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

Study Overview
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Brief Summary
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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).

Official Title
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Preventing Acquired Resistance: Strengthen TB Treatment by Adding Amikacin in the First Treatment Week of Multidrug-resistant Tuberculosis (Stake) Amendment to Study Protocol: All-oral Shorter Treatment Regimen for Multidrug- and Rifampicin-resistant Tuberculosis (MDR/RR-TB): Evaluating Its Effectiveness, Safety and Impact on the Quality of Life of Patients in Rwanda (ShORRT)

Conditions
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Tuberculosis, Multidrug-Resistant

Intervention / Treatment
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* Drug: Amikacin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Amikacin<br> | Drug: Amikacin<br>* In addition to the all-oral RR-TB treatment, add two intramuscular doses each consisting of 30 mg amikacin/kg, a first dose on day 1 and a second dose on day 4, all in the first week of treatment. The amikacin solution will be admixed with a lidocaine solution in the syringe before administration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | After 2 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 | 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 | 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 | during the first two treatment weeks | 
| amikacin concentration | Describe the amikacin concentration stratified by values for different treatment response markers : molecular bacterial load | during the first two treatment weeks | 
| amikacin concentration | Describe the amikacin concentration stratified by values for different treatment response markers : thin-layer agar semi-quantitative culture | during the first two treatment weeks | 
| amikacin concentration | Describe the amikacin concentration stratified by values for different treatment response markers: RNA Synthesis ratio | during the first two treatment weeks | 
| amikacin concentration | Describe the amikacin concentration stratified by values for different treatment response markers : time to culture positivity on liquid culture | during the first two treatment weeks | 
| post-injection pain | Describe post-injection pain on a 0-10 pain scale (The Wong-Baker FACES pain rating scale) (15) | at 0, 15 minutes, 30 minutes and 60 minutes after the injection of amikacin with lidocaine on day 1 and 4, as well as the next morning | 
| all AE, relationship with TB drugs | Describe all AE, by their grade, and their relationship with TB drugs | at the end of the ShORRT study, approximately 23 months after the treatment | 
| treatment outcomes | Describe treatment outcomes, using the following effectiveness endpoints: Month of stable (without reversion) culture conversion End-of-treatment outcomes (treatment failure, death during treatment, LTFU during treatment, cure, treatment completion) Treatment outcomes at 12 months post-treatment (end-of treatment outcome corrected for relapse) Acquired resistance to bedaquiline, fluoroquinolone, amikacin through target deep sequencing on paired baseline and failure sputa | at the end of treatment | 
| post-treatment outcomes | Describe post-treatment outcomes, using the following effectiveness endpoints: Month of stable (without reversion) culture conversion End-of-treatment outcomes (treatment failure, death during treatment, LTFU during treatment, cure, treatment completion) Treatment outcomes at 12 months post-treatment (end-of treatment outcome corrected for relapse) Acquired resistance to bedaquiline, fluoroquinolone, amikacin through target deep sequencing on paired baseline and failure sputa | after post-treatment follow-up (part of ShORRT analysis) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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multidrug- and rifampicin-resistant tuberculosis