An Early Bactericidal Activity, Safety and Tolerability of GSK3036656 in Subjects With Drug-sensitive Pulmonary Tuberculosis

• ClinicalTrials.gov Identifier: NCT03557281
• Recruitment Status: Completed
• First Posted: June 15, 2018
• Last Update Posted: January 3, 2022
• Sponsor: GlaxoSmithKline
• Information provided by (Responsible Party): GlaxoSmithKline

Tracking Information

• First Submitted Date: June 4, 2018
• First Posted Date: June 15, 2018
• Last Update Posted Date: January 3, 2022
• Actual Study Start Date: March 27, 2019
• Actual Primary Completion Date: December 3, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 4, 2018)

Rate of change in log10 CFU per milliliter direct respiratory sputum samples from Baseline to Day 14 [ Time Frame: Baseline and up to day 14 ]

The early bactericidal activity of GSK3036656 will be determined as the rate of change in log10 CFUs of MTB in sputum.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 4, 2018)

• Number of subjects with adverse events and serious adverse events [ Time Frame: Up to 28 days ]
  An adverse event is any untoward medical occurrence in a clinical study subjects, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any untoward medical occurrence resulting in death, life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment will be categorized as serious adverse event.
• Number of subjects with abnormal findings for clinical chemistry parameters [ Time Frame: Up to 28 days ]
  Blood samples will be collected from subjects for the analysis of clinical chemistry parameters as a measure of safety, including blood urea nitrogen, potassium, aspartate aminotransferase, total bilirubin, indirect bilirubin, direct bilirubin, albumin, creatinine, sodium, alanine aminotransferase, gamma-glutamyl transferase, lactate dehydrogenase, sodium, potassium, calcium (corrected for albumin), chloride, total protein, glucose (random/fasting) and alkaline phosphatase.
• Number of subjects with abnormal findings for hematology parameters [ Time Frame: Up to 28 days ]
  Blood samples will be collected from subjects for the analysis of hematology parameters as a measure of safety, including platelet count, mean corpuscular volume, mean corpuscular hemoglobin, percent reticulocytes, neutrophils, lymphocytes, monocytes, eosinophil's, basophils, red blood cells count, hemoglobin, and hematocrit coagulation test.
• Number of subjects with abnormal findings for urinalysis parameters [ Time Frame: Up to 28 days ]
  Urine samples will be collected from subjects for the analysis of urinalysis parameters as a measure of safety, including specific gravity and potential of hydrogen (pH) of urine, presence of glucose, protein, blood, micro-albumin, creatinine, nitrite, ketones, bilirubin, urobilinogen, sodium and leukocytes in urine by dipstick test. Microscopic examination will be performed if blood or protein is abnormal.
• Number of subjects with abnormal values for blood pressure [ Time Frame: Up to 28 days ]
  Systolic and diastolic blood pressure of subjects will be measured in a semi-supine or supine position after at least 5 minutes of rest.
• Number of subjects with abnormal values for respiratory rate [ Time Frame: Up to 28 days ]
  Respiratory rate of subjects will be measured in a semi-supine or supine position after at least 5 minutes of rest.
• Number of subjects with abnormal values for pulse rate [ Time Frame: Up to 28 days ]
  Pulse rate of subjects will be measured in a semi-supine or supine position after at least 5 minutes of rest.
• Number of subjects with abnormal values for oral temperature [ Time Frame: Up to 28 days ]
  Oral temperature of subjects will be measured in a semi-supine position after at least 5 minutes of rest.
• Number of subjects with abnormal values for electrocardiogram parameters [ Time Frame: Up to 28 days ]
  Single 12-lead electrocardiogram will be obtained using an electrocardiogram machine.
• 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 [ Time Frame: Pre-dose on Day 12 and Day 13; Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose on Day 14; and 24 hours post-dose on Day 15 ]
  Blood samples will be collected for pharmacokinetic analysis of GSK3036656.
• Area under the plasma concentration time curve from zero to end of dosing interval (AUC [0-24]) following once daily dosing of GSK3036656 [ Time Frame: Pre-dose on Day 12 and Day 13; Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose on Day 14; and 24 hours post-dose on Day 15 ]
  Blood samples will be collected for pharmacokinetic analysis of GSK3036656.
• Maximum observed plasma drug concentration (Cmax) following once daily dosing of GSK3036656 [ Time Frame: Pre-dose on Day 12 and Day 13; Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose on Day 14; and 24 hours post-dose on Day 15 ]
  Blood samples will be collected for pharmacokinetic analysis of GSK3036656.
• Time to reach Cmax (Tmax) following once daily dosing of GSK3036656 [ Time Frame: Pre-dose on Day 12 and Day 13; Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose on Day 14; and 24 hours post-dose on Day 15 ]
  Blood samples will be collected for pharmacokinetic analysis of GSK3036656.
• Rate of change in log10 CFU per milliliter direct respiratory sputum samples from Baseline to Day 2 [ Time Frame: Baseline and up to Day 2 ]
  The early bactericidal activity of GSK3036656 will be determined as the rate of change in log10 CFUs of MTB in sputum.
• Rate of change in log10 CFU per milliliter direct respiratory sputum samples from Day 2 to Day 14 [ Time Frame: Day 2 and up to Day 14 ]
  The early bacterial activity of GSK3036656 will be determined as the rate of change in log10 CFUs of MTB in sputum.
• Rate of change in time to sputum culture positivity from Baseline to Day 14 [ Time Frame: Baseline and up to Day 14 ]
  The early bacterial activity of GSK3036656 will be determined as the rate of change in log10 CFUs of MTB in sputum.
• Rate of change in time to sputum culture positivity from Baseline to Day 2 [ Time Frame: Baseline and up to Day 2 ]
  The early bacterial activity of GSK3036656 will be determined as the rate of change in time to sputum culture positivity of MTB in sputum.
• Rate of change in time to sputum culture positivity over the time period from Day 2 to Day 14 [ Time Frame: Day 2 and up to Day 14 ]
  The early bacterial activity of GSK3036656 will be determined as the rate of change in time to sputum culture positivity of MTB in sputum.
• Change from Baseline in QT interval corrected using Fridericia's formula (QTcF) [ Time Frame: Baseline and up to Day 14 ]
  The exposure-response relationship between GSK3036656 and QTcF following repeated administration will be assessed.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

