Evaluation of Early Bactericidal Activity and Safety in Pulmonary Tuberculosis With WX-081 (WX-081)

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

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.

Study Overview

• Status: Completed
• Conditions: Pulmonary Tuberculosis
• Intervention / Treatment: Drug: WX-081; Drug: Standard treatment; Drug: Multi-drug background treatment (MBT); Drug: Bedaquiline

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.

• Study Type: Interventional
• Enrollment (Actual): 99
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 101149
      • Beijing Chest Hospital Affiliated to Capital Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

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

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: WX-081; Participants with newly-treated drug sensitivity tuberculosis receive WX-081 150mg orally once daily for 2 weeks.	Drug: WX-081; WX-081 is not licensed yet. WX-081 will be used in arms A, B, C, WX-081+MBT.
Experimental: Arm B: WX-081; Participants with newly-treated drug sensitivity tuberculosis receive WX-081 300mg orally once daily for 2 weeks.	Drug: WX-081; WX-081 is not licensed yet. WX-081 will be used in arms A, B, C, WX-081+MBT.
Experimental: Arm C: WX-081; Participants with newly-treated drug sensitivity tuberculosis receive WX-081 450mg orally once daily for 2 weeks.	Drug: WX-081; WX-081 is not licensed yet. WX-081 will be used in arms A, B, C, WX-081+MBT.
Active Comparator: Arm D: Standard treatment; Participants with newly-treated drug sensitivity tuberculosis receive standard treatment for two weeks.	Drug: Standard treatment; Standard treatment will be used in arm D as positive comparator, according to the recommendations of WHO guidelines for diagnosis and treatment of tuberculosis.
Experimental: Arm E: WX-081+MBT; Participants with drug-resistant tuberculosis receive WX-081 400mg orally once daily for 2 weeks, and then MBT+ WX-081 150mg orally once daily for 6 weeks.	Drug: WX-081; WX-081 is not licensed yet. WX-081 will be used in arms A, B, C, WX-081+MBT.; Drug: Multi-drug background treatment (MBT); MBT will be used in arm E, F as background treatment. The drugs used in MBT are all licensed drugs, and the treatment complies with the recommendations of WHO guidelines for diagnosis and treatment of tuberculosis.
Active Comparator: Arm F: Bedaquiline+MBT; Participants with drug-resistant tuberculosis receive Bedaquiline 400mg orally once daily for 2 weeks, and then MBT+ Bedaquiline 200mg orally 3 times per week for 6 weeks.	Drug: Multi-drug background treatment (MBT); MBT will be used in arm E, F as background treatment. The drugs used in MBT are all licensed drugs, and the treatment complies with the recommendations of WHO guidelines for diagnosis and treatment of tuberculosis.; Drug: Bedaquiline; This licensed drug will be used in arm F as positive comparator.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to positive (TTP)	TTP is measured as time to sputum culture positivity in Liquid Culture Media.	Day 0-14.
Early bactericidal activity (EBA) of WX-081	EBA is measured as the mean rate of colony forming unit (log10CFU) of mycobacterium tuberculosis per ml sputum on solid medium in different time periods.	Day 0-14.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
change of electrocardiogram QT interval	QT interval is calculated as QTcF in milliseconds (ms)	Measured through 8 Weeks.
The percentage of participants with sputum culture-negative conversion.	Percentage of participants with an occurrence of sputum culture-negative through 8 weeks.	Measured through 8 Weeks.
Rate of change of colony forming units (CFU)	Rate of change of colony forming units (CFU) of mycobacterium tuberculosis on sputum culture through 8 weeks.	Measured through 8 Weeks.
The percentage of participants with sputum smear-negative conversion.	Percentage of participants with an occurrence of sputum smear-negative through 8 weeks.	Measured through 8 Weeks.
heart rate	heart rate in times per minute.	Measured through 8 Weeks.
blood pressure	blood pressure in mmHg	Measured through 8 Weeks.
Maximum plasma concentration (Cmax)	Blood samples will be taken at different time points before and after administration on Day1 and Day14 of treatment.	At day1 and 14.
Time to reach maximum plasma concentration (Tmax)	Blood samples will be taken at different time points before and after administration on Day1 and Day14 of treatment.	At day1 and 14.
Area under the plasma concentration versus time curve (AUC(0-t))	Blood samples will be taken at different time points before and after administration on Day1 and Day14 of treatment.	At day1 and 14.
Terminal plasma half-life (t1/2)	Blood samples will be taken at different time points before and after administration on Day1 and Day14 of treatment.	At day1 and 14.

Collaborators and Investigators

• Sponsor: Shanghai Jiatan Pharmatech Co., Ltd
• Investigators: Study Chair: Song AiYun, MD, Shang hai Jiatan Pharma

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 16, 2020
• Primary Completion (Actual): April 13, 2022
• Study Completion (Actual): April 13, 2022

Study Registration Dates

• First Submitted: October 10, 2020
• First Submitted That Met QC Criteria: October 24, 2020
• First Posted (Actual): October 30, 2020

Study Record Updates

• Last Update Posted (Actual): September 11, 2023
• Last Update Submitted That Met QC Criteria: September 6, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Tuberculosis
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Anti-Infective Agents; Anti-Bacterial Agents; Antitubercular Agents; Bedaquiline
• Other Study ID Numbers: JYB0201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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