This study has been transitioned to CTIS with ID 2023-506926-35-00 check the CTIS register for the current data. The primary objective is to demonstrate the superiority of ziltivekimab 15 mg s.c. once-monthly in reducing the risk of MACE (as defined…
ID
Source
Brief title
Condition
- Other condition
- Cardiac disorders, signs and symptoms NEC
- Renal disorders (excl nephropathies)
Synonym
Health condition
systemische ontstekingen
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is time from randomisation to first occurrence of a major
adverse cardiovascular event, a composite endpoint consisting of:
cardiovascular death, non-fatal myocardial infarction (MI) or non-fatal stroke.
Secondary outcome
The confirmatory secondary endpoints are:
• Time from randomisation to first occurrence of an expanded MACE endpoint
consisting of:
CV death, non-fatal MI, non-fatal stroke, or hospitalisation for unstable
angina pectoris requiring urgent coronary revascularisation
• Number of hospitalisations for heart failure or urgent heart failure visit
• Time to occurrence of all-cause mortality
• Time to first occurrence of a composite CKD endpoint consisting of: onset of
persistent >= 40% reduction in estimated glomerular filtration rate
(eGFR)(CKD-EPI) compared with baseline, kidney failure defined as kidney death,
onset of persistent eGFR (CKD-EPI) < 15 mL/min/1.73 m2 or initiation of chronic
kidney replacement therapy (maintenance dialysis or kidney transplantation)
Background summary
Atherosclerotic CV disease (ASCVD) is the leading cause of morbidity and
mortality in patients worldwide. ASCVD represents a major burden for patients
and society, underscoring the need for therapies that lower the risk of CV
events in patients with established ASCVD.
There is a major unmet medical need to improve the treatment of patients with
established ASCVD, especially those with chronic kidney disease (CKD), and
thereby reduce their risk of cardiovascular (CV) events. Inflammation is an
additional important risk factor to address in patients with ASCVD at high risk
of major adverse cardiovascular events (MACE). Ziltivekimab is a fully human
monoclonal antibody directed against the interleukin 6 (IL-6) ligand and
currently available clinical data supports that ziltivekimab oncemonthly
reduces inflammation as measured by high-sensitivity C-reactive protein
(hs-CRP), and thereby has the potential to reduce cardiovascular risk. The aim
of the current study is to demonstrate the efficacy of ziltivekimab in reducing
the risk of MACE in adult patients with established ASCVD, CKD and systemic
inflammation at high risk of CV events.
Study objective
This study has been transitioned to CTIS with ID 2023-506926-35-00 check the CTIS register for the current data.
The primary objective is to demonstrate the superiority of ziltivekimab 15 mg
s.c. once-monthly in reducing the risk of MACE (as defined by the primary
endpoint) compared to placebo, both added to standard of care, in participants
with established ASCVD, CKD and systemic inflammation.
Key secondary objectives are to demonstrate the superiority of ziltivekimab 15
mg s.c. oncemonthly compared to placebo, both added to standard of care, in
participants with established ASCVD, CKD and systemic inflammation, with
regards to the following:
• reducing the risk of expanded MACE
• reducing the risk of heart failure
• reducing all-cause mortality
• delaying the progression of CKD
Study design
This is an interventional, randomised, parallel-group, double-blind,
placebo-controlled, multicentre, multi-national CVOT designed to evaluate the
effects of 15 mg ziltivekimab versus placebo (randomised 1:1), both
administered s.c. once-monthly and added to standard of care, on CV
outcomes in participants with established ASCVD, CKD and systemic inflammation.
The study is event driven; therefore, end-of-study will be scheduled according
to projected study closure. Study duration is expected to be up to 48 months
following randomisation of the first participant.
Intervention
Oncemonthly ziltivekimab/placebo subcutaneous injection, single-use pre-filled
syringe (1 mL) or pen-injector (0.5 mL).
Study burden and risks
Necessary precautions have been implemented in the design and planned conduct
of the trial in order to minimize the risks and inconveniences of participation
in the trial. Additionally standard safety surveillance activities and medical
monitoring will be performed by Novo Nordisk to minimise the risk. Currently,
there are no identified risks with ziltivekimab.
