The study is intended to evaluate whether monthly repeated courses of administration of GSK2315698 followed by GSK2398852 is associated with a reduction in cardiac amyloid load in patients with cardiac amyloidosis, monitored by cardiac magnetic resonance imaging (CMR) and echocardiography (ECHO), and whether this is associated with an improvement in cardiac function. Cohort 1 is transthyretin cardiomyopathy (ATTR-CM) , cohort 2 is patients with immunoglobulin light chain (AL) systemic amyloidosis at greater than 6 months post chemotherapy, cohort 3 newly diagnosed AL systemic amyloidosis undergoing chemotherapy. Primary objectives for the study are assessment of reduction in cardiac amyloid load after repeated administrations of Anti-SAP treatment as evaluated by CMR in all study groups and assessment of safety \& tolerability of repeated administration of Anti-SAP treatment, including compatibility with chemotherapy treatment in patients with AL systemic amyloidosis. This is an open label, non-randomised, three-group, monthly repeat Anti-SAP treatment study in systemic amyloidosis patients with cardiac dysfunction caused by cardiac amyloidosis. Subjects will receive up to 6 courses of Anti-SAP treatment. Maximum total duration for a subject in the study is approximately 18 months.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
7
20mg/hour, IV (in the vein) for up to 72hours followed by 60mg three times daily subcutaneous injection for 11 days. Number of cycles: up to 6. Dose level and frequency adjusted according to renal function
Up to 1200mg, IV divided over days 1 and 3. Number of cycles: up to 6. Dose level adjusted based on tolerability.
GSK Investigational Site
Boston, Massachusetts, United States
GSK Investigational Site
Cambridge, United Kingdom
GSK Investigational Site
London, United Kingdom
Change From Baseline in Left Ventricular (LV) Mass Over Time up to 8-week Follow-up
Left ventricular mass was measured by Cardiac Magnetic Resonance (CMR) imaging to assess reduction in cardiac amyloid load after repeated administration of anti-SAP treatment. Each CMR imaging session took approximately 45-60 minutes, with a maximum scan time inside of the scanner of 90 minutes. Baseline was considered as the latest assessment prior to first administration of either study drug, i.e. CPHPC or anti-SAP mAb. Change from Baseline was calculated as post-dose visit value minus Baseline value. Safety Population comprised of all participants who received at least one dose of study treatment (any dose of CPHPC \[GSK2315698\] or anti-SAP mAb \[GSK2398852\]).
Time frame: Baseline (Day -1) and Session 2 Day 24, Session 3 Day 24, Session 4 Day 24, Session 5 Day 24, 8 Weeks Follow-up
Number of Participants With Any On-treatment Adverse Events (AEs)
AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Number of participants with any on-treatment AEs are presented.
Time frame: Up to 56 days after the last dosing session (up to 265 days)
Number of Participants With Any Serious Adverse Events (SAEs)
AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, events associated with liver injury and impaired liver function, or any other situation according to medical or scientific judgment were categorized as SAE. Number of participants with any SAEs during study are presented.
Time frame: Up to the end of study (Up to 369 days)
Number of Participants With Abnormal Hematology Values
Blood samples were collected for assessment of hematology parameters, which included platelet count, hemoglobin, hematocrit, erythrocytes, reticulocyte count, Mean corpuscular volume (MCV), Mean corpuscular hemoglobin (MCH), Mean corpuscular hemoglobin concentration (MCHC), neutrophils, lymphocytes, monocytes, eosinophils, leukocytes and basophils. Abnormal laboratory results are categorized as high, low or normal with respect to their normal ranges. Data for worst case post Baseline is presented. Participants having both High and Low values from Normal Ranges at any post-baseline visits for any parameter was counted in both the High and Low categories.
Time frame: Up to the end of study (Up to 369 days)
Number of Participants With Abnormal Clinical Chemistry Values
Blood samples were collected for assessment of clinical chemistry parameters, which included aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), urea, creatinine, glucose, chloride, creatinine kinase, potassium, sodium, calcium, total carbon dioxide (CO2), urate, total and direct bilirubin, total protein and albumin. Abnormal laboratory results are categorized as high, low or normal with respect to their normal ranges. Data for worst case post Baseline is presented. Participants having both High and Low values from Normal Ranges at any post-baseline visits for any parameter was counted in both the High and Low categories.
