The primary objective of this study is to evaluate the effect of inclisiran treatment on:•LDL-C levels at Day 510•Time adjusted percent change in LDL-C levels from baseline between Day 90 and Day 540 levels. The secondary objectives of this study…
ID
Source
Brief title
Condition
- Cardiac disorders, signs and symptoms NEC
- Lipid metabolism disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoints of this study are the:
•Percentage change in LDL-C from baseline to Day 510
•Time adjusted percentage change in LDL-C from baseline between Day 90 and Day
540. This is the average percentage change in LDL-C from baseline over the
period between Day 90 and Day 540.
Secondary outcome
The key secondary endpoints of this study are:
•Absolute change in LDL-C from baseline to Day 510
•Time adjusted absolute change in LDL-C from baseline between Day 90 and Day 540
•Percentage change from baseline to Day 510 in PCSK9, total cholesterol, ApoB,
and non-HDL-C
The other secondary endpoints of this study are:
•Mean maximum percentage change in LDL-C
•Absolute change from baseline to Day 510 in PCSK9, total cholesterol, ApoB and
non-HDL-C
•Absolute change and percentage change in LDL-C from baseline to each
assessment time up to Day 540
•Individual responsiveness defined as the number of subjects reaching on
treatment LDL-C levels of <25 mg/dL, <50 mg/dL, <70 mg/dL, and <100 mg/dL at
Day 510
•Proportion of subjects in each group with greater or equal to 50% LDLC
reduction from baseline
•Absolute change and percentage change in other lipids, lipoproteins,
apolipoproteins, and PCSK9 from baseline at each subsequent visit to Day 540
•Proportion of subjects in each group who attain global lipid targets for their
level of ASCVD risk
•Safety and tolerability profile of inclisiran as measured by AEs, SAEs, vital
signs, clinical laboratory values, ECG measurements and formation of ADA and
subsequent characterization of ADA
Background summary
Despite advances in treatment, cardiovascular disease (CVD) is the leading
cause of death worldwide, resulting in over 17 million deaths annually [WHO,
2016]. Eighty percent of all CVD deaths are due to coronary heart disease (CHD)
or strokes. Elevated low-density lipoprotein associated cholesterol (LDL-C) is
a major risk factor for the development of CVD [Grundy et al, 2004; Go et al,
2014]. Lowering LDL-C has been shown to reduce the risk of death or heart
attack and within the range of effects achieved so far, the clinical risk
reduction is linearly proportional to the absolute LDL-C reduction [Baigent et
al 2005]. Recently developed and approved PCSK9-blocking monoclonal antibodies
reduce circulating PCSK9 levels and lower LDL-C levels. Preliminary reports
indicate that treatment with such antibodies can lead to reduction of
cardiovascular events compared with placebo.
The data from PCSK9 blocking antibodies such as Repatha® (evolocumab) and
Praluent® (arilocumab) are very encouraging. However, these products are dosed
SC every 2 to 4 weeks necessitating up to 26 injections per year [Hooper et al,
2005; Navarese et al, 2015; Zhang et al, 2015]. In contrast, one injection of
inclisiran is anticipated to be given three times in the first year and every 6
months thereafter.
Study objective
The primary objective of this study is to evaluate the effect of inclisiran
treatment on:
•LDL-C levels at Day 510
•Time adjusted percent change in LDL-C levels from baseline between Day 90 and
Day 540 levels.
The secondary objectives of this study are to evaluate the effect of
inclisiran on:
•PCSK9, total cholesterol, ApoB and non-HDL-C at Day 510
•LDL-C and PCSK9 levels over time to Day 540
•Mean maximum reduction in LDL-C levels
•LDL-C and PCSK9 levels over time in individual subjects
•Other lipids, lipoproteins, apolipoproteins
•Proportion of subjects achieving prespecified LDL-C targets
•Safety and tolerability profile of inclisiran
Study design
This study is a Phase III, placebo-controlled, double-blind, randomized study
in 1500 subjects with ASCVD (coronary heart
disease [CHD], cerebrovascular disease [CVD] or peripheral arterial disease
[PAD]) or ASCVD-risk equivalents (eg, type 2
diabetes and familial hypercholesterolemia, 20% or greater risk of a CV event
as assessed by Framingham risk score or
equivalent) and elevated LDL-C despite maximum tolerated dose of LDL-C lowering
therapies to evaluate the efficacy, safety,
and tolerability of subcutaneous inclisiran injection(s).
This study is a Phase III, placebo-controlled, double-blind, randomized study
in 1500 subjects with ASCVD (coronary heart
disease [CHD], cerebrovascular disease [CVD] or peripheral arterial disease
[PAD]) or ASCVD-risk equivalents (eg, type 2
diabetes and familial hypercholesterolemia, 20% or greater risk of a CV event
as assessed by Framingham risk score or
equivalent) and elevated LDL-C despite maximum tolerated dose of LDL-C lowering
therapies to evaluate the efficacy, safety,
and tolerability of subcutaneous inclisiran injection(s).
On Day 1, all eligible subjects will be randomized and will receive the first
SC injection of investigational product (inclisiran or
placebo). After the first SC injection, the subject will be observed in the
clinic for at least 4 hours post injection in order to have
additional laboratory assessments and vital signs completed before being
discharged. Subjects will return on Day 90, Day 270,
and Day 450 to receive additional investigational product. During these
subsequent dosing visits, subjects will be observed in
the clinic for at least 30 minutes after administration of each injection and
have additional laboratory assessments completed if
needed. Subjects will also have in clinic visits on Day 30, Day 150, Day 330,
and Day 510 for follow-up and limited laboratory
assessments. The end of study (EOS) visit will be conducted on Day 540.
Pharmacodynamic assessments will be collected at various visits and include
LDL-C levels as well as other lipids and
lipoproteins (eg, total cholesterol, triglycerides, HDL-C, non HDL-C, very
low-density lipoprotein cholesterol [VLDL-C],
apolipoprotein A1 [Apo-A1], apolipoprotein B [ApoB], lipoprotein(a) [Lp(a)],
high sensitivity C-reactive protein [hsCRP], and
PCSK9).
Safety assessments including adverse events (AEs), serious adverse events
(SAEs), ECGs, concomitant medications, and safety laboratory parameters will
also be collected during the study. In addition, formation of ADA and further
characterization of ADA will be evaluated.
End of study evaluations will be conducted at the Day 540 visit. Subjects who
have completed the study to Day 540 will be given the opportunity to enroll in
a separate open label long-term extension study to collect long-term safety and
efficacy data for inclisiran.
The independent Data Monitoring Committee (IDMC) will review safety data after
the first 40 subjects receive the first SC injection of inclisiran or placebo
and have completed 1 month follow-up. Thereafter the IDMC will review safety
data every 3 months until the EOS unless requested otherwise by the IDMC. A
recommendation may be taken to stop or amend the study at any of these reviews.
Intervention
Inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) will be administered
as a single SC injection on Day 1, Day 90, Day
270, and Day 450.
Placebo will be administered as SC injections of saline solution. Placebo
volume will be matched to test product volume within
each dose and injection i.e., the 300 mg dose will be administered as 1.5 mL of
placebo.
Study burden and risks
Inclisiran
In a previous study in subjects with high LDL-C (*bad* cholesterol), 51
subjects received single or multiple doses of inclisiran. In this study
inclisiran at various doses was well tolerated with no serious side effects.
The most common side effects in people who received one dose were cough,
nasopharyngitis (cold-like symptoms), and musculoskeletal (muscle and bone)
pain. One mild local injection site reaction occurred at a dose of inclisiran
that is higher than the doses planned for the study you are being asked to
join. The most common side effects in subjects who received more than one dose
of inclisiran were headache, back pain, diarrhea, nasopharyngitis (cold-like
symptoms) and nausea. Three subjects had mild, local reactions at the site
where they were injected. The total dose given in the previous study was more
than you will receive in this study. Since the study drug is investigational
when taken alone or in combination with other medications, there may be other
risks that are unknown. All drugs have a potential risk of an allergic
reaction, which if not treated promptly, could become life-threatening.
In the second inclisiran clinical study (a dose finding study in almost 500
subjects) , single and multiple doses of inclisiran were well tolerated with a
similar safety profile between the subjects receiving inclisiran compared to
those receiving placebo. Many subjects in this clinical study have been
followed for up to one year. The most common side effects in those receiving
one injection were cold like symptoms, cough, headache, muscle pain, joint pain
and back pain, and the most common side effects in subjects receiving two
inclisiran doses were cold-like symptoms, headache, diarrhea, joint pain,
muscle pain, and back pain.
These side effects may or may not be related to inclisiran. A low number of
subjects, around 5% experienced mild localized reactions at the site of the
injection. These reactions were usually short lived and resolved within 1-2
weeks without requiring any treatment. There were no changes in laboratory
measures considered related to inclisiran.
Placebo
If you are receiving placebo there is a possibility that symptoms of your
disease may return or get worse.
Injection Reactions
Inclisiran will be given under your skin in your abdomen and like with any
injection given under the skin, you could develop a reaction at the site of the
injection. You could develop pain, tenderness, redness, swelling, itching,
rash, formation of sores, skin color changes, or other reactions around an
injection site. If you have a reaction, you may undergo an examination by a
doctor or other health care professional and have photographs taken of the area
of interest. The photographs will, whenever possible, be taken in such a way as
to prevent disclosure of your identity. During the study, the study staff will
check the site of injection for any reactions. In the previous study around 5%
of all patients receiving treatment had an injection site reaction. These were
usually mild and localized and did not require any specific treatment,
resolving usually within 1-2 weeks.
Allergic reactions
There is a remote chance that inclisiran (like any investigational drug) may
cause an allergic reaction, which in some cases can be severe. This severe
reaction may be characterized by sudden shortness of breath, decreased
consciousness, and rash, and may require emergency treatment. These severe
reactions have not been seen in animals who received inclisiran at much higher
doses than are planned in this trial or in clinical trials with inclisiran or
where similar drugs to those used in this study were given to humans.
Risks associated with blood draws
There is a risk of minor discomfort, bruising, bleeding, swelling, or (rarely)
infection at the site of needle insertion for blood drawing.
Risks associated with ECG
Skin irritation is rare but could occur during an ECG from the electrodes or
gel that is used.
Fasting Risks
Fasting could cause dizziness, headache, stomach discomfort, or fainting.
Reproductive risks
It is not known if the study treatment by inclisiran may affect an unborn child
or nursing infant. It is not known if the medicines could affect male sperm.
There is no information on the long-term effects of inclisiran on fertility.
Benefit
If the patiënts are placed on inclisiran, they may benefit from treatment with
inclisiran and it may prove as safe or safer and as effective as or more
effective due to its unique effects on lowering the *bad* cholesterol than
other treatment you might have previously received. In the future, other people
with elevated cholesterol may benefit from the information we learn from this
study.
Sylvan Way 8
Parsippany NJ 07054
US
Sylvan Way 8
Parsippany NJ 07054
US
Listed location countries
Age
Inclusion criteria
1. Male or female subjects >=18 years of age.
2. History of ASCVD (CHD, CVD or PAD; see APPENDIX A in the protocol) or ASCVD-risk equivalents (type 2 diabetes, familial hypercholesterolemia, and including subjects whose 10-year risk of a CV event assessed by Framingham Risk Score or equivalent has a target LDL-C of <100 mg/dL).
3. Serum LDL-C >=1.8 mmol/L (>=70 mg/dL) for ASCVD subjects or >=2.6 mmol/L (>=100 mg/dL) for ASCVD-risk equivalent subjects at screening.
4. Fasting triglyceride <4.52 mmol/L (<400 mg/dL) at screening.
5. Calculated glomerular filtration rate >30 mL/min by estimatedglomerular filtration rate (eGFR) using standardized clinical methodology.
6. Subjects on statins should be receiving a maximally tolerated dose. Maximum tolerated dose is defined as the maximum dose of statin that can be taken on a regular basis without intolerable adverse events. Intolerance to any dose of any statin must be documented as historical AEs attributed to the statin in question in the source documentation and on the Medical History page of the electronic case report form (eCRF) (APPENDIX B from the
protocol).
7. Subjects not receiving statin must have documented evidence of intolerance to all doses of at least two different statins (see APPENDIX B from the protocol).
8. Subjects on lipid-lower therapies (such as a statin and/or ezetimibe) should be on a stable dose for >=30 days before screening with no planned medication or dose change during study participation.
9. Subjects must be willing and able to give informed consent before initiation of any study-related procedures and willing to comply with all required study procedures.
Exclusion criteria
1. Any uncontrolled or serious disease, or any medical or surgical condition, that may either interfere with participation in the clinical study, and/or put the subject at significant risk (according to investigator's [or delegate] judgment) if he/she participates in the clinical study.
2. An underlying known disease, or surgical, physical, or medical condition that, in the opinion of the investigator (or delegate) might interfere with interpretation of the clinical study results.
3. New York Heart Association (NYHA) class III or IV heart failure or last known left ventricular ejection fraction <30%.
4. Cardiac arrhythmia within 3 months prior to randomization that is not controlled by medication or via ablation.
5. Major adverse cardiovascular event within 3 months prior to randomization.
6. Uncontrolled severe hypertension: systolic blood pressure >180mmHg or diastolic blood pressure >110 mmHg prior to randomization despite anti-hypertensive therapy.
7. Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the liver or unexplained elevations in ALT, aspartate aminotransferase (AST), >3x the ULN, or total bilirubin >2x ULN at screening confirmed by a repeat abnormal measurement at least 1 week apart.
8. Severe concomitant noncardiovascular disease that carries the risk of reducing life expectancy to less than 2 years.
9. History of malignancy that required surgery (excluding local and wide-local excision), radiation therapy and/or systemic therapy during the three years prior to randomization.
10. Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least two methods of highly effective contraception (failure rate less than 1% per year) (eg combined oral contraceptives,barrier methods, approved contraceptive implant, longterm injectable contraception, or intrauterine device) for the entire duration of the study. Exemptions from this criterion:
a. Women >2 years postmenopausal (defined as 1 year or longer since last menstrual period) AND more than 55 years of age.
b. Postmenopausal women (as defined above) and less than 55 years of age with a negative pregnancy test within 24 hours of randomization.
c. Women who are surgically sterilized at least 3 months prior to enrolment.
11. Males who are unwilling to use an acceptable method of birth control during the entire study period (ie, condom with spermicide).
12. Known history of alcohol and/or drug abuse within the last 5 years.
13. Treatment with other investigational products or devices within 30 days or five half lives of the screening visit, whichever is longer.
14. Planned use of other investigational products or devices during the course of the study.
15. Any condition that according to the investigator could interfere with the conduct of the study, such as but not limited to:
a. Subjects who are unable to communicate or to cooperate with the investigator.
b. Unable to understand the protocol requirements, instructions and study-related restrictions, the nature, scope, and possible consequences of the study (including subjects whose cooperation is doubtful due to drug abuse or alcohol dependency).
c. Unlikely to comply with the protocol requirements, instructions, and study-related restrictions (eg, uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study).
d. Have any medical or surgical condition, which in the opinion of the investigator would put the subject at increased risk from participating in the study.
e. Persons directly involved in the conduct of the study.
16. Previous or current treatment (within 90 days of screening) with monoclonal antibodies directed towards PCSK9.
Design
Recruitment
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 | EUCTR2017-001846-90-NL |
| CCMO | NL64290.000.17 |