Phase 2 Trial to Evaluate the Early Bactericidal Activity, Safety and Tolerability of Meropenem Plus Amoxycillin/CA and Faropenem Plus Amoxycillin/CA in Adult Patients With Newly Diagnosed Pulmonary Tuberculosis
Phase 2 Trial to Evaluate the Early Bactericidal Activity, Safety and Tolerability of Meropenem Plus Amoxycillin/CA and Faropenem Plus Amoxycillin/CA in Adult Patients With Newly Diagnosed Pulmonary Tuberculosis
To evaluate the early bactericidal activity (EBA), safety, tolerability and pharmacokinetics
 of meropenem administered intravenously three times a day, plus amoxycillin/CA administered
 orally three times a day; and of faropenem administered orally three times a day, plus
 amoxycillin/CA administered orally three times a day; for 14 consecutive days, in adult
 participants with newly diagnosed, smear positive pulmonary tuberculosis, in order to help
 establish proof-of-concept for carbapenem antibiotics as antituberculosis agents and to
 select the appropriate agent and route of administration for later stage clinical
 development.
A single-centre, open-label clinical trial including a total of 45 male or female
 participants (2 groups of 15 participants receiving an IMP and 1 group of 15 participants
 receiving Rifafour e-275), aged between 18 and 65 years (inclusive), with newly diagnosed,
 smear-positive, pulmonary tuberculosis will be enrolled into this trial.

 Treatment will be administered for 14 consecutive days in the following dosing schemes:

 1. Meropenem 2g intravenously 8-hourly; plus amoxycillin/CA 500mg/125mg orally 8- hourly on
 days 1-14.

 2. Faropenem 600mg orally 8-hourly; plus amoxycillin/CA 500mg/125mg orally 8-hourly on days
 1-14.

 3. The third arm 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.

 Participants will be admitted to the in hospital facility for a period of up to 24 days.
 During this period they will await their screening results after which they will receive 14
 day of IMP. on day 14 intensive PK sampling will be done. They will be discharged on day 15
 to the clinic where they will continue on the national TB programme treatment regime.
 Participants will return to the clinical trial site 14 days after receipt of their last study
 drug. for a safety evaluation.
Inclusion Criteria:

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

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

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

 4. Newly diagnosed, previously untreated, pulmonary TB.

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

 6. Sputum positive GeneXpert or TB smear from TB clinic or site of initial diagnosis.

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

 8. Ability to produce an adequate volume of sputum as estimated from a spot assessment
 (estimated 10 ml or more overnight production).

 9. Be of non-childbearing potential or using effective methods of birth control, as
 defined below:

 Non-childbearing potential:

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

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

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

 Effective birth control methods:

 1. Double barrier method which can include a male condom, diaphragm, cervical cap, or
 female condom; or

 2. Barrier method combined with hormone-based contraceptives or an intra-uterine device
 for the female partner; and are willing to continue practicing birth control methods
 throughout participation in the study until Visit 19 (day 28). (Note: hormone-based
 contraception alone may not be reliable when taking IMP; therefore, hormone-based
 contraceptives alone cannot be used by female participants to prevent pregnancy).

 Exclusion Criteria Medical History

 1. Evidence of clinically significant (as judged by the investigator), metabolic,
 gastrointestinal, cardiovascular, musculoskeletal, ophthalmological, pulmonary,
 neurological, psychiatric or endocrine diseases, malignancy, or other abnormalities
 (other than the indication being studied) including malaria.

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

 3. A history of previous TB less than 5 years ago.

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

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

 6. Isoniazid-resistant and/or rifampicin-resistant bacteria detected with a sputum
 specimen collected within the pre-treatment period and tested at the study laboratory.

 7. Known or suspected, current or history of within the past 2 years, alcohol or drug
 abuse, that is, in the opinion of the Investigator, sufficient to compromise the
 safety or cooperation of the participant.

 8. For HIV infected participants:

 1. having a CD4+ count <350 cells/µL;

 2. or having received antiretroviral therapy medication within the last 90 days;

 3. or having received oral or intravenous antifungal medication within the last 90
 days;

 4. or with an AIDS-defining opportunistic infection or malignancies (except
 pulmonary TB).

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

 10. 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.

 11. Diabetes mellitus requiring insulin.

 Specific Treatments

 12. Treatment received with any drug active against MTB within the 3 months prior to Visit
 1 (including but not limited to isoniazid, ethambutol, amikacin, cycloserine,
 fluoroquinolones, rifabutin, rifampicin, streptomycin, kanamycin, para-aminosalicylic
 acid, rifapentine, pyrazinamide, thioacetazone, capreomycin, thioamides,
 metronidazole).

 13. Participants receiving sodium valproate, furosemide, imipenem or probenecid.

 14. Any diseases or conditions in which the use of the standard TB drugs or any of their
 components is contra-indicated, including but not limited to allergy to any TB drug,
 their component or to the IMP.

 Laboratory Abnormalities

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

 1. creatinine grade 2 or greater (>1.5 times upper limit of normal [ULN]);

 2. hemoglobin grade 4 (<6.5 g/dL);

 3. platelets grade 2 or greater (under 50x109 cells/L);

 4. serum potassium grade 2 or greater (<3.0 mEq/L);

 5. aspartate aminotransferase (AST) grade 3 (≥3.0 x ULN) to be excluded;

 6. alanine aminotransferase (ALT) grade 3 (≥3.0 x ULN) to be excluded;

 7. APTT grade 3

 8. INR grade 3

 9. Total white cell count grade 3