Clinical trial NCT03557281: An Early Bactericidal Activity, Safety and Tolerability of GSK3036656 in Subjects With Drug-sensitive Pulmonary Tuberculosis
Official title: A Phase IIa Open-label Trial to Investigate the Early Bactericidal Activity, Safety and Tolerability of GSK3036656 in Participants With Drug-sensitive Pulmonary Tuberculosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Tuberculosis
Keywords: Early bactericidal activity
Mycobacterium Tuberculosis
GSK3036656
Pulmonary tuberculosis
Colony forming units
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2018-06-15
Enrollment: 76
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
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.
Primary purpose: TREATMENT

Brief 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.

Primary outcomes:
measure: Change in log10 Colony Forming Units (CFU) Per (/) Milliliter (mL) of Direct Respiratory Sputum Samples From Baseline to Day 14
timeFrame: Baseline and up to Day 14
Secondary outcomes:
measure: Change in log10 CFU/mL of Direct Respiratory Sputum Samples From Baseline to Day 2
timeFrame: Baseline and up to Day 2
measure: Change in log10 CFU Per mL of Direct Respiratory Sputum Samples From Day 2 to Day 14
timeFrame: Day 2 to Day 14
measure: Change in log10 Time to Sputum Culture Positivity (TTP) From Baseline to Day 14
timeFrame: Baseline and up to Day 14
measure: Change in log10 TTP From Baseline to Day 2
timeFrame: Baseline and up to Day 2
measure: Change in log10 TTP From Day 2 to Day 14
timeFrame: Day 2 to Day 14
measure: Area Under the Plasma Drug Concentration Versus Time Curve From Time Zero to Last Time of Quantifiable Concentration (AUC[0-t]) Following Once Daily Dosing of GSK3036656
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 14
measure: Area Under the Plasma Concentration Time Curve From Zero to 24 Hours (AUC[0-24]) Following Once Daily Dosing of GSK3036656
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 14
measure: Maximum Observed Plasma Drug Concentration (Cmax) Following Once Daily Dosing of GSK3036656
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 14
measure: Time to Reach Cmax (Tmax) Following Once Daily Dosing of GSK3036656
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day 14
measure: Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs)
timeFrame: Up to Day 28 (follow-up visit)
measure: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count
timeFrame: Baseline (Day 1, Pre-dose) and at Day 14
measure: Change From Baseline in Hematology Parameter: Hemoglobin
timeFrame: Baseline (Day 1, Pre-dose) and at Day 14
measure: Change From Baseline in Hematology Parameter: Hematocrit
timeFrame: Baseline (Day 1, Pre-dose) and at Day 14
measure: Change From Baseline in Hematology Parameter: Red Blood Cells Count
timeFrame: Baseline (Day 1, Pre-dose) and at Day 14
measure: Change From Baseline in Hematology Parameter: Mean Corpuscular Volume
timeFrame: Baseline (Day 1, Pre-dose) and at Day 14
measure: Change From Baseline in Hematology Parameter: Mean Corpuscle Hemoglobin
timeFrame: Baseline (Day 1, Pre-dose) and at Day 14
measure: Change From Baseline in Hematology Parameter: Reticulocytes
timeFrame: Baseline (Day 1, Pre-dose) and at Day 14
measure: Change From Baseline in Chemistry Parameters: Glucose, Calcium, Chloride, Potassium, Sodium, Blood Urea Nitrogen
timeFrame: Baseline (Day 1, Pre-dose) and at Day 14
measure: Change From Baseline in Chemistry Parameters: Lactate Dehydrogenase (LDH), Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), Gamma-glutamyl Transferase (GGT)
timeFrame: Baseline (Day 1, Pre-dose) and at Day 14
measure: Change From Baseline in Chemistry Parameters: Creatinine, Indirect Bilirubin, Direct Bilirubin and Total Bilirubin
timeFrame: Baseline (Day 1, Pre-dose) and at Day 14
measure: Change From Baseline in Chemistry Parameter: Total Protein
timeFrame: Baseline (Day 1, Pre-dose) and at Day 14
measure: Number of Participants With Worst-Case Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method
timeFrame: Baseline (Day 1, Pre-dose) and up to Day 28 (follow-up visit)
measure: Number of Participants With Worst Case Vital Sign Results by Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline
timeFrame: Up to Day 28 (follow-up visit)
measure: Number of Participants With Worst Case Post-Baseline Abnormal Electrocardiogram (ECG) Findings
timeFrame: Up to Day 28 (follow-up visit)
measure: Change From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF)
timeFrame: Baseline (Day 1, Pre-dose) and at Day 14
Other outcomes:
Locations:
city: Cape Town
country: South Africa
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Volynets GP, Usenko MO, Gudzera OI, Starosyla SA, Balanda AO, Syniugin AR, Gorbatiuk OB, Prykhod'ko AO, Bdzhola VG, Yarmoluk SM, Tukalo MA. Identification of dual-targeted Mycobacterium tuberculosis aminoacyl-tRNA synthetase inhibitors using machine learning. Future Med Chem. 2022 Sep;14(17):1223-1237. doi: 10.4155/fmc-2022-0085. Epub 2022 Jul 25.