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Trial record 78 of 119 for:    ZIRCONIUM

A Positron Emission Tomography (PET) Imaging Study to Investigate the Biodistribution and Clearance of an Albumin Binding Domain Antibody (AlbudAb) GSK3128349 in Healthy Male Subjects

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ClinicalTrials.gov Identifier: NCT02829307
Recruitment Status : Completed
First Posted : July 12, 2016
Results First Posted : September 7, 2018
Last Update Posted : September 7, 2018
Sponsor:
Collaborator:
PRA Health Sciences for clinical study conduct.
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
GSK3128349 is a small protein molecule (biopharmaceutical) that binds to albumin in the body, and by itself, has no pharmacological action. A pharmacologically active drug can be attached to GSK3128349 with the goal of changing the distribution and/or duration of action of the attached drug. This study will determine the distribution and pharmacokinetics (duration) of GSK3128349 itself after a single intravenous infusion. GSK3128349 has been labeled with and the radioisotope 89Zirconium allowing it to be visualized in the organs of the body using a PET scanner at multiple time points after GSK3128349 dosing. The data from this study will help predict the distribution of future drugs attached to GSK3128349. The total duration of a subject's participation is about approximately 10 weeks, including the screening period.

Condition or disease Intervention/treatment Phase
Drug-Related Side Effects and Adverse Reactions Drug: 89Zr-GSK3128349 1 mg Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 8 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: An Open Label Positron Emission Tomography (PET) Imaging Study Using 89Zirconium Labeled GSK3128349 to Investigate the Biodistribution and Clearance of an Albumin Binding Domain Antibody (AlbudAb) GSK3128349 Following Single Dose Intravenous Administration in Healthy Male Subjects
Actual Study Start Date : August 23, 2016
Actual Primary Completion Date : January 27, 2017
Actual Study Completion Date : January 27, 2017

Arm Intervention/treatment
Experimental: 89Zr-GSK3128349
Subjects will receive a single dose of 89Zr-GSK3128349 as an intravenous (IV) infusion over 20 minutes to deliver a dose of 1 mg
Drug: 89Zr-GSK3128349 1 mg
89Zr-GSK3128349 is a mixture of unlabelled and zirconium-labelled GSK3128349, in the form of solution for IV administration, and is associated with about 15 MBq of radioactivity.




Primary Outcome Measures :
  1. Mean Standardized Uptake Values (SUVs) Derived From Positron Emission Tomography-Computer Tomography (PET-CT) Data [ Time Frame: Up to Day 7 ]
    SUV is a mathematically derived ratio of tissue radioactivity concentration and the injected dose of radioactivity per kilogram of the participant's body weight at a given point in time. SUV was analyzed for each region of interest (ROI) such as liver, kidney, muscle, spleen, heart, lung, bladder, thymus, and if feasible blood and bone. A maximum of 4 PET scans were conducted in each participant. Mean SUV derived from PET-CT has been presented.

  2. Mean Volume of ROI for Each Organ at All Time Points [ Time Frame: Up to Day 7 ]
    Volume of ROI is the volume specified in organs as measured in PET or CT images. Mean volume of ROI for each organ has been presented.


Secondary Outcome Measures :
  1. Area Under Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC [0-t]) and Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinite Time (AUC [0-inf]) of 89Zr-GSK3128349 and GSK3128349 [ Time Frame: Pre-dose, 1 hour (h), 3 h, 6 h, 8h, 24 h post-dose, Day 4, Day 6, Day 14, Day 22, Day 33 and Day 45 ]
    PK parameters included AUC (0-t) and AUC (0-inf). AUC (0-t) and AUC (0-inf) for 89Zr-GSK3128349 was calculated from the whole blood and plasma concentration-time data, measured by scintillation counting. AUC (0-t) and AUC (0-inf) for GSK3128349 was calculated from the whole blood and plasma concentration-time data, measured by mass spectrometry.

  2. Percent Area Under the Curve Obtained by Extrapolation (AUCex) and Percent Area Under the First Moment Curve Obtained by Extrapolation (AUMCex) of 89Zr-GSK3128349 and GSK3128349 [ Time Frame: Pre-dose, 1 h, 3 h, 6 h, 8h, 24 h post-dose, Day 4, Day 6, Day 14, Day 22, Day 33 and Day 45 ]
    PK parameters included AUCex and AUMCex. AUCex and AUMCex for 89Zr-GSK3128349 was calculated from the whole blood and plasma concentration-time data, measured by scintillation counting. AUCex and AUMCex for GSK3128349 was calculated from the whole blood and plasma concentration-time data, measured by mass spectrometry.

