Preventing Acquired Resistance: Strengthen TB Treatment by Adding Amikacin in the First Treatment Week of Multidrug-resistant Tuberculosis

Phase 2RecruitingNCT05555303

Rwanda Biomedical Centre20 enrolled

Overview

Acquired drug-resistance is a major challenge for tuberculosis (TB) care programs. The 2020 WHO guidelines recommends replacing second-line injectables by bedaquiline in rifampicin-resistant TB (RR-TB) treatment regimens. However, recent reports show too high rates of acquired bedaquiline resistance. This may be explained by the delayed onset of action of bedaquiline. The investigators will study whether high-dose amikacin (a second-line injectable), administered during the first week of RR-TB treatment, is safe in 20 patients treated for RR-TB in Rwanda. If safe, further studies will assess whether adding amikacin in the first treatment week protect against acquired bedaquiline resistance. This study is embedded in an ongoing "Master study" of the ShORRT (short oral RR-TB) treatment regimen in Rwanda, a before/after study, with a retrospective cohort (before; the previously recommended second-line injectable-containing RR-TB regimen) and a prospective cohort (after: the newly recommended ShORRT regimen).

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Tuberculosis, Multidrug-Resistant

Interventions

Eligibility

Sex: ALLMin age: 19 YearsMax age: 64 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Enrolled in the Master SHORRT study * Able and willing to provide written informed consent for the present substudy "Stake" Exclusion Criteria: * Any audiometry abnormality (grade 1 or higher) on baseline audiometry * History of kidney disease or baseline creatinine clearance below or equal to 60ml/min * Pregnant or breastfeeding women * History of previous injectable based tuberculosis treatment (including with streptomycin) * \< 18 years and \> 65 years old * Patient on NSAID or on diuretics Master ShORRT study Inclusion criteria: * Is willing and able to give informed consent to be enrolled in the research project and for follow-up * Has bacteriologically or molecularly confirmed TB with evidence of resistance to at least rifampicin Exclusion criteria: * Is unable to take oral medication; * Must take any medications contraindicated with the medicines in the MDR/RR-TB regimen; * Has a known allergy to any of the drugs in the MDR/RR-TB regimen; * Has a QTcF interval of ≥ 500 msec; at baseline that does not correct with medical management.

Outcomes

Primary Outcomes

grade 3-4 AE likely or definitively related to amikacin

Assess whether less than 14% of patients treated with the amikacin-strengthened regimen will experience a grade 3-4 adverse event likely or definitively related to the use of amikacin

Time frame: After 2 weeks of treatment

Secondary Outcomes

turnaround times

Assess the turnaround times to inform the feasibility of doing the tests proposed in this study for the assessment of the response to the use of two doses of amikacin

Time frame: at the end of treatment week 2 (+/- 3 d)

testing coverage

Assess the testing coverage (proportion of patients with a result for each of the tests) to inform the feasibility of doing the tests proposed in this study for the assessment of the response to the use of two doses of amikacin

Time frame: at the end of treatment week 2 (+/- 3 d)

AE likely or definitely related to amikacin

Describe the occurrence of adverse events that are considered as likely or definitely related to the use of amikacin

Time frame: at the end of treatment week 2 (+/- 3 d)

amikacin concentration

Describe the amikacin concentration stratified by values for different treatment response markers : Colony forming units on semi-quantitative culture