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    Summary
    EudraCT Number:2016-003815-37
    Sponsor's Protocol Code Number:MDCO-PCS-16-01
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-01-03
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2016-003815-37
    A.3Full title of the trial
    An open label, active comparator extension trial to assess the effect of long term dosing of inclisiran and evolocumab given as subcutaneous injections in subjects with high cardiovascular risk and elevated LDL-C (ORION-3)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Long term treatment with inclisiran and a comparison to evolocumab
    A.3.2Name or abbreviated title of the trial where available
    ORION-3
    A.4.1Sponsor's protocol code numberMDCO-PCS-16-01
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03060577
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorThe Medicines Company
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportThe Medicines Company
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationThe Medicines Company
    B.5.2Functional name of contact pointGlobal Health Science Center
    B.5.3 Address:
    B.5.3.1Street Address8 Sylvan Way
    B.5.3.2Town/ cityParsippany
    B.5.3.3Post codeNJ 07054
    B.5.3.4CountryUnited States
    B.5.4Telephone number+19732906000
    B.5.6E-mailmedical.information@themedco.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameInclisiran for Injection
    D.3.2Product code Inclisiran for Injection
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNInclisiran
    D.3.9.2Current sponsor codeInclisiran sodium
    D.3.9.3Other descriptive nameALN-60212
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Repatha (evolocumab) 140 mg (pre-filled pen)
    D.2.1.1.2Name of the Marketing Authorisation holderAmgen Europe B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Solution for injection in pre-filled pen
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEVOLOCUMAB
    D.3.9.2Current sponsor codeevolocumab
    D.3.9.3Other descriptive nameevolocumab
    D.3.9.4EV Substance CodeSUB128552
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number140
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hypercholesterolemia
    E.1.1.1Medical 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.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10020604
    E.1.2Term Hypercholesterolemia
    E.1.2System Organ Class 100000004861
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the effect of inclisiran treatment on low density lipoprotein
    cholesterol (LDL-C) levels at Day 210 compared to Baseline of ORION-1
    in Group 1 (inclisiran only arm).
    E.2.2Secondary objectives of the trial
    • To evaluate the effects of inclisiran on the following (Group 1;
    inclisiran only arm):
    - 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 Baseline of
    ORION-1 over time
    - Individual responsiveness to inclisiran
    - Duration of lipid-lowering effect
    • To evaluate the long term safety and tolerability of inclisiran
    (Group 1; inclisiran only arm)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Completion of study MDCO-PCS-15-01 and no contraindications to receiving inclisiran or evolocumab.
    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.
    E.4Principal 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 or tubal ligation) for the entire duration of the trial. Women who are >2 years postmenopausal defined as ≥1 year since last menstrual period AND if less than 55 years old with a negative pregnancy test within 24 hours of entry into the study or surgically sterile are exempt. Exemptions from this exclusion.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 inclisiran or devices within 30 days or five half/lives, whichever is longer.
    8. Planned use of other investigational medicinal products other than inclisiran or 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).
    E.5 End points
    E.5.1Primary end point(s)
    Primary Endpoint (Group 1; inclisiran only arm):
    • Percentage change from Baseline of ORION-1 in LDL-C at Day 210 in
    this study (Group 1; inclisiran only arm)

    E.5.1.1Timepoint(s) of evaluation of this end point
    Included in previous section.
    E.5.2Secondary end point(s)
    Secondary Endpoints (Group 1; Inclisiran Only Arm):
    • Change and percentage change from Baseline of ORION-1 in LDL-C
    over time in this study
    • Change and percentage change from Baseline of ORION-1 in PCSK9
    levels over time in this study
    • Change and percentage change from Baseline of ORION-1 in other
    lipids, lipoproteins, and apolipoproteins over time in this study
    • Proportion of subjects with ≥50% LDL-C reduction from Baseline of
    ORION-1 at each time point
    • Individual responsiveness to inclisiran 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 any time point
    • Duration of lipid-lowering effect (LDL-C beta quantification over time)
    • Change and percentage change in LDL-C at Day 210 compared to Day
    870 of ORION-3
    • Long term safety and tolerability of inclisiran treatment
    E.5.2.1Timepoint(s) of evaluation of this end point
    Included in previous section
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned14
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA34
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Canada
    Germany
    Netherlands
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    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.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 246
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 240
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state80
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 337
    F.4.2.2In the whole clinical trial 486
    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)
    Subjects enrolled into this extension study will receive study drug for 4 years (or until the investigator's recommendation of discontinuation, sponsor's recommendation of discontinuation, the subject's decision to discontinue for any reason, or until an administrative decision is made to end the study). At this time EOS evaluations will be conducted at the EOS visit.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-02-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-02-24
    P. End of Trial
    P.End of Trial StatusOngoing
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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