In other medicines similar to ziltivekimab the below side effects have been
seen. We do not know if these side effects will happen with ziltivekimab or how
often (Infections, low levels of a type of white blood cells (neutropenia), low
levels of the blood cells called *platelets* (thrombocytopenia), elevated
levels of liver enzymes, allergic reactions, skin problem where the injection
is given, stomach ulcers).
One argument that we have seen a very beneficial safety profile for
ziltivekimab in our phase II study is, that the dose used in order to lower the
low grade inflammation in ASCVD, is much lower than the doses used in order to
lower the inflammatory state of autoimmune diseases. This leads us to expect
that the safety profile we have seen in our phase II study is translationable
to our phase III study.
No data are available yet on the safety profile with longer-term exposure.
Hence, the safety of the participants will be monitored closely throughout the
study with specific focus on potential risks of ziltivekimab, the patient
population included in the study and the endpoints defined for the study.
Furthermore, an independent DMC will monitor the safety of participants
enrolled in the study, and thereby protect the safety of the participants and
ensure a positive benefit-risk balance. In completed clinical studies
ziltivekimab has shown a reduction in systemic inflammation, as assessed by
hs-CRP, in participants with CKD. Ziltivekimab may reduce the risk of MACE in
patients with established ASCVD, CKD and systemic inflammation, providing
further benefits to ziltivekimab-treated participants in the study. Considering
the measures taken to minimise risk and burden to study participants, the
potential risks identified in association with ziltivekimab are justified by
the anticipated benefits that may be afforded to participants with established
ASCVD, CKD and systemic inflammation at high risk of CV events.
Flemingweg 8
Alphen aan den Rijn 2408AV
NL
Flemingweg 8
Alphen aan den Rijn 2408AV
NL
Listed location countries
Age
Inclusion criteria
•Chronic kidney disease defined by one of the below:
eGFR >=15 and < 60 mL/min/1.73 m2 (using the Chronic Kidney Disease Epidemiology
Collaboration (CKD-EPI) creatinine equation) or UACR >200 mg/g and eGFR>60
mL/min/1.73 m2 (using the CKD-EPI creatinine equation).
•Serum hs-CRP *2 mg/L
•Evidence of ASCVD by one or more of the following:
a) Coronary heart disease defined as at least one of the following:
i. Documented history of MI
ii. Prior coronary revascularisation procedure
iii. >=50% stenosis in major epicardial coronary artery documented by cardiac
catheterisation or CT coronary angiography
b) Cerebrovascular disease defined as at least one of the following:
i. Prior stroke of atherosclerotic origin
ii. Prior carotid artery revascularisation procedure
iii. >=50% stenosis in carotid artery documented by X-ray angiography, MR
angiography, CT angiography or Doppler ultrasound.
c) Symptomatic peripheral artery disease (PAD) defined as at least one of the
following:
i. Intermittent claudication with an ankle-brachial index (ABI) <= 0.90 at rest
ii. Intermittent claudication with a >=50% stenosis in peripheral artery
(excluding carotid) documented by X-ray angiography, MR angiography, CT
angiography or Doppler ultrasound
iii. Prior peripheral artery (excluding carotid) revascularisation procedure
iv. Lower extremity amputation at or above ankle due to atherosclerotic disease
(excluding e.g. trauma or osteomyelitis).
Exclusion criteria
•Clinical evidence of, or suspicion of, active infection at the discretion of
the investigator.
•Myocardial infarction, stroke, hospitalisation for unstable angina pectoris,
or transient ischaemic attack within 60 days prior to randomisation (visit 2).
•Planned coronary, carotid or peripheral artery revascularisation known on the
day of randomisation
•Major cardiac surgical, non-cardiac surgical, or major endoscopic procedure
(thoracoscopic or laparoscopic) within the past 60 days prior to randomisation
(visit 2) or any major surgical procedure planned at the time of randomisation
(visit 2).
Design
Recruitment
Medical products/devices used
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
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 |
|---|---|
| EU-CTR | CTIS2023-506926-35-00 |
| EudraCT | EUCTR2020-004853-59-NL |
| CCMO | NL77706.018.21 |