primaryTo evaluate the effect of MEDI6570 on non-calcified coronary atherosclerotic plaques compared with placebosecundaryTo evaluate the effect of MEDI6570 on a surrogate biomarker of HF compared with placeboTo evaluate the effect of MEDI6570 on…
ID
Source
Brief title
Condition
- Myocardial disorders
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To evaluate the effect of MEDI6570 on non-calcified coronary atherosclerotic
plaques compared with placebo
Secondary outcome
Relative change from baseline to Day 253 in NT proBNP.
Change from baseline to Day 253 in:
• LVEF
• GLS
as measured by echocardiography
Change from baseline to Day 253 in:
• LVEF
• GLS
as measured by echocardiography
Change from baseline to Day 253 in:
• Global non-calcified plaque volume
• Low attenuation plaque volume
as measured by CTA imaging
Change from baseline to Day 253 in:
• FAI
as measured by CTA imaging
• ADA incidence
• Titer
as measured in serum during the intervention and follow-up periods
•
MEDI6570 as measured in serum during the intervention and follow up periods
During the intervention and follow up periods:
• AEs
• Clinically important changes in:
Vital signs
ECGs
Safety laboratory assessments
Changes from baseline in:
• hs-CRP
• IL-6
• MPO
• MMP9
• Free sLOX-1
as measured in plasma or serum during the intervention and follow up periods
Changes from baseline to Day 253 in:
• End-diastolic volume index
• End-systolic volume index
• Left atrial volume index
• E/e* ratio
as measured by echocardiography
Change from baseline to Day 253 in:
• Percent atheroma volume
• High-risk plaque features (positive remodeling, napkin ring sign, spotty
calcification
and low attenuation plaque)
as measured by CTA imaging
Change from baseline to Day 253 in:
• FRP
as measured by CTA
Time to MACE (composite of CV death, MI, stroke, or coronary revascularization)
from randomization to Day 253.
Time to CV death or HF hospitalization from randomization to Day 253.
Change from baseline to Day 253 in:
• Time spent in MVPA
• Step count
• Acceleration intensity (MMI)
• Uninterrupted sleep time
as measured by a continuously worn physical activity monitor
Background summary
Rationale: This Phase IIB, proof-of-concept, dose-range finding clinical study
is being conducted to evaluate the anti-inflammatory potential of MEDI6570 and
its effect on surrogates for atherosclerotic and heart failure (HF) events in
patients with a history of myocardial infarction. The results of the Phase IIB
study will inform future clinical development options and precision medicine
strategy for future clinical studies.
Study objective
primary
To evaluate the effect of MEDI6570 on non-calcified coronary atherosclerotic
plaques compared with placebo
secundary
To evaluate the effect of MEDI6570 on a surrogate biomarker of HF compared with
placebo
To evaluate the effect of MEDI6570 on left ventricular systolic function
compared with placebo
To evaluate the effect of MEDI6570 on left ventricular systolic function among
participants with reduced ejection fraction (defined as < 50%) compared with
placebo
To evaluate the effect of MEDI6570 on other measures of non-calcified coronary
atherosclerotic plaque compared with placebo
To evaluate the effect of MEDI6570 on coronary inflammation compared with
placebo
To evaluate the immunogenicity of MEDI6570
To evaluate the PK of MEDI6570
safety
To assess the safety and tolerability
exploratory
To evaluate the effect of MEDI6570 on inflammatory and target engagement
biomarkers compared with placeboy of MEDI6570 compared with placebo
To evaluate the effect of MEDI6570 on systolic and diastolic cardiac structure
and function compared with placebo
To evaluate the effect of MEDI6570 on percent atheroma volume and high-risk
plaque features compared with placebo
To evaluate the effect of MEDI6570 on coronary inflammatory changes in the
perivascular space compared with placebo
To evaluate the effect of MEDI6570 on time to MACE compared with placebo.
To evaluate the effect of MEDI6570 on time to CV death or HF hospitalization
To evaluate the effect of MEDI6570 on activity and sleep among participants
with reduced ejection fraction (defined as < 50%) compared with placebo
Study design
This is a randomized, double-blind, placebo-controlled, parallel-group,
multicenter (70 to 100 centers), international study in participants who have
recently (within the previous 30 to 180 days) had a myocardial infarction (MI;
either ST segment elevation MI or non ST segment elevation MI), with persistent
inflammation (high sensitivity C reactive protein [hs CRP] >= 1 mg/L) .
Participants will be randomized in a 2:2 1:1:1 ratio to receive 150, or 400 mg
MEDI6570, subcutaneously (SC), or placebo, SC, every 4 weeks (Q4W) for 32 weeks
(9 doses in total). The randomization will be stratified by geographic region
(North America, Europe, and Japan) and by statin therapy intensity at screening
(no, low- or moderate-intensity statin therapy vs high-intensity statin
therapy).
Participants will undergo an echocardiogram and computed tomography angiography
(CTA) scan before randomization (Day 1; Visit 3) and administration of study
intervention. During the follow up period, participants will also undergo an
echocardiogram and CTA scan.
Intervention Groups and Duration: The study intervention is MEDI6570, a human
Immunoglobulin G1 lambda (IgG1*) triple mutation antibody that binds to human
lectin-like oxidized low density lipoprotein receptor 1 (LOX-1). Going forward
from amendment 2,the study will include 4 intervention groups: 150, and 400 mg
MEDI6570, and 2 injection/volume mathed placebo groups while the participants
previously randomized to 50 mg MEDI6570 or its injection/volume-matched placebo
will continue their assigned treatment to the end of the study.
Participants will be enrolled in the study for approximately 12 months,
comprising a screening and pre randomization period of up to 42 days (6 weeks),
an intervention period of 225 days (31 to 32 weeks), and a follow-up period of
100 days (approximately 14 weeks). Doses of MEDI6570 or placebo, will be
administered in the clinic SC Q4W for 32 weeks (9 doses in total).
Participants who were randomized to a study intervention under Protocol Version
1.0 or Amendment 1 (when there was also a 50 mg dose group) and were allocated
a dosing volume of 0.5 mL will continue on their randomized study intervention
(50 mg MEDI6570, or its injection/volume-matched placebo) to the end of the
study, and the study blind will be maintained with regard to active versus
placebo.
Intervention
Participants will be randomized in a 2:2 1:1:1 ratio to receive, 150, or 400 mg
MEDI6570, subcutaneously (SC), or placebo, SC, every 4 weeks (Q4W) for 32 weeks
(9 doses in total). The randomization will be stratified by geographic region
(North America, Europe, and Japan) and by statin therapy intensity at screening
(no, low- or moderate-intensity statin therapy vs high-intensity statin
therapy).
Participants will undergo an echocardiogram and computed tomography angiography
(CTA) scan before randomization (Day 1; Visit 3) and administration of study
intervention. During the follow up period, participants will also undergo an
echocardiogram and CTA scan. In addition, at least 200 participants group will
undergo an interim CTA between the fifth and sixth doses (Day 122; Visit 9).
Intervention Groups and Duration: The study intervention is MEDI6570, a human
Immunoglobulin G1 lambda (IgG1*) triple mutation antibody that binds to human
lectin-like oxidized low density lipoprotein receptor 1 (LOX-1). The study will
include 6 intervention groups:, 150, and 400 mg MEDI6570, and matching placebo.
Participants will be enrolled in the study for approximately 12 months,
comprising a screening and pre randomization period of up to 42 days (6 weeks),
an intervention period of 225 days (31 to 32 weeks), and a follow-up period of
100 days (approximately 14 weeks). Doses of MEDI6570 or placebo, will be
administered in the clinic SC Q4W for 32 weeks (9 doses in total).
Study burden and risks
Despite improvements made over the last decades in the prevention of secondary
MIs, a clinically significant risk of mortality and morbidity remains for up to
5 years post-MI, with the highest risk in the first months post-MI. Plaque
progression has also been shown to predict ACS independently. Furthermore,
treating the inflammatory pathways associated with MIs results in improved
outcomes.
In preclinical models of atherosclerosis and HF, deletion of the LOX-1 receptor
has demonstrated decreased atherosclerosis, reductions in myocardial fibrosis,
improvements in left ventricular function, and improvements in adverse
remodeling of the heart following MI. Post-MI patients have markedly elevated
sLOX-1 levels and studies have demonstrated that protein expression of LOX-1 is
particularly elevated at the site of human coronary atheromas in vivo. More
extreme inflammatory phenotypes, such as patients with psoriasis, who have an
increased risk of CHD also have elevated sLOX-1 levels. A recent study
demonstrated that treatment with anti-inflammatory therapies in psoriasis
decreased sLOX-1 levels and non calcified plaque burden. Moreover, sLOX-1
levels during treatment predicted regression of non calcified plaque burden. In
the ongoing Phase I study, MEDI6570 markedly decreases sLOX-1 levels. Given the
preclinical and clinical data, MEDI6570 may decrease the severity of
atherosclerosis and HF and is a potential future therapy for the secondary
prevention of CV death, MI, stroke, HF, and revascularization.
Forskargatan 18 Forskargatan 18
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Forskargatan 18 Forskargatan 18
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Age
Inclusion criteria
1 Participant must provide informed consent before any study specific
activities are performed (Appendix A 3), must be able and willing to meet all
requirements for randomization within 42 days after signing the full ICF, and
must adhere to the schedules of activities.
2 Participant must be >= 40 years of age at the time of signing the ICF.
3 Participant must:
(a) be 30 to 365 days after presumed type-1 (ie, due to plaque rupture or
erosion) MI (either STEMI or NSTEMI) at the time of enrollment.
(b) have persistent inflammation, defined as hs CRP >= 1 mg/L, as measured
centrally at screening Visit 1.
4 Participant must have body mass index within the range 18 to 40 kg/m2
inclusive.
5 For female participants, the participant must not be pregnant or lactating
and must be of non-childbearing potential, confirmed at screening Visit 1 by
one of the following:
(a) Postmenopausal, defined as amenorrhea for >= 12 months following cessation
of all exogenous hormonal treatments, and with luteinizing hormone and follicle
stimulating hormone levels in the postmenopausal range.
