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    Summary
    EudraCT Number:2016-003376-49
    Sponsor's Protocol Code Number:MDCO-PCS-16-02
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-01-18
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2016-003376-49
    A.3Full title of the trial
    An Open-Label, Single-Arm, Multicenter Pilot Study to Evaluate Safety, Tolerability, and Efficacy of ALN-PCSSC in Subjects with Homozygous Familial Hypercholesterolemia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to evaluate the effect of ALN-PCSSC treatment in patients with Homozygous Familial Hypercholesterolemia
    A.3.2Name or abbreviated title of the trial where available
    ORION-2
    A.4.1Sponsor's protocol code numberMDCO-PCS-16-02
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02963311
    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 nameALN-PCSSC
    D.3.2Product code ALN-PCSSC
    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 INNALN-60212
    D.3.9.2Current sponsor codeALN-60212
    D.3.9.3Other descriptive nameALN-60212
    D.3.9.4EV Substance CodeSUB182427
    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.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
    Homozygous Familial 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 19.1
    E.1.2Level LLT
    E.1.2Classification code 10057080
    E.1.2Term Homozygous familial hypercholesterolemia
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To characterize the effect of 90 and 180 days of subcutaneous ALN-PCSSC on the percentage change from Day 1 in low-density lipoprotein cholesterol (LDL-C) in subjects with homozygous familial hypercholesterolemia.
    E.2.2Secondary objectives of the trial
    – To assess the effect of ALN-PCSSC on:
    • Absolute change and percentage change in LDL-C from Day 1 to each subsequent visit until Day 180 or final visit
    • Absolute change and percentage change in PCSK9
    • Absolute change and percentage change in total cholesterol, triglycerides, HDL-C, non-HDL-C, VLDL-C, Apo-A1, Apo-B and Lp(a) from Day 1 to each subsequent visit until Day 180 or final visit
    – To evaluate the safety and tolerability of ALN-PCSSC in subjects with homozygous familial hypercholesterolemia

    Exploratory objectives:
    – To evaluate the formation of Anti-drug antibodies (ADA) to ALN- PCSSC
    – To assess response of LDL-C by underlying causal mutations of homozygous familial hypercholesterolemia (HoFH)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Males and females, ≥ 12 years of age with a diagnosis of homozygous familial hypercholesterolemia by genetic confirmation or a clinical diagnosis based on a history of an untreated LDL-C concentration >500 mg/dl (13 mmol/L) together with either xanthoma before 10 years of age or evidence of heterozygous familial hypercholesterolemia in both parents.
    2. Stable on a low-fat diet
    3. Stable on their pre-existing, lipid-lowering therapies (such as statins, cholesterol-absorption inhibitors, bile-acid sequestrants, or combinations thereof) for at least 4 weeks with no planned medication or dose change for the duration of study participation
    4. Fasting central lab LDL-C concentration >130 mg/dl (3.4 mmol/L) and triglyceride concentration < 400 mg/dL (4.5 mmol/L),
    5. Bodyweight of 40 kg or greater at screening.
    6. Subjects should be willing and able to give written informed consent before initiation of any study-related procedures (if the subject is less than 18 years of age, written consent will be obtained from their guardian or legally authorized representative, with verbal assent from the child).
    E.4Principal exclusion criteria
    1. LDL or plasma apheresis within 8 weeks prior to the screening visit, and no plan to receive it during the study because of the attendant difficulty in maintaining stable concentrations of LDL-C while receiving apheresis.
    2. Use of Mipomersen or Lomitapide therapy within 5 months of screening.
    3. Previous treatment with monoclonal antibodies directed towards PCSK9 within 8 weeks of screening.
    4. New York Heart Association (NYHA) class III or IV heart failure or last known left ventricular ejection fraction < 30% or any cardiac arrhythmia within past 3 months that is not controlled by medication.
    5. Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or stroke within 3 months of enrollment
    6. Planned cardiac surgery or revascularization
    7. Uncontrolled severe hypertension: systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg despite anti-hypertensive therapy.
    8. Poorly controlled diabetes mellitus, i.e., glycated hemoglobin A1c (HbA1c) >10.0%.
    9. Estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2
    10. 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 > 3x the upper limit of normal (ULN), at screening confirmed by a repeat measurement at least 1 week apart.
    11. Creatine kinase (CK) > 5x ULN without a known cause
    12. Other serious comorbid disease in which the life expectancy of the subject is shorter than the duration of the trial (e.g., acute systemic infection or other serious illnesses).
    13. Any history of malignant disease, with the exception of treated basal-cell carcinoma occurring >5 years before screening.
    14. Females who are pregnant or nursing, or who are of childbearing potential (includes adolescent females who have reached menarche and are sexually active) and unwilling to use at least two methods of contraception (e.g., 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 of age with a negative pregnancy test within 24 hours of enrollment
    c. Women who are surgically sterilized at least 3 months prior to enrollment
    d. Adolescent females who have not reached menarche
    15. Males who are unwilling to use an acceptable method of birth control during the entire study period (e.g., condom with spermicide).
    16. Known history of alcohol and/or drug abuse within 5 years.
    17. 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 (e.g., 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. Involved with, or a relative of, someone directly involved in the conduct of the study.
    18. Any clinically significant disease or condition affecting a major organ system, including but not limited to gastrointestinal, renal, hepatic, endocrinologic, pulmonary, neurological, metabolic or cardiovascular disease.
    19. Any surgical or medical condition which, in the judgment of the Investigator, might interfere with the pharmacokinetics, distribution, metabolism, or excretion of the study drug (if applicable).
    20. Treatment with other investigational medicinal products or devices within 30 days or 5 half-lives, whichever is longer, prior to the administration of the study drug, planned use of investigational medicinal products or devices.
    21. Previous participation in this study or any preceding study with ALN-PCSSC.
    22. Hypersensitivity to any of the ingredients of the study drug being used.
    E.5 End points
    E.5.1Primary end point(s)
    Percentage change in LDL-C.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The EOS visit and the last estimation of lipids will occur at Day 180.
    E.5.2Secondary end point(s)
    • Absolute change and percentage change in LDL-C
    • Absolute change and percentage change in PCSK9 levels
    • Absolute change and percentage change in other total cholesterol, triglycerides, HDL-C, non-HDL-C, VLDL-C, Apo-A1, Apo-B and Lp(a)

    Exploratory Endpoint(s):
    • Anti-drug antibodies (ADA) to ALN-PCSSC
    • Response of LDL-C reduction by underlying causal mutations of HoFH
    E.5.2.1Timepoint(s) of evaluation of this end point
    Day 180.
    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 No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    tolerability
    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 No
    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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    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
    Netherlands
    South Africa
    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 years1
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months3
    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 Yes
    F.1.1Number of subjects for this age range: 2
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 2
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 8
    F.1.3Elderly (>=65 years) No
    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 state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 3
    F.4.2.2In the whole clinical trial 10
    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)
    After the subject's participation in this trial has ended treatment or medical management will be per routine standard of care clinical practice at the site. If ALN-PCSSC is found to be effective in lowering LDL-C in HoFH, a subsequent study may follow for subjects participating in the study.
    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 Decision2017-01-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-06-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-10-08
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