Early Bactericidal Activity of Rifampin + Meropenem + Amoxicillin/Clavulanate in Adults With Pulmonary TB
Condition: Tuberculosis, Pulmonary
MeSH terms: Tuberculosis; Tuberculosis, Pulmonary
Intervention: Rifampin; MEROPENEM 2 grams TID; MEROPENEM 1 gram TID; MEROPENEM 3 grams QD; Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet; Amoxicillin/Clavulanate Potassium 875 MG-125 MG Oral Tablet
Intervention description: Oral administration of rifampin at a dosage of 20 mg/kg daily; Intravenous administration at a dosage of 2 grams thrice daily; Intravenous administration at a dosage of 1 gram thrice daily; Intravenous administration at a dosage of 3 grams once daily; Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily; Amx/Clv will be administered orally at a dose of 875 mg/125 mg once daily
Intervention MeSH terms: Amoxicillin; Rifampin; Meropenem; Clavulanic Acid; Clavulanic Acids; Amoxicillin-Potassium Clavulanate Combination; Rifamycins
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 112.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No

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.
    

Eligibility 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.