Last updated: 03/02/2022 10:00:08
Biodistribution of 89Zirconium-labelled GSK2398852 using PET Imaging
EudraCT ID
EU CT Number
Not applicable
Trial status
Other
Other
Trial overview
Official title: An Adaptive, Open-Label Study to Evaluate the Biodistribution of 89Zirconium-labelled GSK2398852 in the Heart and Other Organs of Patients with Transthyretin Cardiomyopathy (ATTR-CM) using Positron Emission Tomography (PET) Imaging
Trial description: The principal aim of this study is to investigate the cardiac uptake of 89Zr-GSK2398852 in subjects with transthyretin cardiomyopathy amyloidosis (ATTR-CM), and its biodistribution to other organs. Low doses of GSK2398852 will be co-administered at levels not high enough for therapeutic benefit. This study will be conducted in two parts: Part A and Part B. Subjects in Part A will participate in up to two dosing sessions and subjects in Part B will participate in one dosing session. Subjects will undergo up to 3 PET scans at varying intervals after 89Zr-GSK2398852 administration. The total duration of study will be approximately 3 to 4 months for subjects in Part A and approximately 2 months for subjects in Part B. Part B of the study will be triggered based on data obtained in Part A and other emerging data.
Primary purpose:
Diagnostic
Trial design:
Sequential Assignment
Masking:
None (Open Label)
Allocation:
Non-randomized
Primary outcomes:
Standardized Uptake Values (SUV) in focal anatomical regions of the heart following 80-200 milligrams (mg) dose of anti-SAP mAb
Timeframe: Up to Day 6
SUV in focal anatomical regions of the heart following an anti-SAP mAb dose between 200 mg and <=500 mg
Timeframe: Up to Day 6
SUV of whole heart following 80-200 mg dose of anti-SAP mAb
Timeframe: Up to Day 6
SUV of whole heart following an anti-SAP mAb dose between 200 mg and <=500 mg
Timeframe: Up to Day 6
Secondary outcomes:
Focal radioactivity uptake after 80-200 mg dose of anti-SAP mAb
Timeframe: Up to Day 6
Focal radioactivity uptake after an anti-SAP mAb dose between 200 mg and <=500 mg
Timeframe: Up to Day 6
Total radioactivity uptake after 80-200 mg dose of anti-SAP mAb
Timeframe: Up to Day 6
Total radioactivity uptake after an anti-SAP mAb dose between 200 mg and <=500 mg
Timeframe: Up to Day 6
Maximum concentration in plasma (Cmax) of total mAb
Timeframe: Day 3 (pre-dose, 4 hours, 7 hours post-dose), Day 4, Day 5, Day 6 and Day 7 post-dose
Time associated with Cmax (Tmax) of total mAb
Timeframe: Day 3 (pre-dose, 4 hours, 7 hours post-dose), Day 4, Day 5, Day 6 and Day 7 post-dose
Clearance of total mAb
Timeframe: Day 3 (pre-dose, 4 hours, 7 hours post-dose), Day 4, Day 5, Day 6 and Day 7 post-dose
Terminal half-life (T1/2) of total mAb
Timeframe: Day 3 (pre-dose, 4 hours, 7 hours post-dose), Day 4, Day 5, Day 6 and Day 7 post-dose
Area under the concentration-time profile (AUC) of total mAb
Timeframe: Day 3 (pre-dose, 4 hours, 7 hours post-dose), Day 4, Day 5, Day 6 and Day 7 post-dose
Cmax of 89Zr- GSK2398852 pharmacokinetics of radioactivity (radio-PK)
Timeframe: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Day 4, Day 5 and Day 6 post-dose
Tmax of 89Zr- GSK2398852 radio-PK
Timeframe: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Day 4, Day 5 and Day 6 post-dose
T1/2 of 89Zr- GSK2398852 radio-PK
Timeframe: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Day 4, Day 5 and Day 6 post-dose
AUC of 89Zr- GSK2398852 radio-PK
Timeframe: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Day 4, Day 5 and Day 6 post-dose
Number of subjects with adverse events (AEs) and serious adverse events (SAEs)
Timeframe: Up to Day 28
Number of subjects with skin rashes
Timeframe: Up to Day 28
Number of subjects with cardiac adverse events
Timeframe: Up to Day 28
Number of subjects with infusion related reactions
Timeframe: Up to Day 28
Number of subjects with abnormal hematology parameters
Timeframe: Up to Day 28
Number of subjects with abnormal clinical chemistry parameters
Timeframe: Up to Day 28
Number of subjects with abnormal urine parameters
Timeframe: Up to Day 28
Number of subjects with cardiac safety parameters of clinical significance
Timeframe: Up to Day 28
Number of subjects with abnormal electrocardiogram (ECG)
Timeframe: Up to Day 28
