ClinicalTrials.gov
ClinicalTrials.gov Menu

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

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: NCT03044353
Recruitment Status : Suspended (Pending data review.)
First Posted : February 7, 2017
Last Update Posted : August 23, 2018
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

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.

Condition or disease Intervention/treatment Phase
Amyloidosis Drug: GSK2315698 (CPHPC) Biological: GSK2398852 (anti-SAP mAb) Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : July 10, 2017
Estimated Primary Completion Date : September 23, 2021
Estimated Study Completion Date : September 23, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Amyloidosis

Arm Intervention/treatment
Experimental: GSK2135698+GSK2398852

GSK2315698 20mg/hour, IV (in the vein) for up to 72hours prior to GSK2398852 administration, followed by 60mg three times daily subcutaneous injection for 11 days. Dose level and frequency adjusted according to renal function.

GSK2398852 up to 1200mg, IV divided over days 1 and 3. Dose level adjusted based on tolerability. Number of cycles: up to 6.

Drug: GSK2315698 (CPHPC)
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

Biological: GSK2398852 (anti-SAP mAb)
Up to 1200mg, IV divided over days 1 and 3. Number of cycles: up to 6. Dose level adjusted based on tolerability.




Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. Number of subjects with abnormal clinical chemistry values [ Time Frame: At scheduled intervals up to approximately 30 weeks ]
    Clinical chemistry parameters included aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, lactate dehydrogenase (LDH), blood urea nitrogen (BUN), creatinine, glucose, chloride, creatinine kinase, potassium, sodium, calcium, total carbon dioxide, uric acid, total and direct bilirubin, total protein and albumin.

  5. Number of subjects with abnormal urinalysis results [ Time Frame: At scheduled intervals up to approximately 30 weeks ]
    Urinalysis parameters included specific gravity; pH; glucose, protein, blood and ketones by dipstick; microscopic examination; urine creatinine, albumina and protein.

  6. Body temperature as a measure of safety [ Time Frame: At scheduled intervals up to approximately 30 weeks ]
    Vital signs will be measured after subjects have been rested in semi-supine position for at least 5 minutes

  7. Systolic and diastolic blood pressure as a measure of safety [ Time Frame: At scheduled intervals up to approximately 30 weeks ]
    Vital signs will be measured after subjects have been rested in semi-supine position for at least 5 minutes

  8. Pulse rate as a measure of safety [ Time Frame: At scheduled intervals up to approximately 30 weeks ]
    Vital signs will be measured after subjects have been rested in semi-supine position for at least 5 minutes

  9. 12-lead electrocardiogram (ECG) as a measure of safety [ Time Frame: At scheduled intervals up to approximately 30 weeks ]
    Single 12-lead ECGs will be obtained at each time point during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTcF intervals.

  10. Number of subjects with abnormalities during cardiac monitoring [ Time Frame: At scheduled intervals up to approximately 30 weeks ]
    Lead II telemetry and Cardiac recording devices will be used for electrical cardiac monitoring

  11. ECHO as a measure of safety [ Time Frame: At scheduled intervals up to approximately 30 weeks ]
    ECHO will be performed by a qualified echocardiographer or Cardiologist

  12. Number of subjects with skin rashes classified using the Common Terminology Criteria for Adverse Events (CTCAE) [ Time Frame: Continuous throughout the study, collected from the start of Study Treatment and until the follow-up contact Approximately 30 weeks ]
    Rash is an event of special interest (EOSI). The CTCAE version 4.0 will be used for grading.

  13. Number of subjects in each Grade of skin rashes classified using the CTCAE [ Time Frame: Continuous throughout the study, collected from the start of Study Treatment and until the follow-up contact Approximately 30 weeks ]
    Rash is an event of special interest. The CTCAE version 4.0 will be used for grading.


Secondary Outcome Measures :
  1. 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)

  2. 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

  3. 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).

  4. 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.

  5. Changes in circulating biomarkers [ Time Frame: Baseline and Approximately 30 weeks ]
    Circulating biomarkers will include complement pathway components, acute phase proteins and cytokines

  6. 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.

  7. 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

  8. 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

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. 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

  14. 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



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.


Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Between 18 and 80 years of age inclusive, at the time of signing the informed consent.
  • Male and female.

Males:

Male subjects with female partners of child bearing potential must comply with the following contraception requirements from the time of first dose of study medication for a cycle of spermatogenesis following five terminal half-lives after the last dose of study medication. Vasectomy with documentation of azoospermia.

Male condom plus partner use of one of the contraceptive options below: Contraceptive subdermal implant, Intrauterine device or intrauterine system, Combined Oral Contraceptive or Injectable progestogen, Contraceptive vaginal ring, Percutaneous contraceptive patches .

This is an all-inclusive list of those methods that meet the following GlaxoSmithKline (GSK) definition of highly effective: having a failure rate of less than 1% per year when used consistently and correctly and, when applicable, in accordance with the product label. For non-product methods (e.g., male sterility), the investigator determines what is consistent and correct use. The GSK definition is based on the definition provided by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.

