Study to Evaluate EBA, Safety and Tolerability of Carbapenems in Adults With Pulmonary Tuberculosis
Condition: Pulmonary Tuberculosis
MeSH terms: Tuberculosis; Tuberculosis, Pulmonary
Study type: Interventional
Phase: Phase 2

Summary: 
      The goal of this single-center, open-labelled, clinical trial in two groups aims to proof
      that a specific group of antibiotics (carbapenems) can be used to treat pulmonary
      tuberculosis if it is combined with another antibiotic (amoxicillin/clavulanate). A total of
      113 male or female participants (8 groups and 9 treatment regimens as group 8 was split into
      2 groups of 4 participants receiving Rifafour e-275), aged between 18 and 65 years
      (inclusive), with newly diagnosed, smear-positive, pulmonary TB.
    

Detailed description: 
      The overall objective of this study is to evaluate the 2-week bactericidal activity and
      pharmacokinetics of the following beta-lactam containing combinations with the aim to select
      the most active and implementable solution to be incorporated into a drug-resistant TB
      combination regimen:

        -  Once or twice daily meropenem administered intravenously in combination with once or
           twice daily oral amoxicillin/clavulanic acid;

        -  Once daily ertapenem administered intravenously and intramuscularly in combination with
           twice daily oral amoxicillin/clavulanic acid;

        -  Twice daily oral amoxicillin/clavulanic acid;

        -  Once daily rifampicin administered orally at highest currently established dosage of
           35mg/kg in combination with twice daily oral amoxicillin/clavulanic acid.

      A single-center, open-labeled, clinical trial in two groups. The treatments are:

      Group 1:

        1. Meropenem 6g intravenously once daily; plus amoxicillin/CA 2 x 1000mg/62.5mg orally
           12-hourly on days 1-14.

        2. Ertapenem 1g intramuscularly once daily; plus amoxicillin/CA 2 x 1000mg/62.5mg orally
           12-hourly on days 1-14.

           Group 2:

        3. Meropenem 3g intravenously twice daily; plus amoxicillin/CA 2 x 1000mg/62.5mg orally
           12-hourly on days 1-14.

        4. Ertapenem 1g intravenously once daily; plus amoxicillin/CA 2 x 1000mg/62.5mg orally
           12-hourly on days 1-14.

        5. Amoxicillin/CA 2 x 1000mg/62.5mg orally 12-hourly on days 1-14.

        6. Rifampicin 35 mg/kg once daily; plus amoxicillin/CA 2 x 1000mg/62.5mg orally 12-hourly
           on days 1-14.

        7. Meropenem 6g OR meropenem 4g intravenously once daily; plus amoxicillin/CA 2 x
           1000mg/62.5mg orally once daily on days 1-14.

      A total of 4 participants per group will receive standard first line TB treatment as per the
      South African TB guidelines (Rifafour e-275) and is included as a control for the EBA
      quantitative mycobacteriology and to evaluate whether HRZE gives similar EBA results to that
      demonstrated in prior studies with this combination. The mycobacteriology laboratory will
      remain blinded until closure of the EBA results. Enrollment into group 1 will be completed
      before enrollment into group 2 will start. After completion of enrollment into group 1, there
      will be an interim analysis while enrollment into group 2 is ongoing.
    

Intervention name(s): Meropenem 6g IV over 6 hours; Ertapenem 1g IM; Meropenem 3g IV; Ertapenem 1g IV; Amoxicillin/CA twice daily; Rifampicin 35 mg/kg; Meropenem 6g IV over 60 minutes; Rifafour e-275; Meropenem 4g IV; Amoxicillin/CA once daily
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Meropenem 6g intravenously over 6 hours once daily on days 1-14.; Ertapenem 1g intramuscularly once daily on days 1-14.; Meropenem 3g intravenously twice daily over 60 minutes on days 1-14.; Ertapenem 1g intravenously once daily on days 1-14.; Amoxicillin/CA 2 tablets x 1000mg/62.5mg orally 12-hourly on days 1-14.; Rifampicin 35 mg/kg once daily on days 1-14.; Meropenem 6g intravenously once daily over 60 minutes on days 1-14.; Rifafour e-275 will be supplied as fixed dose combination tablets and administered orally once daily for 14 days as The daily dose is dependent on the participants' weight as follows: 40 - 54kg: 3 tablets; 55 - 70kg: 4 tablets; 71kg and over: 5 tablets.; Meropenem 4g intravenously once daily over 60 minutes on days 1-14.; Amoxicillin/CA 2 tablets x 1000mg/62.5mg orally once daily on days 1-14.
Intervention MeSH terms: Amoxicillin; Rifampin; Meropenem; Ertapenem
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This study will be a standard 14 day EBA design incorporating 2 groups with parallel treatment arms. This design allows comparison of the results of this study with similar prior studies of treatments for TB. No placebo treatment is included in this study - all participants will be given either active study treatment or Rifafour e275® control. The planned sample size is15 participants per treatment group.
Masking: None (Open Label)
Primary purpose: Other
Keywords: EBA; Intravenous Meropenem; Newly Diagnosed; Smear-Positive; Rifampicin-Susceptible; Pulmonary Tuberculosis