A 2-part Randomized, Double-blind (Sponsor-unblinded), Placebo-controlled, Ascending Dose and Parallel Group Study of TLR4 Agonist (GSK1795091) Administered to Healthy Subjects
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 42
- 试验地点
- 1
- 主要终点
- Number of Participants With Non-serious Adverse Events (AE) and Serious Adverse Events (SAE)
研究概览
简要总结
This study is an ascending dose first-time-in-human study to determine the safety, tolerability, pharmacodynamic (PD), and pharmacokinetics (PK) profile of GSK1795091 in healthy subjects. The results will support the design of future clinical trials of GSK1795091 administered to subjects with advanced malignancies in combination with immune system modulators.
Part 1 will be a randomized, double-blind (sponsor-unblinded), placebo-controlled, single center, single dose escalation, sequential group evaluation of intravenously administered GSK1795091 to evaluate the safety and tolerability in healthy subjects. Part 2 will be an open-label, parallel group evaluation of 2 doses of GSK1795091 administered, either 1 week apart (Part 2, Cohort 1) or 2 weeks apart (Part 2, Cohort 2). In Part 2, on Day 1, subjects will receive intravenous GSK1795091 at a dose determined by results from Part 1. The total duration of this study is approximately 10 weeks from screening to the last study visit.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Between 18 and 50 years of age inclusive, at the time of signing the informed consent.
- •Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests, vital signs and 12-lead ECG. (A subject with a clinically insignificant abnormality or laboratory parameter(s) may be included only if the Investigator documents that the finding is unlikely to represent a safety risk and will not interfere with the study procedures.)
- •Body weight 55-95 kilogram (kg) and body mass index within the range 19-30 kg/meter (m)^2 (inclusive).
- •Male or Female of non-childbearing potential:
- •Males: Male subjects with female partners of child bearing potential must comply with the pre specified contraception requirements.
- •Females: A female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum or urine human chorionic gonadotropin test), not lactating, and is either of non-reproductive potential or reproductive potential. If of reproductive potential, then the subject should agree to follow one of the options listed per GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential from 30 days prior to the first dose and until 30 days after the last dose of study medication The Investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception
- •Capable of giving signed informed consent
排除标准
- •History of any significant medical condition (e.g. cardiac, pulmonary, metabolic, renal, gastrointestinal, rheumatological, etc.)
- •History of frequent (>1 per week) headache or myalgia, asthma, syncope.
- •History of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome).
- •Alanine aminotransferase (ALT) and bilirubin >1.1×upper limit of normal (ULN; isolated bilirubin >1.5×ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
- •Vital signs:
- •Systolic blood pressure (SBP) <90 and >140 milliliter of mercury (mmHg); diastolic BP <50 and >90 mmHg; heart rate (HR) <50 and >90 beats per minute (bpm); temperature >37.5 degree Celsius
- •Clinically significant ECG abnormality and/or HR < 50 and >90 bpm; PR interval >220 milliseconds (msec); QRS duration >120 msec; and QTcF > 450 msec
- •Anticipated requirement for any prescription medication during the study
- •History of regular alcohol consumption within 6 months of the study averaging a weekly intake of >14 drinks for males or >7 drinks for females or inability to abstain from alcohol from 1 day prior to the inpatient period of the study until discharge (one drink is equivalent to 8 grams of alcohol: 200 milliliter [mL] of beer, 100 mL of wine or 1 measure (25 mL) of spirits)
- •Urinary cotinine levels indicative of smoking or history or regular use of tobacco or nicotine-containing products within 2 months prior to screening or inability to abstain from smoking during the study
- •History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation
- •Presence of hepatitis B surface antigen, positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. Subjects with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C ribonucleic acid polymerase chain reaction test is obtained.
- •A positive pre-study drug/alcohol screen.
- •A positive test for human immunodeficiency antivirus antibody.
- •Donation of blood or blood products in excess of 500 mL within a 56-day period.
- •The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first visit (Day -2) in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
- •Exposure to more than four new chemical entities within 12 months prior to the first visit (Day -2).
- •Exposure to GSK1795091 in a previous cohort of this study.