Time frame: Up to the end of study (Up to 369 days)
Number of Participants With Abnormal Urinalysis Results
Urine samples were collected to assess potential of hydrogen (pH), specific gravity, albumin excretion rate, creatinine excretion rate and protein excretion rate. Abnormal urinalysis results are categorized as high, low or normal with respect to their normal ranges. Data for worst case post Baseline is presented. Participants having both High and Low values from Normal Ranges at any post-baseline visits for any parameter was counted in both the High and Low categories.
Time frame: Up to the end of study (Up to 369 days)
Number of Participants With Abnormal Urinalysis Results for Character Parameters
Urine samples were collected to assess character parameters which included Cellular Casts, Erythrocytes, Glucose, Ketones, Leukocytes and Occult Blood. Number of participants with abnormal urinalysis results are presented. Data for worst case post Baseline is presented.
Time frame: Up to the end of study (Up to 369 days)
Number of Participants With Body Temperature Shifts From Baseline Relative to Potential Clinical Importance (PCI) Criteria
Vital signs including body temperature was measured after participants rested in semi-supine position for at least 5 minutes. Number of participants with shifts in body temperature from Baseline to worst case post Baseline relative to PCI criteria have been presented. PCI results were categorized as to high, to low and to normal/no change with reference to PCI criteria. PCI criteria for body temperature was: high: \>37.5 degree Celsius; low: not applicable.
Time frame: Up to the end of study (Up to 369 days)
Number of Participants With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Shifts From Baseline Relative to PCI Criteria
Vital signs including SBP and DBP were measured after participants rested in semi-supine position for at least 5 minutes. Number of participants with shifts in SBP and DBP from baseline to worst case post baseline relative to PCI criteria have been presented. PCI results were categorized as to high, to low and to normal/no change with reference to PCI criteria. PCI criteria for SBP was: high: \>180 millimeter of mercury (mmHg); low: \<90 mmHg. PCI criteria for DBP was: high: \>110 mmHg; low: \<30 mmHg.
Time frame: Up to the end of study (Up to 369 days)
Number of Participants With Pulse Rate Shifts From Baseline Relative to PCI Criteria
Vital signs including pulse rate were measured after participants rested in semi-supine position for at least 5 minutes. Number of participants with shifts in pulse rate from baseline to worst case post baseline relative to PCI criteria have been presented. PCI results were categorized as to high, to low and to normal/no change with reference to its PCI criteria. PCI criteria for pulse rate was: high: \>140 beats per minute (bpm); low: \<35 bpm.
Time frame: Up to the end of study (Up to 369 days)
Number of Participants With Abnormal Electrocardiogram (ECG) Findings
Twelve-lead ECGs were performed during the study using an automated ECG machine. The number of participants with worst case post-Baseline abnormal ECG findings were reported and categorized as abnormal-clinically significant and abnormal-not clinically significant.
Time frame: Up to the end of study (Up to 369 days)
Number of Participants With Abnormalities During Cardiac Monitoring
Lead II telemetry and cardiac monitoring devices were used for electrical cardiac monitoring during the study. The number of participants with worst case post-Baseline abnormalities during cardiac monitoring as per investigator's assessment have been reported and categorized as Abnormal-clinically significant and Abnormal-not clinically significant.
Time frame: Up to the end of study (Up to 369 days)
Number of Participants for Which Unscheduled Echocardiography (ECHO) Was Performed for Safety Reasons
Echocardiography was performed by a qualified echocardiographer or cardiologist during the study. Number of participants with unscheduled echocardiograms performed for safety reasons have been presented.
Time frame: Up to the end of study (Up to 369 days)
Number of Participants With Skin Rashes
Skin rash was an event of special interest. Only Rashes that were associated with study drug were categorised as Rash for Common Terminology Criteria for Adverse Events (CTCAE) and are presented. Number of participants with on-treatment skin rash AEs are presented.
Time frame: Up to 56 days after the last dosing session (up to 265 days)
Number of Participants With Skin Rashes Classified Using CTCAE
Skin rash was an event of special interest. All the events of rashes were graded for their severity using CTCAE version 4.0 . Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life threatening, Grade 5: death. Higher the grade, more severe the symptoms. Only Rashes that were associated with study drug were categorised as Rash for CTCAE and are presented here. Number of participants with skin rashes classified by their maximum grade are presented.
