Pharmacokinetic (PK) Study of GSK933776 in Healthy Volunteers

A Randomized, Open Label, Parallel-Group Study to Estimate Bioavailability and to Assess the Pharmacokinetic Profile, Safety and Tolerability of GSK933776 Administered by Subcutaneous or Intramuscular Injection Relative to Intravenous Administration to Healthy Volunteers

This study is intended to enable a possible transition to intramuscular (IM) or subcutaneous (SQ) administration for subsequent studies with GSK933776 by characterizing the safety, tolerability, PK and pharmacodynamic profiles, and immunogenicity of GSK933776 following IM and SQ administration in healthy volunteers. Such alternate routes of administration may provide more options in the selection of an efficacious dose for subsequent development in patients with geographic atrophy. There will be four treatment arms in the study and participants will be assigned to 1 of 4 possible treatment arms in a 1:1:1:1 ratio. The planned number of evaluable participants for this study is 24 with 6 participants completing all critical assessments in each of the four treatment arms. The total duration of participation from screening to follow-up for Treatment Arms A, B and D (single dose of GSK933776), will be approximately 113 days and total duration for Treatment Arm C (repeat dose of GSK933776) will be approximately 134 days.

Study Overview

• Status: Completed
• Conditions: Atrophy, Geographic
• Intervention / Treatment: Drug: GSK933776 for IV administration; Drug: GSK933776 for SQ administration; Drug: GSK933776 for IM administration

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Kansas
    • Overland Park, Kansas, United States, 66211
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female subject 18 to 50 years of age at the time of signing the informed consent
• In general good health as determined by a physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the condition is unlikely to introduce additional risk factors and will not interfere with the study procedures
• Body weight >=55 kilograms (kg) (121 pounds [lbs]) and <=85 kg (187 lbs) with a body mass index (BMI) between 18.5 and 29 kg per meter square (inclusively) at the time of signing the informed consent.
• A female subject is eligible to participate if she is of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) >40 milli international unit (MIU)/milliliter (mL) and estradiol <40 picogram/mL (<140 picomoles/Liter) is confirmatory.
• Male subjects must agree to use one form of acceptable contraception methods if their partner is of childbearing potential. This criterion must be followed from the time of the screening visit through the follow up visit (84 days after last dose of study medication).
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

Exclusion Criteria:

