Clinical trial NCT02647281: First Time in Human Study to Assess the Safety, Tolerability and Pharmacokinetics of GSK3389404 in Healthy Subjects
Official title: A Double-Blind, Placebo-Controlled, Dose-Escalation, First Time in Human Study to Assess the Safety, Tolerability and Pharmacokinetics of Single and Multiple Ascending Doses of GSK3389404 in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hepatitis B
Keywords: Single dose
Multiple ascending doses (MAD)
Pharmacokinetics
Safety
GSK3389404
Tolerability
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2016-01-06
Enrollment: 56
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: This study is a Phase 1, randomized, double-blind (Sponsor unblinded), placebo controlled, dose escalation study to determine the safety, tolerability and pharmacokinetics (PK) profile of GSK3389404 as single (Part 1) and multiple subcutaneous (SC) injections (Part 2) in healthy subjects. This study represents the first administration of GSK3389404 in humans to define the safety, tolerability and PK following single and multiple doses of GSK3389404 in healthy subjects.


Eligibility criteria: Inclusion Criteria:

* Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
* The subject is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions and is likely to complete the study as planned.
* Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and electrocardiograms (ECGs). There should be no evidence of cardiac, pulmonary, hepatic, biliary, gastrointestinal, or renal disorders, or cancer within the past 5 years (except localized or in situ cancer of the skin). A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria and are reported as outside of the normal reference range for healthy subjects may be included only if the Investigator considers the finding unlikely to introduce additional risk to the subject and will not interfere with the study procedures.
* Male or female between 18 and 55 years of age, inclusive, at the time of signing the informed consent form (ICF).
* Body weight \>50 kilograms (kg) (110 pounds \[lb\]) for men and \>45 kg (99 lb) women and a body mass index (BMI) between 18 to 30 kg/meter-squared, inclusive, will be allowed.
* AST, ALT, ALP, bilirubin, and creatinine within the normal reference range. If outside the normal reference range, these values may be repeated once at the discretion of the Investigator or designee.
* WBC count (including neutrophil counts), haemoglobin and platelets within the normal reference range. If outside the normal reference range, these values may be repeated once at the discretion of the Investigator or designee.
* Females of Reproductive Potential (FRP) are not permitted. Eligible females must meet the following criteria:

  * Non-pregnant (as confirmed by a negative serum human chorionic gonadotrophin (hCG) test); AND
  * Non-lactating at screening and prior to dosing; AND
  * Non-reproductive potential as defined by at least one of the following conditions: Pre-menopausal females without reproductive potential defined by one of the following: Documented salpingectomy, Hysterectomy, Documented bilateral oophorectomy; Postmenopausal defined as 12 months of spontaneous amenorrhea; A blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels may be conducted at the discretion of the Investigator or site to confirm non-reproductive potential.
* Male subjects with female partners of child-bearing potential must agree to meet one of the contraception requirements from the time of first dose of study treatment until the last follow-up visit (Part 1 Day 60; Part 2 Day 113).

  * Vasectomy with documentation of azoospermia.
  * Male condom plus partner use of one of the contraceptive options below that meets the standard operating procedure (SOP) effectiveness criteria including a \<1% rate of failure per year, as stated in the product label: Contraceptive subdermal implant; Intrauterine device or intrauterine system; Combined estrogen and progestogen oral contraceptive; Injectable progestogen; Contraceptive vaginal ring; Percutaneous contraceptive patches These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The Investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.

Exclusion Criteria:

* History or other clinical evidence of hypertension, significant or unstable cardiac disease (e.g., prolonged QT syndrome \[torsade de pointes\], angina, congestive heart failure, myocardial infarction, diastolic dysfunction, significant arrhythmia, coronary heart disease and/or clinically significant ECG abnormalities).
* History of, or active diagnosis of, liver disease such as Gilbert's syndrome, cirrhosis, autoimmune hepatitis, non-alcoholic fatty liver disease /non-alcoholic steatohepatitis, or hemochromatosis.
* History of, or active diagnosis of, primary or secondary (e.g., renal disease secondary to diabetes, hypertension, vascular disease, etc.) renal disease.
* History of bleeding diathesis or coagulopathy.
* History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of \>21 units for males or \>14 units for females. One unit is equivalent to 8 grams (g) of alcohol: a half-pint (approximately 240 milliliters \[mL\]) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
* Unwilling to abstain from alcohol for 48 hours prior to the start of dosing until the last dose in each dosing session.
* Regular use of tobacco- or nicotine-containing products within 3 months prior to screening.
* History of sensitivity to GSK3389404 or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
* Use of prescription or non-prescription drugs, including vitamin, dietary and herbal supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study treatment.
* Use of aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) within 7 days prior to the first dose of study treatment.
* A positive hepatitis C antibody.
* A positive pre-study Hepatitis B surface antigen (HBsAg).
* A positive test for human immunodeficiency virus (HIV) antibody.
* Serum creatinine greater than the upper limit of normal (ULN)
* Glomerular filtration rate \<90 mL/minute as calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-epi) formula
* Albumin to creatinine ratio (ACR) \>= 0.03 milligram/milligram (mg/mg). In the event of an ACR above this threshold, eligibility may be confirmed by a second measurement.
* Qualitative test (urinalysis) for blood in urine \>= 0.03 mg/deciliter. In the event of a positive test, the test may be repeated once, and if negative, the subject considered eligible.
* A positive pre-study drug screen. Unwilling to refrain from use of the illicit drugs and adhere to other protocol-stated restrictions while participating in the study.
* Fridericia's QT correction formula (QTcF) \>= 450 milliseconds (msec).
* Where participation in the study would result in 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 dosing day in the current study: 5 half-lives (if known) or twice the duration (if known) of the biological effect of the study drug (whichever is longer) or 90 days (if half-life or duration is unknown).
* Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
* Prior treatment with any oligonucleotide or small interfering ribonucleic acid (siRNA) within 12 months prior to the first dosing day.

