Clinical Trials Register

Summary
EudraCT Number:	2021-003759-40
Sponsor's Protocol Code Number:	CKJX839A12402
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2022-03-28
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Bulgarian Drug Agency

A.2

EudraCT number

2021-003759-40

A.3

Full title of the trial

Efficacy, safety, tolerability and quality of life of ongoing individually optimized  lipid-lowering therapy with or without inclisiran (KJX839) – a randomized, placebo-controlled, double-blind multicenter phase IV study in participants with hypercholesterolemia

Ефикасност, безопасност, поносимост и качество на живот при текуща, индивидуално оптимизирана липидопонижаваща терапия със или без инклисиран (KJX839) – фаза 4, рандомизирано, плацебо-контролирано, двойно-сляпо, многоцентрово изпитване при участници с хиперхолестеролемия

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study to understand if inclisiran is better than a placebo at lowering LDL-cholesterol, is safe and can have an impact on patient quality of life, when given along with other lipid lowering medications.

A.4.1

Sponsor's protocol code number

CKJX839A12402

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Novartis Pharma AG
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Pharma AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Pharma AG
B.5.2	Functional name of contact point	Clinical Trial Information Desk
B.5.3	Address:
B.5.3.1	Street Address	Forum 1, Novartis Campus
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4056
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+41 61 324 1111
B.5.5	Fax number	+41 61 324 8001
B.5.6	E-mail	clinicaltrial.enquiries@novartis.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Leqvio 284 mg solution for injection in pre-filled syringe
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Inclisiran
D.3.2	Product code	KJX839
D.3.4	Pharmaceutical form	Solution for injection in pre-filled syringe
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	INCLISIRAN
D.3.9.1	CAS number	1639324-58-5
D.3.9.2	Current sponsor code	KJX839
D.3.9.3	Other descriptive name	Inclisiran sodium
D.3.9.4	EV Substance Code	SUB182427
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection in pre-filled syringe
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Hypercholesterolemia

E.1.1.1

Medical condition in easily understood language

Hypercholesterolemia, specifically elevated low density lipoprotein cholesterol (LDL-C), is one of the major risk factors for the development of coronary heart disease (CHD)

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10020604
E.1.2	Term	Hypercholesterolemia
E.1.2	System Organ Class	10027433 - Metabolism and nutrition disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Inclisiran, on top of ongoing individually optimized LLT, compared to placebo, on top of ongoing individually optimized LLT, on reaching a participant's individual LDL-C target as defined in 2019 ESC/EAS guidelines for the management of dyslipidemias (Mach et al 2020)

E.2.2

Secondary objectives of the trial

Inclisiran, on top of ongoing individually optimized LLT, compared to placebo, on top of ongoing individually optimized LLT, on:
•Reducing mean LDL-C levels over the double-blind study period.
•Muscle-related adverse events.
•Annualized number of days pain is experienced using a pain diary.
•Pain-related quality of life at day 360 using the Short-Form Brief Pain Inventory (SF-BPI).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

● Male or female participants ≥18 years of age.
● Participants meeting one of the following CV category:
●Very high risk participants with at least one of the following:
● Documented Atherosclerotic cardiovascular disease (ASCVD)
i Acute coronary syndrome: Unstable angina or myocardial infarction.
ii Stable angina.
iii Coronary revascularization.
iv Unequivocally documented ASCVD upon prior imaging.
v Stroke and TIA.
vi Peripheral artery disease (PAD).
● Diabetes mellitus (DM) with target organ damage (defined as microalbuminuria, retinopathy, or neuropathy), or at least ≥ 3 major risk factors, or early onset of Type 1 DM of long duration (> 20 years).
● A calculated SCORE2 ≥ 7.5% for age <50 years; SCORE2 ≥10% for age 50-69 years; SCORE2-OP ≥15% for age ≥70 years to estimate 10-year risk of fatal and non-fatal cardiovascular disease (CVD).
● Pre-existing diagnosis of heterozygous familial hypercholesterolemia (HeFH) with ASCVD or with another major risk factor.

