Optimizing(O) RIfapentine-based(RI) Regimen and shortENing(EN) the Treatment of Drug-sensitive Tuberculosis(T)

Official title

Efficacy and Safety of Short-course Treatment for Drug-sensitive Tuberculosis in China

Overview

Tuberculosis (TB) remains the most important infectious disease in the world. A major barrier to tuberculosis control is poor adherence to long-term and complex treatment regimens. This is a multicenter prospective, non-inferiority randomized controlled study. The purpose of our study is a) to evaluate the tolerability, efficacy and pharmacokinetics/pharmacodynamics (PK/PD) of the high-dose rifapentine, b) to evaluate whether the high-dose rifapentine-containing regimen has the potential to treat the rifampicin-sensitive pulmonary tuberculosis and shorten the course of treatment to 17 weeks. This study is of great significance for shortening the course of treatment, reducing the adverse reactions and economic burden of patients' treatment in rifampicin-sensitive tuberculosis patient.

Detailed description

Tuberculosis (TB) remains the most important infectious disease in the world. A major barrier to tuberculosis control is poor adherence to long-term and complex treatment regimens. Incomplete TB treatment can lead to increased morbidity and mortality, prolonged infectivity and transmission, and the development of drug resistance. The development of new therapeutic strategies with stronger bactericidal activity could lead to shorter and better-tolerated regimens, thereby increasing cure rates, lowering costs, potentially reducing transmission and preventing the emergence of multidrug-resistant tuberculosis (MDR-TB).

This trial is a multicenter prospective, non-inferiority randomized controlled study. Rifampicin-sensitive pulmonary tuberculosis patients will be included in our study. Stage 1 of the study is designed to evaluate the tolerability, efficacy and PK/PD of the high-dose rifapentine in order to select two doses to carry forward into study Stage 2. Study Stage 2 will provide pivotal confirmation of efficacy, safety, and tolerability of the selected rifapentine doses in patients with rifampicin-sensitive pulmonary tuberculosis.

Interventions

• Other Short Regimen with Rifapentine 10mg/kg
  rifapentine 10mg/kg daily; isoniazid 300mg daily; pyrazinamide ≤50kg 1000mg daily, 50-71kg 1200mg daily, \>71kg 1000mg daily; moxifloxacin 400mg daily. All treatment is taken orally.
• Combination product Standardized Regimen
  During the intensive phase, rifampicin ≤55kg 450mg daily, 55-71kg 600mg daily, \>71kg 750mg daily; isoniazid ≤55kg 225mg daily, 55-71kg 300mg daily, \>71kg 375mg daily; pyrazinamide ≤55kg 900mg daily, 55-71kg 1200mg daily, \>71kg 1600mg daily; ethambutol ≤55kg 825mg daily, 55-71kg 1100mg daily, \>71kg 1375mg daily; All treatment is taken orally. During the continuation phase, rifampicin ≤50kg 450mg daily, \>50kg 600mg daily; isoniazid 300mg daily; All treatment is taken orally.
• Other Short Regimen with Rifapentine 15mg/kg
  rifapentine 15mg/kg daily; isoniazid 300mg daily; pyrazinamide ≤50kg 1000mg daily, 50-71kg 1200mg daily, \>71kg 1000mg daily; moxifloxacin 400mg daily. All treatment is taken orally.
• Other Short Regimen with Rifapentine 20mg/kg
  rifapentine 20mg/kg daily; isoniazid 300mg daily; pyrazinamide ≤50kg 1000mg daily, 50-71kg 1200mg daily, \>71kg 1000mg daily; moxifloxacin 400mg daily. All treatment is taken orally.

Primary outcome measures

• Treatment success rate of the short regimen during drug treatment and follow-up. [Time frame: 108 weeks after randomization]

Secondary outcome measures (3)

• The frequency of grade 3 or greater adverse events among patients Over the 108 Week Treatment and Follow-up Period. [Time frame: up to 108 weeks]
• Relapse rate during follow-up. [Time frame: 82-91 weeks after the end of drug treatment.]
• the percentage of participants found to be culture-negative at the end of intensive phase and the end of treatment phase [Time frame: 8 weeks, 17 weeks and 26 weeks after randomization]

Eligibility criteria

Inclusion criteria

• Age between 18 to 60 years;
• Weight between 40 to 80 kg;
• Individuals with smear-positive pulmonary tuberculosis and sensitive to rifampicin ;
• Willing to provide signed informed consent, or parental consent and participant assent.
• If you are a non-menopausal woman, agree to use or have used effective contraception during treatment.

Exclusion criteria

• Combined extrapulmonary tuberculosis;
• Patients with extensive lesion (extent of disease greater than 50% or cavity size greater than 4cm) ;
• Individuals will be excluded from enrollment if, at the time of enrollment, their M. tuberculosis isolate is already known to be resistant to any one or more of the following: rifampin, isoniazid, pyrazinamide, ethambutol, or fluoroquinolones;
• Alcohol abuse#drinking more than 64g of ethanol a day for male, 42g for female#;
• Hemoglobin is less than 70g/L or platelet is less than 100\*10\^9/L;
• Patients with impaired liver function (hepatic encephalopathy, ascites; total bilirubin is higher than the upper limit of normal; Alanine aminotransferase or aspartate aminotransferase is higher than the upper limit of normal);
• Blood creatinine is more than 1.5 times the upper limit of normal;
• More than five days of systemic treatment with any one or more of the following drugs within 6 months preceding initiation of study drugs: isoniazid, rifampin, rifabutin, rifapentine, ethambutol, pyrazinamide, kanamycin, amikacin, streptomycin, capreomycin, moxifloxacin, levofloxacin, gatifloxacin, ofloxacin, ciprofloxacin, other fluoroquinolones, ethionamide, prothionamide, cycloserine, terizidone, para-aminosalicylic acid, linezolid, clofazimine, delamanid or bedaquiline;
• Known history of prolonged QT syndrome;
• Current or planned use within six months following enrollment of one or more of the following medications: HIV protease inhibitors, HIV integrase inhibitors, HIV entry and fusion inhibitors, HIV non-nucleoside reverse transcriptase inhibitors other than efavirenz; quinidine, procainamide, amiodarone, sotalol, disopyramide, ziprasidone, or terfenadine;
• Known allergy or intolerance to any of the study medications;
• AIDS patients;
• Pregnant or breast-feeding.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 6 centers

• Guiyang Public Health Clinical Center — Guiyang
• People's Hospital of Qiandongnan — Kaili
• The Third People's Hospital of Liupanshui — Liupanshui
• Affiliated Hospital of Zunyi Medical University — Zunyi
• Department of Infectious Disease, Huashan Hospital — Shanghai
• People's Hospital of Zhuji, Zhejiang Province — Zhuji

Publications

• Feng Z, Miao Y, Peng Y, Sun F, Zhang Y, Li R, Ge S, Chen X, Song L, Li Y, Wang X, Zhang W. Optimizing (O) rifapentine-based (RI) regimen and shortening (EN) the treatment of drug-susceptible tuberculosis (T) (ORIENT) using an adaptive seamless design: study protocol of a multicenter randomized controlled trial. BMC Infect Dis. 2023 May 8;23(1):300. doi: 10.1186/s12879-023-08264-2. PMID 37158831

Identifiers

NCT: NCT05401071 · ORIENT

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