evaluating the eba of meropenem with amoxicillin/clavulanate and pyrazinamide or bedaquiline in adults with ptb

Conditions: Tuberculosis

Summary: 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).

Eligibility criteria:
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

Keywords: tuberculosis tb early bactericidal activity