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

Still in planning.

Data will become available once all study activities and publications are finalized and will be made available for the maximum time for which it is still clinically relevant.

Still in planning.