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

• Status: Completed
• Trial end date: 2014-12-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: TASK Applied Science; Task Foundation NPC
• Collaborators: Barcelona Centre for International Health Research; Eduardo Mondlane University; GlaxoSmithKline; Research Center Borstel; University Eduardo Mondlane
• Treatments: Amoxicillin; beta-Lactams; Clavulanic Acid; Clavulanic Acids; Meropenem; Thienamycins

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