Primary outcomes:
measure: Number of Participants With Any Non-serious Adverse Event (AE); Any Serious AE (SAE); Any AEs Leading to Discontinuation of Study Treatment (AELD) in Part 1
timeFrame: Up to 62 days
measure: Number of Participants With Any Non-serious AE; Any SAE; Any AELD in Part 2
timeFrame: Up to 115 days
measure: Number of Participants With Laboratory Values of Potential Clinical Importance in Part 1
timeFrame: Up to 62 days
measure: Number of Participants With Laboratory Values of Potential Clinical Importance in Part 2
timeFrame: Up to 115 days
measure: Change From Baseline in Complement Factor Component 3 (C3) and C4 Levels in Part 1
timeFrame: Day 1 (pre-dose) and up to 31 days
measure: Change From Baseline in Complement Split Product C5a Levels in Part 1
timeFrame: Day 1 (pre-dose) and up to 31 days
measure: Change From Baseline in Complement Split Product Bb Levels in Part 1
timeFrame: Day 1 (pre-dose) and up to 31 days
measure: Change From Baseline in Complement Factor C3 and C4 Levels in Part 2
timeFrame: Day 1 (pre-dose) and Day 22
measure: Change From Baseline in Complement Factor C5a Levels in Part 2
timeFrame: Day 1 (pre-dose) and Day 22
measure: Change From Baseline in Complement Factor Bb Levels in Part 2
timeFrame: Day 1 (pre-dose) and Day 22
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Indicated Time Points in Part 1
timeFrame: Day 1 (pre-dose) and up to 30 days
measure: Change From Baseline in Pulse Rate (PR) at the Indicated Time Points in Part 1
timeFrame: Day 1 (pre-dose) and up to 30 days
measure: Change From Baseline in Respiratory Rate (RR) at the Indicated Time Points in Part 1
timeFrame: Day 1 (pre-dose) and up to 30 days
measure: Change From Baseline in Body Temperature at the Indicated Time Points in Part 1
timeFrame: Day 1 (pre-dose) and up to 30 days
measure: Change From Baseline in SBP and DBP at the Indicated Time Points in Part 2
timeFrame: Day 1 (pre-dose) and up to 115 days
measure: Change From Baseline in PR at the Indicated Time Points in Part 2
timeFrame: Day 1 (pre-dose) and up to 115 days
measure: Change From Baseline in RR at the Indicated Time Points in Part 2
timeFrame: Day 1 (pre-dose) and up to 115 days
measure: Change From Baseline in Body Temperature at the Indicated Time Points in Part 2
timeFrame: Day 1 (pre-dose) and up to 115 days
measure: Number of Participants With 12-lead Electrocardiogram (ECG) Findings in Part 1
timeFrame: Day 1 (pre-dose) and up to 31 days
measure: Area Under the Plasma Concentration Curve (AUC) From Time Zero to Infinity [AUC (0-inf)], AUC From Time Zero to the Time of Last Quantifiable Concentration [AUC(0-t)], AUC From Time Zero to 24 Hours [AUC(0-24)] of GSK3389404 After Single Dose in Part 1
timeFrame: Day 1 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 8 and 30 post-dose
measure: Maximum Observed Concentration (Cmax), Observed Concentration at 24 Hours (C24) and at 168 Hours (C168) of GSK3389404 Following Single Dose in Part 1
timeFrame: Day 1 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 8 and 30 post-dose
measure: Time to Maximum Observed Concentration (Tmax), Terminal Half-life (T1/2) and Lag Time (Tlag) of GSK3389404 Following Single Dose in Part 1
timeFrame: Day 1 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 8 and 30 post-dose
measure: Apparent SC Plasma Clearance (CL/F) of GSK3389404 Following Single Dose in Part 1
timeFrame: Day 1 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 8 and 30 post-dose
measure: AUC (0-t), AUC(0-24), AUC From Time Zero to 168 Hours Post-dose [AUC(0-168)] and AUC (0-inf) of GSK3389404 Following Single Dose on Day 1 of Part 2
timeFrame: Day 1 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 8 and 15 post-dose
measure: Cmax, C24 and C168 of GSK3389404 Following Single Dose on Day 1 of Part 2
timeFrame: Day 1 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 8 and 15 post-dose
measure: Tmax, T1/2 and Tlag of GSK3389404 Following Single Dose on Day 1 of Part 2
timeFrame: Day 1 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 8 and 15 post-dose
measure: CL/F of GSK3389404 Following Single Dose on Day 1 of Part 2
timeFrame: Day 1 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 8 and 15 post-dose
measure: AUC(0-24) and AUC From Time Zero to the End of the Dosing Interval [AUC(0-tau)] of GSK3389404 Following Dosing on Day 22 of Part 2