Females

A female subject is eligible to participate if she is not pregnant (as confirmed by a negative Urine human chorionic gonadotrophin [hCG] test), not lactating, and at least one of the following conditions applies:

• Non-reproductive potential defined as: Pre-menopausal females with one of the following: Documented tubal ligation; Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion; Hysterectomy; Documented Bilateral Oophorectomy.

Postmenopausal defined as: 60 years old; Twelve(12) months of spontaneous amenorrhea with an appropriate clinical profile, e.g. age appropriate, > 45 years, in the absence of hormone replacement therapy (HRT) or medical suppression of the menstrual cycle (e.g. leuprolide treatment) in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and oestradiol levels consistent with menopause (refer to laboratory reference ranges for confirmatory levels). Females on HRT and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.

• Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) (As mentioned in study protocol) from 30 days prior to the first dose of study medication and until 3 months after the last dose of study medication.

The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception

  • Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
  • Late-Gadolinum enhancement (LGE) on CMR indicative of cardiac amyloidosis
  • LV mass on CMR > 200 grams (g) Inclusion Criteria for Group 1
  • Transthyretin amyloid (ATTR) cardiomyopathy (CM)
  • Subjects with a diagnosis of hereditary ATTR amyloidosis should have a known amyloidogenic transthyretin (TTR) mutation demonstrated by genotyping AND is recognised to be primarily associated with cardiomyopathy AND one of the following: Definite histochemical identification of amyloid by Congo red staining and green birefringence in crossed polarised light in cardiac or other tissue biopsy and identification of TTR as the amyloid fibril protein either by immunohistochemistry or proteomic analysis.

Or Scintigraphy: 99m^Tc-DPD with Grade 2 cardiac uptake or 99m^Tc-PYP with either Grade 2 or 3 cardiac uptake.

  • Subjects with a diagnosis of wild type ATTR-CM must be negative by genotyping and have one of the following: Definite histochemical identification of amyloid by Congo red staining and green birefringence in crossed polarised light in cardiac or other tissue biopsy and identification of TTR as the amyloid fibril protein either by immunohistochemistry or proteomic analysis OR Scintigraphy 99m^Technetium-dicarboxypropane diphosphonate (99m^Tc-DPD) with Grade 2 cardiac uptake or 99m^ Technetium-pyrophosphate (99m^Tc-PYP) with Grade 2 or 3 cardiac uptake.
  • Clinically stable in New York heart association (NYHA) class 2 or 3 for the 3 months preceding screening

Inclusion Criteria for Group 2

  • Subject medically diagnosed with AL amyloidosis that has required chemotherapy or an autologous stem cell transplant based upon:

AL amyloidosis confirmed by biopsy with immunohistochemical staining or proteomic identification of AL amyloid fibril type, in subjects with definite monoclonal gammopathy in whom causative mutations of all known relevant amyloidogenic genes have been excluded

  • Clinically stable in NYHA class 2 or 3 for the 3 months preceding screening
  • >=6 months after completing any line of chemotherapy, or after autologous stem cell transplantation, and having attained either a very good partial response (VGPR) or a complete response (CR), and without the need for haematological maintenance therapies

Inclusion Criteria for Group 3

  • Newly diagnosed AL amyloidosis based upon:

AL amyloidosis confirmed by biopsy with immunohistochemical staining or proteomic identification of AL amyloid fibril type in subjects with definite monoclonal gammopathy in whom causative mutations of all known relevant amyloidogenic genes have been excluded

  • Mayo stage II or IIIa
  • Confirmed free light chain complete response (CR) during the first three cycles of first-line chemotherapy where at least the first cycle has been with cyclophosphamide, bortezomib, dexamethasone (CyBorD).

Exclusion Criteria:

  • Cardiomyopathy primarily caused by non-amyloid diseases (e.g. ischemic heart disease; valvular heart disease)
  • Interval from the Q wave on the ECG to point T using Fredericia's formula (QTcF) > 500 millisecond (msec)
  • Sustained / symptomatic monomorphic ventricular tachycardia (VT), or rapid polymorphic VT, at screening
  • Unstable heart failure defined as emergency hospitalization for worsening, or decompensated heart failure, or syncopal episode within 1 month of screening.