- •Subject is unable to refrain from taking non-prescription drugs (including vitamins and dietary or herbal supplements), within 7 days prior to the first dose of study medication until completion of the follow-up visit, unless in the opinion of the investigator and sponsor, the medication will not interfere with the study.
- •Subject is able to understand and communicate in German/or native language of the site. Subject, or close relative of the subject, is the investigator or a sub-investigator, research assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of the study at that site
- •Vulnerable subjects (eg subjects kept in detention)
研究组 & 干预措施
Part 1: GSK1795091 or Placebo
In Part 1, subjects in sequential cohorts will receive single ascending doses of intravenous (IV) injection of GSK1795091 or matching placebo, with a starting dose of 7 nanogram (ng), on Day 1 until the highest dose is evaluated.
干预措施: GSK1795091 (Drug)
Part 1: GSK1795091 or Placebo
In Part 1, subjects in sequential cohorts will receive single ascending doses of intravenous (IV) injection of GSK1795091 or matching placebo, with a starting dose of 7 nanogram (ng), on Day 1 until the highest dose is evaluated.
干预措施: Placebo (Drug)
Part 2 Cohort 1: GSK1795091
In Part 2 Cohort 1, subjects will receive IV injection of GSK1795091 on Day 1, at dose determined in part 1, and second dose on Day 8 (one week apart)
干预措施: GSK1795091 (Drug)
Part 2 Cohort 2: GSK1795091
In Part 2 Cohort 2, subjects will receive IV injection of GSK1795091 on Day 1, at dose determined in part 1, and a second dose on Day 15 (two weeks apart)
干预措施: GSK1795091 (Drug)
结局指标
主要结局
Number of Participants With Non-serious Adverse Events (AE) and Serious Adverse Events (SAE)
时间窗: Up to Day 32
An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or events associated with liver injury and impaired liver function were categorized as SAE. All participants enrolled into the study who have received a dose of study medication (GSK1795091 or placebo) were included in the All Subjects Population. Participants with non-serious AEs (5 percentage threshold) and SAEs has been reported.
Change From Baseline in Body Temperature Part 1
时间窗: Baseline, Day 1 (1, 2, 4, 6, 8, 12, 16 hours), Day 2, Day 3, Day 4, Day 5, and Day 7.
Body temperature was measured in semi-supine position after 5 minutes rest. Baseline values are the last non-missing pre-dose assessments. Change from Baseline was defined as difference between the post-Baseline visit value and the Baseline value.
Change From Baseline in Respiratory Rate Part 1
时间窗: Baseline, Day 1 (1, 2, 4, 6, 8, 12, 16 hours), Day 2, Day 3, Day 4, Day 5, and Day 7.
Respiratory rate was measured in semi-supine position after 5 minutes rest. Baseline values are the last non-missing pre-dose assessments. Change from Baseline was defined as difference between the post-Baseline visit value and the Baseline value.
Casts, Round Epithelial Cells (REC), Squamous Epithelial Cells (SEC), Urine Erythrocytes and Urine Leukocytes at Indicated Time Points
时间窗: Pre-dose Day -1 and Day 1, Day 2, Day 4 and Day 7
Urinalysis included microscopic examination parameters like Casts, REC, SEC, Urine erythrocytes and Urine leukocytes. Data at indicated time points were reported. Only those participants with data available at the specified data points were analyzed (represented by n=X in category titles). NA indicates standard deviation could not be calculated as only 1 participant was analyzed at the given time point.
Ketones and Urine Glucose at Indicated Time Points
时间窗: Pre-dose Day -1 and Day 1, Day 2, Day 4 and Day 7
Urinalysis included parameters like ketones and urine glucose. Data at indicated time points were reported.
Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) Part 1
时间窗: Baseline, Day 1 (1, 2, 4, 6, 8, 12, 16 hours), Day 2, Day 3, Day 4, Day 5, and Day 7.
Systolic and diastolic BP was measured in semi-supine position after 5 minutes rest. Baseline values are the last non-missing pre-dose assessments. Change from Baseline was defined as difference between the post-Baseline visit value and the Baseline value.
Change From Baseline in Pulse Rate Part 1
时间窗: Baseline, Day 1 (1, 2, 4, 6, 8, 12, 16 hours), Day 2, Day 3, Day 4, Day 5, and Day 7.
