Clinical Trial: Multiple Treatment Session Study to Assess GSK2398852 Administered Following and Along With GSK2315698

Study Status: Not yet recruiting
Recruit Status: Not yet recruiting
Study Type: Interventional

Official Title: A Multiple Treatment Session, Open Label Phase 2 Clinical Study of GSK2398852 Administered Following and Together With GSK2315698 in Cohorts of Patients With Cardiac Amyloidosis<

Brief Summary: 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.

Detailed Summary:
Sponsor: GlaxoSmithKline

Current Primary Outcome:

  • Change from baseline in left ventricular (LV) mass over time up to 8-week follow-up [ Time Frame: Baseline and Up to 8 Weeks follow-up ]
    The LV mass will be quantified using serial CMR.
  • Number of subjects with any adverse events (AEs) and any serious adverse events (SAEs) [ Time Frame: Continuous throughout the study, collected from the start of Study Treatment up to approximately 30 week ]
    An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as 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, is a congenital anomaly/birth defect, other situations judged by physician, is associated with liver injury and impaired liver function.
  • Number of subjects with abnormal haematology values [ Time Frame: At scheduled intervals up to approximately 30 weeks ]
    Hematology parameters included platelet count, red blood cell (RBC) count, hemoglobin, hematocrit, white blood cell (WBC) count, reticulocyte count, Mean corpuscular volume (MCV), Mean corpuscular hemoglobin (MCH), Mean corpuscular hemoglobin concentration (MCHC), neutrophils, lymphocytes, monocytes, eosinophils and basophils.
  • Number of subjects with abnormal clinical chemistry values [ Time Frame: At scheduled intervals up to approximately 30 weeks ]
    Clinical chemistry parameters i

    Original Primary Outcome:

    • Change from baseline in left ventricular (LV) mass over time up to 8-week follow-up [ Time Frame: Baseline and Up to 8 Weeks follow-up ]
      The LV mass will be quantified using serial CMR.
    • Number of subjects with any adverse events (AEs) and any serious adverse events (SAEs) [ Time Frame: Continuous throughout the study, collected from the start of Study Treatment up to approximately 30 week ]
    • Number of subjects with abnormal haematology values [ Time Frame: At scheduled intervals up to approximately 30 weeks ]
    • Number of subjects with abnormal clinical chemistry values [ Time Frame: At scheduled intervals up to approximately 30 weeks ]
    • Number of subjects with abnormal urinalysis results [ Time Frame: At scheduled intervals up to approximately 30 weeks ]
    • Body temperature as a measure of safety [ Time Frame: At scheduled intervals up to approximately 30 weeks ]
    • Systolic and diastolic blood pressure as a measure of safety [ Time Frame: At scheduled intervals up to approximately 30 weeks ]
      Blood pressure will include systolic and diastolic blood pressure
    • Pulse rate as a measure of safety [ Time Frame: At scheduled intervals up to approximately 30 weeks ]
    • 12-lead electrocardiogram (ECG) as a measure of safety [ Time Frame: At scheduled intervals up to approximately 30 weeks ]
    • Number of subjects with abnormalities during cardia

      Current Secondary Outcome:

