To evaluate the safety, tolerability and efficacy of IZD334 to reduce CRP in cardiovascular high-risk patients.
ID
Source
Brief title
Condition
- Coronary artery disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To assess the safety and tolerability of oral IZD334 in patients with high
cardiovascular risk
To evaluate the efficacy of IZD334 measuring the percent change from baseline
of 450mg IZD334 compared to placebo in plasma CRP after 12 weeks of treatment
Secondary outcome
To evaluate the percent change from baseline of 150mg IZD334 compared to
placebo in plasma CRP after 12 weeks of treatment
To evaluate the percent change from baseline of 50mg IZD334 compared to placebo
in plasma CRP after 12 weeks of treatment
To evaluate the percentage of participants achieving a reduction from baseline
in plasma CRP to <2 mg/L with 450mg IZD334 compared to placebo after 12 weeks
of treatment
To evaluate the percentage of participants achieving a reduction from baseline
in plasma CRP to <2 mg/L with 150mg IZD334 compared to placebo after 12 weeks
of treatment
To evaluate the percentage of participants achieving a reduction from baseline
in plasma CRP to <2 mg/L with 50mg IZD334 compared to placebo after 12 weeks of
treatment
Exploratory objectives:
To characterize the pharmacokinetics (PK) of IZD334
To evaluate levels of inflammatory biomarkers in plasma (such as IL-6, IL-1b,
IL-18, ASC, caspase-1 and TNFa)
To explore biomarkers of cardiac damage, glucose and lipid meta
To explore responder analysis based on IL-1b genetic pattern
Background summary
Coronary Artery Disease (CAD) develops when coronary arteries become too
narrow. The coronary arteries are the blood vessels that supply oxygen and
blood to the heart. CAD is usually caused by hardening of the arteries,
creating plaques.
Plaques cause the arteries to narrow and this results in reducing the blood and
oxygen flow to the heart. Patients with hardening of the arteries are at high
risk of developing major cardiovascular events, including heart attack and
stroke. Such events can lead to death.
IZD334 is expected to stop and prevent hardening of the arteries. IZD334 is
expected to reduce the risk of future occurrence of major cardiovascular events
in patients with a coronary arterial disease.
Inflammation triggers the liver to produce certain proteins, so called
c-reactive proteins (CRP). Measuring the CRP level in the blood is a
non-specific indicator to detect inflammation and to evaluate the severity of
it.
Study objective
To evaluate the safety, tolerability and efficacy of IZD334 to reduce CRP in
cardiovascular high-risk patients.
Study design
The study will explore three dose levels of IZD334 compared to placebo to lower
plasma CRP levels in high-risk CV patients over 12 weeks of treatment, followed
by a 4-week follow-up period.
During the treatment period patients will visit the study centre 6 times and
will receive study treatment or placebo for the period until the next visit.
Both study drug and placebo come in capsules. Patients are instructed to take 3
capsules daily by mouth in the morning 1 hour before breakfast. This is a
double-blind study, which means that neither the patient, nor the investigator
will know which group the patient is in.
Intervention
In this study patients will receive study drug IZD334 or placebo for 12 weeks.
A placebo looks identical to the study drug but does not contain any active
ingredient. Patients have equal chance to be randomized in 1 of 4 treatment
groups:
* IZD334 50mg
* IZD334 150mg
* IZD334 450mg
* Placebo
Study burden and risks
Inflammation driven by IL-1b has been shown to be an independent risk factor
for atherosclerotic diseases and major cardiovascular events. Given that
canakinumab, by inhibiting IL-1b, demonstrated a risk-reduction in the large
outcome trial CANTOS, it is expected that a NLRP3 inhibitor is similarly
effective. The fact that IZD334 also inhibits IL-18 production may add
additional value over canakinumab. It is further assumed that IZD334 lacks an
increased risk of severe infectious episodes during long-term treatment. In
addition, IZD334 is free of major drug-drug interaction issues and the drug may
be admimistered as a once daily oral therapy. This makes IZD334 an attractive
novel drug for the patient population of interest. The herein proposed study
has been designed as a multi-center, randomized, parallel group, placebo
controlled, double-blind trial to provide evidence on dose-dependent effects of
IZD334 on surrogate markers of cardiovascular risk such as CRP and to study the
safety and tolerability profile in the target population over 12 weeks of
treatment. The safety and tolerability profile of IZD334 was found to be
unremarkable during phase I clinical testing in human subjects exposed at the
highest dose of 450 mg qd for one week. The proposed treatment duration of 12
weeks in light of a favourable safety profile as determined in 13 week
toxicology studies in rats and monkeys with exposure levels above those
predicted under the highest dose of 450 mg QD seems justifiable. Further, PK/PD
modelling data derived from the first in man study in healthy subjects allowed
to propose a dose-rationale.