OR

● High risk participants with at least one of the following:
● Markedly elevated single risk factors, in particular total cholesterol >310 mg/dL, LDL-C > 190 mg/dL, or blood pressure ≥ 180/110 mmHg
● Pre-existing diagnosis of HeFH without other major risk factors.
● Diabetes Mellitus (DM) without target organ damage (defined as microalbuminuria, retinopathy, or neuropathy), with DM duration ≥ 10 years or other additional risk factor.
● Moderate chronic kidney disease (eGFR 30-59 mL/min/1.73m2).
● A calculated SCORE2 2.5 to <7.5% for age < 50 years, SCORE2 5 to < 10% for age 50-69 years; SCORE2-OP 7.5 to < 15% for age ≥70 years to estimate 10-year risk of fatal and non-fatal CVD.

● LDL-C levels at screening and baseline:
● in participants with very high cardiovascular risk: serum LDL-C ≥55 mg/dL.
● in participants with high cardiovascular risk: serum LDL-C ≥70 mg/dL.
● Participant on a stable dose of a statin for ≥ 30 days at screening.
● Participants on the individual MTD of statin for ≥ 30 days at baseline.
● Fasting triglyceride < 400 mg/dL at screening and baseline.

E.4

Principal exclusion criteria

● Participants on more than one other lipid-lowering drug on top of statin at screening visit.
● Participants with a known intolerance to rosuvastatin at screening or baseline visit.
● Previous (within 90 days of screening), current or planned treatment with a monoclonal antibody (mAb) directed towards PCSK9 (e.g. evolocumab, alirocumab) at screening or baseline visit.
● Previous exposure to inclisiran or any other non-mAb PCSK9 targeted therapy, either as an investigational or marketed drug within 2 years prior to screening or baseline visit.
● Previous, current or planned treatment with LDL-apheresis at screening or baseline visit.
● Liver and CK: (a) Active liver disease defined as any current infectious, neoplastic, or metabolic pathology of the liver or (b) unexplained alanine aminotransferase (ALT), aspartate aminotransferase (AST) elevation >3x ULN, or total bilirubin elevation > 2x ULN (except for participants with Gilbert's syndrome), or (c) creatine kinase (CK) >5x ULN at screening or baseline visit.
● Participant with severe renal impairment defined by eGFR <30 mL/min/1.73m2 as calculated by the Modification in Diet in Renal Disease (MDRD) formula at screening or baseline visit.
● Acute coronary syndrome, ischemic stroke or TIA, coronary revascularization or peripheral arterial revascularization procedure or amputation due to atherosclerotic disease < 3 months prior to the screening or baseline visit.
● Heart failure New York Heart Association (NYHA) class IV at screening or baseline visit
● Pregnant or nursing (lactating) women at screening or baseline visit.
● Women of child-bearing potential, unless they are using highly effective methods of contraception during dosing of study treatment.

E.5 End points

E.5.1

Primary end point(s)

Proportion of participants achieving individual LDL-C target (< 55 mg/dL or < 70 mg/dL) at day 90

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 90

E.5.2

Secondary end point(s)

•Relative change (percentage from baseline to mean LDL-C level) over the double-blind treatment period.
•Proportion of participants experiencing at least one muscle-related AE as defined in the Standardized MedDRA Queries (SMQ) rhabdomyolysis / myopathy from day 1 to day 360.
•Proportion of participants experiencing self-reported pain.
Annualized number of days participants experiencing self-reported pain from baseline to day 360.
•Change from baseline in SF-BPI pain severity score to day 360
Change from baseline in SF-BPI pain interference score to day 360.
Proportion of participants with clinically relevant change in SF-BPI pain severity score from baseline to day 360.
Proportion of participants with clinically relevant change in SF-BPI pain interference score from baseline to day 360.

E.5.2.1

Timepoint(s) of evaluation of this end point

From baseline to day 360.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

tolerability , quality of life

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

144

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

792

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

968

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

300

F.4.2

For a multinational trial

F.4.2.1

In the EEA

1760

F.4.2.2

In the whole clinical trial

1760

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Participants who complete participation in this trial and continue to derive clinical benefit from the treatment based on the investigator’s evaluation may receive post-trial access, if inclisiran is not locally available.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2022-06-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-05-05

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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