Phase 2 Trial to Evaluate the Early Bactericidal Activity, Safety and Tolerability of Meropenem Plus Amoxycillin/CA and Faropenem Plus Amoxycillin/CA in Adult Patients With Newly Diagnosed Pulmonary Tuberculosis

NCT02349841 | Completed Phase 2

• 1 other identifier: TASK-001
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 1

Brief Summary

To evaluate the early bactericidal activity (EBA), safety, tolerability and pharmacokinetics of meropenem administered intravenously three times a day, plus amoxycillin/CA administered orally three times a day; and of faropenem administered orally three times a day, plus amoxycillin/CA administered orally three times a day; for 14 consecutive days, in adult participants with newly diagnosed, smear positive pulmonary tuberculosis, in order to help establish proof-of-concept for carbapenem antibiotics as antituberculosis agents and to select the appropriate agent and route of administration for later stage clinical development.

Conditions

Pulmonary Tuberculosis

Outcome Measures

Primary Outcomes (1)

• Primary Endpoint (The EBA CFU(0-14) as determined by the rate of change in logCFU per ml sputum)

  The EBA CFU(0-14) as determined by the rate of change in logCFU per ml sputum over the period Day 0 to Day 14 which will be described with at most 3 parameters from a linear, bi-linear or non-linear regression of logCFU on time

  14 days

Secondary Outcomes (4)

• Efficacy (The EBA CFU(0-2) and EBA CFU(2-14) as determined by the rate of change of logCFU in sputum)

  14 days

• Safety and Tolerability (Incidence of treatment emergent adverse events (TEAEs)

  28 days

• Pharmacokinetics (The maximum observed plasma concentration (Cmax), time to reach Cmax (Tmax), the minimum observed plasma concentration (Cmin)

  14 days

• Pharmacokinetics - Pharmacodynamics (descriptive analyses, and no inferential tests will be carried out, of EBA CFU(0-14), EBA CFU(0-2), and EBA CFU(2-14) vs. AUC(0-24) • Time over Minimum inhibitory concentrations (TMIC) (for meropenem; faropenem)

  14 days

Study Arms (3)

Meropenem;amoxycillin/clavulanic acid

EXPERIMENTAL

Meropenem 2g will be administered intravenously 8-hourly; plus amoxycillin/CA 500mg/125mg will be administered orally 8-hourly for 14 days

Drug: Meropenem; Drug: Amoxycillin/clavulanic acid

Faropenem; amoxycillin/CA

EXPERIMENTAL

Faropenem 600mg will be administered orally 8-hourly; plus amoxycillin/CA 500mg/125mg will be administered orally 8-hourly for 14 days

Drug: Faropenem; Drug: Amoxycillin/clavulanic acid

Rifafour e-275

ACTIVE COMPARATOR

Rifafour e-275 will be administered orally once daily for 14 days as per South African National TB Treatment Guidelines

Drug: Rifafour e275

Interventions

Meropenem DRUG

To administer 2g daily 8 hourly for 14 days

Meropenem;amoxycillin/clavulanic acid

Faropenem DRUG

To adminster 600mg 8 hourly daily for 14 days

Faropenem; amoxycillin/CA

Amoxycillin/clavulanic acid DRUG

To administer 625mg 8 hourly daily for 14 days together with the faropenem and meropenem

Faropenem; amoxycillin/CA; Meropenem;amoxycillin/clavulanic acid

Rifafour e275 DRUG

To be taken as per the National TB treatment programme for 14 days

Rifafour e-275

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, pulmonary TB.
• A chest X-ray picture which in the opinion of the Investigator is consistent with TB.
• Sputum positive GeneXpert or TB smear from TB clinic or site of initial diagnosis.
• Sputum positive on direct microscopy for acid-fast bacilli on at least one sputum sample at the trial appointed laboratory(at least 1+ on the IUATLD/WHO scale).
• Ability to produce an adequate volume of sputum as estimated from a spot assessment (estimated 10 ml or more overnight production).
• Be of non-childbearing potential or using effective methods of birth control, as defined below:
• Non-childbearing potential:
• Participant - not heterosexually active or practice 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; or

You may not qualify if:

• Evidence of clinically significant (as judged by the investigator), metabolic, gastrointestinal, cardiovascular, musculoskeletal, ophthalmological, pulmonary, neurological, psychiatric or endocrine diseases, malignancy, or other abnormalities (other than the indication being studied) including malaria.
• Poor general condition where any delay in treatment cannot be tolerated per discretion of the Investigator.
• A history of previous TB less than 5 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 IMP/s or related substances i.e. β-lactams and penicillin, as confirmed by the clinical judgement of the Investigator.
• Isoniazid-resistant and/or rifampicin-resistant bacteria detected with a sputum specimen collected within the pre-treatment period and tested at the study laboratory.
• 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.
• For HIV infected participants:
• having a CD4+ count \<350 cells/µL;
• or having received antiretroviral therapy medication within the last 90 days;
• or having received oral or intravenous antifungal medication within the last 90 days;
• or with an AIDS-defining opportunistic infection or malignancies (except pulmonary TB).
• 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.
• Diabetes mellitus requiring insulin.

Sponsors & Collaborators

• TASK Applied Science: lead
• Eduardo Mondlane University: collaborator
• GlaxoSmithKline: collaborator
• Barcelona Centre for International Health Research: collaborator
• Research Center Borstel: collaborator

Study Sites (1)

TASK Foundation NPC

Cape Town, Western Cape, 7530, South Africa

Location

MeSH Terms

Conditions

Tuberculosis, Pulmonary

Interventions

Meropenem; fropenem; Amoxicillin-Potassium Clavulanate Combination

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; Clavulanic Acid; Clavulanic Acids; Amoxicillin; Ampicillin; Penicillin G; Penicillins; Sulfur Compounds; Drug Combinations; Pharmaceutical Preparations

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor Andreas H Diacon

Study Record Dates

• First Submitted: January 23, 2015
• First Posted: January 29, 2015
• Study Start: September 1, 2014
• Primary Completion: December 1, 2014
• Study Completion: December 1, 2014
• Last Updated: September 13, 2018

Record last verified: 2018-09

Locations

ZA (1)