  3. Maximum Observed Plasma Concentration (Cmax) of 89Zr-GSK3128349 [ Time Frame: Pre-dose, 1 h, 3 h, 6 h, 8h, 24 h post-dose, Day 4, Day 6, Day 14, Day 22, Day 33 and Day 45 ]
    PK parameters included Cmax. Cmax for 89Zr-GSK3128349 was calculated from the whole blood and plasma concentration-time data, measured by scintillation counting.

  4. Cmax of GSK3128349 [ Time Frame: Pre-dose, 1 h, 3 h, 6 h, 8h, 24 h post-dose, Day 4, Day 6, Day 14, Day 22, Day 33 and Day 45 ]
    PK parameters included Cmax. Cmax for GSK3128349 was calculated from the whole blood and plasma concentration-time data, measured by mass spectrometry.

  5. Apparent Terminal Phase Half-life (t1/2) and Mean Residence Time (MRT) of 89Zr-GSK3128349 and GSK3128349 [ Time Frame: Pre-dose, 1 h, 3 h, 6 h, 8h, 24 h post-dose, Day 4, Day 6, Day 14, Day 22, Day 33 and Day 45 ]
    PK parameters included t1/2 and MRT. t1/2 and MRT for 89Zr-GSK3128349 was calculated from the whole blood and plasma concentration-time data, measured by scintillation counting. t1/2 and MRT for GSK3128349 was calculated from the whole blood and plasma concentration-time data, measured by mass spectrometry.

  6. Elimination Rate Constant (Lambda-z) of 89Zr-GSK3128349 [ Time Frame: Pre-dose, 1 h, 3 h, 6 h, 8h, 24 h post-dose, Day 4, Day 6, Day 14, Day 22, Day 33 and Day 45 ]
    PK parameters included lambda-z. Cmax for 89Zr-GSK3128349 was calculated from the whole blood and plasma concentration-time data, measured by scintillation counting.

  7. Volume of Distribution at a Steady State (Vss) and Volume of Distribution in the Terminal Phase (Vz) of 89Zr-GSK3128349 and GSK3128349 [ Time Frame: Pre-dose, 1 h, 3 h, 6 h, 8h, 24 h post-dose, Day 4, Day 6, Day 14, Day 22, Day 33 and Day 45 ]
    PK parameters included Vss and Vz. Vss and Vz for 89Zr-GSK3128349 was calculated from the whole blood and plasma concentration-time data, measured by scintillation counting. Vss and Vz for GSK3128349 was calculated from the whole blood and plasma concentration-time data, measured by mass spectrometry.

  8. Area Under the First Moment Curve From Pre-dose Extrapolated to Infinite Time (AUMC [0-inf]) and Area Under the First Moment Curve From Pre-dose Extrapolated to Last Time of Quantifiable Concentration (AUMC [0-t]) of 89Zr-GSK3128349 [ Time Frame: Pre-dose, 1 h, 3 h, 6 h, 8h, 24 h post-dose, Day 4, Day 6, Day 14, Day 22, Day 33 and Day 45 ]
    PK parameters included AUMC (0-inf) and AUMC (0-t). AUMC (0-inf) and AUMC (0-t) for 89Zr-GSK3128349 was calculated from the whole blood and plasma concentration-time data, measured by scintillation counting.

  9. AUMC (0-inf) and AUMC (0-t) of GSK3128349 [ Time Frame: Pre-dose, 1 h, 3 h, 6 h, 8h, 24 h post-dose, Day 4, Day 6, Day 14, Day 22, Day 33 and Day 45 ]
    PK parameters included AUMC (0-inf) and AUMC (0-t). AUMC (0-inf) and AUMC (0-t) for GSK3128349 was calculated from the whole blood and plasma concentration-time data, measured by mass spectrometry.

