Primary objective:To demonstrate superiority of three dose levels of oral NNC0385-0434 versus placebo on percent change in LDL-C from baseline to week 12 in patients with established ASCVD or ASCVD risk on maximally tolerated statin dose and other…
ID
Source
Brief title
Condition
- Cardiac disorders, signs and symptoms NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change in LDL-cholesterol From baseline (week 0) to visit 9 (week 12) %
Secondary outcome
Supportive secondary endpoints
% Change in total cholesterol From baseline (week 0) to visit 9 (week 12)
% Change in HDL-cholesterol From baseline (week 0) to visit 9 (week 12)
% Change in VLDL-cholesterol From baseline (week 0) to visit 9 (week 12)
% Change in triglycerides From baseline (week 0) to visit 9 (week 12)
% Change in total Apo B From baseline (week 0) to visit 9 (week 12)
% Change in total Apo CIII From baseline (week 0) to visit 9 (week 12)
Ratio Change in total Lp(a) From baseline (week 0) to visit 9 (week 12)
Number of adverse events: Treatment-emergent adverse events From baseline (week
0) to visit 10 (19 weeks + 4 days)
Number of events
Background summary
The LDL-receptor is located on liver cells and involved in the removal of LDL-C
from the circulation. When LDL-C binds to the LDL-receptor, this complex moves
into the cell. The LDL-receptor releases LDL-C in the endosome for degradation
whilst the LDL-receptor is recycled back to the cell surface. If PCSK9 binds to
the LDL-receptor on its epidermal growth factor-like repeat A (EGF-A) domain,
the LDL-receptor is no longer recycled back to the cell surface but degraded
along with the bound LDL-C. Therefore, when inhibiting PCSK9, more
LDL-receptors will be recycled to the cell surface and more LDL-C can be taken
up by the liver cells, reducing LDL-C in the circulation.
Study objective
Primary objective:
To demonstrate superiority of three dose levels of oral NNC0385-0434 versus
placebo on percent change in LDL-C from baseline to week 12 in patients with
established ASCVD or ASCVD risk on maximally tolerated statin dose and other
lipid-lowering therapy requiring further LDL-C reduction.
Secondary objectives
To compare the effect on lipid/lipoprotein parameters excluding LDL-C of three
dose levels of oral NNC0385-0434 versus placebo in patients with established
ASCVD or ASCVD risk on maximally tolerated statin dose and other lipid-lowering
therapy requiring further LDL-C reduction.
To compare the effect on lipid/lipoprotein parameters of three dose levels of
oral NNC0385-0434 versus s.c. evolocumab in patients with established ASCVD or
ASCVD risk on maximally tolerated statin dose and other lipid-lowering therapy
requiring further LDL-C reduction.
To compare the safety and tolerability of three dose levels of oral
NNC0385-0434 versus placebo in patients with established ASCVD or ASCVD risk on
maximally tolerated statin dose and other lipid-lowering therapy requiring
further LDL-C reduction.
Study design
This is a randomised, multicentre, multinational, seven-armed, parallel group,
dose finding trial. The trial will be double-blinded within dose level of oral
NNC0385-0434 and size-matched placebo arm. The s.c. evolocumab arm will be open
label. The trial population includes patients with established ASCVD or ASCVD
risk on maximally tolerated statin dose and other lipid-lowering therapy
requiring further LDL-C reduction. A PK sub-study in Japanese and non-Japanese
patients will be performed following the 12 weeks of treatment.
Patients will be randomised 3:1:3:1:3:1:3 according to the following treatment
arms:
* Oral NNC0385-0434 15 mg
* Oral placebo (size-matched to oral NNC0385-0434 15 mg)
* Oral NNC0385-0434 40 mg
* Oral placebo (size-matched to oral NNC0385-0434 40 mg)
* Oral NNC0385-0434 100 mg
* Oral placebo (size-matched to oral NNC0385-0434 100 mg)
* S.c. evolocumab
Randomisation will be stratified according to participation in the PK
sub-study, country and population (inclusion criteria a/b). Within each
stratum, each patient will be randomly allocated to one of the treatment arms.
For the main statistical analyses, the 3 placebo arms will be pooled into one
placebo group.
Intervention
Patients will be randomised 3:1:3:1:3:1:3 according to the following treatment
arms:
* Oral NNC0385-0434 15 mg
* Oral placebo (size-matched to oral NNC0385-0434 15 mg)
* Oral NNC0385-0434 40 mg
* Oral placebo (size-matched to oral NNC0385-0434 40 mg)
* Oral NNC0385-0434 100 mg
* Oral placebo (size-matched to oral NNC0385-0434 100 mg)
* S.c. evolocumab
Study burden and risks
Currently, there are no identified risk with evidence of a causal association
with NNC0385-0434.
Potential risk:
Hypersensitivity/allergic reaction
As with all protein-based pharmaceuticals, patients treated with NNC0385-0434
are at risk of developing immunogenic and allergic reactions.
As a precaution, patients with known or suspected hypersensitivity to trial
product or related products are excluded. In addition, patients will be
instructed to contact the site staff as soon as possible for further guidance
if suspicion of a hypersensitivity reaction to the trial product occurs.
Considering the measures taken to minimise risk to patients participating in
this trial, the potential risks identified in association with NNC0385-0434 are
justified by the anticipated benefits that may be afforded to patients with
established ASCVD or ASCVD risk.
Flemingweg 8
Alphen aan den Rijn 2408AV
NL
Flemingweg 8
Alphen aan den Rijn 2408AV
NL
Listed location countries
Age
Inclusion criteria
- Male patient or female patient of non-childbearing potential.
- Established atherosclerotic cardiovascular disease (ASCVD) (criteria a) or
ASCVD risk (criteria b):
a)Age greater than or equal to 40 years at the time of signing informed consent
and history of ASCVD
b)Age greater than 50 years at the time of signing informed consent and with
ASCVD risk
- Serum LDL-C greater than or equal to1.8 mmol/L (greater than or equal to 70
mg/dL) as measured by the central laboratory at screening.
Japanese patients: Serum LDL-C greater than or equal to 2.6 mmol/L (greater
than or equal to 100 mg/dL) for patients of greater than or equal to 40 years
of age and with a history of coronary heart disease, and serum LDL-C greater
than or equal to 3.1 mmol/L (greater than or equal to 120 mg/dL) for all other
Japanese patients
- Patients must be on maximally tolerated dose of statins.
- Patients not receiving statin must have documented evidence of intolerance to
all doses of at least two different statins.
Exclusion criteria
- Treatment with PCSK9i therapy (alirocumab or evolocumab within 90 days prior
to screening) or PCSK9 siRNA therapy (inclisiran within 12 months prior to
screening).
- Fasting triglyceride greater than 4.52 mmol/L (greater than 400 mg/dL) as
measured by the central laboratory at screening.
- Myocardial infarction, stroke, hospitalization for unstable angina pectoris
or transient ischaemic attack within 180 days prior to the day of screening.
- Renal impairment with eGFR below 30 ml/min/1.73 m^2 as measured by the
central laboratory at screening.
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 | EUCTR2020-002630-32-NL |
| CCMO | NL77330.041.21 |
| Other | U1111-1252-3392 |