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Refining MDR-TB Treatment (T) Regimens (R) for Ultra(U) Short(S) Therapy(T)-PLUS (TB-TRUSTplus)

Primary Purpose

Multidrug Resistant Tuberculosis

Status
Active
Phase
Not Applicable
Locations
China
Study Type
Interventional
Intervention
Bedaquiline
Pyrazinamide
Linezolid
Cycloserine
Clofazimine
Sponsored by
Huashan Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Multidrug Resistant Tuberculosis focused on measuring Multidrug resistant tuberculosis, shorter treatment, all-oral regimen, PZA sensitivity

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Willing to participate in trial treatment and follow-up and can give informed consent
  • 18-70 years old
  • Has smear-positive pulmonary tuberculosis with initial laboratory results with resistance to rifampicin and isoniazide confirmed by GeneXpert
  • documented resistance to fluoroquinolones at screening
  • Can use bedaquiline, linezolid, cycloserine, clofazimine and pyrazinamide drugs concerning the availability and costs of essential medicines
  • Willing to carry out HIV testing.
  • If the patient is a non-menopausal woman, agree to use or have used effective contraception during treatment.
  • Have an identifiable address and stay in the area during the study period.
  • Willing to follow the follow-up study procedure after the follow-up.

Exclusion Criteria:

  • Combined extrapulmonary tuberculosis;
  • HIV antibody positive and AIDS patients;
  • Critically ill patients, and according to the judgment of the research physician, it is impossible to survive for more than 16 weeks;
  • Known to be pregnant or breastfeeding;
  • Unable to attend or follow treatment or follow-up time;
  • Can not take oral medications;
  • Patients with impaired liver function (hepatic encephalopathy, ascites; total bilirubin is more than 2 times higher than the upper limit of normal; ALT or AST is more than 5 times the upper limit of normal);
  • Blood muscle spasm is more than 1.5 times the upper limit of normal;
  • The investigator believes that there are any social or medical conditions that expose the subject to a safety hazard;
  • Simultaneously apply the drugs (glucocorticoids, interferons) that affect the efficacy of this study; and apply the following drugs contraindicated with the study drug, including non-steroidal anti-inflammatory drugs, monoamine oxidase inhibitors (phenethyl hydrazine, different Carbofurs et al), direct or indirect sympathomimetic drugs (such as pseudoephedrine), vasopressor drugs (such as adrenaline, norepinephrine), dopamine drugs (such as dopamine, dobutamine), 5 a serotonin reuptake inhibitor, a tricyclic antidepressant, a serotonin 5-HTI receptor antagonist (amitriptyline), meperidine or buspirone.
  • Being allergic or intolerant of any study drug;
  • Currently participating in another drug clinical trial;
  • QTc interval ≥ 500 milliseconds during screening;
  • Hemoglobin is less than 90g/L or platelet is less than 75*10^9/L;
  • Have epilepsy, severe depression, irritability or psychosis；
  • Alcohol abuse（drinking more than 64g of ethanol a day for male, 42g for female）.
  • Subjects receive more than 2 weeks of bedaquiline, linezolid, cycloserine, clofazimine or pyrazinamide 3 months prior to enrolment.

Sites / Locations

  • The Third People's Hospital of Shenzhen City
  • Guiyang Public Health Treatment Center
  • The Sixth People's Hospital of Zhengzhou
  • Hunan Chest Hospital
  • Huaihua first people's Hospital
  • Huashan Hospital of Fudan University
  • Shanxi Provincial Tuberculosis Control Institute
  • Chest Hospitalof Xinjiang Uygur Autonomous Region of PRC
  • Baoshan People's Hospital
  • Yunnan Provincial Infectious Disease Hospital
  • Hangzhou Red Cross Hospital
  • Hwa Mei Hosptal,University of Chinese Academy of Sciences(Ningbo No.2 Hospital)
  • Taizhou Enze medical center Enze Hospital
  • The Central Hospital of Wenzhou City
  • Jiangxi Chest Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

