Clinical trial NCT04717908: Refining MDR-TB Treatment (T) Regimens (R) for Ultra(U) Short(S) Therapy(T)-PLUS
Official title: Refining MDR-TB Treatment (T) Regimens (R) for Ultra(U) Short(S) Therapy(T) (TB-TRUST)-PLUS
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Multidrug Resistant Tuberculosis
Keywords: Multidrug resistant tuberculosis
shorter treatment
all-oral regimen
PZA sensitivity
Lead sponsor: Huashan Hospital
Sponsor class: OTHER
First posted: 2021-01-22
Enrollment: 89
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Treatment success rate
timeFrame: 84 weeks after the treatment initiation
Secondary outcomes:
measure: The median time to Sputum Culture Conversion
timeFrame: Time Frame: 12-36 weeks after treatment initiation
measure: The frequency of grade 3 or greater adverse events among patients
timeFrame: 84 weeks after treatment initiation
Other outcomes:
Locations:
city: Shenzhen
country: China
facility: The Third People's Hospital of Shenzhen City
state: Guangzhou
city: Guizhou
country: China
facility: Guiyang Public Health Treatment Center
state: Guizhou
city: Zhengzhou
country: China
facility: The Sixth People's Hospital of Zhengzhou
state: Henan
city: Changsha
country: China
facility: Hunan Chest Hospital
state: Hunan
city: Huaihua
country: China
facility: Huaihua first people's Hospital
state: Hunan
city: Shanghai
country: China
facility: Huashan Hospital of Fudan University
state: Shanghai
city: Xi'an
country: China
facility: Shanxi Provincial Tuberculosis Control Institute
state: Shanxi
city: Urumqi
country: China
facility: Chest Hospitalof Xinjiang Uygur Autonomous Region of PRC
state: Xinjiang
city: Baoshan
country: China
facility: Baoshan People's Hospital
state: Yunnan
city: Kunming
country: China
facility: Yunnan Provincial Infectious Disease Hospital
state: Yunnan
city: Hangzhou
country: China
facility: Hangzhou Red Cross Hospital
state: Zhejiang
city: Ningbo
country: China
facility: Hwa Mei Hosptal,University of Chinese Academy of Sciences(Ningbo No.2 Hospital)
state: Zhejiang
city: Taizhou
country: China
facility: Taizhou Enze medical center Enze Hospital
state: Zhejiang
city: Wenzhou
country: China
facility: The Central Hospital of Wenzhou City
state: Zhejiang
city: Nanchang
country: China
facility: Jiangxi Chest Hospital
Study officials:
affiliation: Huashan Hospital
name: Wenhong Zhang, PhD
role: PRINCIPAL_INVESTIGATOR
References: