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Trial record 3 of 25 for:    amyloid gsk

A Safety Study of GSK3039294 in Healthy Volunteers and Patients With Systemic Amyloidosis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02603172
Recruitment Status : Terminated (A new study will be initiated in order to specifically investigate cardiac safety)
First Posted : November 11, 2015
Results First Posted : September 23, 2019
Last Update Posted : September 23, 2019
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
GSK3039294 has been developed in order to offer an orally available alternative to parenteral CPHPC (GSK2315698 [metabolite of GSK3039294]) for plasma serum amyloid P component (SAP) depletion prior to use of anti SAP monoclonal antibody (mAb) in the treatment of systemic amyloidosis. This phase 1 study is intended to study safety, tolerability and pharmacokinetic (PK) profile of GSK3039294 in humans. This study consists of three parts. Part A will evaluate safety and tolerability of single doses of GSK3039294 in healthy subjects, Part B will evaluate safety and tolerability of repeat doses of GSK3039294 in healthy subjects, and Part C will evaluate safety and tolerability of repeat doses of GSK3039294 in subjects with systemic amyloidosis. Part A is a single dose, open label, dose escalation study. Two cohorts of subjects will be enrolled to provide data from 6 subjects per cohort and up to 4 different doses (2 dose levels per cohort) of GSK3039294 will be tested. For Cohorts 1 and 2, each subject may take part in two dosing periods. Part B is repeat dose, open label, dose escalation study. Sufficient number of subjects will be enrolled in Cohort 3a to ensure 6 completers (Cohort 3b will be conducted if required) and GSK3039294 will be administered repeatedly for a total of 21 days. Each subject will take part in a single study period. In Part C a single dose level of GSK3039294 will be tested for 21 days repeat dose, in 12 subjects with systemic amyloidosis. Each subject will take part in a single study period. The total duration for Part A is approximately 8 weeks, Part B is approximately 8-9 weeks, and Part C is approximately 13 weeks.

Condition or disease Intervention/treatment Phase
Amyloidosis Drug: GSK3039294 Phase 1

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Three-part Open-label, Non-randomised, Dose-escalation Study to Investigate the Safety and Tolerability of GSK3039294 Administered as a Single Dose to Healthy Volunteers, and as Repeat Dose to Healthy Volunteers and Patients With Systemic Amyloidosis
Actual Study Start Date : May 12, 2016
Actual Primary Completion Date : May 10, 2017
Actual Study Completion Date : May 10, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Amyloidosis

Arm Intervention/treatment
Experimental: Part A: Cohort 1
Subjects will receive a single dose of GSK3039294 (Dose level 1) on Day 1 and will remain in-house until Day 4. Wash-out will take place from Day 5 to Day 14. Subjects will receive Dose level 2 on Day 15 (Period 2).
Drug: GSK3039294
GSK3039294 will be provided as white, opaque capsules. A single capsule or multiple capsules (20 mg to 200 mg), depending on the dosage required, will be taken orally with water.

Experimental: Part A: Cohort 2
Subjects will receive a single dose of GSK3039294 (Dose level 3) on Day 1 and will remain in-house until Day 4. Wash-out will take place from Day 5 to Day 14. Subjects will receive Dose level 4 on Day 15 (Period 2).
Drug: GSK3039294
GSK3039294 will be provided as white, opaque capsules. A single capsule or multiple capsules (20 mg to 200 mg), depending on the dosage required, will be taken orally with water.

Experimental: Part B: Cohort 3a
Subjects will receive repeat dosing of GSK3039294 for a total of 21 days. The dose will be escalated every week throughout the study duration. Subjects will first receive a low dose given once daily. After 7 days, if well tolerated, the total daily dose will be increased and, GSK3039294 will be given, for example, as twice daily dosing for 7 days. At the end of this 7 day period and if previous dosing was well tolerated, the dose will be increased to a maximum daily dose that will not exceed pre-clinical safety exposure limits. On Day 4 and 5 GSK3039294 will be administered under fasted and fed conditions, respectively, to investigate the food effect on the PK.
Drug: GSK3039294
GSK3039294 will be provided as white, opaque capsules. A single capsule or multiple capsules (20 mg to 200 mg), depending on the dosage required, will be taken orally with water.

Experimental: Part B: Cohort 3b
Subjects will be enrolled in Cohort 3b only if required for further investigation. Subjects will receive GSK3039294 for 21 consecutive days and more than one dose level or regimen may be investigated, for example on the first 10 days the dose may be administered thrice daily, and on the last 11 days may be administered twice daily.
Drug: GSK3039294
GSK3039294 will be provided as white, opaque capsules. A single capsule or multiple capsules (20 mg to 200 mg), depending on the dosage required, will be taken orally with water.

Experimental: Part C: Cohort 4
Subjects will receive repeat dosing of GSK3039294 at the predicted optimal clinical dose determined from Part B for a total of 21 days.
Drug: GSK3039294
GSK3039294 will be provided as white, opaque capsules. A single capsule or multiple capsules (20 mg to 200 mg), depending on the dosage required, will be taken orally with water.




Primary Outcome Measures :
  1. Part A:Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to Day 14 ]
    An AE is any untoward medical occurrence in a participants or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose: results in death, is life-threatening, requires inpatient hospitalization clinical chemor prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect and other important medical events judged by the investigator that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention. Safety population consist of all participants who received at least one dose of the study medication.

  2. Part A: Number of Participants With Emergent Clinical Chemistry by Potentially Clinical Importance (PCI) Criteria [ Time Frame: Day 1 ]
    PCI ranges for the clinical chemistry parameters were as follows : albumin (low: <0.86 gram [g] per liter [L]), calcium (low: <0.91 millimole [mmol]/L and high: >1.06 mmol/L), glucose (low: <0.71 mmol/L and high: >1.41 mmol/L), magnesium (low: <0.63 mmol/L and high: >1.03 mmol/L), phosphorous (low: <0.80 mmol/L and high: >1.14 mmol/L), potassium (low: <0.86 mmol/L and high: >1.10 mmol/L), sodium (low: <0.96 mmol/L and high: >1.03 mmol/L), and total carbon dioxide (CO2) (low: <0.86 mmol/L and high: >1.14 mmol/L).

  3. Part A: Number of Participants With Emergent Hematology by PCI Criteria [ Time Frame: Day 1 ]
    PCI ranges for the hematology parameters were as follows: white blood cell (WBC) count (low: <0.67 10^9 cells/L and high: >1.82 10^9 cells/L), neutrophil count (low: <0.83 10^9 cells/L), hemoglobin (high: >1.03 g/L in male, >1.13 g/L in female), hemocrit (high: >1.02 proportion of red blood cell [RBC] in blood for male, >1.17 proportion of RBC in blood for female), platelet count (low: <0.67 10^9 cells/L and high: 1.57 10^9 cells/L), and lymphocytes (low: <0.81 10^9 cells/L).

  4. Part A: Number of Participants With Abnormal Urinalysis Data by Dipstick [ Time Frame: Day 1 ]
    Urine samples were collected and urinalysis included analysis of specific gravity, potential of hydrogen (pH), glucose, protein, blood, ketones by dipstick. The dipstick test gives results in a semi-quantitative manner.

  5. Part A: Mean Change From Baseline in 12-lead Electrocardiogram (ECG) [ Time Frame: Baseline (pre-dose) and 15, 30 minutes, 1, 2, 4, 6, 8, 12, 24, 48 and 72 hours post-dose ]
    Triplicate ECG was measured in semi-supine position after 5 minutes (min) rest. A single 12-lead ECG was measured by using ECG machine that automatically measured PR, QRS, QT, and Fridericia's formula (QTcF) intervals. Baseline is defined as the latest available assessment pre the first dose of study drug within each period in Part A. Change from Baseline was calculated as any visit post Baseline value minus Baseline value.

  6. Part A: Mean Change From Baseline in Heart Rate by 12-lead ECG [ Time Frame: Baseline (pre-dose) and 15, 30 minutes, 1, 2, 4, 6, 8, 12, 24, 48 and 72 hours post-dose ]
    Triplicate ECG was measured in semi-supine position after 5 min rest. A single 12-lead ECG was measured by using ECG machine that automatically measures the heart rate. Baseline is defined as the latest available assessment pre the first dose of study drug within each period in Part A. Change from Baseline was calculated as any visit post Baseline value minus Baseline value.

  7. Part A: Mean Change From Baseline in Blood Pressure (BP) [ Time Frame: Baseline (pre-dose) and 15, 30 minutes, 1, 2, 4, 6, 8, 12, 24, 48 and 72 hours post-dose ]
    Systolic BP and diastolic BP were measured in semi-supine position after 5 min rest for the participants at indicated time points. Baseline is defined as the latest available assessment pre the first dose of study drug within each period in Part A. Change from Baseline was calculated as any visit post Baseline value minus Baseline value.

  8. Part A: Mean Change From Baseline in Pulse Rate [ Time Frame: Baseline (pre-dose) and 15, 30 minutes, 1, 2, 4, 6, 8, 12, 24, 48 and 72 hours post-dose ]
    Pulse rate was measured in semi-supine position after 5 minutes rest for the participants at indicated time points. Baseline is defined as the latest available assessment pre the first dose of study drug within each period in Part A. Change from Baseline was calculated as any visit post Baseline value minus Baseline value.

  9. Part A: Mean Change From Baseline in Temperature [ Time Frame: Baseline (pre-dose) and 15, 30 minutes, 1, 2, 4, 6, 8, 12, 24, 48 and 72 hours post-dose ]
    Temperature was measured in semi-supine position after 5 min rest for the participants at indicated time points. Baseline is defined as the latest available assessment pre the first dose of study drug within each period in Part A. Change from Baseline was calculated as any visit post Baseline value minus Baseline value.

  10. Part B:Number of Participants With AEs and SAEs [ Time Frame: Cohort 3: Up to Day 21; Cohort 4: Up to Day 35 ]
    An 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. 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 and other important medical events judged by the investigator that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention.

  11. Part B: Number of Participants With Emergent Clinical Chemistry by PCI Criteria [ Time Frame: Cohort 3 and 4: Up to Day 3 ]
    PCI ranges for the clinical chemistry parameters were as follows: albumin (low: <0.86 g/L), calcium (low: <0.91 mmol/L and high: >1.06 mmol/L), glucose (low: <0.71 mmol/L and high: >1.41 mmol/L), magnesium (low: <0.63 mmol/L and high: >1.03 mmol/L), phosphorous (low: <0.80 mmol/L and high: >1.14 mmol/L), potassium (low: <0.86 mmol/L and high: >1.10 mmol/L), sodium (low: <0.96 mmol/L and high: >1.03 mmol/L), and total CO2 (low: <0.86 mmol/L and high: >1.14 mmol/L).

  12. Part B: Number of Participants With Emergent Hematology by PCI Criteria [ Time Frame: Cohort 3 and 4: Up to Day 3 ]
    PCI ranges for the hematology parameters were as follows: WBC count (low: <0.67 10^9 cells/L and high: >1.82 10^9 cells/L), neutrophil count (low: <0.83 10^9 cells/L), hemoglobin (high: >1.03 g/L in male, >1.13 g/L in female), hemocrit (high: >1.02 proportion of RBC in blood for male, >1.17 proportion of RBC in blood for female), platelet count (low: <0.67 10^9 cells/L and high: 1.57 10^9 cells/L), and lymphocytes (low: <0.81 10^9 cells/L).

  13. Part B: Number of Participants With Abnormal Urinalysis Data by Dipstick [ Time Frame: Cohort 3 and 4: Up to Day 3 ]
    Urine samples were collected and urinalysis included analysis of specific gravity, pH, glucose, protein, blood, ketones by dipstick. The dipstick test gives results in a semi-quantitative manner.

  14. Part B: Mean Change From Baseline in 12-lead ECG [ Time Frame: Cohort 3: Baseline (pre-dose), Day 1 (1 hour), Days 2, 3, 4, 5, 6, 7 (pre-dose and 1 hour), 8 and 21; Cohort 4: Up to Day 35 ]
    Triplicate ECG was measured in semi-supine position after 5 minutes rest. A single 12-lead ECG was measured by using ECG machine that automatically measured PR, QRS, QT, and QTcF intervals. Baseline is defined as the latest available assessment pre the first dose of study drug in Part B. Change from Baseline was calculated as any visit post Baseline value minus Baseline value.

  15. Part B: Mean Change From Baseline in Heart Rate by 12-lead ECG [ Time Frame: Cohort 3: Baseline (pre-dose), Day 1 (1 hour), Days 2, 3, 4, 5, 6, 7 (pre-dose and 1 hour), 8 and 21; Cohort 4: Up to Day 35 ]
    Triplicate ECG was measured in semi-supine position after 5 min rest. A single 12-lead ECG was measured by using ECG machine that automatically measures heart rate. Baseline is defined as the latest available assessment pre the first dose of study drug within each period in Part B. Change from Baseline was calculated as any visit post Baseline value minus Baseline value.

  16. Part B: Number of Participants With Abnormal Cardiac Telemetry Findings [ Time Frame: Cohort 3: Up to Day 8 ]
    The cardiac monitoring was measured by using an appropriate nonimplantable recording device which is acceptable to the participants. This was evaluated the arrhythmic background of eligible cardiac amyloidosis participants such that false positive attribution of arrhythmias to GSK3039294 during repeat dosing was minimized.

  17. Part C: Number of Participants With AEs and SAEs [ Time Frame: Up to Day 63 ]
    An 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. 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 and other important medical events judged by the investigator that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention. This analysis was planned but not performed for Part C as the study was terminated early during Part B.

  18. Part C: Number of Participants With Emergent Clinical Chemistry by PCI Criteria [ Time Frame: Up to Day 63 ]
    PCI parameters for the clinical chemistry that were planned for analysis are as follows: albumin, calcium, glucose, magnesium, phosphorous , potassium , sodium , and total CO2. This analysis was planned but not performed for Part C as the study was terminated early during Part B.

  19. Part C: Number of Participants With Emergent Hematology Parameters by PCI Criteria [ Time Frame: Up to Day 63 ]
    Hematology parameters that were planned for analysis were as follows: WBC count , neutrophil count , hemoglobin , hemocrit , platelet count , and lymphocytes. This analysis was planned but not performed for Part C as the study was terminated early during Part B.

  20. Part C: Number of Participants With Emergent Urinalysis Parameters by PCI Criteria [ Time Frame: Up to Day 63 ]
    Urine samples were planned to be collected and urinalysis included analysis of specific gravity, pH, glucose, protein, blood, ketones by dipstick. This analysis was planned but not performed for Part C as the study was terminated early during Part B.

  21. Part C: Number of Participants With Abnormal 12-lead ECG Findings [ Time Frame: Up to Day 35 ]
    Triplicate ECG was planned to be measured in semi-supine position after 5 minutes rest. A single 12-lead ECG was measured by using ECG machine that automatically measured PR, QRS, QT, and QTcF intervals. Baseline is defined as the latest available assessment pre the first dose of study drug within each period in Part C. Change from Baseline was calculated as any visit post Baseline value minus Baseline value. This analysis was planned but not performed for Part C as the study was terminated early during Part B.

  22. Part C: Number of Participants With Abnormal Vital Signs [ Time Frame: Up to Day 35 ]
    Vital signs included systolic and diastolic BP, pulse rate, heart rate and temperature. This analysis was planned but not performed for Part C as the study was terminated early during Part B.

  23. Part C: Number of Participants With Abnormal Cardiac Telemetry Findings [ Time Frame: Up to Day 35 ]
    The cardiac monitoring was planned to be measured by using an appropriate nonimplantable recording device which is acceptable to the participants. This was evaluated the arrhythmic background of eligible cardiac amyloidosis participants such that false positive attribution of arrhythmias to GSK3039294 during repeat dosing was minimized. This analysis was planned but not performed for Part C as the study was terminated early during Part B.


Secondary Outcome Measures :
  1. Part A: Area Under the Concentration-time Curve Extrapolated to Infinity (AUC[0-inf]) of GSK3039294 and GSK2315698 [ Time Frame: Pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 and 48 hours post-dose ]
    Blood samples were collected at specified time points for GSK3039294 and GSK2315698. AUC(0-inf) was determined using standard non-compartmental methods. Pharmacokinetic (PK) population consists of all participants administered at least one dose of study medication and who had at least one PK sample taken and analyzed.

  2. Part A: AUC(0-inf) Corrected for Dose of Prodrug (AUC[0-inf]/D) of GSK3039294 and GSK2315698 [ Time Frame: Pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 and 48 hours post-dose ]
    Blood samples were collected at specified time points for GSK3039294 and GSK2315698. AUC(0-inf)/D was determined using standard non-compartmental methods.

  3. Part A: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0-t]) of GSK3039294 and GSK2315698 [ Time Frame: Pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 and 48 hours post-dose ]
    Blood samples were collected at specified time points for GSK3039294 and GSK2315698. AUC(0-t) was determined using standard non-compartmental methods.

  4. Part A: AUC(0-t) Corrected for Dose of Prodrug (AUC[0-t]/D) of GSK3039294 and GSK2315698 [ Time Frame: Pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 and 48 hours post-dose ]
    Blood samples were collected at specified time points for GSK3039294 and GSK2315698. AUC(0-t)/D was determined using standard non-compartmental methods.

  5. Part A: Maximum Observed Plasma Concentration (Cmax) of GSK3039294 and GSK2315698 [ Time Frame: Pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 and 48 hours post-dose ]
    Blood samples were collected at specified time points for GSK3039294 and GSK2315698. Cmax was determined using standard non-compartmental methods.

  6. Part A: Cmax Corrected for Dose of Prodrug (Cmax/D) of GSK3039294 and GSK2315698 [ Time Frame: Pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 and 48 hours post-dose ]
    Blood samples were collected at specified time points for GSK3039294 and GSK2315698. Cmax/D was determined using standard non-compartmental methods.

  7. Part A: Terminal Half-life (t1/2) of GSK3039294 and GSK2315698 [ Time Frame: Pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 and 48 hours post-dose ]
    Blood samples were collected at specified time points for GSK3039294 and GSK2315698. t1/2 was determined using standard non-compartmental methods.

  8. Part A: Time to Reach Cmax (Tmax) of GSK3039294 and GSK2315698 [ Time Frame: Pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 and 48 hours post-dose ]
    Blood samples were collected at specified time points for GSK3039294 and GSK2315698. tmax was determined using standard non-compartmental methods.

  9. Part B: Area Under the Concentration-time Curve From Time Zero to 6 Hours Post Dose (AUC[0-6]) of GSK3039294 and GSK2315698 [ Time Frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose) ]
    Blood samples were collected at specified time points for GSK3039294 and GSK2315698. AUC(0-6) was determined using standard non-compartmental methods.

  10. Part B: AUC(0-inf) of GSK3039294 and GSK2315698 [ Time Frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose) ]
    Blood samples were collected at specified time points for GSK3039294 and GSK2315698. AUC(0-inf) was determined using standard non-compartmental methods.

  11. Part B: AUC([0-inf]/D) of GSK3039294 and GSK2315698 [ Time Frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose) ]
    Blood samples were collected at specified time points for GSK3039294 and GSK2315698. AUC(0-inf)/D was determined using standard non-compartmental methods.

  12. Part B: AUC(0-t) of GSK3039294 and GSK2315698 [ Time Frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose) ]
    Blood samples were collected at specified time points for GSK3039294 and GSK2315698. AUC(0-t) was determined using standard non-compartmental methods.

  13. Part B: AUC(0-t)/D of GSK3039294 and GSK2315698 [ Time Frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose) ]
    Blood samples were collected at specified time points for GSK3039294 and GSK2315698. AUC(0-t)/D was determined using standard non-compartmental methods.

