Primary:• To evaluate the effect of inclisiran treatment on low density lipoprotein cholesterol (LDL-C) levels at Day 210 compared to Day 1 of this extension study. Secondary:• To evaluate the effects of inclisiran on the following: LDL-C levels…
ID
Source
Brief title
Condition
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Parameters to be assessed will include: total cholesterol (TC), triglycerides,
LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, very
low-density lipoprotein (VLDL), apolipoprotein A1 (Apo-AI), apolipoprotein B
(Apo-B), lipoprotein(a) [Lp(a)], C-reactive protein (CRP), and PCSK9.
Secondary outcome
n/a
Background summary
This is an open-label comparator study in male and female subjects with
atherosclerotic cardiovascular disease (ASCVD) or ASCVD-risk equivalents and
elevated low-density lipoprotein cholesterol (LDL-C) despite maximum tolerated
dose of LDL-C lowering therapies. This study is an extension trial to the
ORION-1 study (MDCO-PCS-15-01, EudraCT: 2015-003772-74) and will evaluate the
efficacy, safety and tolerability of the investigational product, inclisiran
(formerly known as ALN-PCSSC) in comparison with evolocumab.
The overall safety data from inclisiran in nonclinical studies and clinical
data from the Phase I ALN-PCSSC-001 study, the ALN PCS02-001 study (ALN-PCS02
2014), and multiple PCSK9 antibody studies demonstrated that potent lowering of
PCSK9 is well-tolerated in human subjects and support the dose and dosing
schedule proposed in this Phase II extension study. A comparator arm has been
added to this long-term extension to evaluate safety, tolerability and patient
reported outcomes (PRO) compared to an active comparator (evolucumab).
Study objective
Primary:
• To evaluate the effect of inclisiran treatment on low density lipoprotein
cholesterol (LDL-C) levels at Day 210 compared to Day 1 of this extension
study.
Secondary:
• To evaluate the effects of inclisiran on the following:
LDL-C levels over time
PCSK9 levels over time
Other lipids, lipoproteins, and apolipoproteins over time
Proportion of subjects achieving target levels prespecified in global lipid
guidelines
Proportion of subjects at least 50% LDL-C reduction from Day 1 over time
Individual responsiveness to inclisiran
Duration of lipid-lowering effect
• To compare the effects of inclisiran and evolocumab at Day 210 on the
proportion of subjects achieving prespecified global lipid guidelines
• To compare the effects of switching from evolocumab to inclisiran on the
proportion of subjects achieving prespecified global lipid guidelines after 210
days of treatment (Day 570) (LDL-C beta quantification)
• To evaluate the long term safety and tolerability of inclisiran
• To collect/evaluate (and compare where applicable) patient reported outcomes
(PRO)
Treatment Satisfaction Questionnaire for Medications (TSQM)
Patient reported adherence to self injectable evolucumab
Exploratory:
• To collect/evaluate the effect of inclisiran on the following:
Cardiovascular (CV) events
Anti-drug antibodies (ADA) to the investigational product
• To compare the effects of inclisiran and evolocumab from Day 1 to 360 on the
following:
LDL-C levels over time
PCSK9 levels over time
Other lipids, lipoproteins, and apolipoproteins over time
Proportion of subjects with at least 50% LDL-C reduction from Day 1
• To compare the effects of switching from evolocumab to inclisiran from Day
360 to End of study (EOS) on the following:
LDL-C levels over time
PCSK9 levels over time
Other lipids, lipoproteins, and apolipoproteins over time
Proportion of subjects with at least 50% LDL-C reduction from Day 1 over time
Study design
This study will be an open label, long term extension trial with an active
comparator (evolocumab) in up to 490 subjects with atherosclerotic
cardiovascular disease (ASCVD) or ASCVD-risk equivalents (eg, diabetes and
familial hypercholesterolemia) and elevated LDL-C despite maximum tolerated
dose of LDL-C lowering therapies who have completed study MDCO-PCS-15-01
(ORION-1), to evaluate the efficacy, safety, and tolerability of long-term
dosing of inclisiran. Informed consent will be obtained from subjects before
the initiation of any study-specific procedures.