Number of subjects with abnormal inpatient cardiac telemetry
Timeframe: Up to Day 11
Number of subjects with abnormal outpatient cardiac telemetry
Timeframe: Up to Day 18
Number of subjects with abnormal temperature
Timeframe: Up to Day 28
Number of subjects with abnormal blood pressure
Timeframe: Up to Day 28
Number of subjects with abnormal pulse rate
Timeframe: Up to Day 28
Number of subjects with abnormal respiratory rate
Timeframe: Up to Day 28
Number of subjects with abnormal physical examination findings
Timeframe: Up to Day 11
Interventions:
Enrollment:
2
Primary completion date:
2018-20-07
Observational study model:
Not applicable
Time perspective:
Not applicable
Clinical publications:
Ashutosh Wechalekar, Gunnar Antoni, Wasfi Al-Azzam, Mats Bergström, Swethajit Biswas, Chao Chen, Joseph Cheriyan, Matthew Cleveland, Louise Cookson, Paul Galette, Robert Kaniczek, Raymond Y. Kwong, Mary Ann Lukas, Helen Millns, Duncan Richards, Ian Schneider, Scott Solomon¸ Jens Sörensen, Jim Storey, Douglas Thompson, Guusvan Dongen, Danielle J. Vugts, Anders Wall, Gerhard Wikström, Rodney Falk.Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis: an open-label Phase 2 study and an adjunctive immuno-PET imaging study.BMC Cardiovasc Disord.2022;22(1):49
DOI: https://doi.org/10.1186/s12872-021-02407-6
PMID: 35152886
Medical condition
Amyloidosis
Product
dezamizumab, miridesap
Collaborators
Not applicable
Study date(s)
April 2018 to July 2018
Type
Interventional
Phase
1
Participation criteria
Sex
Female & Male
Age
65 - 80 years
Accepts healthy volunteers
No
- Subject must be 65 to 80 years of age inclusive, at the time of signing the informed consent.
- Subjects with a diagnosis of ATTR-CM: a) Wild-type ATTR status must be confirmed by genotyping and have one of the following: i) Definite histochemical identification of amyloid by Congo red staining and green birefringence in crossed polarized light in cardiac or other tissue biopsy and identification of Transthyretin amyloidosis (TTR) as the amyloid fibril protein either by immunohistochemistry or proteomic analysis OR ii) Scintigraphy Technetium-99m-labeled 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) with confirmed myocardial uptake. b) Hereditary ATTR amyloidosis (example, TTR Val30Met) should have a known amyloidogenic TTR mutation demonstrated by genotyping and is recognized to be primarily associated with cardiomyopathy and one of the following: i) Definite histochemical identification of amyloid by Congo red staining and green birefringence in crossed polarized light in cardiac or other tissue biopsy and identification of TTR as the amyloid fibril protein either by immunohistochemistry or proteomic analysis. ii) Scintigraphy: 99mTc-DPD with confirmed myocardial uptake.
- Cardiomyopathy primarily caused by non-amyloid diseases (example, ischemic heart disease; valvular heart disease).
- Interval from the Q wave on the ECG to point T using Fredericia’s formula (QTcF) >500 milliseconds (msec).
Inclusion and exclusion criteria
Inclusion criteria:
- Subject must be 65 to 80 years of age inclusive, at the time of signing the informed consent.
- Subjects with a diagnosis of ATTR-CM: a) Wild-type ATTR status must be confirmed by genotyping and have one of the following: i) Definite histochemical identification of amyloid by Congo red staining and green birefringence in crossed polarized light in cardiac or other tissue biopsy and identification of Transthyretin amyloidosis (TTR) as the amyloid fibril protein either by immunohistochemistry or proteomic analysis OR ii) Scintigraphy Technetium-99m-labeled 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) with confirmed myocardial uptake. b) Hereditary ATTR amyloidosis (example, TTR Val30Met) should have a known amyloidogenic TTR mutation demonstrated by genotyping and is recognized to be primarily associated with cardiomyopathy and one of the following: i) Definite histochemical identification of amyloid by Congo red staining and green birefringence in crossed polarized light in cardiac or other tissue biopsy and identification of TTR as the amyloid fibril protein either by immunohistochemistry or proteomic analysis. ii) Scintigraphy: 99mTc-DPD with confirmed myocardial uptake.
