Evaluating the EBA of Meropenem With Amoxicillin/Clavulanate and Pyrazinamide or Bedaquiline in Adults With PTB

A Phase 2 Trial to Evaluate the Early Bactericidal Activity and Safety of Meropenem With Amoxicillin/Clavulanate Plus Either Pyrazinamde or Bedaquiline in Adults With Newly Diagnosed Rifampicin-susceptible Pulmonary Tuberculosis

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