Multiple treatment session study to assess GSK2398852 administered following and along with GSK2315698
Trial overview
Change from baseline in left ventricular (LV) mass over time up to 8-week follow-up
Timeframe: Baseline and Up to 8 Weeks follow-up
Number of subjects with any adverse events (AEs) and any serious adverse events (SAEs)
Timeframe: Continuous throughout the study, collected from the start of Study Treatment up to approximately 30 week
Number of subjects with abnormal haematology values
Timeframe: At scheduled intervals up to approximately 30 weeks
Number of subjects with abnormal clinical chemistry values
Timeframe: At scheduled intervals up to approximately 30 weeks
Number of subjects with abnormal urinalysis results
Timeframe: At scheduled intervals up to approximately 30 weeks
Body temperature as a measure of safety
Timeframe: At scheduled intervals up to approximately 30 weeks
Systolic and diastolic blood pressure as a measure of safety
Timeframe: At scheduled intervals up to approximately 30 weeks
Pulse rate as a measure of safety
Timeframe: At scheduled intervals up to approximately 30 weeks
12-lead electrocardiogram (ECG) as a measure of safety
Timeframe: At scheduled intervals up to approximately 30 weeks
Number of subjects with abnormalities during cardiac monitoring
Timeframe: At scheduled intervals up to approximately 30 weeks
ECHO as a measure of safety
Timeframe: At scheduled intervals up to approximately 30 weeks
Number of subjects with skin rashes classified using the Common Terminology Criteria for Adverse Events (CTCAE)
Timeframe: Continuous throughout the study, collected from the start of Study Treatment and until the follow-up contact Approximately 30 weeks
Number of subjects in each Grade of skin rashes classified using the CTCAE
Timeframe: 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
Timeframe: 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 + blood biomarkers
Timeframe: 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
Timeframe: Continuous throughout the study, collected from the start of Study Treatment and until the follow-up contact approximately 30 weeks
Immunohistochemical examination of blood biomarkers
Timeframe: Continuous throughout the study, collected from the start of Study Treatment and until the follow-up contact approximately 30 weeks
Changes in circulating biomarkers
Timeframe: Baseline and Approximately 30 weeks
Change in Global Longitudinal Strain (GLS) over time
Timeframe: Baseline and Up to 8 Weeks follow-up
Change in left ventricular (LV) twist over time
Timeframe: Baseline and Up to 8 Weeks follow-up
Change in Stroke Volume (SV) over time
Timeframe: Baseline and Up to 8 Weeks follow-up
Chnge in ejection fraction over time
Timeframe: Baseline and Up to 8 Weeks follow-up
Change in End Diastolic Volume (EDV) over time
Timeframe: Baseline and Up to 8 Weeks follow-up
Change in ratio of mitral peak velocity of early filling to early diastolic mitral annual velocity.
Timeframe: Baseline and Up to 8 Weeks follow-up
Maximum concentration (Cmax) of GSK2315698 and GSK2398852
Timeframe: Approximately 30 weeks
The time associated with Cmax (Tmax) of GSK2315698 and GSK2398852
Timeframe: Approximately 30 weeks
Area under the concentration-time profile (AUC) of GSK2315698 and GSK2398852
Timeframe: Approximately 30 weeks
Participation criteria
- Between 18 and 80 years of age inclusive, at the time of signing the informed consent.
- Male and female.
- 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)
- Between 18 and 80 years of age inclusive, at the time of signing the informed consent.
- 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).
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:
- 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)
- 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
Contraindication for MRI scanning (as assessed by local MRI safety questionnaire), which includes but is not limited to:
Trial location(s)
Study documents
If you wish to request for full study report, please contact - [email protected]
Results overview
Results posted on ClinicalTrials.gov
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.