• Known risk history of Central nervous system (CNS) disorders: History and/or evidence (computed tomography or magnetic resonance imaging scan performed within the past 12 months) of cerebral haemorrhage OR a known risk of cerebral haemorrhage, including uncontrolled hypertension, cerebrovascular malformation, coagulopathy, central nervous system (CNS) vasculitis, degenerative or inflammatory/demyelinating CNS conditions or any other condition that the Investigator and/or the medical monitor considers as a relevant risk factor for cerebral haemorrhage. Transient ischemic attack (TIA)/cerebrovascular accident (CVA) in the last year, or other uncontrolled risk factors for stroke; History of seizures (except febrile seizures in childhood) or recent unprovoked seizure; Uncontrolled type 2 diabetes mellitus (glycated hemoglobin >10%), active cardiovascular disease (e.g., moderate-severe angina, unstable angina, myocardial infarction (MI) within the last 2 years, symptomatic congestive heart failure, clinically significant arrhythmia); Current blood clotting or bleeding disorder or conditions that predispose to these (e.g. cancer); Diagnosis of currently active, or, in remission but chronic relapsing, systemic autoimmune disease or condition (e.g. multiple sclerosis, lupus erythematosus etc) that the Investigator and/or the medical monitor considers as a relevant risk factor for concomitant administration of a therapeutic monoclonal antibody.
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Use of prescription drugs or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
• A positive pre-study drug/alcohol screen. Current or recent drug or alcohol abuse or dependence. History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of >14 units for males or >7 units for females. One drink is equivalent to 12 gram (g) of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits. Use of illegal drugs.
• 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 GSK Medical Monitor, contraindicates their participation.
• Seated systolic blood pressure >140 millimeter of mercury (mmHg) or seated diastolic blood pressure of > 90 mmHg
• QTc >450 millisecond (msec).
• Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) >= 2xupper limit of normal (ULN); alkaline phosphatase and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
• Significant abnormalities on hematology screen: clinically significant anemia (i.e. hemoglobin <11 g/deciliter [dL] for males or <10 g/dL for females), or platelet counts below 124 Giga/L; International Normalized Ratio > 2.
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
• A positive test for human immunodeficiency virus antibody
• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
• Exposure to more than four new chemical entities within 12 months prior to screening.
• Prior allergic reactions to biological products (vaccines, antibodies) or known hypersensitivity to any of the components of the drug formulation.
• Prior participation in clinical investigations involving therapeutic monoclonal antibodies with a similar mode of action or proteins derived from monoclonal antibodies with any risk of cross- reactivity or any investigations of treatments or use of any other investigational medication or device within 2 months prior to screening or within 5 half-lives of use of such a medication prior to screening, whichever is longer.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Arm A; Participants in this arm will receive single 200 milligram (mg) dose of GSK933776 administered by IV infusion	Drug: GSK933776 for IV administration; Antibody solution for intravenous injection with unit dose strength of 50mg/mL administered as 200 mg single dose through an IV catheter over approximately 1 hour
EXPERIMENTAL: Arm B; Participants in this arm will receive single 200 mg dose of GSK933776 administered SQ	Drug: GSK933776 for SQ administration; Antibody solution for subcutaneous injection with unit dose strength of 50mg/mL administered as 200 mg single dose or as repeat dose of 50 mg weekly for 4 weeks
EXPERIMENTAL: Arm C; Participants in this arm will receive 50 mg dose of GSK933776 administered SQ once weekly for 4 weeks (total dose = 200 mg).	Drug: GSK933776 for SQ administration; Antibody solution for subcutaneous injection with unit dose strength of 50mg/mL administered as 200 mg single dose or as repeat dose of 50 mg weekly for 4 weeks
EXPERIMENTAL: Arm D; Participants in this arm will receive single 200 mg dose of GSK933776 administered IM	Drug: GSK933776 for IM administration; Antibody solution for intramuscular injection with unit dose strength of 50mg/mL administered as 200 mg single dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relative bioavailability of GSK933776 after single dose SQ or IM administration as compared to IV infusion	Bioavailability is defined as the rate and extent to which drug reaches the systemic circulation. The relative bioavailability will be calculated from the ratio of area under concentration time curve from time zero to infinity (AUC [0-infinity]) following single dose SQ and IM injection to intravenous (IV) infusion	Blood samples will be collected at following time points: pre-dose and at (0.25, 0.5, 0.75, 1, 2, 4 hours only for IV infusion), 6, 24, 48, 72, 96, 120, 216, 336, 504, 672, 1344 and 2016 hours post dose
Relative bioavailability of GSK933776 after repeat dose SQ administration as compared to IV infusion	Bioavailability is defined as the rate and extent to which drug reaches the systemic circulation. The relative bioavailability will be calculated from the ratio of AUC (0-infinity) following SQ repeat dose injections to intravenous (IV) infusion	Blood samples will be collected at following time points: pre-dose, 6, 24, 48, 72, 96 and 120 hours post dose in each of the 4 dosing weeks and additionally at 216, 336, 504, 672, 1344 and 2016 hours post last dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of PK parameters of GSK933776 following single dose IM and SQ administration as compared to IV administration	PK parameters include: area under the concentration-time curve over the dosing interval (AUC[0-tau]), maximum concentration (Cmax), time of occurrence of Cmax (Tmax), terminal phase half-life (T1/2), clearance, and volume of distribution as data permit	Samples will be collected at following time points: pre-dose and at (0.25, 0.5, 0.75, 1, 2, 4 hours only for IV infusion), 6, 24, 48, 72, 96, 120, 216, 336, 504, 672, 1344 and 2016 hours post dose
Composite of PK parameters of GSK933776 following repeat dose SQ administration as compared to IV administration	PK parameters include: AUC(0-tau), Cmax, Tmax, T1/2, clearance, and volume of distribution as data permit	Blood samples will be collected at following time points: pre-dose, 6, 24, 48, 72, 96 and 120 hours post dose in each of the 4 dosing weeks and additionally at 216, 336, 504, 672, 1344 and 2016 hours post last dose.
Number of participants with adverse events as a measure of safety and tolerability following single dose administration	AEs will be collected from the start of Study Treatment and until the follow-up contact	Up to 113 days
Clinical observation following IV, SQ and IM single dose administration as a measure of safety and tolerability	AEs will be collected from the start of Study Treatment and until the follow-up contact	Up to 134 days
Clinical observation following IV, SQ and IM repeat dose administration as a measure of safety and tolerability	Clinical observation include: physical examination, medical history, and review of concomitant medication	Up to 113 days
Vital sign measurement following single dose administration as a measure of safety and tolerability	Vital sign measurements will include systolic and diastolic blood pressure, pulse rate, and body temperature measurement.	Up to 134 days
Vital sign measurement following repeat dose administration as a measure of safety and tolerability	Vital sign measurements will include systolic and diastolic blood pressure, pulse rate, and body temperature measurement.	Up to 134 days
Electrocardiogram (ECG) measurement following single dose administration to assess safety and tolerability	12-lead ECGs will be obtained at each time point during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QT interval corrected for heart rate (QTc interval).	Up to 113 days
ECG measurement following repeat dose administration to assess safety and tolerability	12-lead ECGs will be obtained at each time point during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc interval.	Up to 134 days
Clinical laboratory parameters assessment following single dose administration as a measure of safety and tolerability	Clinical laboratory assessment include: hematology, clinical chemistry, urinalysis and additional parameters.	Up to 113 days
Clinical laboratory parameters assessment following repeat dose administration as a measure of safety and tolerability	Clinical laboratory assessment include: hematology, clinical chemistry, urinalysis and additional parameters.	Up to 134 days
Plasma concentrations of GSK933776, total amyloid beta (AB), total AB fragments, as well as unbound concentrations of AB, fragments containing the epitope 1-22, as data permit following single dose administrationof GSK933776	The relationship between plasma concentration of GSK933776 and plasma concentration of total and free amyloid beta will be explored as data permit	Up to 113 days
Plasma concentration of GSK933776, AB, total AB fragments, as well as unbound concentrations of AB, fragments containing the epitope 1-22, as data permit following repeat dose administration	The relationship between plasma concentration of GSK933776 and plasma concentration of total and free amyloid beta will be explored as data permit	Up to 134 days
Presence of antibodies to GSK933776 in serum samples following single dose administration of GSK933776	To characterize the immunogenicity profile of GSK933776 following IV, IM and SQ administration. Samples will be analyzed for the presence of anti-GSK933776 antibodies by immuno-electrochemiluminescent (ECL) screening and neutralization assays.	Up to 113 days
Presence of antibodies to GSK933776 in serum samples following repeat dose administration	To characterize the immunogenicity profile of GSK933776 following IV, IM and SQ administration. Samples will be analyzed for the presence of anti-GSK933776 antibodies by immuno-electrochemiluminescent (ECL) screening and neutralization assays.	Up to 134 days