Subjects completing study MDCO-PCS-15-01 and fulfilling all inclusion and
exclusion criteria of this study will receive inclisiran or evolocumab, based
on the treatment received in study MDCO-PCS-15-01. Those subjects who received
inclisiran in MDCO-PCS-15-01 will receive inclisiran 300 mg throughout this
study, and those subjects who received placebo in MDCO-PCS-15-01 will receive
evolocumab as comparator for 1 year, and then switch to inclisiran for the
remainder of the study. Until study drug is available, subjects will have
monthly observation visits until study drug administration commences.
Day 1 is the day when eligible subjects will receive the first SC
administration of inclisiran or evolocumab. After first study drug
administration, all subjects will be observed in the clinic for at least 4
hours post injection before being discharged. Subjects will return for follow
up at Day 30, Day 90 and Day 180. Thereafter all subjects will return 30 and 90
days after study drug administration on Days 180, 360 and 540 and then every 90
days from Day 720 until the end of the study. Subjects receiving inclisiran
will receive the second injection at the Day 180 visit and every 180 days
thereafter.
Subjects receiving evolocumab will receive the first dose on Day 1,
administered by the investigator, and after that point will self administer
drug every 14 days until Day 336. At Day 360 these subjects will switch to and
receive inclisiran. From Day 360 onwards, all subjects will receive inclisiran
every 180 days until the EOS.
Efficacy assessments will measure the effects of inclisiran on levels of LDL-C
lipids and lipoproteins including total cholesterol (TC), triglycerides,
high-density lipoprotein cholesterol (HDL-C), non-HDL-C, very low-density
lipoprotein cholesterol (VLDL-C), apolipoprotein A1 (Apo-A1), apolipoprotein B
(Apo-B), lipoprotein(a) [Lp(a)], C-reactive protein (CRP), and PCSK9.
At each visit, adverse events (AEs), serious adverse events (SAEs), concomitant
medications, and safety laboratory assessments will be collected.
Formation of ADA will be assessed on Day 1 of inclisiran treatment (prior to
and 4 hours after the injection) and on Days 90, 180, 270, 360, and then every
90 days until EOS for those subjects taking inclisiran.
Patient reported outcomes (PRO) questionnaires will assess satisfaction with
treatment in all subjects during the first year of inclisiran treatment,
andadherence to self injection for those subjects who take evolocumab for the
first year.
A Safety Review Committee (which includes Data Monitoring Committee [DMC]
members) will review safety data every 2 months until the end of the trial. A
recommendation may be taken to stop or amend the study at any of these reviews.
All subjects will receive study drug for approximately 4 years (or until the
investigator's recommendation of discontinuation, sponsor's recommendation of
discontinuation, the subject's decision to discontinue for any reason, until an
administrative decision is made to end the study, or until inclisiran has
received regulatory approval in the respective country, whichever occurs
first). At this time EOS evaluations will be conducted at the EOS visit.
An interim analysis of lipids and PCSK9 will be conducted upon completion of
Day 210 by all subjects, and a further interim analysis will be conducted at
Day 720 to support an assessment of PRO.
Intervention
Subjects completing study MDCO-PCS-15-01 and fulfilling all inclusion and
exclusion criteria of this study will receive inclisiran or evolocumab, based
on the treatment received in study MDCO-PCS-15-01. Those subjects who received
inclisiran in MDCO-PCS-15-01 will receive inclisiran 300 mg throughout this
study, and those subjects who received placebo in MDCO-PCS-15-01 will receive
evolocumab as comparator for 1 year, and then switch to inclisiran for the
remainder of the study. Until study drug is available, subjects will have
monthly observation visits until study drug administration commences.
Study burden and risks
Reactions at injection site
Inclisiran will be given under your skin (subcutaneous) 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, 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.