  14. Part B: Cmax of GSK3039294 and GSK2315698 [ Time Frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose) ]
    Blood samples were collected at specified time points for GSK3039294 and GSK2315698. Cmax was determined using standard non-compartmental methods. NA indicates data could not be calculated because only one participant was analyzed.

  15. Part B: Cmax/D of GSK3039294 and GSK2315698 [ Time Frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose) ]
    Blood samples were collected at specified time points for GSK3039294 and GSK2315698. Cmax/D was determined using standard non-compartmental methods. NA indicates that, data could not be calculated because only one participant was analyzed.

  16. Part B: t1/2 of GSK3039294 and GSK2315698 [ Time Frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose) ]
    Blood samples were collected at specified time points for GSK3039294 and GSK2315698. t1/2 was determined using standard non-compartmental methods.

  17. Part B: Tmax of GSK3039294 and GSK2315698 [ Time Frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose) ]
    Blood samples were collected at specified time points for GSK3039294 and GSK2315698. tmax was determined using standard non-compartmental methods.

  18. Part B: Plasma Serum Amyloid P Component (SAP) Level of GSK3039294 [ Time Frame: Cohort 3:Days1(pre-dose, 2hour post-dose),2(pre-dose),4(pre-dose),5(pre-dose, 30min,1,2,3,4,6 hours post-dose),7(pre-dose)and 21post-dose;Cohort4:Days1(pre-dose, 2 hour post-dose),2(pre-dose),4(pre-dose), 5(pre-dose, and 2 hours post-dose) and 35post-dose ]
    Blood samples were collected at specified time points for GSK3039294. Pharmacodynamic (PD) population consist of all participants who received at least one dose of study medication and who also had a baseline measurement and at least one post-treatment PD measure.

  19. Part C: AUC(0-inf) of GSK3039294 and GSK2315698 [ Time Frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5 ]
    This analysis was planned but not performed for Part C as the study was terminated early during Part B.

  20. Part C: AUC(0-inf)/D of GSK3039294 and GSK2315698 [ Time Frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5 ]
    This analysis was planned but not performed for Part C as the study was terminated early during Part B.

  21. Part C: AUC(0-t) of GSK3039294 and GSK2315698 [ Time Frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5 ]
    This analysis was planned but not performed for Part C as the study was terminated early during Part B.

  22. Part C: AUC(0-t)/D of GSK3039294 and GSK2315698 [ Time Frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5 ]
    This analysis was planned but not performed for Part C as the study was terminated early during Part B.

  23. Part C: Cmax of GSK3039294 and GSK2315698 [ Time Frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5 ]
    This analysis was planned but not performed for Part C as the study was terminated early during Part B.

  24. Part C: Cmax/D of GSK3039294 and GSK2315698 [ Time Frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5 ]
    This analysis was planned but not performed for Part C as the study was terminated early during Part B.

  25. Part C: t1/2 of GSK3039294 and GSK2315698 [ Time Frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5 ]
    This analysis was planned but not performed for Part C as the study was terminated early during Part B.

  26. Part C: Tmax of GSK3039294 and GSK2315698 [ Time Frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5 ]
    This analysis was planned but not performed for Part C as the study was terminated early during Part B.

  27. Part C: Plasma SAP Levels of GSK3039294 [ Time Frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5 ]
    This analysis was planned but not performed for Part C as the study was terminated early during Part B.

