Safety, Tolerability and Pharmacokinetics (PKs) Investigation of GSK3186899 in Healthy Subjects

NCT03874234 | Terminated Phase 1 Results

• 1 other identifier: 208436
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to evaluate the safety, tolerability and PK profile of single and repeat ascending doses of GSK3186899 in healthy subjects. This is a Phase 1 first time in human study, to investigate the effect of food on PK of GSK3186899. This study will consists of two parts. Part A (dose escalation phase) will be a single ascending, sequential cross-over design in cohorts 1, 2 and 3 of subjects. Cohort 1 and 2 will be 4-way cross-over which includes 4 dosing regimens of GSK3186899 and placebo (3:1 ratio) under fasted conditions. Cohort 3 will be 2-way cross-over which includes 2 treatment periods, 2 dosing regimens in fasted and fed conditions. In Part B (repeat dose escalation phase) subjects will be randomized to receive repeat doses of either GSK3186899 or placebo (3:1 ratio) in either fed or fasted conditions. Part B will be conducted based on the review of all safety, tolerability and PK data from Part A. The study duration includes screening, treatment periods and follow-up.

Conditions

Leishmaniasis

Keywords

Dose escalation phase; First time in human; Single ascending dose; Multiple ascending dose; GSK3186899

Outcome Measures

Primary Outcomes (21)

• Part A- Cohorts 1 and 2: Number of Participants With Non-serious Adverse Events (Non-SAEs) and SAEs

  An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, important medical events that may jeopardize the participant or require medical or surgical intervention to prevent one of the outcomes listed above. Safety Population consisted of all randomized participants who received at least one dose of study treatment.

  Up to Week 12

• Part A- Cohort 3: Number of Participants With Non-SAEs and SAEs

  An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, important medical events that may jeopardize the participant or require medical or surgical intervention to prevent one of the outcomes listed above.

  Up to Week 9

• Part B: Number of Participants With Non-SAEs and SAEs

  An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, important medical events that may jeopardize the participant or require medical or surgical intervention to prevent one of the outcomes listed above.

  Up to Week 9

• Part A- Cohorts 1 and 2: Number of Participants With Worst Case Hematology Results by Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline

  PCI ranges were \<0.0 or \>0.1\*10\^9 cells per(/)liter(L)(basophils), \<37 or \>50 proportion of red blood cells(RBC) in blood(hematocrit),\<130 or \>170 grams/L(hemoglobin\[Hb\]), \<1.2 or \>3.65\*10\^9cells(c)/L (lymphocytes),\<0.2 or \>1\*10\^9c/L(monocytes), \<2 or \>7.5\*10\^9c/L(neutrophils), \<150 or \>400\*10\^9 c/L(platelets), \<3.0 or \>10\*10\^9c/L(white blood cell\[WBC\]count), \<4.4 or \>5.8\*10\^12 c/L(RBC count), \<80 or \>99 femtoliter(mean corpuscular\[MC\] volume), \<26.0 or \>33.5 picogram(MC Hb), \<0.0 or \>0.4\*10\^9 c/L(eosinophils). Participants were counted in worst case category that their value changes to (low, within range or no change or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., High to High) or whose value became within range, were recorded in To within Range or No Change category.Participants were counted twice if participant had values that changed To Low and To High, so the percentages may not add to 100 percentage(%).

  Up to Week 12

• Part A- Cohort 3: Number of Participants With Worst Case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline

  Blood samples were planned to be collected to analyze hematology parameters.

  Up to Week 9

• Part B: Number of Participants With Worst Case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline

  Blood samples were planned to be collected to analyze hematology parameters.

  Up to Week 9

• Part A- Cohorts 1 and 2: Number of Participants With Worst Case Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline

  PCI ranges were \<34 or \>50 grams/L(albumin),\<40 or \>129 international units/L\[IU/L\](alkaline phosphatase),\<10 or \>50 IU/L(alanine aminotransferase),\<0 or \>37(aspartate aminotransferase), \<0 or \>20 micromoles(mcmol)/L (direct bilirubin),\<0 or \>20 mcmol/L(bilirubin), \<2.2 or \>2.6 millimoles/L(mmol/L)(calcium),\<66 or \>112 upper limit of normal mmol/L(creatinine), \<3.5 or \>5.1 mmol/L (potassium),\<0.6 or \>1 mmol/L (magnesium),\<0.87 or \>1.45mmol/L (phosphate),\<63 or \>83 g/L (protein),\<135 or \>145 mmol/L (sodium), \<0.0 or \>5.0 mg/L (C-reactive protein). Participants were counted in worst case category that their value changes to(low, within range \[WR\] or no change\[NC\] or high), unless there is NC in their category. Participants whose laboratory value category was unchanged (e.g. High to High) or whose value became WR, were recorded in To WR or NC category. Participants were counted twice if participant had values that changed To Low and To High, so percentages may not add to 100%.

  Up to Week 12

• Part A- Cohort 3: Number of Participants With Worst Case Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline

  Blood samples were planned to be collected to analyze chemistry parameters.

