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

Primary Purpose

Multidrug Resistant Tuberculosis

Status
Active
Phase
Phase 4
Locations
China
Study Type
Interventional
Intervention
PZA sensitivity guided ultra-short all Oral Regimen
Standardized Shorter Regimen
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

Eligibility Criteria

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

Inclusion Criteria:

1.Willing to participate in trial treatment and follow-up and can give informed consent 2.18-70 years old 3.Has smear-positive pulmonary tuberculosis with initial laboratory results with resistance to rifampicin confirmed by GeneXpert 4.Willing to carry out HIV testing. 5. If you are a non-menopausal woman, agree to use or have used effective contraception during treatment.

6. Have an identifiable address and stay in the area during the study period. 7.Willing to follow the follow-up study procedure after the follow-up.

Exclusion Criteria:

  1. Molecular drug resistance test for infected strains resistant to second-line injection;
  2. Molecular drug resistance assay for infected strains resistant to fluoroquinolone;
  3. Combined extrapulmonary tuberculosis;
  4. HIV antibody positive and AIDS patients;
  5. Critically ill patients, and according to the judgment of the research physician, it is impossible to survive for more than 16 weeks;
  6. Known to be pregnant or breastfeeding;
  7. Unable to attend or follow treatment or follow-up time;
  8. Can not take oral medications;
  9. 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);
  10. Blood muscle spasm is more than 1.5 times the upper limit of normal;
  11. The investigator believes that there are any social or medical conditions that expose the subject to a safety hazard;
  12. 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.
  13. Being allergic or intolerant of any study drug;
  14. Currently participating in another drug clinical trial;
  15. QTc interval ≥ 500 milliseconds during screening;
  16. Hemoglobin is less than 90g/L or platelet is less than 75*10^9/L;
  17. Have epilepsy, severe depression, irritability or psychosis;
  18. Alchol abuse(drinking more than 64g of ethanol a day for male, 42g for female).

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
  • Xuzhou Infectious Disease Hospital
  • Huashan Hospital of Fudan University
  • Shanxi Provincial Tuberculosis Control Institute
  • Southwest Medical University Affiliated Hospital
  • Chest Hospitalof Xinjiang Uygur Autonomous Region of PRC
  • Hangzhou Red Cross Hospital
  • Zhejiang Provincial Center for Disease Control and Prevention
  • The Central Hospital of Wenzhou City
  • Jiangxi Chest Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

PZA sensitivity guided ultra-short all Oral Regimen

Standardized Shorter Regimen

Arm Description

The PZA sensitivity guided ultra-short 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 levofloxacin, linezolid, cycloserine, pyrazinamide, and clofazimine. Then based on molecular PZA drug sensitivity results, patients will be in divided into two sub-groups: pyrazinamide-susceptible (PZA-S) patients and pyrazinamide-resistant (PZA-R) patients. The Regimen for PZA-S patients, consisting of levofloxacin, 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 levofloxacin, linezolid, cycloserine, and clofazimine given until 36th week (prolonged to 40 or 44 weeks if no smear conversion by end of 16th and 20th week)

WHO standardized shorter regimen group consists of 36-44 weeks with two phases of treatment. The first is an intensive phase of 16 weeks (extended up a maximum of 20 or 24 weeks in case of lack of smear conversion at the end of 16 or 20 weeks), and included moxifloxacin, amikacin, prothionamide, pyrazinamide, high-dose isoniazid, ethambutol and clofazimine. This is followed by a continuation phase of 20 weeks with the following agents: moxifloxacin, pyrazinamide, ethambutol and clofazimine.

Outcomes

Primary Outcome Measures

Treatment success rate of the ultra short regimen
To compare the treatment success rate without relapse between the PZA sensitivity guided all oral ultra short regimen group and the WHO standardized shorter regimen group. Treatment outcomes will be classified into favourable outcome and unfavourble 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 between the ultra short regimen group and the standardized short regimen group;
The frequency of grade 3 or greater adverse events among patients treated with the ultra short regimen
to compare 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, on the experimental regimen when compared to the control regimen;

Full Information

First Posted
March 6, 2019
Last Updated
April 5, 2023
Sponsor
Huashan Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT03867136
Brief Title
Refining MDR-TB Treatment (T) Regimens (R) for Ultra(U) Short(S) Therapy(T)
Acronym
TB-TRUST
Official Title
Refining Multidrug Tuberculosis Treatment With the Ultra Short All Oral Regimen
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
June 1, 2020 (Actual)
Primary Completion Date
May 1, 2023 (Anticipated)
Study Completion Date
November 1, 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 levofloxacin, linezolid, cycloserine and pyrazinamide (or clofazimine if resistant to pyrazinamide) treatments for 24 to 32 weeks (regimen consisted of clofazimine for 36~44 weeks) in subjects with multidrug-resistant tuberculosis (MDR-TB) compared to WHO standardized shorter regimen of 36-44 weeks.
Detailed Description
The TB-TRUST is a phaseIII, multicenter, open-label, randomized controlled trial. The purpose of this study is to assess the feasibility of the ultra-short treatment regimen of all-oral anti-TB drugs among selected MDR-TB patients who are susceptible to fluoroquinolones. A total of 354 participants with MDR-TB will be recruited and followed up until 84 weeks after randomization. During randomization, eligible patients will be assigned to in a 1:1 ratio to one of the following groups: The WHO standardized shorter regimen group and a PZA sensitivity guided ultra-short regimen group. WHO standardized shorter regimen group consists of 36-44 weeks with two phases of treatment. The first is an intensive phase of 16 weeks (extended up a maximum of 20 or 24 weeks in case of lack of smear conversion at the end of 16 or 20 weeks), and included moxifloxacin, amikacin, prothionamide, pyrazinamide, high-dose isoniazid, ethambutol, and clofazimine. This is followed by a continuation phase of 20 weeks with the following agents: moxifloxacin, pyrazinamide, ethambutol, and clofazimine. The PZA sensitivity guided ultra-short 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 levofloxacin, linezolid, cycloserine, pyrazinamide, and clofazimine. Then based on molecular PZA drug sensitivity results, patients will be in divided into two sub-groups: pyrazinamide-susceptible (PZA-S) patients and pyrazinamide-resistant (PZA-R) patients. The Regimen for PZA-S patients, consisting of levofloxacin, 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 levofloxacin, linezolid, cycloserine, and clofazimine given 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 compare the treatment success rate without relapse between the WHO standardized shorter regimen group and the PZA sensitivity guided ultra-short regimen group. The secondary objective is to compare the median time to sputum culture conversion. Safety evaluations performed are the routine lab tests, blood glucose, hearing, 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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
354 (Actual)

