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
Information source: Task Foundation NPC
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Pulmonary Tuberculosis
Intervention: Meropenem (Drug); Faropenem (Drug); Amoxycillin/clavulanic acid (Drug); Rifafour e275 (Drug)
Phase: Phase 2
Status: Completed
Sponsored by: Task Foundation NPC
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.
Clinical Details
Official title: A Phase 2 Trial to Evaluate the Early Bactericidal Activity, Safety and Tolerability of Meropenem, Administered Intravenously, Plus Amoxycillin/CA and Faropenem, Administered Orally, Plus Amoxycillin/CA in Adult Patients With Newly Diagnosed, Smear-positive Pulmonary Tuberculosis.
Study design: Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Primary Endpoint (The EBA CFU(0-14) as determined by the rate of change in logCFU per ml sputum)
Secondary outcome: Efficacy (The EBA CFU(0-2) and EBA CFU(2-14) as determined by the rate of change of logCFU in sputum)Safety and Tolerability (Incidence of treatment emergent adverse events (TEAEs) Pharmacokinetics (The maximum observed plasma concentration (Cmax), time to reach Cmax (Tmax), the minimum observed plasma concentration (Cmin) 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)
Detailed description:
A single-centre, open-label clinical trial including a total of 45 male or female
participants (2 groups of 15 participants receiving an IMP and 1 group of 15 participants
receiving Rifafour e-275), aged between 18 and 65 years (inclusive), with newly diagnosed,
smear-positive, pulmonary tuberculosis will be enrolled into this trial.
Treatment will be administered for 14 consecutive days in the following dosing schemes:
1. Meropenem 2g intravenously 8-hourly; plus amoxycillin/CA 500mg/125mg orally 8- hourly
on days 1-14.
2. Faropenem 600mg orally 8-hourly; plus amoxycillin/CA 500mg/125mg orally 8-hourly on
days 1-14.
3. The third arm 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. The mycobacteriology laboratory
will remain blinded until closure of the EBA results.
Participants will be admitted to the in hospital facility for a period of up to 24 days.
During this period they will await their screening results after which they will receive 14
day of IMP. on day 14 intensive PK sampling will be done. They will be discharged on day
15 to the clinic where they will continue on the national TB programme treatment regime.
Participants will return to the clinical trial site 14 days after receipt of their last
study drug. for a safety evaluation.
Eligibility
Minimum age: 18 Years.
Maximum age: 65 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria:
1. Provide written, informed consent prior to all trial-related procedures including HIV
testing.
2. Male or female, aged between 18 and 65 years, inclusive.
3. Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive.
4. Newly diagnosed, previously untreated, pulmonary TB.
5. A chest X-ray picture which in the opinion of the Investigator is consistent with TB.
6. Sputum positive GeneXpert or TB smear from TB clinic or site of initial diagnosis.
7. 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).
8. Ability to produce an adequate volume of sputum as estimated from a spot assessment
(estimated 10 ml or more overnight production).
9. Be of non-childbearing potential or using effective methods of birth control, as
defined below:
Non-childbearing potential:
1. Participant - not heterosexually active or practice sexual abstinence; or
2. 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
3. Male participant/sexual partner - vasectomised or has had a bilateral orchidectomy
minimally three month prior to screening;
Effective birth control methods:
1. Double barrier method which can include a male condom, diaphragm, cervical cap, or
female condom; or
2. 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). (Note: hormone-based
contraception alone may not be reliable when taking IMP; therefore, hormone-based
contraceptives alone cannot be used by female participants to prevent pregnancy).
Exclusion Criteria Medical History
1. 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.
2. Poor general condition where any delay in treatment cannot be tolerated per
discretion of the Investigator.
3. A history of previous TB less than 5 years ago.
4. Clinically significant evidence of extrathoracic TB (miliary TB, abdominal TB,
urogenital TB, osteoarthritic TB, TB meningitis), as judged by the Investigator.
5. 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.
6. Isoniazid-resistant and/or rifampicin-resistant bacteria detected with a sputum
specimen collected within the pre-treatment period and tested at the study
laboratory.
7. 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.
8. For HIV infected participants:
1. having a CD4+ count <350 cells/µL;
2. or having received antiretroviral therapy medication within the last 90 days;
3. or having received oral or intravenous antifungal medication within the last 90
days;
4. or with an AIDS-defining opportunistic infection or malignancies (except
pulmonary TB).
9. Having participated in other clinical studies with investigational agents within 8
weeks prior to trial start.
10. 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.
11. Diabetes mellitus requiring insulin.
Specific Treatments
12. Treatment received with any drug active against MTB within the 3 months prior to
Visit 1 (including but not limited to isoniazid, ethambutol, amikacin, cycloserine,
fluoroquinolones, rifabutin, rifampicin, streptomycin, kanamycin, para-aminosalicylic
acid, rifapentine, pyrazinamide, thioacetazone, capreomycin, thioamides,
metronidazole).
13. Participants receiving sodium valproate, furosemide, imipenem or probenecid.
14. Any diseases or conditions in which the use of the standard TB drugs or any of their
components is contra-indicated, including but not limited to allergy to any TB drug,
their component or to the IMP.
Laboratory Abnormalities
15. Participants with the following toxicities at screening as defined by the enhanced
CTCEA toxicity table
1. creatinine grade 2 or greater (>1. 5 times upper limit of normal [ULN]);
2. hemoglobin grade 4 (<6. 5 g/dL);
3. platelets grade 2 or greater (under 50x109 cells/L);
4. serum potassium grade 2 or greater (<3. 0 mEq/L);
5. aspartate aminotransferase (AST) grade 3 (≥3. 0 x ULN) to be excluded;
6. alanine aminotransferase (ALT) grade 3 (≥3. 0 x ULN) to be excluded;
7. APTT grade 3
8. INR grade 3
9. Total white cell count grade 3
Locations and Contacts
TASK Foundation NPC, Cape Town, Western Cape 7530, South Africa
Additional Information
Starting date: September 2014
Last updated: January 28, 2015
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