A PAN-USR TB Multi-Center Trial

Официальное название

A Pan-Ultrashort Regimen for Drug-susceptible and Drug-resistant Pulmonary Tuberculosis: A Multi-Center Randomized Controlled Trial

Обзор

Tuberculosis (TB) remains a major public health issue and one of the top ten causes of death from a single infectious disease worldwide. China is among the countries with the highest TB burden, ranking third globally for total TB cases and second for drug-resistant TB cases. PAN-TB is an innovative concept in TB treatment, aiming to develop a universal regimen effective for all forms of active TB, including both drug-susceptible and drug-resistant strains. The primary goal of the PAN-TB regimen is to simplify the treatment process, reduce costs, and improve treatment success rates. The ideal Target Regimen Profile (TRP) for PAN-TB includes superior efficacy compared to standard treatment for non-drug-resistant TB, a reduced treatment duration from the current 4-6 months to 2-3 months, and improved safety and tolerability. This project aims to explore a new ultra-short-course treatment regimen for both drug-sensitive (DS-TB) and drug-resistant TB (MDR/RR-TB), which aligns with the latest trends in TB treatment both domestically and internationally. The regimen also has significant practical implications for enhancing treatment efficacy and reducing patient burden. Furthermore, the study will explore the identification of new biomarkers closely linked to treatment outcomes over the course of full-cycle therapy.

Вмешательства

• Препарат Bedaquiline (B)
  The initial dose of bedaquiline is 400 mg daily for 2 weeks, followed by 200 mg three times a week.
• Препарат Sitafloxacin (S)
  200mg once daily
• Препарат Linezolid (L)
  600mg once daily
• Препарат Pyrazinamide (Z)
  20-30 mg/kg/day; 1000 mg for patients weighing \<50 kg, 1500 mg for patients weighing ≥50 kg but \<75 kg, and 2000 mg for patients weighing ≥75 kg.
• Препарат Isoniazid (H)
  4-6 mg/kg once daily, 300 mg once daily
• Препарат Rifampicin (R)
  8-12 mg/kg once daily, 450 mg for patients weighing \<50 kg, 600 mg for patients weighing ≥50 kg but \<75 kg, and 750 mg for patients weighing ≥75 kg.
• Препарат Ethambutol (E)
  15-25 mg/kg once daily, 750 mg once daily
• Препарат Moxifloxacin (M)
  400mg once daily
• Препарат Pretomanid (Pa)
  200mg once daily

Первичные конечные точки

• Unfavorable outcomes [Срок оценки: 12 months (52 weeks)]
• Safety [Срок оценки: 2 months (9 weeks)]

Вторичные конечные точки (9)

• Sputum culture conversion rate [Срок оценки: 2 months (9 weeks) after randomization]
• Unfavorable outcomes (short-term) [Срок оценки: 6 months (26 weeks) after randomization]
• Unfavorable outcomes (mid-term) [Срок оценки: 18 months (78 weeks) after randomization]
• Time to sputum culture conversion [Срок оценки: Median time]
• Serious adverse events or grade 3 or higher adverse events (short-term) [Срок оценки: 12 months (52 weeks) after randomization]
• Serious adverse events or grade 3 or higher adverse events (mid-term) [Срок оценки: 18 months (78 weeks) after randomization]
• Adverse events during treatment [Срок оценки: 9 or 13 weeks (A1, A2); 26 weeks (B, C)]
• QTcF prolongation during treatment [Срок оценки: 9 or 13 weeks (A1, A2); 26 weeks (B, C)]
• Liver function damage during treatment [Срок оценки: 9 or 13 weeks (A1, A2); 26 weeks (B, C)]

Критерии участия

Критерии включения

• Age range from 18 to 65 years old, regardless of gender;
• Clinical symptoms and/or pulmonary imaging (chest X-ray or chest CT) support the diagnosis of active pulmonary tuberculosis;
• Microbiological testing (molecular or phenotypic) confirms the presence of Mycobacterium tuberculosis, whether resistant to rifampicin or not; Recommend using respiratory specimens for GeneXpert MTB/RIF testing;
• Voluntarily sign the informed consent form for participating in this project and be able and willing to accept follow-up visits;
• Willing to undergo HIV testing;
• Willing to preserve samples including DNA;
• For women with fertility, they have a negative serum or urine pregnancy test within 3 days before enroll the study and be willing to use effective contraceptive measures during the study period. Female subjects without fertility must have records of menopause, hysterectomy, bilateral oophorectomy, or bilateral tubal ligation. Acceptable forms of contraception include condoms, intrauterine devices, cervical caps with spermicides, and diaphragm with spermicides.