Pulse rate was measured in semi-supine position after 5 minutes rest. Baseline values are the last non-missing pre-dose assessments. Change from Baseline was defined as difference between the post-Baseline visit value and the Baseline value.
Urine Potential of Hydrogen (pH) at Indicated Time Points
时间窗: Pre-dose Day -1 and Day 1, Day 2, Day 4 and Day 7
Urinalysis parameters included urine pH. pH is calculated on a scale of 0 to 14, values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0).
Number of Participants With Abnormal Electrocardiograms (ECG) Findings Worst Case Post-Baseline
时间窗: Up to Day 32
Single measurements of 12-lead ECGs were obtained after 10 minutes of rest in a semi-supine position for the participant. Participants with abnormal ECG findings that are clinically not significant (NCS) and clinically significant (CS) data has been presented here. The data of worst case post-Baseline is presented here.
Number of Participants With Hematology Parameters Outside Reference Range Part 1
时间窗: Up to Day 7
Hematology parameters included hemoglobin (HGB), hematocrit (HCT), Red Blood Cell (RBC) count, White Blood Cell (WBC) count with differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelet count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC). Reference range for basophil was 0.01 - 0.07\*10\^9/Liters (L), eosinophils 0.03 - 0.5\*10\^9/L, HCT 0.38 - 0.48 proportion of RBC in blood, HGB 126 - 165\*gram (g)/L, lymphocytes 1.08 - 3\*10\^9/L, MCH 26.3 - 32.8\*picogram (pg), MCHC 324 - 359\*g/L, MCV 77 - 94.9\*femtoliter (fL), monocytes 0.3 - 0.92\*10\^9/L, neutrophils 1.46 - 5.85\*10\^9/L, platelets 155 - 342\*10\^9/L, erythrocytes 4.12 - 5.74\*10\^12/L, leukocytes 3.19 - 8.71\*10\^9/L. Values below these ranges were considered as low and above these ranges were considered as high (H). Data for participants from any visit post-screening with values \> reference range high and \< reference range low are report.
Number of Participants With Clinical Chemistry Parameters Outside Reference Range
时间窗: Up to Day 7
Clinical chemistry parameters with reference range were albumin 35-52\*g/L, Alkaline phosphatase (ALP) 30-120\*International units/L (IU/L), Alanine aminotransferase (ALT) 0-50 \* IU/L, Aspartate aminotransferase (AST) 0-50\*IU/L, direct bilirubin 0-3.4\* micromoles/L (µmol/L), bilirubin 5-21\*µmol/L, calcium 2.2-2.65\* millimoles/L (mmol/L), cholesterol 0-5.19\* mmol/L, creatinine 59-104\* µmol/L, C-reactive protein (CRP) 0-5\*milligram (mg)/L,Gamma Glutamyl Transferase (GGT) 4.1-5.9\*mmol/L, high density lipoproteins (HDL) cholesterol 0.99-2.32\*mmol/L, potassium 3.5-5.1\*mmol/L, low density lipoproteins (LDL) cholesterol 0-3.3\*mmol/L, protein 66-83\*g/L, sodium 136-146 \* mmol/L, triglycerides 0-2.25 \* mmol/L, glucose 4.1-5.9\*mmol/L, and urea 2.8-7.2\*mmol/L. Values below these ranges were considered as low and above these ranges were considered as high. Data for participants from any visit post-screening with values \> reference range high and \< reference range low are reported.
Occult Blood at Indicated Time Points
时间窗: Pre-dose Day -1 and Day 1, Day 2, Day 4 and Day 7
Urinalysis included parameter like Occult blood. Data at indicated time points were reported.
Urine Protein at Indicated Time Points
时间窗: Pre-dose Day -1 and Day 1, Day 2, Day 4 and Day 7
Urinalysis included parameter like Urine protein. Data at indicated time points were reported.
Specific Gravity at Indicated Time Points
时间窗: Pre-dose Day -1 and Day 1, Day 2, Day 4 and Day 7
Urinalysis included parameter like specific gravity. Urinary specific gravity is a measure of the concentration of solutes in the urine. It measures the ratio of urine density compared with water density and provides information on the kidney's ability to concentrate urine.