  Up to Week 9

• Part B: Number of Participants With Worst Case Chemistry Results Relative to Normal Range Post-Baseline Relative to Baseline

  Blood samples were planned to be collected to analyze chemistry parameters.

  Up to Week 9

• Part A- Cohorts 1 and 2: Number of Participants With Worst-Case Any Increase in Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method

  Urine samples were collected for analysis of occult blood, ketones and protein by a dipstick method. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters of urine occult blood and protein can be read as negative, trace, 1+, 2+, 3+ indicating proportional concentrations in the urine sample. Any increase means any increase to trace, 1+, 2+ or 3+ post-Baseline relative to Baseline. Number of participants with worst case any increase in urinalysis results post-Baseline relative to Baseline has been presented.

  Up to Week 12

• Part A- Cohort 3: Number of Participants With Worst-Case Any Increase in Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method

  Urine samples were planned to be collected to analyze urine parameters.

  Up to Week 9

• Part B: Number of Participants With Worst-Case Any Increase in Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method

  Urine samples were planned to be collected to analyze urine parameters.

  Up to Week 9

• Part A- Cohorts 1 and 2: Number of Participants With Worst Case Post-Baseline Abnormal Electrocardiogram (ECG) Findings

  Twelve lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and corrected QT intervals. Abnormal findings were categorized as clinically significant (CS) and not clinically significant (NCS). Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Data for number of participants with worst case post-Baseline abnormal ECG findings have been presented.

  Up to Week 12

• Part A- Cohort 3: Number of Participants With Worst Case Post-Baseline Abnormal ECG Findings

  Twelve lead ECGs were planned to be performed to measure PR interval, QRS duration, QT interval and corrected QT intervals.

  Up to Week 9

• Part B: Number of Participants With Worst Case Post-Baseline Abnormal ECG Findings

  Twelve lead ECGs were planned to be performed to measure PR interval, QRS duration, QT interval and corrected QT intervals.

  Up to Week 9

• Part A- Cohorts 1 and 2: Number of Participants With Worst Case Vital Sign Results by PCI Criteria Post-Baseline Relative to Baseline

  Vital signs included systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse rate, respiratory rate and body temperature and were measured in a semi-supine position after 5 minutes rest. PCI ranges were, SBP (millimeters of mercury \[mmHg\]): \<85 (low) or \>160 (high), DBP (mmHg): \<45 (low) or \>100 (high), pulse rate (beats per minute): \<40 (low) or \>110 (high), respiration rate (breaths per minute): \<10(low) or \>25(high) and body temperature (degrees Celsius) \<35 (low) or \>38 (high). Participants were counted in the worst case category that their value changes to (low, within range or no change, or high), unless there is no change in their category. Participants whose vital signs value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the "To within Range or No Change" category. Participants were counted twice if the participant had values that changed "To Low" and "To High", so the percentages may not add to 100%.

  Up to Week 12

• Part A- Cohort 3: Number of Participants With Worst Case Vital Sign Results by PCI Criteria Post-Baseline Relative to Baseline

  Vital signs were planned to be measured in a semi-supine position after 5 minutes of rest.

  Up to Week 9

• Part B: Number of Participants With Worst Case Vital Sign Results by PCI Criteria Post-Baseline Relative to Baseline

  Vital signs were planned to be measured in a semi-supine position after 5 minutes of rest.

  Up to Week 9

• Part A- Cohorts 1 and 2: Number of Participants With Abnormal Cardiac Telemetry Findings

  Continuous cardiac telemetry was performed in a supine position after at least 5 minutes of rest. Abnormal findings were categorized as CS and not NCS. Clinically significant abnormal findings were those which were not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.

  Up to 24 hours post-dose

• Part A- Cohort 3: Number of Participants Abnormal Cardiac Telemetry Findings

  Continuous cardiac telemetry was planned to be performed in a supine position after at least 5 minutes of rest.

  Up to 24 hours post-dose

• Part B: Number of Participants Abnormal Cardiac Telemetry Findings

  Continuous cardiac telemetry was planned to be performed in a supine position after at least 5 minutes of rest.

  Up to 24 hours post-dose

Secondary Outcomes (34)

• Part A- Cohorts 1 and 2: Plasma Concentration After Single Dose Administration of GSK3186899

  Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period

• Part A- Cohort 3: Plasma Concentration After Single Dose Administration of GSK3186899

  Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period

• Part A- Cohorts 1 and 2: Area Under the Plasma Concentration-time Curve From Time 0 to Last Time of Quantifiable Concentration (AUC[0-t]) After Single Dose Administration of GSK3186899

  Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period

• Part A- Cohort 3: AUC(0-t) After Single Dose Administration of GSK3186899

  Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period

• Part A- Cohorts 1 and 2: Area Under the Plasma Concentration-time Curve From Time 0 to Extrapolated to Infinity (AUC[0-infinity]) After Single Dose Administration of GSK3186899

  Pre-dose, 10, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose in each treatment period

Study Arms (5)

Part A: Subjects receiving GSK3186899 + placebo in Cohort 1

EXPERIMENTAL

Subjects will receive 3 single ascending oral doses (SAD) of GSK3186899 and 1 dose of placebo as spray dried powder, under fasted conditions on Day 1 of cohort 1 in each of the four treatment periods. In each treatment period GSK3186899 and placebo will be administered in a 3:1 ratio. A wash out period of at least 10 days will be maintained between each treatment period.

