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

Primary Purpose

Pulmonary Tuberculosis

Status

Completed

Phase

Phase 2

Locations

China

Study Type

Interventional

Intervention

WX-081

Bedaquiline

Standard treatment

Multi-drug background treatment (MBT)

About this trial

This is an interventional treatment trial for Pulmonary Tuberculosis focused on measuring Tuberculosis

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Male or female, aged between 18 and 65 years.
Body weight between 40 and 90 kg.
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.
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.
Patients must consent to HIV-testing, or provide HIV-negative report within 6 months.
Women are not breastfeeding or pregnant, and agree to practice effective contraception throughout the trial.
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:

Patients with HIV infection.
Patients with miliary tuberculosis or extrapulmonary tuberculosis judged by the investigator.
Patients with certain QT/QTc interval characteristics as described in the protocol.
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.
Patients who have participated in other clinical studies within 8 weeks prior to trial start.
Patients having a known or suspected hypersensitivity or serious adverse reaction to drugs used in this trial.
Women who are pregnant, breastfeeding, or planning to become pregnant.
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.

Sites / Locations

Beijing Chest Hospital affiliated to Capital Medical University

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Active Comparator

Experimental

Active Comparator

Arm Label

Arm A: WX-081

Arm B: WX-081

Arm C: WX-081

Arm D: Standard treatment

Arm E: WX-081+MBT

Arm F: Bedaquiline+MBT

Arm Description

Participants with newly-treated drug sensitivity tuberculosis receive WX-081 150mg orally once daily for 2 weeks.

Participants with newly-treated drug sensitivity tuberculosis receive WX-081 300mg orally once daily for 2 weeks.

Participants with newly-treated drug sensitivity tuberculosis receive WX-081 450mg orally once daily for 2 weeks.

Participants with newly-treated drug sensitivity tuberculosis receive standard treatment for two weeks.

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.

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.

Outcomes

Primary Outcome Measures

Time to positive (TTP)

TTP is measured as time to sputum culture positivity in Liquid Culture Media.

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.

Secondary Outcome Measures

change of electrocardiogram QT interval

QT interval is calculated as QTcF in milliseconds (ms)

The percentage of participants with sputum culture-negative conversion.

Percentage of participants with an occurrence of sputum culture-negative 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.

The percentage of participants with sputum smear-negative conversion.

Percentage of participants with an occurrence of sputum smear-negative through 8 weeks.

heart rate

heart rate in times per minute.

blood pressure

blood pressure in mmHg

Maximum plasma concentration (Cmax)

Blood samples will be taken at different time points before and after administration on Day1 and Day14 of treatment.

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.

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.

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.

Full Information

NCT ID

NCT04608955

First Posted

October 10, 2020

Last Updated

September 6, 2023

Sponsor

Shanghai Jiatan Pharmatech Co., Ltd

1. Study Identification

Unique Protocol Identification Number

NCT04608955

Brief Title

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

Acronym

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

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Completed

Study Start Date

October 16, 2020 (Actual)

Primary Completion Date

April 13, 2022 (Actual)

Study Completion Date

April 13, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Shanghai Jiatan Pharmatech Co., Ltd

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Pulmonary Tuberculosis

Keywords

Tuberculosis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Model Description

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

99 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm A: WX-081

Arm Type

Experimental

Arm Description

Participants with newly-treated drug sensitivity tuberculosis receive WX-081 150mg orally once daily for 2 weeks.

Arm Title

Arm B: WX-081

Arm Type

Experimental

Arm Description

Participants with newly-treated drug sensitivity tuberculosis receive WX-081 300mg orally once daily for 2 weeks.

Arm Title

Arm C: WX-081

Arm Type

Experimental

Arm Description

Participants with newly-treated drug sensitivity tuberculosis receive WX-081 450mg orally once daily for 2 weeks.

Arm Title

Arm D: Standard treatment

Arm Type

Active Comparator

Arm Description

Participants with newly-treated drug sensitivity tuberculosis receive standard treatment for two weeks.

