| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10021428 |
| E.1.2 | Term | Immune system disorders |
| E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10002022 |
| E.1.2 | Term | Amyloidosis |
| E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
-Assessment of reduction in cardiac
amyloid load after repeated administrations
of Anti-SAP treatment as evaluated by
CMR in all study groups
-Assessment of safety & tolerability of
repeated administration of Anti-SAP
treatment, including compatibility with
chemotherapy treatment in Group 3. |
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| E.2.2 | Secondary objectives of the trial |
-Investigation of rash associated with Anti-
SAP treatment.
-Characterisation of the pharmacokinetics
of anti-SAP mAb.
-Assessment of changes in circulating markers associated with pharmacodynamic
effect during repeated administrations.
-Evaluation of changes in imaging markers of cardiac dysfunction monitored by serial CMR and / or ECHO. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study only if all of the following criteria apply:
AGE
1. Between 18 and 80 years of age inclusive, at the time of signing the informed consent.
SEX
2. Gender: 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.
a. Vasectomy with documentation of azoospermia.
b. 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 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 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, not lactating, and at least one of the following conditions applies:
a.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:
>or= 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.
b. 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) (see Appendix 7) 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
INFORMED CONSENT
3. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
OTHER
4. Late-Gadolinum enhancement (LGE) on CMR indicative of cardiac amyloidosis
Inclusion Criteria for Group 1
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
5. ATTR cardiomyopathy (ATTR-CM)
a) Subjects with a diagnosis of hereditary ATTR amyloidosis should have a known
amyloidogenic 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: 99mTc-DPD with Grade 2 cardiac uptake or 99mTc-PYP with either Grade 2 or 3 cardiac uptake.
b) 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 99mTc-DPD with Grade 2 cardiac uptake or 99mTc-PYP with Grade 2 or 3 cardiac uptake.
6. LVmass on CMR >200g
7. Clinically stable in New York heart association (NYHA) class 2 or 3 for the 3 months preceding screening
Inclusion Criteria for Group 2 and 3
LVmass on CMR >150g; for all other criteria refer to Protocol page 46.
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|
| E.4 | Principal exclusion criteria |
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER FUNCTION AND QTc INTERVAL)
1. Cardiomyopathy primarily caused by non-amyloid diseases
2. Interval from the Q wave on the ECG to point T using Fredericia's formula
(QTcF) > 500 msec
3. Sustained / symptomatic monomorphic ventricular tachycardia (VT), or rapid polymorphic VT, at screening
4. Unstable heart failure defined as emergency hospitalization for worsening, or decompensated heart failure, or syncopal episode within 1 month of screening.
5. Implantable cardiac defibrillator (ICD) or permanent pacemaker (PPM) at screening
6. NT-proBNP >8500ng/L
7. Glomerular filtration rate (GFR) at Screening < 40 mL/min
8. Any active and persistent dermatological condition
9. Existing diagnosis of any type of dementia
10. 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.
11. 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.
12. Acute coronary syndrome, or any form of coronary revascularization procedure, within 6 months of screening.
13. Stroke within 6 months of screening, or transient ischaemic attack (TIA) within 3 months of screening
14. Symptomatic, clinically significant autonomic neuropathy which the Principal Investigator (PI) feels will preclude administration of study treatment
15. Hypoalbuminaemia (serum albumin < 30 g/L)
16. Uncontrolled hypertension during screening
17. 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%)
18. Peripheral oedema at Screening that in the opinion of the PI or designee might prevent adequate absorption of subcutaneously administered CPHPC
19. 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
20. 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
21. 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
22. Unwillingness or inability to follow the procedures outlined in the protocol
CONCOMITANT MEDICATIONS
23. Use of GSK2315698 (CPHPC), or participation in a separate clinical trial involving CPHPC within 3 months of screening
24. Any prohibited concomitant medication as per Section 6.10.2 within 28 days of screening
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
25. Donation of blood or blood products in excess of 500 mL within 84 days of screening
26. Lactating females
27. Poor or unsuitable venous access
OTHER
28. 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.
CONTRAINDICATIONS
29. 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
30. Orthopnoea of sufficient severity to preclude supine scanning as determined at screening
31. Contraindication to MRI contrast agents
32. Inability to fit inside scanner due to body size (girth)
33. Contraindication for MRI scanning (as assessed by local MRI safety questionnaire), which includes but is not limited to:
a. Intracranial aneurysm clips (except Sugita) or other metallic objects
b. Intra- orbital metal fragments that have not been removed
c. Pacemakers or other implanted cardiac rhythm management/monitoring devices and non-MR conditional heart valves
d. Inner ear implants
e. History of claustrophobia
99mTC-PYP OR 99mTC-DPD BONE TRACER RADIOSCINTOGRAPHY
34. Orthopnoea of sufficient severity to preclude supine scanning as determined at
Screening
35. Previous allergic reaction to radioisotope bone tracers
36. Previous inclusion in a research protocol involving nuclear medicine, positron emission tomography (PET) or radiological investigations with significant radiation burden.
Refer to protocol page 49 for the following:
-Exclusion Criteria for Group 1
-Exclusion criteria for Group 2
-Exclusion criteria for Group 3
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| E.5 End points |
| E.5.1 | Primary end point(s) |
-Change in LV mass over time from baseline to 8-week follow-up
-Clinical safety data from adverse events (AEs), clinical laboratory tests, vital signs, 12-lead electrocardiogram (ECG), cardiac monitoring and ECHO to 8-week follow-up
Incidence and grading of skin rashes classified using the Common Terminology Criteria for Adverse Events (CTCAE)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
ECHO – Baseline/Sessions 1-6/8-week follow-up
Adverse events - Monitored throughout the study
Clinical lab tests – Baseline/Sessions 1-6 ( in patient daily and outpatient days 17 and 24)/All follow-ups
Vital signs - Baseline/Sessions 1-6 ( in patient days 1-6, day 9 and day 11 and out patient days 17 and 24)/Follow-ups
12 lead ECG - Baseline/Sessions 1-6 ( in patient daily and out patient days 17 and 24)/Follow-ups
Cardiac monitoring/ECHO – Baseline/Sessions 1-6/Follow ups
Incidence and grading of rash - Monitored throughout the study
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|
| E.5.2 | Secondary end point(s) |
Histopathological & immunohistochemical examination of skin biopsies + blood biomarkers (as data permit)
Descriptive pharmacokinetic (PK) parameters including the maximum concentration (Cmax), the time associated with Cmax (tmax), and the area under the concentration-time profile (AUC).
Circulating biomarkers including but not limited to complement pathway components, acute phase proteins (e.g. CRP, SAA) and cytokines (e.g. IL6, IL8, IL10, TNF?).
Change in cardiac functional measures, including, but not limited to strain (e.g. global longitudinal strain [GLS]), LV twist, stroke volume (SV), ejection fraction (EF), end diastolic volume (EDV) & E/e’ ratio over time from baseline to 8 week follow-up
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Skin biopsy & blood sample - Monitored throughout the study
PK – Sessions 1-6/Day 17/Day 24
Blood biomarkers – Baseline/ Sessions 1-6/Day 17/Day 24
MRI & ECHO - Baseline/Sessions 1-6/Follow ups
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|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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