Time frame: Up to 56 days after the last dosing session (up to 265 days)
Number of Participants With Abnormalities in Histopathological Examination of Skin Biopsies
Skin biopsy samples were collected for histopathological examination only on any rash development (\>= Grade 1) as decided by clinical judgment of the Investigator and/or dermatologist. Number of participants with abnormalities in histopathological examination of skin biopsies are presented.
Time frame: Up to the end of study (Up to 369 days)
Number of Participants With Abnormalities in Immunohistochemical Examination of Skin Biopsies
Skin biopsy samples were collected for immunohistochemical examination only on any rash development (\>= Grade 1) as decided by clinical judgment of the Investigator and/or dermatologist. Number of participants with abnormalities in immunohistochemical examination of skin biopsies are presented.
Time frame: Up to the end of study (Up to 369 days)
Number of Participants With Abnormalities in Histopathological Examination of Blood Biomarkers
Blood samples were to be collected along with each skin biopsy sample for histopathological examination of blood biomarkers only on any rash development (\>= Grade 1) as decided by clinical judgment of the Investigator and/or dermatologist.
Time frame: Up to the end of study (Up to 369 days)
Number of Participants With Abnormalities in Immunohistochemical Examination of Blood Biomarkers
Blood samples were to be collected along with each skin biopsy sample for immunohistochemical examination of blood biomarkers only on any rash development (\>= Grade 1) as decided by clinical judgment of the Investigator and/or dermatologist.
Time frame: Up to the end of study (Up to 369 days)
Change From Baseline in Plasma Cytokines Over Time
Blood samples were collected for assessment of plasma cytokines biomarkers which included Tumor Necrosis Factor (TNF), Interleukin 1 beta (IL-1 beta), IL-6, IL-10, Interferon gamma (INF gamma), IL-12, IL-13, IL-2, IL-4 and IL-8. Baseline was considered as the latest assessment prior to first administration of either study drug, i.e. CPHPC or anti-SAP mAb. Change from Baseline was calculated as post-dose visit value minus Baseline value. Absolute values below the lower limit of quantification (LLQ) were imputed with half the LLQ and those above the upper limit of quantification (ULQ) were imputed with the ULQ.
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Time frame: Baseline (Day -1) and Session 1: Day 1 (predose, 1,3,6 hours), Day 2, Day 3 (predose, 1,3,6 hours), Day 4, Day 5; Session 2 to 6: Day -2, Day 1 (predose, 1,3,6 hours), Day 2, Day 3 (predose, 1,3,6 hours), Day 4, Day 5
Change From Baseline in Fluid Phase Complement Marker-Complement 3 (C3) Over Time
Blood samples were collected for assessment of Fluid Phase Complement Markers which included complement 3 (C3). Baseline was considered as the latest assessment prior to first administration of either study drug, i.e. CPHPC or anti-SAP mAb. Change from Baseline was calculated as post-dose visit value minus Baseline value.
Time frame: Baseline (Day -1) and Session 1 to 6: Day 1 (predose, 2,4,8 hours), Day 2, Day 3 (predose, 2,4,8 hours), Day 5, Day 6
Change From Baseline in Fluid Phase Complement Marker-Complement 4 (C4) Over Time
Blood samples were collected for assessment of Fluid Phase Complement Markers which included complement 4 (C4). Baseline was considered as the latest assessment prior to first administration of either study drug, i.e. CPHPC or anti-SAP mAb. Change from Baseline was calculated as post-dose visit value minus Baseline value.
Time frame: Baseline (Day -1) and Day 2, Day 5, Day 6
Change From Baseline in Fluid Phase Complement Marker-Total Complement (CH50) Over Time
Blood samples were collected for assessment of Fluid Phase Complement Markers which included total complement (CH50). Baseline was considered as the latest assessment prior to first administration of either study drug, i.e. CPHPC or anti-SAP mAb. Change from Baseline was calculated as post-dose visit value minus Baseline value.
