Study to look at the affect of anti-SAP treatment in patients with cardiac amyloidosis

• Register: EUCTR
• Last refreshed on: 16 December 2019
• Main ID: EUCTR2016-000276-23-GB
• Date of registration: 11/07/2016
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline Research & Development Ltd
• Public title: Study to look at the affect of anti-SAP treatment in patients with cardiac amyloidosis
• Scientific 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
• Date of first enrolment: 06/12/2016
• Target sample size: 30
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-000276-23
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

United Kingdom, United States

Contacts

• Name: GSK Clinical Support Help Desk
• Affiliation: GlaxoSmithKline Research & Development Ltd

• Name: GSK Clinical Support Help Desk
• Affiliation: GlaxoSmithKline Research & Development Ltd

Key inclusion & exclusion criteria

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
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


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Systemic amyloidosis
MedDRA version: 20.0 Level: SOC Classification code 10021428 Term: Immune system disorders System Organ Class: 10021428 - Immune system disorders
MedDRA version: 20.0 Level: PT Classification code 10002022 Term: Amyloidosis System Organ Class: 10021428 - Immune system disorders

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Intervention(s)

Product Name: GSK2315698
Product Code: GSK2315698
Pharmaceutical Form: Solution for injection/infusion
INN or Proposed INN: miridesap
CAS Number: 224624-80-A
Current Sponsor code: GSK2315698
Other descriptive name: CPHC (carboxy pyrrolidine hexanoyl pyrrolidone carboxylate)
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 200-

Product Name: GSK2398852
Product Code: GSK2398852
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: dezamizumab
Current Sponsor code: GSK2398852
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 100-

Primary Outcome(s)

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

Main Objective: -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.

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)

Secondary Objective: -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.

Secondary Outcome(s)

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

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

Secondary ID(s)

201464

Source(s) of Monetary Support

GlaxoSmithKline Research & Development Ltd

Ethics review

Status: Approved
Approval date:
Contact:

Results

• Results available: Yes
• Date Posted: 12/10/2019
• Date Completed: 03/01/2019
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-000276-23/results