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

NCT04629378 | Completed Phase 2

• 1 other identifier: TASK-005_TB_COMBO_01
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

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.

Conditions

Tuberculosis

Keywords

tuberculosis; TB; early bactericidal activity

Outcome Measures

Primary Outcomes (1)

• Early bactericidal activity (EBA) over 14 treatment days based on the rate of change in colony forming unit (CFU) count per treatment arm

  CFU count will be determined from Mycobacterium tuberculosis (M.tb) grown on solid culture. The rate of change in CFU count per ml sputum will be determined from overnight sputum samples collected for at least 2 day before study treatment till day 4 on treatment, followed by alternate days till day 14 on treatment.

  14 days

Secondary Outcomes (6)

• EBA over 14 treatment days based on the rate of change in time to positive culture (TTP) per treatment arm

  14 days

• Safety and tolerability of study treatments administered over 14 consecutive days

  14 days

• Cmax: Maximum observed plasma drug concentration.

  14 days

• Tmax: Time at which Cmax is observed (obtained without interpolation).(interventional arms only) after 14 consecutive days - Analyte, Meropenem; amoxicillin; CA; bedaquiline

  14 days

• Cmin: Minimum observed plasma drug concentration 24 hours following the last dose.

  14 days

Study Arms (3)

Meropenem and amoxicillin/clavulanate plus pyrazinamide

EXPERIMENTAL

Meropenem administered intravenously once daily over 6 hours plus amoxicillin/clavulanate 2 x 1000/62.5 mg once daily orally plus pyrazinamide 20-30 mg/kg orally once daily. All study treatments will be administered for 14 consecutive days.

Drug: Meropenem Injection; Drug: Amoxicillin Clavulanate; Drug: Pyrazinamide

Meropenem and amoxicillin/clavulanate plus bedaquiline

EXPERIMENTAL

Meropenem administered intravenously once daily over 6 hours plus amoxicillin/clavulanate 2 x 1000/62.5 mg once daily orally plus bedaquiline 400 mg orally once daily. All study treatments will be administered for 14 consecutive days.

Drug: Meropenem Injection; Drug: Amoxicillin Clavulanate; Drug: Bedaquiline

Rifafour standard of care treatment

ACTIVE COMPARATOR

Rifafour e275® administered orally once daily for 14 consecutive days. Rifafour e275® will be administered according to the South African National TB Treatment Guidelines. The daily dose is dependent on the participants' weight as follows: 40 - 54kg: 3 tablets; 55 - 70kg: 4 tablets; 71kg and over: 5 tablets.

Drug: Rifafour

Interventions

Meropenem Injection DRUG

Meropenem IV 6 grams

Meropenem and amoxicillin/clavulanate plus bedaquiline; Meropenem and amoxicillin/clavulanate plus pyrazinamide

Amoxicillin Clavulanate DRUG

Amx/CA oral 1000/62.5mg 2 tablets

Meropenem and amoxicillin/clavulanate plus bedaquiline; Meropenem and amoxicillin/clavulanate plus pyrazinamide

Pyrazinamide DRUG

Pyrazinamide 20-30mg/kg

Meropenem and amoxicillin/clavulanate plus pyrazinamide

Bedaquiline DRUG

Bedaquiline 400mg

Meropenem and amoxicillin/clavulanate plus bedaquiline

Rifafour DRUG

Rifafour (HRZE) Standard dose

Rifafour standard of care treatment

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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
• Male participant/sexual partner - vasectomised or has had a bilateral orchidectomy minimally three month prior to screening;
• Effective birth control methods:
• Participant - not heterosexually active or practicing sexual abstinence; or
• 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
• Barrier method combined with hormone-based contraceptives or an intra-uterine device for the female partner.

You may not qualify if:

• 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

Sponsors & Collaborators

• TASK Applied Science: lead

Study Sites (1)

TASK Clinical Research Centre

Cape Town, Western Cape, 7530, South Africa

Location

MeSH Terms

Conditions

Tuberculosis

Interventions

Meropenem; Amoxicillin-Potassium Clavulanate Combination; Pyrazinamide; bedaquiline

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Thienamycins; Carbapenems; beta-Lactams; Lactams; Amides; Organic Chemicals; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Clavulanic Acid; Clavulanic Acids; Amoxicillin; Ampicillin; Penicillin G; Penicillins; Sulfur Compounds; Drug Combinations; Pharmaceutical Preparations; Pyrazines; Heterocyclic Compounds, 1-Ring

Study Officials

• Veronique R De Jager, MBChB

  TASK

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 12, 2020
• First Posted: November 16, 2020
• Study Start: August 17, 2020
• Primary Completion: June 4, 2021
• Study Completion: June 4, 2021
• Last Updated: January 25, 2022

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: 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.
• Access Criteria: Still in planning.

Locations

ZA (1)