Implantable cardiac defibrillator (ICD) or permanent pacemaker (PPM) at screening

  • N-terminal pro b-type Natriuretic Peptide [(NT)-proBNP] >8500 nanograms (ng)/ Liter (L)
  • Glomerular filtration rate (GFR) at Screening < 40 milliliter (mL)/minute (min)
  • Any active and persistent dermatological condition
  • Existing diagnosis of any type of dementia
  • History of allogeneic stem cell transplantation, prior solid organ transplant, or anticipated to undergo solid organ transplantation, or left ventricular assist device (LVAD) implantation, during the course of the study.
  • Malignancy within last 5 years, except for basal or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix that has been successfully treated.
  • Acute coronary syndrome, or any form of coronary revascularization procedure (including coronary artery bypass grafting [CABG]), within 6 months of screening.
  • Stroke within 6 months of screening, or transient ischaemic attack (TIA) within 3 months of screening
  • Symptomatic, clinically significant autonomic neuropathy which the Principal Investigator (PI) feels will preclude administration of study treatment
  • Hypoalbuminaemia (serum albumin < 30 g/L)
  • Uncontrolled hypertension during screening
  • Alanine transaminase ALT >3x upper limit of normal (ULN) AND bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
  • Peripheral oedema at Screening that in the opinion of the Prinicpal Investigator (PI) or designee might prevent adequate absorption of subcutaneously administered CPHPC
  • Urine dipstick positive (>1+) for blood during screening with investigation indicating glomerular haematuria. If other causes are identified, subjects may be enrolled on resolution of the abnormality
  • Presence of any co-morbid or an uncontrolled medical condition (e.g. diabetes mellitus), which in the opinion of the investigator would increase the potential risk to the subject. Investigator should liaise with the Medical Monitor where there is uncertainty as to the eligibility of a patient
  • Positive test for hepatitis B hepatitis C, and / or human immunodeficiency virus (HIV) during screening, or within 3 months prior to first dose of study treatment
  • Unwillingness or inability to follow the procedures outlined in the protocol
  • Use of GSK2315698 (CPHPC), or participation in a separate clinical trial involving CPHPC within 3 months of screening
  • Any prohibited concomitant medication as per protocol within 28 days of Screening
  • Donation of blood or blood products in excess of 500 mL within 84 days of screening
  • Lactating females
  • Poor or unsuitable venous access
  • Treatment with another investigational drug, biological agent, or device within 6 months of screening, or 5 half-lives of the study agent, whichever is longer.
  • 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 CARDIAC MAGNETIC RESONANCE (CMR) SCANNING
  • Orthopnoea of sufficient severity to preclude supine scanning as determined at screening
  • Contraindication to magnetic resonance imaging (MRI) contrast agents
  • Inability to fit inside scanner due to body size (girth)
  • Contraindication for MRI scanning (as assessed by local MRI safety questionnaire), which includes but is not limited to:

    • Intracranial aneurysm clips (except Sugita) or other metallic objects
    • Intra- orbital metal fragments that have not been removed
    • Pacemakers or other implanted cardiac rhythm management/monitoring devices and non-MR conditional heart valves
    • Inner ear implants
    • History of claustrophobia

      99m^TC-PYP OR 99mTC-DPD BONE TRACER RADIOSCINTOGRAPHY

  • Orthopnoea of sufficient severity to preclude supine scanning as determined at Screening
  • Previous allergic reaction to radioisotope bone tracers
  • Previous inclusion in a research protocol involving nuclear medicine, positron emission tomography (PET) or radiological investigations with significant radiation burden (a significant radiation burden being defined as 10 mSv in addition to natural background radiation, in the previous 3 years).

Exclusion Criteria for Group 1

Has any of the following:

  • Fulfilment of diagnostic criteria for AL amyloidosis
  • TTR polyneuropathy and / or intracranial TTR involvement including ophthalmological disease
  • Non-amyloidosis related chronic liver disease (with the exception of Gilbert's syndrome or clinically asymptomatic gallstones)
  • Platelet count < 125x10^9 / L

Exclusion criteria for Group 2

  • Chronic liver disease or current active liver or biliary disease not attributable to amyloidosis (with the exception of Gilbert's syndrome or asymptomatic gallstones).

Exclusion criteria for Group 3

  • Chronic liver disease or current active liver or biliary disease not attributable to amyloidosis (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • Platelet count < 75x10^9 /L

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): NCT03044353


Locations
United States, Massachusetts
GSK Investigational Site
Boston, Massachusetts, United States, 02115
United Kingdom
GSK Investigational Site
Cambridge, United Kingdom, CB2 0GG
GSK Investigational Site
London, United Kingdom, NW10 7EW
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  Study Documents (Full-Text)

Documents provided by GlaxoSmithKline:
Study Protocol  [PDF] March 5, 2018
Statistical Analysis Plan  [PDF] May 1, 2018


Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT03044353     History of Changes
Other Study ID Numbers: 201464
First Posted: February 7, 2017    Key Record Dates
Last Update Posted: August 23, 2018
Last Verified: August 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by GlaxoSmithKline:
echocardiography (ECHO)
skin biopsy
monoclonal anti-serum amyloid p component antibody (anti-SAP mAb)
Amyloidosis
cardiac magnetic resonance imaging (CMR)
biomarkers
cardiac functional measures
left ventricular mass

Additional relevant MeSH terms:
Amyloidosis
Proteostasis Deficiencies
Metabolic Diseases