PZA sensitivity guided all oral regimen

Arm Description

This regimen consists of two periods of 24-36 weeks. During the first 4-8 weeks(waiting for pyrazinamide drug sensitivity test), the regimen consists of bedaquiline, linezolid, cycloserine, clofazimine and pyrazinamide. Then based on molecular PZA drug sensitivity results, patients will be divided into three sub-groups. The regimen for PZA-S patients, consisting of bedaquiline, linezolid, cycloserine and pyrazinamide, are given until the 24th week (prolonged to 28 or 32 weeks if no smear conversion by end of 16th and 20th week). PZA-R sub-group regimen, consisting of bedaquiline, linezolid, cycloserine and clofazimine ,are given until 36th week (prolonged to 40 or 44 weeks if no smear conversion by end of 16th and 20th week) . PZA-U sub-group continue the previous regimen, consisting of bedaquiline, linezolid, cycloserine , clofazimine and pyrazinamide ,until 36th week (prolonged to 40 or 44 weeks if no smear conversion by end of 16th and 20th week) .

Outcomes

Primary Outcome Measures

Treatment success rate
To access the treatment success rate without relapse .Treatment outcomes will be classified into favourable outcome and unfavourable outcome.

Secondary Outcome Measures

The median time to Sputum Culture Conversion
time from treatment initiation to the first of two consecutive negative sputum cultures without an intervening positive culture in liquid media
The frequency of grade 3 or greater adverse events among patients
to access the proportion of patients who experience grade 3 or greater adverse events (graded according to the Division of AIDS severity criteria for adverse events) during treatment or follow-up;

Full Information

First Posted
January 17, 2021
Last Updated
April 5, 2023
Sponsor
Huashan Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT04717908
Brief Title
Refining MDR-TB Treatment (T) Regimens (R) for Ultra(U) Short(S) Therapy(T)-PLUS
Acronym
TB-TRUSTplus
Official Title
Refining MDR-TB Treatment (T) Regimens (R) for Ultra(U) Short(S) Therapy(T) (TB-TRUST)-PLUS
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
January 20, 2021 (Actual)
Primary Completion Date
April 30, 2023 (Anticipated)
Study Completion Date
November 30, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Huashan Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to assess the efficacy, safety and tolerability of a combination of bedaquiline, linezolid, cycloserine, clofazimine and pyrazinamide treatments guided by PZA sensitivity for 24 to 36 weeks in subjects with fluoroquinolone-resistant MDR-TB .
Detailed Description
The TB-TRUST-plus is a phaseIII, multicenter, open-label trial. The purpose of this study is to assess the feasibility of the ultra-short treatment regimen guided by PZA sensitivity among fluoroquinolone-resistant MDR-TB patients.A total of 200 participants with MDR-TB will be recruited and followed up until 84 weeks after the treatment initiation. This regimen consists of two periods of 24-36 weeks. During the first 4-8 weeks(waiting for pyrazinamide drug sensitivity test), the regimen consists of bedaquiline, linezolid, cycloserine, clofazimine and pyrazinamide. Then based on molecular PZA drug sensitivity results, patients will be in divided into 3 sub-groups: pyrazinamide-susceptible (PZA-S) patients , pyrazinamide-resistant (PZA-R) patients and pyrazinamide-unavailable (PZA-U)patients. The Regimen for PZA-S patients, consisting of bedaquiline, linezolid, cycloserine and pyrazinamide, are given until the 24th week (prolonged to 28 or 32 weeks if no smear conversion by end of 16th and 20th week). PZA-R sub-group regimen, consisting of bedaquiline, linezolid, cycloserine and clofazimine ,are given until 36th week (prolonged to 40 or 44 weeks if no smear conversion by end of 16th and 20th week) . PZA-U sub-group continue the previous regimen, consisting of bedaquiline, linezolid, cycloserine , clofazimine and pyrazinamide ,until 36th week (prolonged to 40 or 44 weeks if no smear conversion by end of 16th and 20th week) . The primary objective is to access the treatment success rate without relapse of the PZA sensitivity guided ultra short regimen. The secondary objective is to access the median time to sputum culture conversion. Safety evaluations performed are the routine lab tests, blood glucose, vital signs, electrocardiograph (ECG), reporting of adverse events, peripheral neuropathy brief examining with the use of a Brief Peripheral Neuropathy rating scale(BPNS) and ophthalmologic examination, including assessment of visual acuity and color vision，physical examinations and chest CT. Adverse events will be monitored and promptly managed during the whole treatment course.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multidrug Resistant Tuberculosis
Keywords
Multidrug resistant tuberculosis, shorter treatment, all-oral regimen, PZA sensitivity

