An Early Bactericidal Activity, Safety and Tolerability of GSK3036656 in Subjects With Drug-sensitive Pulmonary Tuberculosis
Condition: Tuberculosis
MeSH terms: Tuberculosis; Tuberculosis, Pulmonary
Intervention: GSK3036656; Rifafour e-275
Intervention description: GSK3036656 will be administered; Rifafour e-275 will be administered
Intervention MeSH terms: GSK656
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Sequential Assignment
Intervention model description: Eligible subjects in each cohort will be randomized to receive sequential doses of either GSK3036656 or standard-of-care (RIFAFOUR) regimen. This study will employ dose escalation, where the decision to proceed to each subsequent dose level will be made based on safety, tolerability and preliminary pharmacokinetic data from the prior cohort.
Masking: None (Open Label)
Masking description: This will be an open label study. Hence, there will be no masking.
Enrollment: 76.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Early bactericidal activity; Mycobacterium Tuberculosis; GSK3036656; Pulmonary tuberculosis; Colony forming units

Summary:

      Tuberculosis remains a concerning health problem, with Mycobacterium Tuberculosis (MTB) now
      causing more deaths than acquired immune deficiency syndrome (AIDS). GSK3036656 is a compound
      with a novel mechanism of action under development for the treatment of tuberculosis. It
      suppresses protein synthesis in MTB by selectively inhibiting the enzyme Leucyl t-ribose
      nucleic acid (RNA) synthetase. Thus, this study will investigate the early bactericidal
      activity, safety and tolerability of GSK3036656 in up to four sequential cohorts of subjects
      with rifampicin-susceptible tuberculosis. The primary objective of this dose-escalation study
      is to establish the anti-tuberculosis effect of GSK3036656 on serial colony forming units
      (CFU) counts of MTB in sputum over 14 days of therapy. Subjects in each cohort will be
      randomized in 3:1 ratio to one of two treatments: either GSK3036656 or standard-of-care
      (RIFAFOUR® e-275) regimen. The approximate duration of the study for an individual subject
      will be 5 weeks, including 1 week of screening, 2 weeks of treatment period and another 2
      weeks of final follow-up visit. RIFAFOUR e-275 is a registered trademark of Sanofi-Aventis.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subjects must be 18 to 65 years of age inclusive, at the time of signing the informed
             consent.

          -  In addition, subjects recruited into cohorts that are planned to undergo
             fluorodeoxyglucose (FDG) positron emission tomography/ Computed Tomography (PET/CT)
             must be >=25 years of age, at the time of signing the informed consent.

          -  New episode of untreated, rifampicin-susceptible pulmonary tuberculosis.

          -  A chest X-ray picture which in the opinion of the Investigator is consistent with
             tuberculosis.

          -  At least one sputum sample positive on direct microscopy for acid-fast bacilli (at
             least 1+ on the International Union Against Tuberculosis and Lung Disease/ World
             Health Organization [IUATLD/WHO] scale) or molecular test (Xpert MTB/ rifampicin) with
             result of either medium or high positive for MTB: Ability to produce an adequate
             volume of sputum as estimated from an overnight sputum collection sample (estimated 10
             milliliter or more); estimated from a spot sputum sample at screening; confirmed at
             the first overnight collection; if less than 10 milliliter is collected overnight this
             may be repeated once.

          -  Normal echocardiogram or echocardiogram with normal left ventricular function with at
             most trace to mild valvular regurgitation and no valvular stenosis.

          -  Within the normal range for the assay for troponin and b-type natriuretic peptide at
             screening.

          -  Body weight (in light clothing and with no shoes) between 40 and 90 kilograms,
             inclusive, at screening.

          -  Male or female of non-childbearing potential will be included in the study. A male
             subject with female partners of child-bearing potential must agree to use
             contraception during the treatment period and for at least 6 weeks, corresponding to
             time needed to eliminate study treatment plus an additional 90 days (a spermatogenesis
             cycle) for study treatments with teratogenic potential after the last dose of study
             treatment and refrain from donating sperm during this period. A female subject is
             eligible to participate if she is not pregnant, not breastfeeding, and at least one of
             the following conditions applies: Pre-menopausal females with one of the following;
             documented tubal ligation; documented hysteroscopic tubal occlusion procedure with
             follow-up confirmation of bilateral tubal occlusion or documented bilateral
             salpingectomy; hysterectomy; documented Bilateral Oophorectomy. Postmenopausal will be
             defined as 12 months of spontaneous amenorrhea without an alternative medical cause.
             Post-menopausal status will be confirmed by a simultaneous follicle-stimulating
             hormone and estradiol levels test.

          -  Capable of giving signed informed consent.

        Exclusion Criteria:

          -  Evidence of a clinically significant (as judged by the Investigator) condition or
             abnormality (other than the indication being studied) that might compromise safety or
             the interpretation of trial efficacy or safety endpoints.

          -  Poor general condition where any delay in treatment cannot be tolerated per discretion
             of the Investigator.

          -  A previous episode of treated tuberculosis less than 3 years ago.

          -  Clinically significant evidence of extrathoracic tuberculosis (miliary tuberculosis,
             abdominal tuberculosis, urogenital tuberculosis, osteoarthritic tuberculosis,
             tuberculosis meningitis), as judged by the Investigator.

          -  Corrected QT Interval > 450 milliseconds.

          -  History of allergy to any of the trial investigational product/s or related substances
             as confirmed by the clinical judgement of the Investigator.

          -  History of photosensitivity.

          -  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 subject.

          -  HIV infected subjects: having a cluster of differentiation 4+ (CD4+) count <350 cells
             per microliter; 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 tuberculosis).

          -  Participated in other clinical studies with investigational agents within 8 weeks
             prior to the first dosing day in the current study.

          -  Subjects with diabetes (Type 1 or 2), point of care glycated hemoglobin above 6.5
             millimoles per mole, or random glucose over 11.1 millimoles per liter will be excluded
             from cohorts undergoing FDGPET/CT. Subjects not undergoing FDG-PET/CT will be excluded
             if they have unstable diabetes or insulin dependency.

          -  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 tumor necrosis factor -alpha inhibitors or systemic or inhaled
             corticosteroids, within 2 weeks prior to screening.

          -  Subjects with the following abnormal laboratory values at screening as defined by the
             enhanced Common Terminology Criteria for Adverse Events toxicity table: creatinine
             grade 2 or greater (>1.5 times upper limit of normal [ULN]); hemoglobin <10.0 grams
             per deciliter; thrombocytopenia grade 2 or greater (under 50 times 10^9 cells per
             liter); serum potassium grade 2 or greater (<3.0 milliequivalents per liter);
             aspartate aminotransferase grade 3 (>=3.0 times ULN); alanine aminotransferase grade 3
             (>=3.0 times ULN); activated partial thromboplastin time grade 3 (>=2.5 times ULN);
             international normalized ratio grade 3 (>=2.5 times ULN); total white cell count grade
             3 (<2.0 times 10^9 cells per liter).

          -  Subjects who are selected to undergo FDG-PET/CT who have been estimated to have been
             exposed to ionizing radiation in excess of 10 millisievert above background over the
             previous three-year period as a result of occupational exposure to radiation or as a
             result of research studies. This will be judged through clinical history taking.

          -  Women who are susceptible to heavy periods or heavy vaginal bleeding or spotting will
             be excluded in order to minimize blood loss and avoid confounding effects on the
             interpretation of hematology parameters.