Stake: Preventing Acquired Resistance: Strengthen TB Treatment by Adding Amikacin in the First Treatment Week of Multidrug-resistant Tuberculosis
Study Details
Study Description
Brief Summary
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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Other: Amikacin
|
Drug: Amikacin
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.
|
Outcome Measures
Primary Outcome Measures
- grade 3-4 AE likely or definitively related to amikacin [After 2 weeks of treatment]
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
Secondary Outcome Measures
- turnaround times [at the end of treatment week 2 (+/- 3 d)]
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
- testing coverage [at the end of treatment week 2 (+/- 3 d)]
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
- AE likely or definitely related to amikacin [at the end of treatment week 2 (+/- 3 d)]
Describe the occurrence of adverse events that are considered as likely or definitely related to the use of amikacin
- amikacin concentration [during the first two treatment weeks]
Describe the amikacin concentration stratified by values for different treatment response markers : Colony forming units on semi-quantitative culture
- amikacin concentration [during the first two treatment weeks]
Describe the amikacin concentration stratified by values for different treatment response markers : molecular bacterial load
- amikacin concentration [during the first two treatment weeks]
Describe the amikacin concentration stratified by values for different treatment response markers : thin-layer agar semi-quantitative culture
- amikacin concentration [during the first two treatment weeks]
Describe the amikacin concentration stratified by values for different treatment response markers: RNA Synthesis ratio
- amikacin concentration [during the first two treatment weeks]
Describe the amikacin concentration stratified by values for different treatment response markers : time to culture positivity on liquid culture
- post-injection pain [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]
Describe post-injection pain on a 0-10 pain scale (The Wong-Baker FACES pain rating scale) (15)
- all AE, relationship with TB drugs [at the end of the ShORRT study, approximately 23 months after the treatment]
Describe all AE, by their grade, and their relationship with TB drugs
- treatment outcomes [at the end of treatment]
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
- post-treatment outcomes [after post-treatment follow-up (part of ShORRT analysis)]
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
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Enrolled in the Master SHORRT study
-
Able and willing to provide written informed consent for the present substudy "Stake"
Exclusion Criteria:
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Any audiometry abnormality (grade 1 or higher) on baseline audiometry
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History of kidney disease or baseline creatinine clearance below or equal to 60ml/min
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Pregnant or breastfeeding women
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History of previous injectable based tuberculosis treatment (including with streptomycin)
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< 18 years and > 65 years old
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Patient on NSAID or on diuretics
Master ShORRT study
Inclusion criteria:
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Is willing and able to give informed consent to be enrolled in the research project and for follow-up
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Has bacteriologically or molecularly confirmed TB with evidence of resistance to at least rifampicin
Exclusion criteria:
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Is unable to take oral medication;
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Must take any medications contraindicated with the medicines in the MDR/RR-TB regimen;
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Has a known allergy to any of the drugs in the MDR/RR-TB regimen;
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Has a QTcF interval of ≥ 500 msec; at baseline that does not correct with medical management.
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Rwanda Biomedical Centre
- Institute of Tropical Medicine
- World Health Organization
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- RBC/RIDS012022