- Both male and female subjects are eligible to participate. a) Male subjects: A male subject must agree to use contraception during the treatment period and for at least 3 months after the last scan and refrain from donating sperm during this period. b) Female subjects: A female subject is eligible to participate if she is not of childbearing potential.
- Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and protocol.
- New York Heart Association (NYHA) up to class 3; subjects should be clinically stable for at least 3 months preceding to Screening.
Exclusion criteria:
- Cardiomyopathy primarily caused by non-amyloid diseases (example, ischemic heart disease; valvular heart disease).
- Interval from the Q wave on the ECG to point T using Fredericia’s formula (QTcF) >500 milliseconds (msec).
- Sustained (at a rate of >=120 beats per minute for >=30 seconds), or symptomatic monomorphic ventricular tachycardia (VT), or rapid polymorphic VT, at Screening/Baseline cardiac monitoring.
- Systolic blood pressure <=100 millimeters of mercury (mm/Hg) based on triplicate readings 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.
- Estimated Glomerular filtration rate (eGFR) at Screening <50 milliliters per minute (mL/min) calculated using modification of diet in renal disease (MDRD).
- Any active and persistent dermatological condition, which in the opinion of the Investigator and Medical Monitor would preclude safe participation.
- History of allogeneic stem cell transplantation, prior solid organ transplant, or anticipated to undergo solid organ transplantation, or left ventricular assist device (LVAD) implantation.
- 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.
- Symptomatic, clinically significant autonomic neuropathy which the Principal Investigator (PI) feels will preclude administration of study treatment.
- Uncontrolled hypertension during Screening.
- ALT >3 times upper limit of normal (ULN) OR bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
- Peripheral edema at Screening that in the opinion of the PI or designee might prevent adequate absorption of subcutaneously administered CPHPC.
- Presence of any co-morbid (example, steroid refractory rheumatoid arthritis), or an uncontrolled medical condition (example, 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 subject.
- 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.
- Clinically significant multiple or severe drug allergies, intolerance to topical corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear immunoglobulin A [IgA] dermatosis, toxic epidermal necrolysis and exfoliative dermatitis).
- Inability to comprehend and/or understand the study patient information sheet, and/or unwillingness or inability to follow the procedures outlined in the protocol.
- Has any of the following: a) Fulfillment of diagnostic criteria for Amyloid Light-chain (AL) amyloidosis. b) Fulfillment of diagnostic criteria for amyloid A (AA) or non-TTR hereditary amyloidosis.
- ATTR Disease Load: c) Histologically proven or clinically suspected gastrointestinal TTR amyloidosis; d) Diffuse skeletal muscle uptake of 99m(Tc)-DPD on Single-photon emission computed tomography (SPECT) imaging (where available); e) Peripheral neuropathy causing more than mild morbidity (example, walking disability; neuropathic pain affecting activities of daily living); f) Proven or clinically suspected intracranial TTR involvement including ophthalmological disease.
- Non-amyloidosis related chronic liver disease (with the exception of Gilbert’s syndrome or clinically asymptomatic gallstones).
- Participation in a separate clinical trial involving CPHPC within 3 months of Screening.
- Any prohibited concomitant medication within referenced timeframe.
- 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.
- Orthopnea of sufficient severity to preclude supine scanning as determined at Screening.
- Inability to fit inside scanner due to body size (girth).
- History of claustrophobia.
- Contraindication to magnetic resonance imaging (MRI) contrast agents.
- 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-magnetic resonance (MR) conditional heart valves; d) Inner ear implants.
- Donation of blood or blood products in excess of 500 milliliters (mL) within 84 days of Screening.
- Poor or unsuitable venous access.
Trial location(s)
Study documents
Protocol
Available language(s): English
Statistical analysis plan
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Results posted on ClinicalTrials.gov
Recruitment status
Other
Actual primary completion date
2018-20-07
Actual study completion date
2018-20-07
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.
Additional information about the trial
Additional information
Not applicable
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