Time frame: Baseline (Day -1) and Session 1 to 6: Day 1 (predose, 2,4,8 hours), Day 2, Day 3 (predose, 2,4,8 hours), Day 5, Day 6
Change From Baseline in Inflammatory Biomarkers Over Time
Blood samples were collected for assessment of inflammatory biomarkers which included C-Reactive protein (CRP), high-sensitivity C-reactive protein (hsCRP), serum amyloid A protein (SAA). Baseline was considered as the latest assessment prior to first administration of either study drug, i.e. CPHPC or anti-SAP mAb. Change from Baseline was calculated as post-dose visit value minus Baseline value.
Time frame: Baseline (Day -1) and Session 1 to 6: Day 1 (predose, 2,4,8 hours), Day 2, Day 3 (predose, 2,4,8 hours), Day 5, Day 6
Maximum Concentration (Cmax) of GSK2398852
Blood samples were collected for evaluation of Pharmacokinetic (PK) parameters including Cmax at indicated time points. Geometric mean and geometric coefficient of variation of Cmax is presented.
Time frame: Session 1 to 6: Day 1 (Pre-dose, 6, 8, 12 hour), Day 2, Day 3 (Pre-dose and at 6 hour), Day 4, Day 7 and Day 11
Time Associated With Cmax (Tmax) of GSK2398852
Blood samples were collected for evaluation of PK parameters including Tmax at indicated time points. Median and full range of Tmax is presented.
Time frame: Session 1 to 6: Day 1 (Pre-dose, 6, 8, 12 hour), Day 2, Day 3 (Pre-dose and at 6 hour), Day 4, Day 7 and Day 11
Area Under the Plasma Concentration-time Curve From Time Zero to Time t (AUC 0-t) of GSK2398852
Blood samples were collected for evaluation of PK parameters including AUC 0-t at indicated time points. Geometric mean and geometric coefficient of variation of AUC0-t is presented.
Time frame: Session 1 to 6: Day 1 (Pre-dose, 6, 8, 12 hour), Day 2, Day 3 (Pre-dose and at 6 hour), Day 4, Day 7 and Day 11
Cmax of GSK2315698 for Newly Diagnosed Mayo Stage II/IIIa AL Amyloidosis Participants
Blood samples were planned to be collected for evaluation of PK parameters including Cmax at indicated time points for GSK2315698 for newly diagnosed Mayo stage II/IIIa AL Amyloidosis participants. However, no participant was enrolled in 'Group 3: Newly diagnosed Mayo stage II/IIIa AL participants.'
Time frame: Day 1: Pre-dose; Day 2 (pre-dose and 2 hours post-dose); Day 3: Pre-dose in each session (each session of 24 days)
Tmax of GSK2315698 for Newly Diagnosed Mayo Stage II/IIIa AL Amyloidosis Participants
Blood samples were planned to be collected for evaluation of PK parameters including Tmax at indicated time points for GSK2315698 for newly diagnosed Mayo stage II/IIIa AL Amyloidosis participants. However, no participant was enrolled in 'Group 3: Newly diagnosed Mayo stage II/IIIa AL participants'.
Time frame: Day 1: Pre-dose; Day 2: pre-dose and 2 hours post-dose; Day 3: Pre-dose in each session (each session of 24 days)
AUC 0-t of GSK2315698 for Newly Diagnosed Mayo Stage II/IIIa AL Amyloidosis Participants
Blood samples were planned to be collected for evaluation of PK parameters including AUC0-t at indicated time points for GSK2315698 for newly diagnosed Mayo stage II/IIIa AL Amyloidosis participants. However, no participant was enrolled in 'Group 3: Newly diagnosed Mayo stage II/IIIa AL participants'.
Time frame: Day 1: Pre-dose; Day 2 (pre-dose and 2 hours post-dose); Day 3: Pre-dose in each session (each session of 24 days)
Change From Baseline in Global Longitudinal Strain (GLS) by CMR
Global Longitudinal Strain was measured by CMR at indicated time points. GLS included feature tracking and tagging by CMR. Baseline was considered as the latest assessment prior to first administration of either study drug, i.e. CPHPC or anti-SAP mAb. Change from Baseline was calculated as post-dose visit value minus Baseline value.
Time frame: Baseline (Day -1) and Session 2 to 5: Day 24; 8 week follow-up; 6 months follow-up
Change From Baseline in GLS by ECHO
Global Longitudinal Strain was measured by ECHO at indicated time points. GLS included speckle tracking by ECHO. Baseline was considered as the latest assessment prior to first administration of either study drug, i.e. CPHPC or anti-SAP mAb. Change from Baseline was calculated as post-dose visit value minus Baseline value.