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
89 (Actual)

8. Arms, Groups, and Interventions

Arm Title
PZA sensitivity guided all oral regimen
Arm Type
Experimental
Arm Description
This regimen consists of two periods of 24-36 weeks. During the first 4-8 weeks(waiting for pyrazinamide drug sensitivity test), the regimen consists of bedaquiline, linezolid, cycloserine, clofazimine and pyrazinamide. Then based on molecular PZA drug sensitivity results, patients will be divided into three sub-groups. The regimen for PZA-S patients, consisting of bedaquiline, linezolid, cycloserine and pyrazinamide, are given until the 24th week (prolonged to 28 or 32 weeks if no smear conversion by end of 16th and 20th week). PZA-R sub-group regimen, consisting of bedaquiline, linezolid, cycloserine and clofazimine ,are given until 36th week (prolonged to 40 or 44 weeks if no smear conversion by end of 16th and 20th week) . PZA-U sub-group continue the previous regimen, consisting of bedaquiline, linezolid, cycloserine , clofazimine and pyrazinamide ,until 36th week (prolonged to 40 or 44 weeks if no smear conversion by end of 16th and 20th week) .
Intervention Type
Drug
Intervention Name(s)
Bedaquiline
Other Intervention Name(s)
BDQ
Intervention Description
400 mg once daily for 2 weeks then 200mg 3 times per week;
Intervention Type
Drug
Intervention Name(s)
Pyrazinamide
Other Intervention Name(s)
PZA
Intervention Description
1500 mg daily
Intervention Type
Drug
Intervention Name(s)
Linezolid
Other Intervention Name(s)
LZD
Intervention Description
600 mg daily
Intervention Type
Drug
Intervention Name(s)
Cycloserine
Other Intervention Name(s)
Cs
Intervention Description
≤50kg 500 mg daily, >50kg 750mg daily;
Intervention Type
Drug
Intervention Name(s)
Clofazimine
Other Intervention Name(s)
CFZ
Intervention Description
100 mg daily;
Primary Outcome Measure Information:
Title
Treatment success rate
Description
To access the treatment success rate without relapse .Treatment outcomes will be classified into favourable outcome and unfavourable outcome.
Time Frame
84 weeks after the treatment initiation
Secondary Outcome Measure Information:
Title
The median time to Sputum Culture Conversion
Description
time from treatment initiation to the first of two consecutive negative sputum cultures without an intervening positive culture in liquid media
Time Frame
Time Frame: 12-36 weeks after treatment initiation
Title
The frequency of grade 3 or greater adverse events among patients
Description
to access the proportion of patients who experience grade 3 or greater adverse events (graded according to the Division of AIDS severity criteria for adverse events) during treatment or follow-up;
Time Frame
84 weeks after treatment initiation