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.

Primary Purpose: Treatment

• Condition: Tuberculosis

Intervention

• Drug: GSK3036656
  GSK3036656 will be available as an oral capsule with dosing strengths of 1 milligrams or 5 milligrams or 25 milligrams.
• Drug: RIFAFOUR e-275
  RIFAFOUR will be available as an oral tablet with a standard dose of 150/75/400/275 milligrams of rifampicin, isoniazid, pyrazinamide and ethambutol per tablet respectively.

Study Arms

• Experimental: Subjects receiving GSK3036656
  Eligible subjects will receive sequential doses of GSK3036656 at a starting dose of 5 milligrams given orally during treatment period.
  Intervention: Drug: GSK3036656
• Active Comparator: Subjects receiving RIFAFOUR e-275
  Eligible subjects will receive RIFAFOUR e-275 tablet given daily orally as standard-of-care therapy.
  Intervention: Drug: RIFAFOUR e-275

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 30, 2021): 76
• Original Estimated Enrollment (submitted: June 4, 2018): 100
• Actual Study Completion Date: December 14, 2021
• Actual Primary Completion Date: December 3, 2021 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: South Africa

Administrative Information

• NCT Number: NCT03557281
• Other Study ID Numbers: 201214
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
• URL: http://clinicalstudydatarequest.com

• Current Responsible Party: GlaxoSmithKline
• Original Responsible Party: Same as current
• Current Study Sponsor: GlaxoSmithKline
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

• PRS Account: GlaxoSmithKline
• Verification Date: December 2021