  10. Clearance of 89Zr-GSK3128349 and GSK3128349 [ Time Frame: Pre-dose, 1 h, 3 h, 6 h, 8h, 24 h post-dose, Day 4, Day 6, Day 14, Day 22, Day 33 and Day 45 ]
    PK parameters included clearance. Clearance for 89Zr-GSK3128349 was calculated from the whole blood and plasma concentration-time data, measured by scintillation counting. Clearance for GSK3128349 was calculated from the whole blood and plasma concentration-time data, measured by mass spectrometry.

  11. Mean Organ and Effective Dose [ Time Frame: Up to Day 7 ]
    Organ dose was defined as the amount of radiation delivered to a particular organ. Effective dose was defined as the tissue-weighted sum of the organ doses in all specified tissues and organs of the human body. The organ and effective dose is a fraction of milliSievert (mSv) and MegaBecquerel (MBq). The mean relative uptake of 89Zr-GSK3128349 in different organs for all participants across all PET scans is presented.

  12. Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) [ Time Frame: Up to 45 days ]
    AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant or is associated with liver injury or impaired liver function.

  13. Number of Participants With Clinical Chemistry Data of Potential Clinical Concern [ Time Frame: Up to 45 days ]
    The potential clinical concern range for clinical chemistry parameters were: glucose (low: < 3 millimole [mmol]/L and high: > 9 mmol/L), creatinine (high: Change from Baseline or Day 1 should be positive and > 44.2 mmol/L), phosphorous (low: < 0.8 mmol/L and high: > 1.6 mmol/L), magnesium (low: < 0.5 mmol/L and high: > 1.23 mmol/L), calcium (low: <2 mmoL/L and high: > 2.75 mmol/L), carbon dioxide content (low: < 18 mmol/L and high: > 32 mmol/L), albumin (low: < 30 mmol/L), potassium (low: < 3.0 mmol/L and high: > 5.5 mmol/L) and sodium (low: < 130 mmol/L and high: > 130 mmol/L). Number of participants with clinical chemistry abnormalities of potential clinical importance are presented

  14. Number of Participants With Hematology Data of Potential Clinical Concern [ Time Frame: Up to 45 days ]
    The potential clinical concern range for hematology parameters were: Hemoglobin (low: > 25 gram per Liter change from Baseline/Day 1 and high: > 180 gram per Liter), lymphocytes (low: < 0.8 gigacells/L), hematocrit (low: > 0.075 ratio change from Baseline and high: > 0.54 ratio), neutrophil count (low: < 1.5*10^9/Liter), platelet count (low: < 100 gigacells/L and high: > 550 gigacells/L), white blood cell (WBC) count (low: < 3 gigacells/L and high: > 20 gigacells/L). Number of participants with hematology abnormalities of potential clinical importance are presented.

  15. Number of Participants With Electrocardiogram (ECG) Values of Potential Clinical Concern [ Time Frame: Pre-dose on Day 1, 1 h and 24 h post-dose on Day 1 and Day 45 ]
    ECG measurements were made with the participant in a supine position having rested in this position for at least 5 minutes before each reading. Triplicate 12-lead ECGS were obtained pre dose at Day 1 and single 12-lead ECGs will be obtained at other time points during the study. The potential clinical concern range for ECG parameters was as follows: Absolute corrected QT (QTc) interval (lower: >450 milliseconds [msec], >450 msec, >=480 msec and >=500 msec) and (higher: <=479 msec and <=499 msec); absolute PR interval (lower: <110 and higher >220 msec) and absolute QRS interval (lower: <75 msec and >110 msec). Number of participants with ECG values of potential clinical concern are presented.

  16. Number of Participants With Vital Signs of Potential Clinical Concern [ Time Frame: Up to 45 days ]
    Vital signs included pulse rate, systolic and diastolic blood pressure and body temperature. All vital sign measurements were made with the participant in a supine position and rested in this position for at least 5 minutes before each reading. The potential clinical concern range for systolic blood pressure: <85 and >160 millimeters of mercury (mmHg), for diastolic: <45 and >100 mmHg and heart rate: <40 and >110 beats per minute. Number of participants with vital signs of potential clinical concern are presented.