Drug: GSK3186899; Drug: Placebo

Part A: Subjects receiving GSK3186899 + placebo in Cohort 2

EXPERIMENTAL

Subjects will receive 3 SAD of GSK3186899 and 1 dose of placebo as spray dried powder, under fasted conditions on Day 1 of cohort 2 in each of the four treatment periods. In each treatment period GSK3186899 and placebo will be administered in a 3:1 ratio. A wash out period of at least 10 days will be maintained between each treatment period.

Drug: GSK3186899; Drug: Placebo

Part A: Subjects receiving GSK3186899 in Cohort 3

EXPERIMENTAL

Subjects will receive GSK3186899 orally, under fasted condition and fed conditions on Day 1 of cohort 3 in each of the two treatment periods. There will be a wash out period of at least 10 days between each treatment period. A dose level will be determined based on the effect of food on the safety, tolerability and PK of a single dose of GSK3186899, with dose level selected from Cohorts 1 and 2.

Drug: GSK3186899

Part B: Subjects receiving GSK3186899

EXPERIMENTAL

Subjects will receive GSK3186899, orally, twice daily (BID) on Days 1 to 10. Subjects will receive each dose after either fed or fasted conditions. Part B will be initiated based on the review of all safety, tolerability and PK data from Part A.

Drug: GSK3186899

Part B: Subjects receiving placebo

PLACEBO COMPARATOR

Subjects will receive placebo, orally, BID on Days 1 to 10. Subjects will receive each dose after either fed or fasted conditions. Part B will be initiated based on the review of all safety, tolerability and PK data from Part A.

Drug: Placebo

Interventions

GSK3186899 DRUG

GSK3186899 will be available as white to slightly colored, spray dried powder in a bottle to be administered orally along with mixture of propylene glycol and water.

Part A: Subjects receiving GSK3186899 + placebo in Cohort 1; Part A: Subjects receiving GSK3186899 + placebo in Cohort 2; Part A: Subjects receiving GSK3186899 in Cohort 3; Part B: Subjects receiving GSK3186899

Placebo DRUG

Placebo will be available as white to slightly colored, blend powder in a bottle to be administered orally along with mixture of propylene glycol and water.

Part A: Subjects receiving GSK3186899 + placebo in Cohort 1; Part A: Subjects receiving GSK3186899 + placebo in Cohort 2; Part B: Subjects receiving placebo

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Subject must be 18 to 55 years of age inclusive, at the time of signing the informed consent.

You may not qualify if:

• Body weight \>=50 kilogram (kg) and body mass index (BMI) within the range 18.5 to 28 kilogram per square meter (kg/m\^2) (inclusive).
• Male and/or female subjects: A male subject with a female partner of reproductive potential must agree to use contraception during the treatment period and for at least 90 days 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 a woman of childbearing potential (WONCBP).
• Capable of giving signed informed consent.
• History or presence of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of data.
• Previous history of leishmaniasis.
• ALT \>1.5\* upper limit of normal (ULN).
• Bilirubin \>1.5\*ULN (isolated bilirubin \>1.5\*ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35 percent).
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Current or past history of clinically significant gastritis or gastroduodenal ulcers or regular use of non-steroidal anti-inflammatory drugs (NSAID).
• ECG QT interval corrected for heart rate (QTc) \>450 milliseconds (msec).
• Past or intended use of over-the-counter or prescription medication, including herbal medications, NSAIDs, proton-pump inhibitors (PPIs) or anti-H2 antagonists within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is the longest) prior to dosing. Other concomitant medication may be considered on a case by case basis by the Investigator in consultation with the medical monitor.
• Participation in the study would result in loss of blood or blood products in excess of 500 milliliter (mL) within a 56-day period.
• Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
• The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
• Sensitivity to any of the study treatments, or components thereof, or drug or other allergy that, in the opinion of the Investigator or GlaxoSmithKline (GSK) Medical Monitor, contraindicates participation in the study.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Cambridge, CB2 2GG, United Kingdom

Location

MeSH Terms

Conditions

Leishmaniasis

Interventions

GSK3186899

Condition Hierarchy (Ancestors)

Euglenozoa Infections; Protozoan Infections; Parasitic Diseases; Infections; Skin Diseases, Parasitic; Vector Borne Diseases; Skin Diseases, Infectious; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: This will be a double-blind study. Subjects and Investigator will be blinded to the study treatment.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Subjects will receive escalating doses of GSK3186899 and placebo in Part A of the study. Subjects will receive repeat doses either of GSK3186899 or placebo in Part B of the study.

Study Record Dates

• First Submitted: March 12, 2019
• First Posted: March 14, 2019
• Study Start: April 30, 2019
• Primary Completion: October 17, 2019
• Study Completion: October 17, 2019
• Last Updated: February 27, 2023
• Results First Posted: February 27, 2023

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, 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.

Locations

GB (1)