Early Bactericidal Activity of Rifampin + Meropenem + Amoxicillin/Clavulanate in Adults With Pulmonary TB

• Status: Recruiting
• Trial end date: 2023-07-01
• Target enrollment: 0
• Participant gender: All

Summary

The overall goal of this exploratory proof-of-concept study is to determine whether, in participants with pulmonary tuberculosis caused by M. tuberculosis (MTB) with or without rifampin resistance-conferring rpoB-gene mutations, the combination of meropenem and amoxicillin/clavulanate with rifampin has greater early bactericidal activity (EBA) than the combination of meropenem and amoxicillin/clavulanate without rifampin. Funding Source- FDA OOPD.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Johns Hopkins University
• Treatments: Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Clavulanic Acid; Clavulanic Acids; Meropenem; Rifampin; Rifamycins; Thienamycins

Criteria

Inclusion Criteria:

• New or recurrent pulmonary TB with one or both of the following:

• sputum positive for acid-fast bacilli on direct microscopy of at least grade 1+ (International Union Against Tuberculosis and Lung Disease (IUATLD) scale) on at least one pre-treatment sputum sample

• sputum positive for M. tuberculosis by Xpert® MTB/RIF testing, with semiquantitative result of 'medium' or 'high' on at least one pre-treatment sputum sample

• Age ≥18 and ≤65 years at study screening

• Ability and willingness to provide informed consent

• Body weight 40 kg to 90 kg, inclusive

• Laboratory values obtained within 30 days prior to or at study screening:

• Absolute neutrophil count (ANC) > 750 cells/mm3

• Hemoglobin 7.0 g/dL

• Platelet count 50,000/mm3

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 X upper limit of normal (ULN)

• Total bilirubin ≤ 2.5 X ULN

• Creatinine < 1.5 X ULN

• HIV infection must be documented as either absent or present

• For HIV-positive candidates only: CD4+ cell count of ≥ 100 cells/cu mm, performed within 30 days prior to or at study screening

• For females of reproductive potential, negative serum or urine pregnancy test within 7 days prior to or at study screening. Female participants who are participating in sexual activity that could lead to pregnancy must agree to use one reliable non-hormonal method of contraception (condoms or an IUD), or another method (diaphragm or cervical cap) if it is approved by the national regulatory authority and used according to package insert, while receiving study medications.

• Willingness to be hospitalized for a minimum of 16 consecutive days

• Ability to produce an overnight sputum sample of sufficient quality and quantity. As a guideline, this should be 10 ml or more during a 16-hour collection period. Volume is clinically estimated from a spot sample provided at screening and verified upon the first overnight collection (which can be repeated upon retraining).

• Xpert® MTB/RIF result performed on sputum within 14 days prior to or at study screening that shows EITHER 'Rifampin resistance detected' OR 'Rifampin resistance not detected'

Exclusion Criteria:

• Treatment with any drug active against M. tuberculosis within the 3 months prior to study screening.

• Breast-feeding

• Known allergy or sensitivity to any of the study drugs

• Participants receiving valproate sodium or probenecid

• Karnofsky score < 60 OR poor general condition such that, in the opinion of the investigator at screening, any delay in initiation of definitive TB treatment cannot be tolerated

• Known current neurological TB or seizure disorder

• Any condition as determined by physical examination, medical history, laboratory data, or chest x-ray which, in the opinion of the investigator, would interfere with safety or endpoint assessments in the study.