8. Arms, Groups, and Interventions

Arm Title
PZA sensitivity guided ultra-short all Oral Regimen
Arm Type
Experimental
Arm Description
The PZA sensitivity guided ultra-short 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 levofloxacin, linezolid, cycloserine, pyrazinamide, and clofazimine. Then based on molecular PZA drug sensitivity results, patients will be in divided into two sub-groups: pyrazinamide-susceptible (PZA-S) patients and pyrazinamide-resistant (PZA-R) patients. The Regimen for PZA-S patients, consisting of levofloxacin, 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 levofloxacin, linezolid, cycloserine, and clofazimine given until 36th week (prolonged to 40 or 44 weeks if no smear conversion by end of 16th and 20th week)
Arm Title
Standardized Shorter Regimen
Arm Type
Active Comparator
Arm Description
WHO standardized shorter regimen group consists of 36-44 weeks with two phases of treatment. The first is an intensive phase of 16 weeks (extended up a maximum of 20 or 24 weeks in case of lack of smear conversion at the end of 16 or 20 weeks), and included moxifloxacin, amikacin, prothionamide, pyrazinamide, high-dose isoniazid, ethambutol and clofazimine. This is followed by a continuation phase of 20 weeks with the following agents: moxifloxacin, pyrazinamide, ethambutol and clofazimine.
Intervention Type
Drug
Intervention Name(s)
PZA sensitivity guided ultra-short all Oral Regimen
Intervention Description
Pyrazinamide 1500 mg daily; Levofloxacin ≤50kg 500 mg daily, >50kg 750mg daily; Linezolid: 600 mg daily; Cycloserine ≤50kg 500 mg daily, >50kg 750mg daily; Clofazimine 100 mg daily; All treatment is taken daily;
Intervention Type
Drug
Intervention Name(s)
Standardized Shorter Regimen
Intervention Description
Pyrazinamide 1500 mg daily;Levofloxacin 400 mg daily,; Prothionamide ≤50kg 500 mg daily, >50kg 750mg daily; Ethambutol: ≤50kg 750 mg daily, >50kg 1000mg daily; Clofazimine: 100 mg daily; Amikacin 600mg daily; High-dose isoniazid 600mg daily. All treatment is taken daily.
Primary Outcome Measure Information:
Title
Treatment success rate of the ultra short regimen
Description
To compare the treatment success rate without relapse between the PZA sensitivity guided all oral ultra short regimen group and the WHO standardized shorter regimen group. Treatment outcomes will be classified into favourable outcome and unfavourble outcome.
Time Frame
84 weeks after randomization.
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 between the ultra short regimen group and the standardized short regimen group;
Time Frame
12-36 weeks after treatment initiation
Title
The frequency of grade 3 or greater adverse events among patients treated with the ultra short regimen
Description
to compare 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, on the experimental regimen when compared to the control regimen;
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: 1.Willing to participate in trial treatment and follow-up and can give informed consent 2.18-70 years old 3.Has smear-positive pulmonary tuberculosis with initial laboratory results with resistance to rifampicin confirmed by GeneXpert 4.Willing to carry out HIV testing. 5. If you are a non-menopausal woman, agree to use or have used effective contraception during treatment. 6. Have an identifiable address and stay in the area during the study period. 7.Willing to follow the follow-up study procedure after the follow-up. Exclusion Criteria: Molecular drug resistance test for infected strains resistant to second-line injection; Molecular drug resistance assay for infected strains resistant to fluoroquinolone; 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; Alchol abuse(drinking more than 64g of ethanol a day for male, 42g for female).
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
Xuzhou Infectious Disease Hospital
City
Xuzhou
State/Province
Jiangsu
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
Southwest Medical University Affiliated Hospital
City
Luzhou
State/Province
Sichuan
Country
China
Facility Name
Chest Hospitalof Xinjiang Uygur Autonomous Region of PRC
City
Urumqi
State/Province
Xinjiang
Country
China
Facility Name
Hangzhou Red Cross Hospital
City
Hangzhou
State/Province
Zhejiang
Country
China
Facility Name
Zhejiang Provincial Center for Disease Control and Prevention
City
Hangzhou
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

Citations:
PubMed Identifier
33596848
Citation
Weng T, Sun F, Li Y, Chen J, Chen X, Li R, Ge S, Zhao Y, Zhang W. Refining MDR-TB treatment regimens for ultra short therapy (TB-TRUST): study protocol for a randomized controlled trial. BMC Infect Dis. 2021 Feb 17;21(1):183. doi: 10.1186/s12879-021-05870-w.
Results Reference
derived

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

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