Clinical trial NCT04629378: Evaluating the EBA of Meropenem With Amoxicillin/Clavulanate and Pyrazinamide or Bedaquiline in Adults With PTB
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Tuberculosis
Keywords: tuberculosis
TB
early bactericidal activity
Lead sponsor: TASK Applied Science
Sponsor class: OTHER
First posted: 2020-11-16
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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

Primary outcomes:
measure: Early bactericidal activity (EBA) over 14 treatment days based on the rate of change in colony forming unit (CFU) count per treatment arm
timeFrame: 14 days
Secondary outcomes:
measure: EBA over 14 treatment days based on the rate of change in time to positive culture (TTP) per treatment arm
timeFrame: 14 days
measure: Safety and tolerability of study treatments administered over 14 consecutive days
timeFrame: 14 days
measure: Cmax: Maximum observed plasma drug concentration.
timeFrame: 14 days
measure: Tmax: Time at which Cmax is observed (obtained without interpolation).(interventional arms only) after 14 consecutive days - Analyte, Meropenem; amoxicillin; CA; bedaquiline
timeFrame: 14 days
measure: Cmin: Minimum observed plasma drug concentration 24 hours following the last dose.
timeFrame: 14 days
measure: AUC(0-24): Area under the drug concentration-time curve calculated using linear trapezoidal summation from time zero to time 24 hours.
timeFrame: 14 days
Other outcomes:
Locations:
city: Cape Town
country: South Africa
facility: TASK Clinical Research Centre
state: Western Cape
Study officials:
affiliation: TASK
name: Veronique R De Jager, MBChB
role: PRINCIPAL_INVESTIGATOR
References: