Primary :The primary objective 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 after Day 90 up to Day 540 levelsSecondary:The secondary objectives are to…
ID
Source
Brief title
Condition
- Cardiac disorders, signs and symptoms NEC
- Cardiac and vascular disorders congenital
- Lipid metabolism disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoints:
* Percentage change in LDL-C from baseline to Day 510
* Tine adjusted percentage change in LDL-C from baseline after Day 90 up to Day
540. This is the average percentage change in LDL-C from baseline over the
period after Day 90 up to Day 540.
Secondary outcome
Key Secondary Endpoints:
* Absolute change in LDL-C from baseline to Day 510
* Time adjusted absolute change in LDL-C from baseline after Day 90 up to Day
540
* Percentage change from baseline to Day 510 in PCSK 9, total cholesterol,
ApoB, and non-HDL-C
Other Secondary Endpoints:
* 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% LDL-C
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
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
Primary :
The primary objective 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 after Day 90 up to
Day 540 levels
Secondary:
The secondary objectives are to evaluate the effect of inclisiran on:
* Proprotein convertase subtilisin/kexin type 9 (PCSK9), total cholesterol,
ApoB, and non-high-density lipoprotein cholesterol (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
Exploratory:
The exploratory objectives are to collect/evaluate the effect of inclisiran on
the following:
* Cardiovascular (CV) events such as CV death, resuscitated cardiac arrest,
non-fatal myocardial infarction (MI), and non-fatal stroke (ischemic and
hemorrhagic)
* Response of LDL-C reduction by underlying causal mutations of HeFH
Study design
This study is a Phase III, placebo-controlled, double-blind, randomized study
in 400 subjects with HeFH 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).
Subjects will be screened and approximately 400 eligible subjects will be
randomized: 200 subjects will be randomized to inclisiran sodium 300 mg and 200
subjects randomized to placebo. Treatment allocation will be stratified by
country and by current use of statins or other lipid-modifying therapies. Each
subject will receive four subcutaneous injections of blinded inclisiran or
placebo on Day 1, Day 90, Day 270, and Day 450.
On Day 1, all eligible subjects will be randomized and will receive the first
subcutaneous (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).
All subjects will be invited to consent to pharmacogenetic analyses, unless
underlying causal mutations of HeFH are well documented by a validated
specialized laboratory. A blood sample will be collected, preferably during
screening, only from subjects who sign a separate consent for pharmacogenetics.
Safety assessments including adverse events (AEs), serious adverse events
(SAEs), electrocardiograms (ECGs), concomitant medications, and safety
laboratory parameters will also be collected during the study. In addition,
formation of anti-drug antibodies (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 theend of study 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
ie, 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.
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
Subjects may be included in the study if they meet all of the following
criteria:
1. Male or female subjects *18 years of age.
2. History of HeFH with a diagnosis of HeFH by genetic testing; and/or a
documented history of untreated LDL-C of >190 mg/dL, and a family history of
FH, elevated cholesterol or early heart disease may indicate FH
3. Stable on a low-fat diet (eg, NCEP)
4. Serum LDL-C *2.6 mmol/L (*100 mg/dL) at screening
5. Fasting triglyceride <4.52 mmol/L (<400 mg/dL) at screening.
6. Calculated glomerular filtration rate >30 mL/min by estimated glomerular
filtration rate (eGFR) using standardized clinical methodology.
7. 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)
8. Subjects not receiving statin must have documented evidence of intolerance
to all doses of at least two different statins
9. 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.
10. 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
Subjects will be excluded from the study if any of the following exclusion
criteria apply prior to randomization:
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 IV heart failure or last known left
ventricular ejection fraction <25%.
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 >180 mmHg 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 alanine
aminotransferase (ALT), aspartate aminotransferase (AST), >3x the upper limit
of normal (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 enrollment.
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. Treatment (within 90 days of screening) with monoclonal antibodies directed
towards PCSK9.Subjects excluded for any of the above reasons may not be
re-screened for participation at any time even if the exclusion characteristic
has changed.font>
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 | EUCTR2017-002472-30-NL |
| CCMO | NL63081.000.17 |