's urban treatment plan to ensure medication compliance.

Exclusion Criteria:

• The acid-fast smear of sputum or respiratory specimen is strongly positive (≥ 2+)
• Chest X-ray or lung computed tomography combined with open lesions
• Chest X-ray or lung computed tomography shows extensive lesions and the clinician judges that short-term treatment is not suitable
• Simultaneous combination of intrapulmonary and extrapulmonary tuberculosis
• People who are unable to take oral medications
• People who have participated in this research
• Have used anti-tuberculosis drugs for more than 14 days
• A history of tuberculosis suspected or diagnosed as central nervous system tuberculosis, bone or joint tuberculosis, miliary tuberculosis or tuberculous pericarditis.
• Known history of allergy or intolerance to this study drug
• Patients with HIV infection, organ transplantation, and chronic renal failure
• Long-term use of immunosuppressive drugs, including steroid use >10mg/day (more than 30 consecutive days in the last three months)
• Late exclusion: Mycobacterium tuberculosis is known to be resistant to any one or more of the following drugs: rifampin, isoniazid, ethambutol

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: Intervention/Treatment; Two months of isoniazid (H), ethambutol (E), rifampicin (R) and Pyrazinamide (Z) followed by HR(E) for another two months	Drug: 4-month regimen (2HERZ/2HRE); 4-month (2HERZ/2HRE)
Active Comparator: 6-months HERZ (2HERZ/4HRE); Two months of isoniazid (H), pyrazinamide (Z), rifampicin (R) and Pyrazinamide (Z) followed by HR(E) for another four months	Drug: 6-month (2HERZ/4HRE); 2 months of HREZ followed by 4 months of HR/HRE

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Grade 3-5 adverse events	Development of Grade3-5 adverse events during treatment	From enrollment to the end of treatment at 4 or 6 months
TB disease free survival at 12 months post-randomization	Number of participants without TB disease at 12 months after randomization	12 months
TB disease free survival at 24 months post randomization	Number of participants without TB disease at 24 months after randomization	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Early sterilizing activity	The proportion of patients with a negative sputum culture at the end of intensive phase therapy at 8 weeks	8 weeks
All-cause mortality	All-cause mortality at 4 months and 12 months post-treatment assignment	4, 12 months
Attributable mortality	Attributable mortality at 4 months and 12 months post-treatment assignment	4, 12 months
Sputum culture conversion	Time to stable sputum culture conversion	4, 8, 12, 16,20,24 weeks,3, 6, 12 and 24 months after treatment
Changes in interferon-gamma levels	Changes in interferon-gamma levels during treatment compared to baseline	2, 4, 8, 12,16or 24 weeks
Changes in tumor necrosis factor-alpha levels	Changes in tumor necrosis factor-alpha levels during treatment compared to baseline	2, 4, 8, 12,16or 24 weeks
Changes in interleukin-12 and interleukin-6 levels	Changes in interleukin-12 and interleukin-6 levels during treatment compared to baseline	2, 4, 8, 12,16or 24 weeks
Changes in triggering receptor expressed on myeloid cells-1 (TREM-1) levels	Changes in triggering receptor expressed on myeloid cells-1 (TREM-1) levels during treatment compared to baseline	2, 4, 8, 12,16or 24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
HLA associations with severe drug adverse events	HLA Genotyping to detect predictors for occurrence of severe drug adverse events including skin rash and hepatitis.	Upon joining or within two weeks of study entry

Collaborators and Investigators

• Sponsor: Kaohsiung Veterans General Hospital.
• Collaborators: National Taiwan University Hospital; Chang Gung Memorial Hospital; Taipei Veterans General Hospital, Taiwan; Far Eastern Memorial Hospital; Kaohsiung Medical University; E-DA Hospital
• Investigators: Principal Investigator: Susan Shin-Jung Lee, MD, PhD, Kaohsiung Veterans General Hospital.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2024
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: December 6, 2024
• First Submitted That Met QC Criteria: December 6, 2024
• First Posted (Actual): December 11, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 21, 2025
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: safety; tuberculosis; recurrence rate; sputum conversion; short course regimen
• Additional Relevant MeSH Terms: Respiratory Tract Infections; Infections; Respiratory Tract Diseases; Lung Diseases; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary
• Other Study ID Numbers: KSVGH24-CT2-16

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

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