timeFrame: Day 22 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 29, 36, 50, 71 and at Follow-up (Day 115)
measure: Observed Concentration at the End of the Dosing Interval (Ctau), C24 and Cmax of GSK3389404 Following Dosing on Day 22 of Part 2
timeFrame: Day 22 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 29, 36, 50, 71 and at Follow-up (Day 115)
measure: Tmax, T1/2 and Tlag of GSK3389404 Following Dosing on Day 22 of Part 2
timeFrame: Day 22 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 29, 36, 50, 71 and at Follow-up (Day 115)
measure: Cl/F of GSK3389404 Following Dosing on Day 22 of Part 2
timeFrame: Day 22 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 29, 36, 50, 71 and at Follow-up (Day 115)
Secondary outcomes:
measure: Dose Proportionality of GSK202007 for Dose Range 10 mg - 120 mg After Single Dose Administrations
timeFrame: Day 1 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 8 and 30 post-dose; Day 1 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 8 and 15 post-dose in Part 2.
measure: Dose Proportionality of GSK202007 for Dose Range 30 mg - 120 mg After Multiple Dose Administrations
timeFrame: Day 22 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 29, 36, 50, 71 and at Follow-up (Day 115) in Part 2
measure: Accumulation Ratio by AUC (RAUC), by Cmax (RCmax), by C24 (RC24) and by Ctau (RCtau) of GSK3389404 in Part 2
timeFrame: Day 1 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 8 and 15 post-dose; Day 22 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 29, 36, 50, 71 and at Follow-up (Day 115)
measure: Time Invariance (LI) of GSK3389404 in Part 2
timeFrame: Day 1 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 8 and 15 post-dose; Day 22 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 29, 36, 50, 71 and at Follow-up (Day 115)
measure: Trough Plasma Concentrations of GSK3389404 in Part 2
timeFrame: Pre-dose on Days 8, 15, 22 and 29
measure: AUC (0-inf), AUC(0-t), AUC(0-24) of the Metabolite of GSK3389404 After Single Dose in Part 1
timeFrame: Day 1 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 8 and 30 post-dose
measure: Cmax, C24 and C168 of the Metabolite of GSK3389404 Following Single Dose in Part 1
timeFrame: Day 1 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 8 and 30 post-dose
measure: Tmax, T1/2 and Tlag of the Metabolite of GSK3389404 Following Single Dose in Part 1
timeFrame: Day 1 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 8 and 30 post-dose
measure: AUC (0-t), AUC(0-24), AUC(0-168) and AUC (0-inf) of the Metabolite of GSK3389404 Following Single Dose on Day 1 of Part 2
timeFrame: Day 1 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 8 and 15 post-dose
measure: Cmax, C24 and C168 of the Metabolite of GSK3389404 Following Single Dose on Day 1 of Part 2
timeFrame: Day 1 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 8 and 15 post-dose
measure: Tmax, T1/2 and Tlag of the Metabolite of GSK3389404 Following Single Dose on Day 1 of Part 2
timeFrame: Day 1 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 8 and 15 post-dose
measure: AUC(0-24) and AUC(0-tau) of the Metabolite of GSK3389404 Following Dosing of GSK3389404 on Day 22 of Part 2
timeFrame: Day 22 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 29, 36, 50, 71 and at Follow-up (Day 115)
measure: Ctau, C24 and Cmax of the Metabolite of GSK3389404 Following Dosing of GSK3389404 on Day 22 of Part 2
timeFrame: Day 22 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 29, 36, 50, 71 and at Follow-up (Day 115)
measure: Tmax, T1/2 and Tlag of the Metabolite of GSK3389404 Following Dosing on Day 22 of Part 2
timeFrame: Day 22 (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose; and on Days 29, 36, 50, 71 and at Follow-up (Day 115)
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Han K, Cremer J, Elston R, Oliver S, Baptiste-Brown S, Chen S, Gardiner D, Davies M, Saunders J, Hamatake R, Losos J, Leivers M, Hood S, van der Berg F, Paff M, Ritter JM, Theodore D. A Randomized, Double-Blind, Placebo-Controlled, First-Time-in-Human Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of GSK3389404 in Healthy Subjects. Clin Pharmacol Drug Dev. 2019 Aug;8(6):790-801. doi: 10.1002/cpdd.670. Epub 2019 Mar 12.