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

Phase 2

Recruiting

• Conditions: Tuberculosis, Multidrug-Resistant
• Interventions: Drug: Amikacin

• Registration Number: NCT05555303
• Lead Sponsor: Rwanda Biomedical Centre

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).

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2022-09-16
• Study First Submitted QC: 2022-09-23
• Study First Posted: 2022-09-26
• Status Verified: 2023-03
• Study Start: 2023-03-01
• Last Update Submitted: 2023-03-24
• Last Update Posted: 2023-03-29
• Primary Completion: 2024-03
• Study Completion: 2026-02

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 20

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Amikacin	Amikacin	-

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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
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 : time to culture positivity on liquid culture

Trial Locations

Locations (1)

Kabutare hospital; 🇷🇼 Kabutare, Rwanda