次要结局
- Partial Area Under the Concentration-time Curve to Time t (AUC[0-t]), Area Under the Concentration-time Curve (AUC) From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-inf]) of GSK1795091 for Part 1(Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose)
- Percentage Fold Change of Concentration of Tumor Necrosis Factor (TNF)-Alpha From Baseline for Part 1(Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours)
- Percentage Fold Change of Colony Stimulating Factor 2 (GCSF) From Baseline for Part 1(Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours)
- Clearance (CL) of GSK1795091 for Part 1(Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose)
- Maximum Observed Drug Concentration (Cmax) of GSK1795091 for Part 1(Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose)
- Time of Occurrence of Cmax (Tmax) and Terminal Half Life (t1/2) of GSK1795091 for Part 1(Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose)
- Volume of Distribution of GSK1795091 for Part 1(Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose)
- Percentage Fold Change of Concentration of Interleukin 6 (IL-6) From Baseline for Part 1(Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours)
- Change From Baseline in CRP for Part 1(Baseline, Days 2, 4 and 7)
- Maximum Observed Drug Concentration (Cmax) of GSK1795091 for Part 2(Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose)
- Time of Occurrence of Cmax (Tmax) and Terminal Half Life (t1/2) of GSK1795091 for Part 2(Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose)
- Partial Area Under the Concentration-time Curve to Time = t (AUC[0-t]), Area Under the Concentration-time Curve (AUC) From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-inf]) of GSK1795091 for Part 2(Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose)
- Area Under the Concentration-time Curve (AUC) Time Curve for a Dosing Interval (AUC[0-tau]), AUC (0-last) of GSK1795091 for Part 2(Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose)
- Volume of Distribution of GSK1795091 for Part 2(Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose)
- Percentage Fold Change of Concentration of Interferon (IFN)-Gamma From Baseline for Part 1(Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours)
- Percentage Fold Change of Concentration of Inducible Protein (IP)-10 From Baseline for Part 1(Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours)
- Percentage Fold Change of Concentration of Monocyte Chemotactic Protein 1 (MCP-1) From Baseline for Part 1(Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours)
- Percentage Fold Change of Interleukin 1 Receptor Antagonist (IL-1Ra) From Baseline for Part 1(Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours)
- Percentage Fold Change of Interleukin 10 (IL-10) From Baseline for Part 1(Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours)
- Change From Baseline in WBC Differential for Part 1(Baseline, 4, 24 and 144 hours)
- Clearance (CL) of GSK1795091 for Part 2(Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose)
- Accumulation Ratio of GSK1795091 for Part 2(Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose)
- Time Invariance of GSK1795091 for Part 2(Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose)
- Percentage Fold Change of Concentration of Interleukin 6 (IL-6) From Baseline for Part 2(Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours)
- Percentage Fold Change of Concentration of TNF-alpha From Baseline for Part 2(Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours)
- Percentage Fold Change of Concentration of IFN-gamma From Baseline for Part 2(Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours)
- Percentage Fold Change of Concentration of IP-10 From Baseline for Part 2(Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours)
- Percentage Fold Change of Concentration of MCP-1 From Baseline for Part 2(Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours)
- Percentage Fold Change of Concentration of GCSF From Baseline for Part 2(Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours)
- Percentage Fold Change of Concentration of IL-1Ra From Baseline for Part 2(Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours)
- Percentage Fold Change of Concentration of IL-10 From Baseline for Part 2(Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours)
- Change From Baseline in WBC Differential for Part 2(Baseline, 2, 24 and 144 hours)
- Number of Participants With Urinalysis Parameters Outside Reference Range for Part 2(Up to Day 7)
- Number of Participants With Hematology Parameters Outside Reference Range in Part 2(Up to Day 7)
- Number of Participants With Clinical Chemistry Parameters Outside Reference Range in Part 2(Up to Day 7)
- Change From Baseline in CRP for Part 2(Baseline and Pre-dose, 1, 2, 4, 8, 12, 16, 24, and 48 hours post dose)
- Change From Baseline in Body Temperature for Part 2(Baseline and up to Day 7)
- Change From Baseline in SBP and DBP for Part 2(Baseline and up to Day 7)
- Change From Baseline in Respiratory Rate for Part 2(Baseline and up to Day 7)
- Change From Baseline in Pulse Rate for Part 2(Baseline and up to Day 7)