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

Tuberculosis, Multidrug-Resistant Clinical Trial

— Stake  

Official title:

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05555303
• Other study ID #: RBC/RIDS012022
• Status: Recruiting
• Phase: Phase 2
• Start date: March 1, 2023
• Est. completion date: February 2026

Study information

• Verified date: March 2023
• Source: Rwanda Biomedical Centre
• Contact: Yves Habimana-Mucyo, MSc
• Phone: +250733436765
• Email: yves.mucyo[@]rbc.gov.rw
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: February 2026
• Est. primary completion date: March 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 19 Years to 64 Years

Eligibility

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.

Related Conditions & MeSH terms

• Tuberculosis
• Tuberculosis, Multidrug-Resistant

Intervention

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.

Locations

Country	Name	City	State
Rwanda	Kabutare hospital	Kabutare

Sponsors (3)

Lead Sponsor	Collaborator
Rwanda Biomedical Centre	Institute of Tropical Medicine, World Health Organization

Country where clinical trial is conducted

Rwanda, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	amikacin concentration	Describe the amikacin concentration stratified by values for different treatment response markers : molecular bacterial load	during the first two treatment weeks
Secondary	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
Secondary	amikacin concentration	Describe the amikacin concentration stratified by values for different treatment response markers: RNA Synthesis ratio	during the first two treatment weeks
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)