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Willing to participate in trial treatment and follow-up and can give informed consent 18-70 years old Has smear-positive pulmonary tuberculosis with initial laboratory results with resistance to rifampicin and isoniazide confirmed by GeneXpert documented resistance to fluoroquinolones at screening Can use bedaquiline, linezolid, cycloserine, clofazimine and pyrazinamide drugs concerning the availability and costs of essential medicines Willing to carry out HIV testing. If the patient is a non-menopausal woman, agree to use or have used effective contraception during treatment. Have an identifiable address and stay in the area during the study period. Willing to follow the follow-up study procedure after the follow-up. Exclusion Criteria: Combined extrapulmonary tuberculosis; HIV antibody positive and AIDS patients; Critically ill patients, and according to the judgment of the research physician, it is impossible to survive for more than 16 weeks; Known to be pregnant or breastfeeding; Unable to attend or follow treatment or follow-up time; Can not take oral medications; Patients with impaired liver function (hepatic encephalopathy, ascites; total bilirubin is more than 2 times higher than the upper limit of normal; ALT or AST is more than 5 times the upper limit of normal); Blood muscle spasm is more than 1.5 times the upper limit of normal; The investigator believes that there are any social or medical conditions that expose the subject to a safety hazard; Simultaneously apply the drugs (glucocorticoids, interferons) that affect the efficacy of this study; and apply the following drugs contraindicated with the study drug, including non-steroidal anti-inflammatory drugs, monoamine oxidase inhibitors (phenethyl hydrazine, different Carbofurs et al), direct or indirect sympathomimetic drugs (such as pseudoephedrine), vasopressor drugs (such as adrenaline, norepinephrine), dopamine drugs (such as dopamine, dobutamine), 5 a serotonin reuptake inhibitor, a tricyclic antidepressant, a serotonin 5-HTI receptor antagonist (amitriptyline), meperidine or buspirone. Being allergic or intolerant of any study drug; Currently participating in another drug clinical trial; QTc interval ≥ 500 milliseconds during screening; Hemoglobin is less than 90g/L or platelet is less than 75*10^9/L; Have epilepsy, severe depression, irritability or psychosis； Alcohol abuse（drinking more than 64g of ethanol a day for male, 42g for female）. Subjects receive more than 2 weeks of bedaquiline, linezolid, cycloserine, clofazimine or pyrazinamide 3 months prior to enrolment.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Wenhong Zhang, PhD
Organizational Affiliation
Huashan Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Third People's Hospital of Shenzhen City
City
Shenzhen
State/Province
Guangzhou
Country
China
Facility Name
Guiyang Public Health Treatment Center
City
Guizhou
State/Province
Guizhou
Country
China
Facility Name
The Sixth People's Hospital of Zhengzhou
City
Zhengzhou
State/Province
Henan
Country
China
Facility Name
Hunan Chest Hospital
City
Changsha
State/Province
Hunan
Country
China
Facility Name
Huaihua first people's Hospital
City
Huaihua
State/Province
Hunan
Country
China
Facility Name
Huashan Hospital of Fudan University
City
Shanghai
State/Province
Shanghai
ZIP/Postal Code
200040
Country
China
Facility Name
Shanxi Provincial Tuberculosis Control Institute
City
Xi'an
State/Province
Shanxi
Country
China
Facility Name
Chest Hospitalof Xinjiang Uygur Autonomous Region of PRC
City
Urumqi
State/Province
Xinjiang
Country
China
Facility Name
Baoshan People's Hospital
City
Baoshan
State/Province
Yunnan
Country
China
Facility Name
Yunnan Provincial Infectious Disease Hospital
City
Kunming
State/Province
Yunnan
Country
China
Facility Name
Hangzhou Red Cross Hospital
City
Hangzhou
State/Province
Zhejiang
Country
China
Facility Name
Hwa Mei Hosptal,University of Chinese Academy of Sciences(Ningbo No.2 Hospital)
City
Ningbo
State/Province
Zhejiang
Country
China
Facility Name
Taizhou Enze medical center Enze Hospital
City
Taizhou
State/Province
Zhejiang
Country
China
Facility Name
The Central Hospital of Wenzhou City
City
Wenzhou
State/Province
Zhejiang
Country
China
Facility Name
Jiangxi Chest Hospital
City
Nanchang
Country
China

12. IPD Sharing Statement

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Refining MDR-TB Treatment (T) Regimens (R) for Ultra(U) Short(S) Therapy(T)-PLUS

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