  28. Part C: Time to Repletion of SAP [ Time Frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5 ]
    This analysis was planned but not performed for Part C as the study was terminated early during Part B.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age: 18 to 70 years of age inclusive at the time of signing the informed consent.
  • Non-smokers and Smokers. Smokers (<5 /day) are permitted but must be willing to abstain for the duration of residential study sessions and / or dosing period (whichever is longer).
  • Body weight >50 kilograms (kg) and body mass index (BMI) within the range 18.5-32 kg/square meter (m^2) (inclusive) and excluding the effects of peripheral oedema.
  • Male or female
  • Female subjects are eligible to participate if they are of non-childbearing potential defined as premenopausal females with a documented tubal ligation or hysterectomy or bilateral oophorectomy; or postmenopausal defined as 12 month of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) >40 milli-international units (MIU)/milliliter (mL) and estradiol < 40 picograms (pg)/mL (147 picomoles [pmol]/liter [L]) is confirmatory
  • Male subjects with female partners of child bearing potential must comply with one of the following contraception requirements from the time of first dose of study medication until completion of the follow-up visit: (a.) Vasectomy with documentation of azoospermia; (b.) Male condom plus partner use of one of the following contraceptive options: Contraceptive subdermal implant that meets the effectiveness criteria of a <1% rate of failure per year, as stated in the product label, Intrauterine device or intrauterine system that meets the standard operating procedure (SOP) effectiveness criteria including a <1% rate of failure per year, as stated in the product label, Oral Contraceptive either combined or progestogen alone, Injectable progestogen, Contraceptive vaginal ring, Percutaneous contraceptive patches, Occlusive cap (female diaphragm or cervical/vault cap) with a vaginal spermicide (foam, gel, cream or suppository). 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.
  • Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in the protocol.
  • Additional Inclusion Criteria - Healthy Volunteers: Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring.
  • Additional Inclusion Criteria - Healthy Volunteers: A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the investigator in consultation with the Medical Monitor if required agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
  • Additional Inclusion Criteria - Healthy Volunteers: aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase and bilirubin <=1.5 upper limit of normal (ULN) (isolated bilirubin >1.5 ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
  • Additional Inclusion Criteria - Patients: Subject medically diagnosed with systemic amyloidosis
  • Additional Inclusion Criteria - Patients: serum amyloid P component (SAP) scan identifying amyloid at any anatomical site, including subset of patients with moderate-large amyloid load in the liver
  • Additional Inclusion Criteria - Patients: Up to and including New York Heart Association (NYHA) class 2 with a stable clinical cardiac status 12 weeks prior to screening
  • Additional Inclusion Criteria - Patients: For Amyloid Light-chain (AL) amyloidosis patients, >=12 months post-chemotherapy with a stable free light chain (FLC) ratio in the preceding 4 months
  • Additional Inclusion Criteria - Patients: estimated glomerular filtration rate (eGFR) >50 mL/minute
  • Additional Inclusion Criteria - Patients: Alanine amino transferase (ALT) <=3x upper limit of normal (ULN) and bilirubin <=1.5x ULN (isolated bilirubin >1.5 xULN is acceptable if bilirubin was fractionated and direct bilirubin <35%), irrespective of alkaline phosphatase (ALP) level
  • Additional Inclusion Criteria - Patients: Subject is ambulant and capable of attending the clinical unit

Exclusion Criteria:

  • Prohibited medication
  • History of regular alcohol consumption within 6 months of the study defined as: For United Kingdom (UK )sites - healthy volunteers: 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 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
  • History of sensitivity to any of the study medications, or metabolite 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 (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.
  • A positive pre-study drug/alcohol screen
  • A positive test for human immunodeficiency virus (HIV) antibody
  • Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 84 days
  • 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). Prior to Part A for subjects participating in Parts A and B
  • Exposure to more than four new chemical entities within 12 months prior to the first dosing day Lactating females
  • Poor or unsuitable venous access
  • Additional Exclusion Criteria - Healthy Volunteer: Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
  • Additional Exclusion Criteria - Healthy Volunteer: corrected QT interval using Fridericia's formula (QTcF) >450 milliseconds (msec) from a mean of triplicate readings triplicate readings taken 5 minutes apart
  • Additional Exclusion Criteria - Patients: Subject with mean QTcF of >480 msec from a mean of triplicate readings
  • Additional Exclusion Criteria - Patients: First degree heart block deemed to require pacing; Second degree atrioventricular (AV) block Mobitz Type II; Trifasicular block; Ventricular tachyarrthymias - with the exception of bundle branch block, atrial fibrillation & first degree heart block not requiring pacing, or second degree AV block Mobitz Type I
  • Additional Exclusion Criteria - Patients: 24 hour proteinuria >=5 g
  • Additional Exclusion Criteria - Patients: A syncopal episode, of any causation, within 4 weeks of screening
  • Additional Exclusion Criteria - Patients: Average systolic blood pressure (SBP) <=90 millimeter of mercury (mmHg) at Screening from triplicate readings
  • Additional Exclusion Criteria - Patients: Implantable cardiac defibrillator (ICD)
  • Additional Exclusion Criteria - Patients: Evidence of severe cardiac dysfunction within 12 months of screening, as diagnosed by a cardiologist, using Echocardiography or cardiac magnetic resonance imaging (MRI) i.e. markedly impaired ejection fraction (EF) (EF < 50% for cardiac amyloidosis patients), or cardiac imaging parameters of severe diastolic dysfunction (grade 3 or 4)
  • Additional Exclusion Criteria - Patients: Anaemia hemoglobin <9 g/deciliter (dL)
  • Additional Exclusion Criteria - Patients: Uncontrolled hypertension in a known hypertensive patient, or fulfilling diagnostic criteria of essential hypertension at screening
  • Additional Exclusion Criteria - Patients: Presence of any co-morbid condition (e.g. severe or unstable coronary artery disease; moderate to severe chronic obstructive pulmonary disease) which in the opinion of the investigator would increase the potential risk to the subject
  • Additional Exclusion Criteria - Patients: Non-amyloidosis causes of chronic liver disease (with the exception of Gilbert's syndrome or clinically asymptomatic gallstones)
  • Additional Exclusion Criteria - Patients: Diabetes Mellitus
  • Additional Exclusion Criteria - Patients: Glycosuria at Screening
  • Additional Exclusion Criteria - Patients: Urine power of Hydrogen (pH) <6.0 at screening
  • Additional Exclusion Criteria - Patients: Hypoalbuminemia (<30 nanomoles [nmol]/L)
  • Additional Exclusion Criteria - Patients: Hypophosphatemia (less than 0.8 millimoles [mmol]/L)
  • Additional Exclusion Criteria - Patients: Prothombin time >1.5xULN
  • Additional Exclusion Criteria - Patients: Malabsorption syndrome of any aetiology
  • Additional Exclusion Criteria - Patients: Compassionate use of CPHPC (GSK2315698) or participation in a separate clinical trial involving CPHPC within 3 months of screening
  • Additional Exclusion Criteria - Patients: Currently taking any of the following esterase-cleaved prodrug medications: cerebyx, aquavan, spectracef, hepsera, viread
  • Additional Exclusion Criteria - Patients: Anticoagulation therapy within 4 weeks of Screening
  • Additional Exclusion Criteria - Patients: Currently receiving or have received within 12 weeks of screening immunosuppressive anti-cytokine monoclonal antibodies (e.g. anti-tumor necrosis factor [anti-TNF] or anti-interleukin 1[anti-IL-1]), disease modifying drugs (e.g. methotrexate, gold or cyclophosphamide), or high-dose infusional steroids (e.g. methylprednisolone), with the exception of low-dose maintenance oral corticosteroids (e.g. <=30 milligrams (mg) prednisolone per day)

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): NCT02603172


Locations
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United Kingdom
GSK Investigational Site
Cambridge, United Kingdom, CB2 2GG
Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
  Study Documents (Full-Text)

Documents provided by GlaxoSmithKline:
Study Protocol  [PDF] November 30, 2016
Statistical Analysis Plan  [PDF] November 9, 2017

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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02603172    
Other Study ID Numbers: 201664
2015-003088-13 ( EudraCT Number )
First Posted: November 11, 2015    Key Record Dates
Results First Posted: September 23, 2019
Last Update Posted: September 23, 2019
Last Verified: August 2019
Keywords provided by GlaxoSmithKline:
GSK3039294
GSK2315698
systemic amyloidosis
CPHPC
dose-escalation
Additional relevant MeSH terms:
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Amyloidosis
Proteostasis Deficiencies
Metabolic Diseases