Time frame: Baseline (Day -1) and Session 1 to 6: Day 24; 8 week follow-up; 6 months follow-up
Change From Baseline in LV Twist Over Time
LV twist was measured by CMR at indicated time points. Baseline was considered as the latest assessment prior to first administration of either study drug, i.e. CPHPC or anti-SAP mAb. Change from Baseline was calculated as post-dose visit value minus Baseline value.
Time frame: Baseline (Day -1) and Session 2 to 5: Day 24; 8 week follow-up; 6 months follow-up
Change From Baseline in Stroke Volume (SV) by CMR
Stroke volume is the amount of blood ejected by the left ventricle in one contraction. SV was measured by CMR at indicated time points. Baseline was considered as the latest assessment prior to first administration of either study drug, i.e. CPHPC or anti-SAP mAb. Change from Baseline was calculated as post-dose visit value minus Baseline value.
Time frame: Baseline (Day -1) and Session 2 to 5: Day 24; 8 week follow-up; 6 months follow-up
Change From Baseline in SV by ECHO
Stroke volume is the amount of blood ejected by the left ventricle in one contraction. SV was measured by ECHO at indicated time points. Baseline was considered as the latest assessment prior to first administration of either study drug, i.e. CPHPC or anti-SAP mAb. Change from Baseline was calculated as post-dose visit value minus Baseline value.
Time frame: Baseline (Day -1) and Session 1 to 6: Day 24; 8 week follow-up; 6 months follow-up
Change From Baseline in Left Ventricular Ejection Fraction (EF) by CMR
Left ventricular ejection fraction is a measurement of the percentage of blood leaving the heart each time it contracts. EF was measured by CMR at indicated time points. Baseline was considered as the latest assessment prior to first administration of either study drug, i.e. CPHPC or anti-SAP mAb. Change from Baseline was calculated as post-dose visit value minus Baseline value.
Time frame: Baseline (Day -1) and Session 2 to 5: Day 24; 8 week follow-up; 6 months follow-up
Change From Baseline in Left Ventricular EF by ECHO
Left ventricular ejection fraction is a measurement of the percentage of blood leaving the heart each time it contracts. EF was measured by ECHO at indicated time points. Baseline was considered as the latest assessment prior to first administration of either study drug, i.e. CPHPC or anti-SAP mAb. Change from Baseline was calculated as post-dose visit value minus Baseline value.
Time frame: Baseline (Day -1) and Session 1 to 6: Day 24; 8 week follow-up; 6 months follow-up
Change From Baseline in Left Ventricle End Diastolic Volume (EDV) by CMR
Left ventricle EDV is the volume of blood in the left ventricle at end load or filling in (diastole) or the amount of blood in the ventricles just before systole. EDV was measured by CMR at indicated time points. Baseline was considered as the latest assessment prior to first administration of either study drug, i.e. CPHPC or anti-SAP mAb. Change from Baseline was calculated as post-dose visit value minus Baseline value.
Time frame: Baseline (Day -1) and Session 2 to 5: Day 24; 8 week follow-up; 6 months follow-up
Change From Baseline in Left Ventricle End Diastolic Volume (EDV) by ECHO
Left ventricle EDV is the volume of blood in the left ventricle at end load or filling in (diastole) or the amount of blood in the ventricles just before systole. EDV was measured by ECHO at indicated time points. Baseline was considered as the latest assessment prior to first administration of either study drug, i.e. CPHPC or anti-SAP mAb. Change from Baseline was calculated as post-dose visit value minus Baseline value.
Time frame: Baseline (Day -1) and Session 1 to 6: Day 24; 8 week follow-up; 6 months follow-up
Change From Baseline in Ratio of Mitral Peak Velocity of Early Filling to Early Diastolic Mitral Annual Velocity (E/e' Ratio)
E/e' ratio was measured by ECHO at indicated time points. It had 2 separate measurements: lateral and septal. Baseline was considered as the latest assessment prior to first administration of either study drug, i.e. CPHPC or anti-SAP mAb. Change from Baseline was calculated as post-dose visit value minus Baseline value.
Time frame: Baseline (Day -1) and Session 1 to 6: Day 24; 8 week follow-up; 6 months follow-up