Collaborators and Investigators

• Sponsor: GlaxoSmithKline
• Collaborators: Quintiles, Inc.

Publications and helpful links

Helpful Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 22, 2014
• Primary Completion (ACTUAL): July 15, 2014
• Study Completion (ACTUAL): July 15, 2014

Study Registration Dates

• First Submitted: January 9, 2014
• First Submitted That Met QC Criteria: January 9, 2014
• First Posted (ESTIMATE): January 13, 2014

Study Record Updates

• Last Update Posted (ACTUAL): May 15, 2017
• Last Update Submitted That Met QC Criteria: May 12, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: Pharmacokinetics; monoclonal antibody; bioavailability; intravenous; amyloid beta; subcutaneous and intramuscular administration
• Additional Relevant MeSH Terms: Eye Diseases; Retinal Degeneration; Retinal Diseases; Macular Degeneration; Geographic Atrophy
• Other Study ID Numbers: 116891

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study Data/Documents

1. Statistical Analysis Plan
   Information identifier: 116891
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Clinical Study Report
   Information identifier: 116891
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Dataset Specification
   Information identifier: 116891
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Annotated Case Report Form
   Information identifier: 116891
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Study Protocol
   Information identifier: 116891
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Individual Participant Data Set
   Information identifier: 116891
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Informed Consent Form
   Information identifier: 116891
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register