Clinical Trials Register

Summary
EudraCT Number:	2017-005066-22
Sponsor's Protocol Code Number:	CTSU_MDCO-PCS-17-01
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2018-04-16
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

UK - MHRA

A.2

EudraCT number

2017-005066-22

A.3

Full title of the trial

HPS-4/TIMI 65/ORION-4: A double-blind randomized placebo-controlled trial assessing the effects of inclisiran on clinical outcomes among people with atherosclerotic cardiovascular disease

A.3.1

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

A research study to find out whether inclisiran sodium, given as injection under the skin every 6 months for about 5 years, helps to prevent heart attacks, strokes or the need for urgent procedures to unblock the arteries supplying the heart, in people who already have vascular disease.

A.3.2

Name or abbreviated title of the trial where available

ORION-4

A.4.1

Sponsor's protocol code number

CTSU_MDCO-PCS-17-01

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	University of Oxford
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point
B.Sponsor: 2
B.1.1	Name of Sponsor	The Medicines Company
B.1.3.4	Country	United States
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	The Medicines Company
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	No
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 for Injection
D.3.2	Product code	Inclisiran for Injection
D.3.4	Pharmaceutical form	Solution for injection
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	Inclisiran sodium
D.3.9.3	Other descriptive name	ALN-60212
D.3.9.4	EV Substance Code	AS1
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
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

Atherosclerotic cardiovascular disease

E.1.1.1

Medical condition in easily understood language

Circulatory problems (such as heart attacks and strokes) caused by narrowing of the vessels supplying blood to the brain, heart and other organs

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10051615
E.1.2	Term	Atherosclerotic cardiovascular disease
E.1.2	System Organ Class	100000004866

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of ORION-4 is to determine the effect of inclisiran sodium, given 3 times in the first year and then 6 monthly for a total of around 5 years, on 'major adverse cardiovascular events' (defined as any occurrence of non-fatal myocardial infarction [heart attack], death from coronary disease, ischaemic stroke [stroke due to insufficient blood supply rather than bleeding] or urgent coronary revascularization procedure [angioplasty or bypass surgery]) during the scheduled treatment period.

E.2.2

Secondary objectives of the trial

The secondary objectives include the assessment of the effect of inclisiran on;
(1) A composite of myocardial infarction (heart attack) or death from coronary disease
(2) Cardiovascular death.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

(1) Age ≥55 years
(2) History or evidence of at least one of the following:
Myocardial infarction
Ischaemic stroke
Peripheral arterial disease (evident by lower extremity artery revascularization or aortic aneurysm repair)

E.4

Principal exclusion criteria

(1) Acute coronary syndrome or stroke less than 4 weeks before the Screening visit or during the Run-in period;
(2) Coronary revascularization procedure planned within the next 6 months;
(3) Known chronic liver disease;
(4) Current or planned renal dialysis or transplantation;
(5) Previous exposure to inclisiran or participation in a randomized trial of inclisiran;
(6) Previous, current or planned treatment with a monoclonal antibody targeting PCSK9, or with a drug known to be contra-indicated with inclisiran;
(7) Known to be poorly compliant with clinic visits or prescribed medication;
(8) Medical history that might limit the individual’s ability to take trial treatments for the duration of the study (e.g. severe respiratory disease; cancer or evidence of spread within approximately the last 5 years, other than non-melanoma skin cancer; or history of alcohol or substance misuse);
(9) Women of child-bearing potential (unless using adequate contraception); or
(10) Current participation in a clinical trial with an unlicensed drug or device.
(11) Staff personnel directly involved with the study and any family member of the investigational study staff

Those with a capillary blood point-of-care total cholesterol of less than 4 mmol/l at Screening will not be eligible to continue in the study.

E.5 End points

E.5.1

Primary end point(s)

The primary assessment will involve an intention-to-treat comparison among all randomized participants of the effects of allocation to inclisiran versus placebo on time to first occurrence of major adverse cardiovascular events (MACE, defined as coronary heart disease death, myocardial infarction, fatal or non-fatal ischaemic stroke, or urgent coronary revascularization procedure) during the scheduled treatment period.

E.5.1.1

Timepoint(s) of evaluation of this end point

The analysis will be undertaken at the end of the study after an average follow-up of 5 years and will include primary outcomes which have occurred during the scheduled follow-up period.

E.5.2

Secondary end point(s)

Secondary assessments will involve intention-to-treat comparisons among all randomized participants of the effects of allocation to inclisiran versus placebo during the scheduled treatment period on time to first occurrence of:

(i) The composite outcome of coronary heart disease death or myocardial infarction; and

(ii) Cardiovascular death.

E.5.2.1

Timepoint(s) of evaluation of this end point

The analysis will be undertaken at the end of the study after an average follow-up of 5 years and will include secondary outcomes which have occurred during the scheduled follow-up period.

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

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)

Yes

E.7.4

Therapeutic use (Phase IV)

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

100

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

United States

E.8.7

Trial has a data monitoring committee

Yes

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