(b) Documentation of irreversible surgical sterilization by hysterectomy,
bilateral oophorectomy, or bilateral salpingectomy. Tubal ligation is not
considered as irreversible surgical sterilization.
6 Participant must have an evaluable, pre-randomization CTA with quantifiable,
non calcified plaque, as confirmed by the core laboratory.
Participants will be reassessed for study eligibility before study intervention
is administered on Day 1 (Visit 3). Participants should be considered for a
high-intensity statin based on existing guidelines for long-term management of
patients after an MI. Participants should ideally be on a stable dose of
lipid-lowering therapy throughout the treatment period of the study; therefore,
efforts should be made to maximize statin intensity before randomization.
The proportion of participants with an NT-proBNP value < 125 pg/mL at screening
who can be randomized to a study intervention may be capped. If this proportion
is capped, a baseline NT proBNP value of >= 125 pg/mL will be required for
inclusion in the study. During the study, randomization to an intervention
group may also be capped within other specific participant subgroups.
In addition to the inclusion criteria specified above, study participants may
elect to take part in the Genomics Initiative; participants who chose to do
this must provide written informed consent before samples are collected for the
optional genetic research that supports the Genomics Initiative (Appendix D 2).
Exclusion criteria
1 History of any clinically important disease or disorder which, in the opinion
of the investigator, may either put the participant at risk because of
participation in the study, or influence the results or the participant*s
ability to participate in the study.
2 Percutaneous coronary intervention [PCI] planned after screening Visit 1.
Eligible participants who have a PCI planned after screening Visit 1 may be
rescreened after the PCI has been performed (Section 5.4).
3 History of or planned coronary artery bypass grafting.
4 Documented episode of post-MI pericarditis (eg, Dressler*s Syndrome) in the 3
months before enrollment.
5 Ongoing New York Heart Association Class IV (severe) HF.
6 Increased risk of bleeding
(a) Patients with history or presence of any bleeding disorder.
(b) Active bleeding or high risk for major bleeding (eg, gastrointestinal
pathology, malignancy with high risk of bleeding, active peptic ulcer).
(c) Need for chronic anticoagulation therapy (prophylactic doses of heparin are
allowed).
(d) Known severe liver disease (eg, ascites and/or clinical signs of
coagulopathy).
7 History or presence of any of the following:
(a) Ongoing infection or febrile illness that in the opinion of the
investigator may be the cause of elevated hs-CRP on screening (Visit 1).
(b) Ongoing atrial fibrillation or flutter.
(c) Cancer within 5 years before randomization (Day 1; Visit 3), with the
exception of non melanoma skin cancer.
(d) Alcohol or substance abuse within 6 months before randomization (Day 1;
Visit 3), as judged by the investigator.
(e) Known history of hypersensitivity reactions to other biologics, to human
IgG preparations, or to any component of MEDI6570, or ongoing severe allergy as
judged by the investigator.
(f) Patients with active positive results on screening for serum hepatitis B
surface antigen, hepatitis C antibody, or HIV.
8 Any clinically important abnormalities in clinical chemistry, hematology,
coagulation parameters, as judged by the investigator, including but not
limited to:
(a) Aspartate transaminase (AST) > 2.0 × ULN.
(b) Alanine transaminase (ALT) > 2.0 × ULN.
(c) Total bilirubin (TBL) > 1.5 x ULN (unless due to Gilbert*s syndrome).
(d) Platelet count < 100000 platelets/µl.
9 Blood pressure (BP) values at screening Visit 1:
(a) Systolic BP < 90 mmHg or > 180 mmHg.
(b) Diastolic BP > 100 mmHg.
(c) Participants who are excluded based on elevated BP may be rescreened
following adequate treatment.
The eligibility assessment is based on measurements taken starting from after 5
minutes of rest; if the result is outside these limits, additional BP
measurements can be taken over the following 5 minutes, ie, up to a total of 10
minutes of rest (repeated a maximum of 3 times). If the result is outside these
limits during this period, the participant is considered a screen fail.
10 Participants with any of the following contraindications to CTA:
(a) eGFR < 50 mL/min/1.73 m2 by the Chronic Kidney Disease Epidemiology
Collaboration equation, or end stage renal disease treated with kidney
transplant or renal replacement therapy.
(b) Allergy to iodinated contrast.
(c) History of contrast-induced nephropathy.
(d) Contraindication to nitroglycerin.
(e) Rapid heart rate that is uncontrolled by medical therapy.
(f) Inability to hold breath for at least 6 seconds.
11 Receipt of any investigational device or therapy within 6 months or 5 half
lives before screening (whichever is longer).
This criterion does NOT apply for inactive, non replicating COVID-19 vaccines
approved by Health Authorities or under emergency use authorization.
12 Planned participation in an additional study of an intervention or biologic
before the end of the follow-up period.
13 Participants who are legally institutionalized.
14 An employee or close relative of an employee of the sponsor, the CRO, or the
study site, regardless of the employee or close relative*s role.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-000840-75-NL |
| CCMO | NL75194.091.20 |