PNU-100480 In Newly Diagnosed, Drug Sensitive Patients With Pulmonary TB; Early Bactericidal Activity; Whole Blood Assay

Overview

PNU-100480 is being developed for the treatment of both drug resistant and sensitive tuberculosis. This is an efficacy and safety study to characterize the effect of PNU-100480 when given for 14 days to treatment-naive patients with drug-sensitive pulmonary tuberculosis.

Full Title of Study: “A Phase 2a, Open-Label, Randomized Study In Treatment-Naive, Sputum Smear Positive Subjects With Drug-Sensitive Pulmonary Tuberculosis To Assess Early Bactericidal Activity (EBA) And Whole Blood Activity (WBA) Of PNU-100480 (PF-02341272)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: December 2011

Interventions

  • Drug: PNU-100480
    • 600 mg twice daily (BID) for 14 days
  • Drug: PNU-100480
    • 1200 mg once daily (QD) for 14 days
  • Drug: RHZE
    • Combination tablet (RHZE) dosed by weight. Dosage strength per tablet is 150 mg Rifampicin (R)/75 mg Isoniazid (H)/400 mg Pyrazinamide (Z)/275 mg Ethambutol (E)

Arms, Groups and Cohorts

  • Experimental: PNU-100480 600 mg BID
  • Experimental: PNU-100480 1200 mg QD
  • Active Comparator: RHZE
    • conjugated tablet with 4 drug combination of RHZE, Rifafour® e275 will be used in countries where can be sourced locally

Clinical Trial Outcome Measures

Primary Measures

  • The primary endpoint is rate of change in sputum log CFU/mL count (EBA) from Days 0-2.
    • Time Frame: Days 0-2

Secondary Measures

  • Rate of change in sputum log CFU/mL count (extended EBA).
    • Time Frame: Days 2-14
  • Rate of change in sputum log CFU/mL count (extended EBA).
    • Time Frame: Days 0-14
  • Rate of change in culture time to positivity (TTP) measured by MGIT and in log transformed TTP
    • Time Frame: Days 02-; 2-14; 0-14
  • Cumulative whole blood bactericidal activity (measured as log reduction in CFU) against intracellular M. tuberculosis relative to administered dose and drug PK
    • Time Frame: Day 1
  • Cumulative whole blood bactericidal activity (measured as log reduction in CFU) against intracellular M. tuberculosis relative to administered dose and drug PK
    • Time Frame: Day 13-14
  • Plasma concentrations of PNU-100480 and PNU-101603 will be used to determine PK parameters (AUCtau, AUC tau,ss, Cmax, Tmax, terminal half-life t1/2, Cavg, Rac) as data permit
    • Time Frame: Day 1
  • Plasma concentrations of PNU-100480 and PNU-101603 will be used to determine PK parameters (AUCtau, AUC tau,ss, Cmax, Tmax, terminal half-life t1/2, Cavg, Rac) as data permit
    • Time Frame: Day 13-14
  • Safety assessments including physical exams, AEs, laboratory tests, ECGs, and vital signs.
    • Time Frame: Phys exam, AEs, and vitals are done at every visit (Screening through Day 15, Day 42/Follow-up)
  • Safety assessments including physical exams, AEs, laboratory tests, ECGs, and vital signs.
    • Time Frame: ECGs are done at Screening, Day 1, Day 14, 15 and 42/Follow-up
  • Safety assessments including physical exams, AEs, laboratory tests, ECGs, and vital signs.
    • Time Frame: Lab tests at Screening, Day 1, Day 15 and 42/Follow-up

Participating in This Clinical Trial

Inclusion Criteria

  • Adult males or females between 18 and 65 years; women of childbearing potential must be willing to adhere to lifestyle requirements regarding contraception/pregnancy prevention. – Newly diagnosed sputum smear-positive pulmonary TB confirmed with acid-fast bacillus (AFB) smear and chest x-ray. Patients with TB more than 5 years ago who completed treatment, are healthy, and meet other inclusion criteria may be included. – Body weight between 40 and 90 kg, inclusive (in light clothing, no shoes). – Reasonably normal hemoglobin (>=8 gm/dL), renal function (serum creatinine <2 mg/dL), hepatic function (serum AST <3xULN and total bilirubin <1.3 mg/dL), and random glucose <150 mg/dL. Exclusion Criteria:

  • HIV infection with helper/inducer T-lymphocytes (CD4 cell) count of <=350×10-6/L. – Presence of significant hemoptysis. Subjects who cough up frank blood (more than blood streaked sputum) will not be eligible. – Pregnant or nursing females; females of childbearing potential unwilling or unable to adhere to contraception guidelines. – Significant respiratory impairment (respiratory rate >35/minute). – Clinical suspicion of disseminated TB or tuberculosis meningitis. – Subjects with diabetes mellitus on insulin and/or who have poorly controlled disease. – Subjects with confirmed or suspected multi-drug resistant TB.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 65 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Sequella, Inc.
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Lisa Beth Ferstenberg, M.D., Study Director, Sequella, Inc.

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