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

NCT ID: NCT04629378

Last Updated: 2022-01-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 22 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-08-17
• Study Completion Date: 2021-06-04

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).

Conditions

Tuberculosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Meropenem and amoxicillin/clavulanate plus pyrazinamide

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.

Group Type: EXPERIMENTAL

Meropenem Injection

Intervention Type: DRUG

Meropenem IV 6 grams

Amoxicillin Clavulanate

Intervention Type: DRUG

Amx/CA oral 1000/62.5mg 2 tablets

Pyrazinamide

Intervention Type: DRUG

Pyrazinamide 20-30mg/kg

Meropenem and amoxicillin/clavulanate plus bedaquiline

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.

Group Type: EXPERIMENTAL

Meropenem Injection

Intervention Type: DRUG

Meropenem IV 6 grams

Amoxicillin Clavulanate

Intervention Type: DRUG

Amx/CA oral 1000/62.5mg 2 tablets

Bedaquiline

Intervention Type: DRUG

Bedaquiline 400mg

Rifafour standard of care treatment

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.

Group Type: ACTIVE_COMPARATOR

Rifafour

Intervention Type: DRUG

Rifafour (HRZE) Standard dose

Interventions

Meropenem Injection

Meropenem IV 6 grams

Intervention Type: DRUG

Amoxicillin Clavulanate

Amx/CA oral 1000/62.5mg 2 tablets

Intervention Type: DRUG

Pyrazinamide

Pyrazinamide 20-30mg/kg

Intervention Type: DRUG

Bedaquiline

Bedaquiline 400mg

Intervention Type: DRUG

Rifafour

Rifafour (HRZE) Standard dose

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

TASK Applied Science

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Veronique R De Jager, MBChB

Role: PRINCIPAL_INVESTIGATOR

TASK

Locations

TASK Clinical Research Centre

Cape Town, Western Cape, South Africa

Countries

South Africa

Other Identifiers

TASK-005_TB_COMBO_01

Identifier Type: -

Identifier Source: org_study_id