Evaluating the EBA of Meropenem With Amoxicillin/Clavulanate and Pyrazinamide or Bedaquiline in Adults With PTB
Evaluating the EBA of Meropenem With Amoxicillin/Clavulanate and Pyrazinamide or Bedaquiline in Adults With PTB
A single-center, open-label clinical trial to determine the early bactericidal activity (EBA)
 and safety of the combination of meropenem and amoxicillin/clavulanate plus pyrazinamide vs.
 meropenem and amoxicillin/clavulanate plus bedaquiline administered for 14 consecutive days.
 This study forms part of a series of 2-week EBA studies to determine the relative
 bactericidal activity of several new or repurposed anti-tuberculosis agents from which to
 determine the most effective and safe combination to evaluate in larger and longer duration
 regimen-based trials.
Study design

 A single-center, open-label clinical trial. Study treatments include:

 1. Meropenem 6g intravenously once daily plus amoxicillin/clavulante 2 x 1000mg/62.5mg
 orally once daily and pyrazinamide 20-30mg/kg orally once daily on days 1-14. Ten
 participants will be included in this treatment arm.

 2. Meropenem 6g intravenously once daily plus amoxicillin/clavulanate 2 x 1000mg/62.5mg
 orally once daily and bedaquiline 400mg orally once daily on days 1-14. Ten participants
 will be included in this treatment arm.

 3. Rifafour e- 275® (HRZE) orally once daily on days 1-14, with weight-banded dosing. Two
 participants 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.

 Patient Population:

 A total of 22 male and female participants aged between 18 and 65 years (inclusive), with
 newly diagnosed, smear-positive, pulmonary TB will be included.

 Treatment

 The Investigational Product (IP) will be supplied as:

 -  Meropenem 1g reconstitution vials

 -  Amoxicillin/CA 1000/62.5mg tablets

 -  Pyrazinamide 500mg tablets

 -  Bedaquiline 100mg tablets

 Statistical Methods:

 This is a descriptive study with no inferential statistics or hypothesis testing. The planned
 sample size of 10 participants per treatment group is in keeping with other phase 2 trials of
 this type and accounts for the possibility of up to 3 drop-outs per arm, which based on
 previous studies of this type conducted at these sites, represents a conservative estimate of
 the expected drop-out rate.

 Trial Duration:

 37 days (up to 9 days pre-treatment plus 15 days treatment period plus 14 days post-
 treatment follow- up).
Inclusion Criteria:

 -  Provide written, informed consent prior to all trial-related procedures including HIV
 testing.

 -  Male or female, aged between 18 and 65 years, inclusive.

 -  Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive.

 -  Newly diagnosed, previously untreated, rifampicin-susceptible pulmonary TB.

 -  A chest X-ray picture which in the opinion of the Investigator is consistent with TB.

 -  Sputum positive on microscopy for acid-fast bacilli on at least one sputum sample (at
 least 1+ on the IUATLD/WHO scale).

 -  Ability to produce an adequate volume of sputum as estimated from an overnight sputum
 collection sample (estimated 10 ml or more).

 -  Be of non-childbearing potential or using effective methods of birth control
 throughout participation in the study until Visit 19 (day 28).

 Non-childbearing potential:

 1. Female participant/sexual partner - bilateral oophorectomy, bilateral tubal ligation
 and/or hysterectomy or hasbeen postmenopausal with a history of no menses for at least
 12 consecutive months; or

 2. Male participant/sexual partner - vasectomised or has had a bilateral orchidectomy
 minimally three month prior to screening;

 Effective birth control methods:

 1. Participant - not heterosexually active or practicing sexual abstinence; or

 2. Double barrier method which can include a male condom, diaphragm, cervical cap, or
 female condom (male and female condoms should not be used together); or

 3. Barrier method combined with hormone-based contraceptives or an intra-uterine device
 for the female partner.

 Exclusion Criteria:

 -  Evidence of clinically significant conditions or findings, other than the indication
 being studied, particularly epilepsy, that might compromise safety or the
 interpretation of trial endpoints, per discretion of the Investigator.

 -  Poor general condition where any delay in treatment cannot be tolerated per discretion
 of the Investigator.

 -  Clinically significant evidence of extrathoracic TB (miliary TB, abdominal TB,
 urogenital TB, osteoarthritic TB, TB meningitis), as judged by the Investigator.

 -  Significant history of cardiovascular disease such as heart failure, a personal or
 family history of congenital QT prolongation, Torsade de Pointes, or QTcF interval >
 500 ms (confirmed by repeat electrocardiogram).

 -  History of allergy to any of the trial IP/s or related substances i.e. β-lactams and
 penicillin, as confirmed by the clinical judgement of the Investigator.

 -  Alcohol or drug abuse, that in the opinion of the Investigator, is sufficient to
 compromise the safety or cooperation of the participant.

 -  HIV positive ONLY IF:

 -  CD4 < 350cells/mm3

 -  On ART

 -  Having participated in other clinical studies with investigational agents within 8
 weeks prior to trial start.

 -  Female participant who is pregnant, breast-feeding, or planning to conceive a child
 within the anticipated period of participating in the trial. Male participant planning
 to conceive a child within the anticipated period of participating in the trial.

 -  Subjects with diabetes (Type 1 or 2), or random glucose over 11.1 mmol/L.

 -  Hypersensitivity to local anaesthesia of amide type.

 -  Treatment received with any drug active against Mtb (including but not limited to
 isoniazid, ethambutol, amikacin, cycloserine, fluoroquinolones, rifabutin, rifampicin,
 streptomycin, kanamycin, para-aminosalicylic acid, rifapentine, pyrazinamide,
 thioacetazone, capreomycin, thioamides, metronidazole), or with immunosuppressive
 medications such as TNF-alpha inhibitors or systemic corticosteroids, within 2 weeks
 prior to screening.

 -  Participants with the following toxicities at screening as defined by the enhanced
 CTCEA toxicity table

 1. creatinine >1.5 times upper limit of normal (ULN);

 2. haemoglobin <8.0 g/dL;

 3. platelets equal to or <50x10E9 cells/L);

 4. serum potassium <3.0 mEq/L;

 5. aspartate aminotransferase (AST) ≥3.0 x ULN;

 6. alanine aminotransferase (ALT) ≥3.0 x ULN;

 7. APTT grade 3

 8. INR grade 3

 9. Total white cell count grade 3