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    Summary
    EudraCT Number:2017-002472-30
    Sponsor's Protocol Code Number:MDCO-PCS-17-03
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-10-02
    Trial results View 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 ConcernedSweden - MPA
    A.2EudraCT number2017-002472-30
    A.3Full title of the trial
    A PLACEBO-CONTROLLED, DOUBLE-BLIND, RANDOMIZED TRIAL TO EVALUATE THE EFFECT OF 300 MG OF INCLISIRAN SODIUM GIVEN AS SUBCUTANEOUS INJECTIONS IN SUBJECTS WITH HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (HeFH) AND ELEVATED LOW-DENSITY LIPOPROTEIN CHOLESTEROL (LDL-C)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial to study the effects of 300mg of Inclisiran sodium given as subcutaneous injection in subjects with an inherited disorder, known as Heterozygous familial Hypercholesterolemia, that causes elevated blood cholesterol levels (LDL-Cholesterol)
    A.3.2Name or abbreviated title of the trial where available
    ORION-9
    A.4.1Sponsor's protocol code numberMDCO-PCS-17-03
    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.3.9.1CAS number 1639324-58-5
    D.3.9.2Current sponsor codeInclisiran sodium
    D.3.9.3Other descriptive nameALN-60212
    D.3.9.4EV Substance CodeSUB182427
    D.3.10 Strength
    D.3.10.1Concentration unit mg/l milligram(s)/litre
    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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    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
    The primary objective of this study 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 between Day 90 and Day 540 levels
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are to evaluate the effect of inclisiran on:
    •PCSK9, total cholesterol, ApoB and non-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
    E.2.3Trial contains a sub-study No
    E.3Principal 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 (APPENDIX A)
    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) (see APPENDIX B).
    8. Subjects not receiving statin must have documented evidence of intolerance to all doses of at least two different statins (see APPENDIX B).
    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.
    E.4Principal 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, long- term 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.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoints of this study are:
    •Percentage change in LDL-C from baseline to Day 510
    •Time adjusted percentage change in LDL-C from baseline between Day 90 and Day 540. This is the average percentage change in LDL-C from baseline over the period between Day 90 and Day 540.
    E.5.1.1Timepoint(s) of evaluation of this end point
    •From baseline to Day 510
    •From baseline between Day 90 and Day 540
    E.5.2Secondary end point(s)
    The key secondary endpoints of this study are:
    •Absolute change in LDL-C from baseline to Day 510
    •Time adjusted absolute change in LDL-C from baseline between Day 90 and Day 540
    •Percentage change from baseline to Day 510 in PCSK9, total cholesterol, ApoB, and non-HDL-C

    The other secondary endpoints of this study are:
    •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
    •Safety and tolerability profile of inclisiran as measured by AEs, SAEs, vital signs, clinical laboratory values, ECG measurements and formation of ADA and subsequent characterization of ADA
    E.5.2.1Timepoint(s) of evaluation of this end point
    • From baseline to Day 510
    • From baseline to Day 540
    • From baseline between Day 90 and Day 540
    • Safety and tolerability to Day 540
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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) No
    E.8.2.2Placebo Yes
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA65
    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
    Czech Republic
    Denmark
    Israel
    Netherlands
    South Africa
    Spain
    Sweden
    United Kingdom
    United States
    E.8.7Trial 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.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    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: 280
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 120
    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 state35
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 200
    F.4.2.2In the whole clinical trial 400
    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 who have completed the study to Day 540 will be given the opportunity to enroll in a seperate open-label, long-term extension study to collect long-term safety and efficacy data for Inclisiran.
    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 Decision2017-11-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-11-29
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-08-27
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