Study to Evaluate EBA, Safety and Tolerability of Carbapenems in Adults With Pulmonary Tuberculosis

NCT05896930 | Completed Phase 2

• 1 other identifier: TASK 003
• Study Type: interventional
• Target: 134
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this single-center, open-labelled, clinical trial in two groups aims to proof that a specific group of antibiotics (carbapenems) can be used to treat pulmonary tuberculosis if it is combined with another antibiotic (amoxicillin/clavulanate). A total of 113 male or female participants (8 groups and 9 treatment regimens as group 8 was split into 2 groups of 4 participants receiving Rifafour e-275), aged between 18 and 65 years (inclusive), with newly diagnosed, smear-positive, pulmonary TB.

Conditions

Pulmonary Tuberculosis

Keywords

EBA; Intravenous Meropenem; Newly Diagnosed; Smear-Positive; Rifampicin-Susceptible; Pulmonary Tuberculosis

Outcome Measures

Primary Outcomes (2)

• Early bactericidal activity by change in logCFU over 14 days

  The EBACFU(0-14) as determined by the rate of change in logCFU (colony forming units) per ml sputum over the period Day 0 to Day 14 which will be summarised and described with a statistical model as an estimated average decrease per day for patients in each group.

  14 days

• Early bactericidal activity by change in time-to-positivity over 14 days

  The EBATTP(0-14) as determined by the percentage rate of change in TTP (time to positivity) per ml sputum over the period Day 0 to Day 14, which will be summarised and described with a statistical model as an estimated average increase per day for patients in each group.

  14 days

Secondary Outcomes (1)

• Early bactericidal activity by change in logCFU and TTP per ml over 0-2 days, 0-7 days, and 2-14 days

  0-2 days, 0-7 days, 2-14 days

Study Arms (8)

Group 1 Arm 1

EXPERIMENTAL

Meropenem 6g IV over 6 hours plus amoxicillin/CA

Drug: Meropenem 6g IV over 6 hours; Drug: Amoxicillin/CA twice daily

Group 1 Arm 2

EXPERIMENTAL

Ertapenem 1g IM plus amoxicillin/CA

Drug: Ertapenem 1g IM; Drug: Amoxicillin/CA twice daily

Group 2 Arm 1

EXPERIMENTAL

Meropenem 3g over 1 hour twice daily plus amoxicillin/CA

Drug: Meropenem 3g IV; Drug: Amoxicillin/CA twice daily

Group 2 Arm 2

EXPERIMENTAL

Ertapenem 1g IV plus amoxicillin/CA

Drug: Ertapenem 1g IV; Drug: Amoxicillin/CA twice daily

Group 2 Arm 3

EXPERIMENTAL

Amoxicillin; CA

Drug: Amoxicillin/CA twice daily

Group 2 Arm 4

EXPERIMENTAL

Rifampicin 35mg/kg plus amoxicillin/CA

Drug: Amoxicillin/CA twice daily; Drug: Rifampicin 35 mg/kg

Group 2 Arm 5

EXPERIMENTAL

Meropenem 6g or 4g IV over 60 minutes plus amoxicillin/CA

Drug: Meropenem 6g IV over 60 minutes; Drug: Meropenem 4g IV; Drug: Amoxicillin/CA once daily

Group 1

ACTIVE COMPARATOR

Rifafour e-275

Drug: Rifafour e-275

Interventions

Meropenem 6g IV over 6 hours DRUG

Meropenem 6g intravenously over 6 hours once daily on days 1-14.

Group 1 Arm 1

Ertapenem 1g IM DRUG

Ertapenem 1g intramuscularly once daily on days 1-14.

Group 1 Arm 2

Meropenem 3g IV DRUG

Meropenem 3g intravenously twice daily over 60 minutes on days 1-14.

Group 2 Arm 1

Ertapenem 1g IV DRUG

Ertapenem 1g intravenously once daily on days 1-14.

Group 2 Arm 2

Amoxicillin/CA twice daily DRUG

Amoxicillin/CA 2 tablets x 1000mg/62.5mg orally 12-hourly on days 1-14.

Group 1 Arm 1; Group 1 Arm 2; Group 2 Arm 1; Group 2 Arm 2; Group 2 Arm 3; Group 2 Arm 4

Rifampicin 35 mg/kg DRUG

Rifampicin 35 mg/kg once daily on days 1-14.

Group 2 Arm 4

Meropenem 6g IV over 60 minutes DRUG

Meropenem 6g intravenously once daily over 60 minutes on days 1-14.

Group 2 Arm 5

Rifafour e-275 DRUG

Rifafour e-275 will be supplied as fixed dose combination tablets and administered orally once daily for 14 days as 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 1

Meropenem 4g IV DRUG

Meropenem 4g intravenously once daily over 60 minutes on days 1-14.

Group 2 Arm 5

Amoxicillin/CA once daily DRUG

Amoxicillin/CA 2 tablets x 1000mg/62.5mg orally once daily on days 1-14.

Group 2 Arm 5

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 direct 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, as defined below:
• Non-childbearing potential:
• Participant - not heterosexually active or practicing sexual abstinence; or
• Female participant/sexual partner - bilateral oophorectomy, bilateral tubal ligation and/or hysterectomy or has been 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:
• 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; and are willing to continue practicing birth control methods throughout participation in the study until Visit 19 (day 28).

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.
• A history of TB less than 3 years ago.
• Clinically significant evidence of extrathoracic TB (miliary TB, abdominal TB, urogenital TB, osteoarthritic TB, TB meningitis), as judged by the Investigator.
• 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.
• Known or suspected, current or history of within the past 2 years, alcohol or drug abuse, that is, in the opinion of the Investigator, sufficient to compromise the safety or cooperation of the participant.
• HIV infected participants.
• 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), point of care HbA1c above 6.5, 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 or inhaled corticosteroids, within 2 weeks prior to screening
• Participants with the following toxicities at screening as defined by the enhanced CTCEA toxicity table
• creatinine grade 2 or greater (\>1.5 times upper limit of normal \[ULN\]);
• haemoglobin \<7.5 g/dL;

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, Pulmonary

Interventions

Meropenem; Ertapenem; Rifampin

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Thienamycins; Carbapenems; beta-Lactams; Lactams; Amides; Organic Chemicals; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Study Officials

• Prof Andreas H Diacon, MD, PhD

  TASK

  PRINCIPAL INVESTIGATOR

Study Design

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

Model Details: This study will be a standard 14 day EBA design incorporating 2 groups with parallel treatment arms. This design allows comparison of the results of this study with similar prior studies of treatments for TB. No placebo treatment is included in this study - all participants will be given either active study treatment or Rifafour e275® control. The planned sample size is15 participants per treatment group.

Study Record Dates

• First Submitted: April 11, 2023
• First Posted: June 9, 2023
• Study Start: November 9, 2017
• Primary Completion: January 4, 2021
• Study Completion: January 4, 2021
• Last Updated: June 9, 2023

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will not share

Locations

ZA (1)