Clinical trial NCT04608955: Evaluation of Early Bactericidal Activity and Safety in Pulmonary Tuberculosis With WX-081
Official title: A Multi-center, Randomized, Positive-controlled Phase 2 Clinical Trial to Evaluate the Early Bactericidal Activity, Safety and Tolerability of WX-081 in Participants With Drug-naive&Susceptible or Drug-Resistant Pulmonary Tuberculosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary Tuberculosis
Keywords: Tuberculosis
Lead sponsor: Shanghai Jiatan Pharmatech Co., Ltd
Sponsor class: INDUSTRY
First posted: 2020-10-30
Enrollment: 99
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel Assignment
Primary purpose: TREATMENT

Brief summary: This is a multi-center, randomized, parallel, open-label, positive-controlled Phase 2 clinical trial, which aims to evaluate the early bactericidal activity, safety and tolerability of WX-081 in patients with drug-naive\&susceptible and drug-resistant tuberculosis. Also the efficacy of WX-081 will be explored in participants with drug-resistant tuberculosis.

Detailed description: This is a Phase 2, multi-center, randomized, parallel, open-label, positive-controlled clinical trial. The objective of this trial is to evaluate the early bactericidal activity, safety and tolerability of WX-081 patients with drug-naive\&susceptible and drug-resistant tuberculosis. and the efficacy in participants with drug-resistant tuberculosis.

This trial will be divided into core research stage (stage 1) and extended research stage (stage 2). During stage 1, a panel of 59 participants with drug-naive\&susceptible tuberculosis will be randomized to receive either WX-081(including 3 groups:150mg qd, 300mg qd, 450mg qd. n=12 per group) or standard treatment (n=8) for 2 weeks, and then followed by a follow-up period of 2 weeks. A panel of 40 participants with drug-resistant tuberculosis will be randomized to receive either WX-081 (400mg qd, n=20) or bedaquiline (400mg qd, n=20) for 2 weeks. During stage 2, the 40 participants with drug-resistant tuberculosis will receive WX-081(150mg qd) + MBT treatment (ie. multi-drug background treatment) and bedaquiline (200mg tiw) +MBT treatment for 6 weeks respectively, and then followed by a follow-up period of 4 weeks.

Eligibility criteria: Inclusion Criteria:

1. Male or female, aged between 18 and 65 years.
2. Body weight between 40 and 90 kg.
3. Newly-treated drug sensitivity tuberculosis: clinically diagnosed as pulmonary tuberculosis, without treatment, sputum smear-positive for acid-fast bacilli (AFB at least 1+), and no resistant to rifampicin or isoniazid in the drug sensitivity test.
4. Drug-resistant tuberculosis: re-treatment pulmonary tuberculosis patients, diagnosed as rifampicin resistance (RR-TB) or isoniazid and rifampicin resistance (MDR-TB) by molecular biology methods, and sputum smear-positive for acid-fast bacilli. Patients must be willing to discontinue all TB drugs to allow 7 days washout.
5. Patients must consent to HIV-testing, or provide HIV-negative report within 6 months.
6. Women are not breastfeeding or pregnant, and agree to practice effective contraception throughout the trial.
7. Provide voluntary and written informed consent prior to all trial-related procedures, agree to comply with the requirements and restrictions listed in the informed consent form and agreement.

Exclusion Criteria:

1. Patients with HIV infection.
2. Patients with miliary tuberculosis or extrapulmonary tuberculosis judged by the investigator.
3. Patients with certain QT/QTc interval characteristics as described in the protocol.
4. the patients have a history of, or current evidence of clinically relevant unstable or severe cardiovascular, kidney, liver, blood, tumor, endocrine and metabolic, mental or rheumatic diseases, or any other condition that will not be suitable to participate in this study, according to the judgement of the investigator.
5. Patients who have participated in other clinical studies within 8 weeks prior to trial start.
6. Patients having a known or suspected hypersensitivity or serious adverse reaction to drugs used in this trial.
7. Women who are pregnant, breastfeeding, or planning to become pregnant.
8. Current or past history of alcohol and/or drug use that, in the investigator's opinion, would compromise the participant's safety or compliance to the study protocol procedures.

Primary outcomes:
measure: Time to positive (TTP)
timeFrame: Day 0-14.
measure: Early bactericidal activity (EBA) of WX-081
timeFrame: Day 0-14.
Secondary outcomes:
measure: change of electrocardiogram QT interval
timeFrame: Measured through 8 Weeks.
measure: The percentage of participants with sputum culture-negative conversion.
timeFrame: Measured through 8 Weeks.
measure: Rate of change of colony forming units (CFU)
timeFrame: Measured through 8 Weeks.
measure: The percentage of participants with sputum smear-negative conversion.
timeFrame: Measured through 8 Weeks.
measure: heart rate
timeFrame: Measured through 8 Weeks.
measure: blood pressure
timeFrame: Measured through 8 Weeks.
measure: Maximum plasma concentration (Cmax)
timeFrame: At day1 and 14.
measure: Time to reach maximum plasma concentration (Tmax)
timeFrame: At day1 and 14.
measure: Area under the plasma concentration versus time curve (AUC(0-t))
timeFrame: At day1 and 14.
measure: Terminal plasma half-life (t1/2)
timeFrame: At day1 and 14.
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Chest Hospital affiliated to Capital Medical University
state: Beijing
Study officials:
affiliation: Shang hai Jiatan Pharma
name: Song AiYun, MD
role: STUDY_CHAIR
References:
citation: Huang Z, Luo W, Xu D, Guo F, Yang M, Zhu Y, Shen L, Chen S, Tang D, Li L, Li Y, Wang B, Franzblau SG, Ding CZ. Discovery and preclinical profile of sudapyridine (WX-081), a novel anti-tuberculosis agent. Bioorg Med Chem Lett. 2022 Sep 1;71:128824. doi: 10.1016/j.bmcl.2022.128824. Epub 2022 May 27.