Allergic reactions
There is a remote chance that inclisiran (like any pharmaceutical product) may
cause an allergic reaction, which in some cases can be severe - otherwise known
as an anaphylactic reaction. This anaphylactic reaction may be characterized by
sudden shortness of breath, decreased consciousness, and rash, and may require
emergency treatment. Anaphylactic reactions have not been seen in animals who
received inclisiran or in clinical trials 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 evolocumab (for patients in the comparator arm)
Evolocumab will be injected under the skin (subcutaneously) and like all
medicines, this medicine may cause side effects, although not everybody gets
them.
Common side effects: may affect up to 1 in 10 people
• Flu (high temperature, sore throat, runny nose, cough and chills)
• Common cold, such as runny nose, sore throat or sinus infections
(nasopharyngitis or upper respiratory
tract infections)
• Feeling sick (nausea)
• Back pain
• Joint pain (arthralgia)
• Injection site reactions, including rash, redness, bruising or pain
Uncommon side effects: may affect up to 1 in 100 people
• Hives, red itchy bumps on your skin (urticaria)
Risks associated with ECG
Skin irritation is rare but could occur during an ECG from the electrodes or
gel that is used.
Risks associated with Fasting
Fasting could cause dizziness, headache, stomach discomfort, or fainting.
Reproductive Risks
Inclisiran & Evolocumab
The effects of inclisiran and evolocumab on the unborn child are unknown. It is
not known if the medicines could affect male sperm. There is no information on
the long-term effects of inclisiran and evolocumab on fertility.
In order to reduce the risk of pregnancy, female subjects of child-bearing
potential must use two effective methods of birth control while participating
in this study. If you are already using a method of birth control, the study
doctor or study staff will discuss with you whether your current method of
birth control is acceptable for use during this study.
Acceptable birth control methods include, but are not limited to, oral
contraceptives, barrier methods (diaphragm), approved contraceptive implant,
long-term injectable contraception,intrauterine device (IUD) and tubal
litigation (tubes tied).
Male subjects must agree to use an effective method of birth control during the
entire study (ie, condom with spermicide).
Lichtstrasse 35
Basel 4056
CH
Lichtstrasse 35
Basel 4056
CH
Listed location countries
Age
Inclusion criteria
1. Completion of study MDCO-PCS-15-01 and no contraindications to receiving
inclisiran or evolucumab.
2. Willing and able to give informed consent before initiation of any
study-related procedures and willing to comply with all required study
procedures.
3. Willing to self-inject
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*s]
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. Serious comorbid disease in which the life expectancy of the subject is
shorter than the duration of the trial (eg, acute systemic infection, cancer,
or other serious illnesses).
4. Active liver disease defined as any known current infectious, neoplastic, or
metabolic pathology of the liver or unexplained alanine aminotransferase (ALT),
aspartate aminotransferase (AST), elevation >2x the upper limit of normal
(ULN), or total bilirubin elevation >1.5x ULN at study entry visit, confirmed
by a repeat abnormal measurement at least 1 week apart.
5. Females who are pregnant or nursing, or who are of childbearing potential
and unwilling to use at least two methods of contraception (eg, oral
contraceptives, barrier methods, approved contraceptive implant, long-term
injectable contraception, 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 their last
menstrual period) AND more than 55 years of age
b. Postmenopausal women (as defined above) and less than 55 years old with a
negative pregnancy test within 24 hours of enrollment
c. Women who are surgically sterilized at least 3 months prior to enrollment
6. Males who are unwilling to use an acceptable method of birth control during
the entire study period (ie, condom with spermicide).
7. Treatment with investigational medicinal products other than inclisiranor
devices within 30 days or five half*lives, whichever is longer.
8. Planned use of other investigational medicinal products other than
inclisiranor devices during the course of the study.
9. Subjects with a history of a serious hypersensitivity reaction to
evolocumab or any of the excipients.
10. Previous or current treatment (within 90 days of study entry) with
monoclonal antibodies directed towards PCSK9.
11. Any condition that according to the investigator could interfere with the
conduct of the study, such as but not limited to:
a. Inappropriate for this study, including 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. Involved with, or a relative of, someone directly involved in the conduct of
the study.
e. Any known cognitive impairment (eg, Alzheimer*s disease).
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 | EUCTR2016-003815-37-NL |
| CCMO | NL60283.000.17 |