Arm Title

Arm E: WX-081+MBT

Arm Type

Experimental

Arm Description

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.

Arm Title

Arm F: Bedaquiline+MBT

Arm Type

Active Comparator

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

WX-081

Intervention Description

WX-081 is not licensed yet. WX-081 will be used in arms A, B, C, WX-081+MBT.

Intervention Type

Drug

Intervention Name(s)

Bedaquiline

Intervention Description

This licensed drug will be used in arm F as positive comparator.

Intervention Type

Drug

Intervention Name(s)

Standard treatment

Intervention Description

Standard treatment will be used in arm D as positive comparator, according to the recommendations of WHO guidelines for diagnosis and treatment of tuberculosis.

Intervention Type

Drug

Intervention Name(s)

Multi-drug background treatment (MBT)

Intervention Description

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.

Primary Outcome Measure Information:

Title

Time to positive (TTP)

Description

TTP is measured as time to sputum culture positivity in Liquid Culture Media.

Time Frame

Day 0-14.

Title

Early bactericidal activity (EBA) of WX-081

Description

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.

Time Frame

Day 0-14.

Secondary Outcome Measure Information:

Title

change of electrocardiogram QT interval

Description

QT interval is calculated as QTcF in milliseconds (ms)

Time Frame

Measured through 8 Weeks.

Title

The percentage of participants with sputum culture-negative conversion.

Description

Percentage of participants with an occurrence of sputum culture-negative through 8 weeks.

Time Frame

Measured through 8 Weeks.

Title

Rate of change of colony forming units (CFU)

Description

Rate of change of colony forming units (CFU) of mycobacterium tuberculosis on sputum culture through 8 weeks.

Time Frame

Measured through 8 Weeks.

Title

The percentage of participants with sputum smear-negative conversion.

Description

Percentage of participants with an occurrence of sputum smear-negative through 8 weeks.

Time Frame

Measured through 8 Weeks.

Title

heart rate

Description

heart rate in times per minute.

Time Frame

Measured through 8 Weeks.

Title

blood pressure

Description

blood pressure in mmHg

Time Frame

Measured through 8 Weeks.

Title

Maximum plasma concentration (Cmax)

Description

Blood samples will be taken at different time points before and after administration on Day1 and Day14 of treatment.

Time Frame

At day1 and 14.

Title

Time to reach maximum plasma concentration (Tmax)

Description

Blood samples will be taken at different time points before and after administration on Day1 and Day14 of treatment.

Time Frame

At day1 and 14.

Title

Area under the plasma concentration versus time curve (AUC(0-t))

Description

Blood samples will be taken at different time points before and after administration on Day1 and Day14 of treatment.

Time Frame

At day1 and 14.

Title

Terminal plasma half-life (t1/2)

Description

Blood samples will be taken at different time points before and after administration on Day1 and Day14 of treatment.

Time Frame

At day1 and 14.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Male or female, aged between 18 and 65 years. Body weight between 40 and 90 kg. 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. 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. Patients must consent to HIV-testing, or provide HIV-negative report within 6 months. Women are not breastfeeding or pregnant, and agree to practice effective contraception throughout the trial. 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: Patients with HIV infection. Patients with miliary tuberculosis or extrapulmonary tuberculosis judged by the investigator. Patients with certain QT/QTc interval characteristics as described in the protocol. 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. Patients who have participated in other clinical studies within 8 weeks prior to trial start. Patients having a known or suspected hypersensitivity or serious adverse reaction to drugs used in this trial. Women who are pregnant, breastfeeding, or planning to become pregnant. 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Song AiYun, MD

Organizational Affiliation

Shang hai Jiatan Pharma

Official's Role

Study Chair

Facility Information:

Facility Name

Beijing Chest Hospital affiliated to Capital Medical University

City

Beijing

State/Province

Beijing

ZIP/Postal Code

101149

Country

China

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

35636648

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.

Results Reference

derived

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

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