  17. Number of Participants With Positive Anti-GSK3128349 Antibody Assay [ Time Frame: Pre-dose on Day 1 and Day 43 ]
    Blood samples for testing antibodies against GSK3128349 will be collected on Day 1 (pre-dose) and on Day 43. The actual date and time of each blood sample collection was recorded. The first blood sample was taken pre-dose on Day 1 to determine the presence, if any, of pre-existing Anti Drug Antibodies (ADAs). The presence of such antibodies was assessed using an electrochemiluminescent (ECL) immuno assay. If sera contain anti-GSK3128349 antibodies, they were further analyzed for the antibody specificity and titres. Number of participants who were found to have anti-GSK3128349 antibodies are presented.

  18. Serum Titers of Anti-GSK3128349 Antibodies [ Time Frame: Pre-dose on Day 1 and Day 43 ]
    Blood samples for testing antibodies against GSK3128349 will be collected on Day 1 (pre-dose) and on Day 43. The actual date and time of each blood sample collection was recorded. The first blood sample was taken pre-dose on Day 1 to determine the presence, if any, of pre-existing ADAs. The presence of such antibodies and serum titers of anti-GSK3128349 antibodies was assessed using an ECL immuno-assay. If sera contain anti-GSK3128349 antibodies, they were further analyzed for the antibody specificity and titers.



Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. - Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase and bilirubin <=1.5x Upper Limit Normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent).
  • Body Mass Index (BMI) within the range 19.0 - 31.0 kilogram (kg)/meter (m^2) (inclusive).
  • Subjects must agree to use one of the contraception methods listed in the protocol.
  • Capable of giving written informed consent, which includes compliance with the study requirements and restrictions.
  • Average Corrected QT interval (QTc) <=450 milliseconds (msec)

Exclusion Criteria:

  • Current evidence or history of an influenza-like illness.
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • History of, or current, acute renal failure, known renal disease, or a renal disorder or abnormality that may compromise renal function. This includes having one kidney.
  • Previous inclusion in a research and/or medical protocol involving nuclear medicine, PET or radiological investigations or occupational exposure that, together with the proposed study, will result in a total radiation exposure greater than 10 mSv over a 3 year period. Clinical exposure from which the subject receives a direct benefit (example, diagnostic test) is not included in these calculations.
  • History of regular alcohol consumption within 6 months of the study defined as:

An average weekly intake of >21 units. One unit is equivalent to 8 g of alcohol: a half-pint (~240 milliliter [mL]) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.

  • Unable to refrain from the use of prescription drugs within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study treatment, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
  • Subject is a smoker >=5 cigarettes/day or with a smoking history of >5 pack years
  • History of sensitivity to any of the study treatment 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.
  • Subject suffers from claustrophobia that limits the ability to remain still in the PET/CT scanner for the required amount of time.
  • Subject has metal present in their body that will interfere with the PET/CT scanning.
  • Estimate glomerular filtration rate (eGFR) <60 mL/min/1.73 m^2 (utilizing the Chronic Kidney Disease Epidemiology Collaboration (CKI-EPI) equation).
  • Urine mg protein/mg creatinine Urine Protein Creatinine Ratio (UPCR) >0.3.
  • Evidence of hematuria by urinalysis (1plus or greater dipstick test).
  • A positive pre-study Hepatitis B surface antigen or positive Hepatitis C (Hep C) antibody result within 3 months of screening.
  • A positive test for Human Immunodeficiency Virus (HIV) antibody.
  • A positive pre-study drug/alcohol screen.
  • 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).
  • Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
  • Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02829307


Locations
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Netherlands
GSK Investigational Site
Zuidlaren, Netherlands, 9471 GP
Sponsors and Collaborators
GlaxoSmithKline
PRA Health Sciences for clinical study conduct.
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
  Study Documents (Full-Text)

Documents provided by GlaxoSmithKline:
Study Protocol  [PDF] May 23, 2016
Statistical Analysis Plan  [PDF] March 6, 2017


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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02829307     History of Changes
Other Study ID Numbers: 117169
First Posted: July 12, 2016    Key Record Dates
Results First Posted: September 7, 2018
Last Update Posted: September 7, 2018
Last Verified: July 2018
Keywords provided by GlaxoSmithKline:
89Zirconium
Open label
Pharmacokinetics
Radioactive
Clearance
Biodistribution
Additional relevant MeSH terms:
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Drug-Related Side Effects and Adverse Reactions
Chemically-Induced Disorders
Antibodies
Immunologic Factors
Physiological Effects of Drugs