      • Histopathological examination of skin biopsies [ Time Frame: Continuous throughout the study, collected from the start of Study Treatment and until the follow-up contact approximately 30 weeks ]
        Histopathological examination of skin biopsies will be performed only on any rash development (that is >= Grade 1)
      • Histopathological examination of skin biopsies + blood biomarkers [ Time Frame: Continuous throughout the study, collected from the start of Study Treatment and until the follow-up contact approximately 30 weeks ]
        Histopathological examination of skin biopsies will be performed only on any rash development (that is >= Grade 1). Each biopsy will be paired with blood sample
      • Immunohistochemical examination of skin biopsies [ Time Frame: Continuous throughout the study, collected from the start of Study Treatment and until the follow-up contact approximately 30 weeks ]
        Immunohistochemical examination of skin biopsies will be performed only on any rash development (that is >= Grade 1).
      • Immunohistochemical examination of blood biomarkers [ Time Frame: Continuous throughout the study, collected from the start of Study Treatment and until the follow-up contact approximately 30 weeks ]
        Immunohistochemical examination of skin biopsies will be performed only on any rash development (that is >= Grade 1). Each biopsy will be paired with blood sample.
      • Changes in circulating biomarkers [ Time Frame: Baseline and Approximately 30 weeks ]
        Circulating biomarkers will include complement pathway components, acute phase proteins and cytokines
      • Change in Global Longitudinal Strain (GLS) over time [ Time Frame: Baseline and Up to 8 Weeks follow-up ]
        GLS will be assessed using automated speckle-tracking echocardiography for detecting and quantifying subtle disturbances in LV systolic function.
      • Change in left ventricular (LV) twist over time [ Time Frame: Baseline and Up to 8 Weeks follow-up ]
        Speckle tracking echocardiography will be used for measuring parameters of cardiac mechanics: LV twist
      • Change in Stroke Volume (SV) over time [ Time Frame: Baseline and Up to 8 Weeks follow-up ]
        Stroke volume is the amount of blood ejected by the left ventricle in one contraction
      • Chnge in ejection fraction over time [ Time Frame: Baseline and Up to 8 Weeks follow-up ]
        Ejection fraction is a measurement of the percentage of blood leaving your heart each time it contracts.
      • Change in End Diastolic Volume (EDV) over time [ Time Frame: Baseline and Up to 8 Weeks follow-up ]
        Volume of blood in the right and/or left ventricle at end load or filling in (diastole) or the amount of blood in the ventricles just before systole.
      • Change in ratio of mitral peak velocity of early filling to early diastolic mitral annual velocity. [ Time Frame: Baseline and Up to 8 Weeks follow-up ]
        Change in ratio will be calculated for mitral peak velocity of early filling to early diastolic mitral annual velocity.
      • Maximum concentration (Cmax) of GSK2315698 and GSK2398852 [ Time Frame: Approximately 30 weeks ]
        Blood samples will be collected at pre-dose, 6 h, 8h. 12h, On Day 2, at pre-dose and at 6h on Day 3; Day 4; Day 7 and on Day 11
      • The time associated with Cmax (Tmax) of GSK2315698 and GSK2398852 [ Time Frame: Approximately 30 weeks ]
        Blood samples will be collected at pre-dose, 6 h, 8h. 12h, On Day 2, at pre-dose and at 6h on Day 3; Day 4; Day 7 and on Day 11
      • Area under the concentration-time profile (AUC) of GSK2315698 and GSK2398852 [ Time Frame: Approximately 30 weeks ]
        Blood samples will be collected at pre-dose, 6 h, 8h. 12h, On Day 2, at pre-dose and at 6h on Day 3; Day 4; Day 7 and on Day 11


      Original Secondary Outcome:

      • Histopathological examination of skin biopsies [ Time Frame: Continuous throughout the study, collected from the start of Study Treatment and until the follow-up contact approximately 30 weeks ]
        Histopathological examination of skin biopsies will be performed only on any rash development (that is >= Grade 1)
      • Histopathological examination of skin biopsies + blood biomarkers [ Time Frame: Continuous throughout the study, collected from the start of Study Treatment and until the follow-up contact approximately 30 weeks ]
        Histopathological examination of skin biopsies will be performed only on any rash development (that is >= Grade 1). Each biopsy will be paired with blood sample
      • Immunohistochemical examination of skin biopsies [ Time Frame: Continuous throughout the study, collected from the start of Study Treatment and until the follow-up contact approximately 30 weeks ]
        Immunohistochemical examination of skin biopsies will be performed only on any rash development (that is >= Grade 1).
      • Immunohistochemical examination of blood biomarkers [ Time Frame: Continuous throughout the study, collected from the start of Study Treatment and until the follow-up contact approximately 30 weeks ]
        Immunohistochemical examination of skin biopsies will be performed only on any rash development (that is >= Grade 1). Each biopsy will be paired with blood sample.
      • Changes in circulating biomarkers [ Time Frame: Baseline and Approximately 30 weeks ]
        Circulating biomarkers will include complement pathway components, acute phase proteins and cytokines
      • Change in Global Longitudinal Strain (GLS) over time [ Time Frame: Baseline and Up to 8 Weeks follow-up ]
      • Change in left ventricular (LV) twist over time [ Time Frame: Baseline and Up to 8 Weeks follow-up ]
      • Change in Stroke Volume (SV) over time [ Time Frame: Baseline and Up to 8 Weeks follow-up ]
        Stroke volume is the amount of blood ejected by the left ventricle in one contraction
      • Chnge in ejection fraction over time [ Time Frame: Baseline and Up to 8 Weeks follow-up ]
        Ejection fraction is a measurement of the percentage of blood leaving your heart each time it contracts.
      • Change in End Diastolic Volume (EDV) over time [ Time Frame: Baseline and Up to 8 Weeks follow-up ]
        Volume of blood in the right and/or left ventricle at end load or filling in (diastole) or the amount of blood in the ventricles just before systole.
      • Change in ratio of mitral peak velocity of early filling to early diastolic mitral annual velocity. [ Time Frame: Baseline and Up to 8 Weeks follow-up ]
      • Maximum concentration (Cmax) of GSK2315698 and GSK2398852 [ Time Frame: Approximately 30 weeks ]
      • The time associated with Cmax (Tmax) of GSK2315698 and GSK2398852 [ Time Frame: Approximately 30 weeks ]
      • Area under the concentration-time profile (AUC) of GSK2315698 and GSK2398852 [ Time Frame: Approximately 30 weeks ]


      Information By: GlaxoSmithKline

      Dates:
      Date Received: June 27, 2016
      Date Started: June 20, 2017
      Date Completion: September 21, 2020
      Last Updated: May 2, 2017
      Last Verified: May 2017