Критерии исключения

• Prior to this study, patients who were diagnosed with active pulmonary tuberculosis and had received anti-tuberculosis treatment (including first-line and second-line anti-tuberculosis drugs);
• Intolerance or allergy to any investigational drug (i.e., bedaquiline, linezolid, fluoroquinolones \[including moxifloxacin, sitagliptin\], pyrazinamide);
• Resistance to any investigational drug (i.e., bedaquiline, linezolid, fluoroquinolones \[including moxifloxacin, sitagliptin\], pyrazinamide). The following detection methods can be used: tNGS or other drug sensitivity testing methods (such as GeneXpert MTB/XDR, dissolution curve method, phenotypic drug sensitivity, etc.);
• Suffering from hematogenous disseminated tuberculosis or coexisting with extrapulmonary tuberculosis (as specified in this study, the scope of pulmonary tuberculosis includes: simple pulmonary tuberculosis, pulmonary tuberculosis + tuberculous pleurisy/bronchial tuberculosis/mediastinal lymph node tuberculosis. Extrapulmonary tuberculosis refers to tuberculosis other than the chest-related types mentioned above);
• Presence of non-tuberculous mycobacteria or other microbial lung infections that affect treatment outcomes;
• Simultaneously using drugs that affect the efficacy of this study or have contraindications for combination therapy;
• Use of any immunosuppressive medication or systemic glucocorticoids for more than 2 weeks before screening;
• Any medication currently used or planned to be used that is known to significantly prolong the QTc interval, including but not limited to: amiodarone, amitriptyline, chloroquine, chlorpromazine, cisapride, dipyridamole, itraconazole, procaine, quinidine, or sotalol;
• Uncontrolled blood sugar in diabetes, with no likelihood of improving blood sugar status according to the judgment of the researchers;
• HIV positive;
• Coexisting with severe autoimmune diseases, severe liver and kidney dysfunction, psychiatric disorders, hematological disorders, or malignant tumors;
• Laboratory parameters within 14 days prior to recruitment: (1) Serum AST and ALT levels ≥ 3 times the upper limit of normal (ULN); (2) Blood creatinine ≥ 2 times ULN; (3) Hemoglobin ≤ 70 g/L; (4) Platelet count ≤ 50 × 10\^9/L; (5) Blood potassium levels are ≥ 5.5 mmol/L or ≤ 3.5 mmol/L;
• ECG QTcF ≥450 ms (allowing for one re-test during the screening phase to reassess eligibility for inclusion); Presence of one or more risk factors that could cause QT interval prolongation, such as arrhythmia, myocardial ischemia, etc.; history or family history of long QT syndrome;
• Women who are pregnant or breastfeeding;
• Weight <30 kg, or ≥90 kg;
• The patient has participated in clinical trials of other drugs within the past 3 months during the screening period;
• Other conditions deemed unsuitable for participation in the study by the research doctors.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 3 центра

• Beijing Chest Hospital of Capital Medical University — Пекин
• Shenzhen Third People's Hospital — Шэньчжэнь
• The Sixth People's Hospital of the Xinjiang Uygur Autonomous Region — Ürümqi

Публикации

• Paton NI, Cousins C, Suresh C, Burhan E, Chew KL, Dalay VB, Lu Q, Kusmiati T, Balanag VM, Lee SL, Ruslami R, Pokharkar Y, Djaharuddin I, Sugiri JJR, Veto RS, Sekaggya-Wiltshire C, Avihingsanon A, Sarin R, Papineni P, Nunn AJ, Crook AM; TRUNCATE-TB Trial Team. Treatment Strategy for Rifampin-Susceptible Tuberculosis. N Engl J Med. 2023 Mar 9;388(10):873-887. doi: 10.1056/NEJMoa2212537. Epub 2023 Fe PMID 36808186
• Conradie F, Bagdasaryan TR, Borisov S, Howell P, Mikiashvili L, Ngubane N, Samoilova A, Skornykova S, Tudor E, Variava E, Yablonskiy P, Everitt D, Wills GH, Sun E, Olugbosi M, Egizi E, Li M, Holsta A, Timm J, Bateson A, Crook AM, Fabiane SM, Hunt R, McHugh TD, Tweed CD, Foraida S, Mendel CM, Spigelman M; ZeNix Trial Team. Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis. N PMID 36053506
• Nyang'wa BT, Berry C, Kazounis E, Motta I, Parpieva N, Tigay Z, Solodovnikova V, Liverko I, Moodliar R, Dodd M, Ngubane N, Rassool M, McHugh TD, Spigelman M, Moore DAJ, Ritmeijer K, du Cros P, Fielding K; TB-PRACTECAL Study Collaborators. A 24-Week, All-Oral Regimen for Rifampin-Resistant Tuberculosis. N Engl J Med. 2022 Dec 22;387(25):2331-2343. doi: 10.1056/NEJMoa2117166. PMID 36546625
• Nyang'wa BT, Berry C, Kazounis E, Motta I, Parpieva N, Tigay Z, Moodliar R, Dodd M, Solodovnikova V, Liverko I, Rajaram S, Rassool M, McHugh T, Spigelman M, Moore DA, Ritmeijer K, du Cros P, Fielding K; TB-PRACTECAL team. Short oral regimens for pulmonary rifampicin-resistant tuberculosis (TB-PRACTECAL): an open-label, randomised, controlled, phase 2B-3, multi-arm, multicentre, non-inferiority tri PMID 37980911
• Zhang Y, Shi W, Zhang W, Mitchison D. Mechanisms of Pyrazinamide Action and Resistance. Microbiol Spectr. 2014 Aug;2(4):MGM2-0023-2013. doi: 10.1128/microbiolspec.MGM2-0023-2013. PMID 26104205
• Zhang Y, Chiu Chang K, Leung CC, Wai Yew W, Gicquel B, Fallows D, Kaplan G, Chaisson RE, Zhang W. 'Z(S)-MDR-TB' versus 'Z(R)-MDR-TB': improving treatment of MDR-TB by identifying pyrazinamide susceptibility. Emerg Microbes Infect. 2012 Jul;1(7):e5. doi: 10.1038/emi.2012.18. Epub 2012 Jul 25. PMID 26038418
• Fu L, Zhang X, Xiong J, Sun F, Weng T, Li Y, Zhang P, Li H, Yang Q, Cai Y, Liang H, Chen Q, Wang Z, Liu L, Chen X, Zhang W, Deng G. Selecting an appropriate all-oral short-course regimen for patients with multidrug-resistant or pre-extensive drug-resistant tuberculosis in China: A multicenter prospective cohort study. Int J Infect Dis. 2023 Oct;135:101-108. doi: 10.1016/j.ijid.2023.08.001. Epub 20 PMID 37567554

Идентификаторы

NCT: NCT06905522 · SMART-C2405002

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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