In summary, the benefit-risk assessment is considered positive and supportive
of conducting the herein proposed study in patients with CAD and increased
systemic inflammation.
Harcourt Street 88
Dublin 2 D02 DK18
IE
Harcourt Street 88
Dublin 2 D02 DK18
IE
Listed location countries
Age
Inclusion criteria
1. Signed and dated informed consent form obtained before any study assessment
is performed
2. Male or female patients aged *18 years
3. Stable coronary artery disease (CAD) where stable coronary artery disease
refers to any of the following:
a. a reversible supply/demand mismatch related to ischemia or
b. a history of myocardial infarction (minimum 30 days prior to randomization)
or
c. the presence of coronary artery plaque of any severity documented by cardiac
catheterization or computed tomography angiography.
Patients are considered stable if they are asymptomatic or their symptoms are
adequately controlled by medications or revascularization.
4. Elevated plasma CRP level of * 2 mg/L at screening visit 1 (local lab) and
confirmed at screening visit 2 by central lab
5. Negative pregnancy test for females of child-bearing potential
(premenopausal, * 2 years post-menopausal, not surgically sterile)
6. Stable concomitant medication for at least 4 weeks prior to randomization
7. Patients with creatinine clearance * 30 mL/min/1.73m2 by the MDRD
(modification of diet in renal disease) equation may be included
Exclusion criteria
1. Any use of NSAIDs or steroids or cholchicine or anti-IL-1 inhibitors within
4 weeks prior to randomization (ASS 100mg as part of SOC treatment is allowed /
topical, inhaled, local steroid use in doses that are not considered to cause
systemic effects are permitted)
2. Any investigational drugs or participation in a clinical trial within 4
weeks or five half-lives (whichever is longer) prior to randomization
3. Active systemic infections (other than common cold) during the two weeks
prior to randomization
4. Positive test for hepatitis B virus surface antigen (HBsAg) or Hepatitis C
virus RNA at screening
5. Positive test for HIV at screening
6. History of severe hypersensitivity according to the investigator*s judgement
to previous drugs of similar chemical classes
7. Any severe, progressive or uncontrolled medical condition at baseline that
in the judgment of the investigator prevents the patient from participating in
the study including uncontrolled hypertension, uncontrolled diabetes and severe
hepatic disease
8. Symptomatic patients with Class IV heart failure (HF) (New York Heart
Association)
9. Planned Percutaneous Coronary Intervention (PCI) or Coronary Artery Bypass
Grafting (CABG)
10. Any clinically significant abnormal laboratory tests at screening
11. A history of alcohol and/or substance abuse that could interfere with the
conduct of the trial
12. Inability or unwillingness to undergo repeated venipunctures (e.g., due to
poor tolerability or lack of access to veins)
13. Pregnant or nursing (lactating) women, where pregnancy is defined as the
state of a female after conception and until the termination of gestation,
confirmed by a positive human chorionic gonadotropin (HCG) laboratory test (> 5
mIU/mL)
14. Women of childbearing potential unwilling or unable to practice effective
method of contraception
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 | EUCTR2020-000942-32-NL |
| CCMO | NL73726.018.20 |