CompletedNCT02597127ORION-1Updated May 17, 2019Results posted

Trial to Evaluate the Effect of ALN-PCSSC Treatment on Low Density Lipoprotein Cholesterol (LDL-C)

A Phase 2 interventional study of ALN-PCSSC and Normal Saline in Atherosclerotic Cardiovascular Disease, Familial Hypercholesterolemia and Diabetes, sponsored by The Medicines Company. Completed at 54 sites in 5 countries. Open to participants aged 18 Years to 99 Years. Per ClinicalTrials.gov, last updated 2019-05-17.

Sponsored by The Medicines Company · Phase 2, Interventional, and Treatment

Phase: Phase 2
Study type: Interventional
Enrollment: 501
Allocation: Randomized
Ages: 18 Years to 99 Years
Sex: All

Study summary

This study is a Phase II, placebo-controlled, double-blind, randomized trial in 480 participants with atherosclerotic cardiovascular disease (ASCVD) or ASCVD-risk equivalents (for example, diabetes and familial hypercholesterolemia) and elevated LDL-C despite maximum tolerated dose of LDL-C lowering therapies to evaluate the efficacy, safety, and tolerability of ALN-PCSSC injection(s).

Read the detailed description

Participants will be screened and 480 eligible participants will be randomized: 60 participants per each of six ALN-PCSSC dose groups plus 120 participants total across the placebo groups (20 participants each to match each of the six drug dose groups). Treatment allocation will be stratified by country and by current use of statins or other lipid-modifying therapies. Each participant will receive either one or two injections on Day 1 or a single injection on Day 1 and on Day 90 of blinded ALN-PCSSC or placebo.

Formation of anti-drug antibodies (ADA) will be assessed on Day 1 (prior to and 4 hours after the injection) and on Days 30, 60, 90, 120, 150, 180 (Days 150 and 180 only in participants who receive a second dose of study drug), and 210 or until any ADA response becomes negative within the study duration.

The independent Data Monitoring Committee (DMC) will review safety data beginning after the first 40 participants receive the first injection of ALN-PCSSC or placebo and complete the Day 14 follow-up visit. Thereafter, the DMC will review safety data every 2 months until the end of the trial. A recommendation may be taken to stop or amend the study at any of these reviews.

On Day 1, all eligible participants will be randomized and receive the first subcutaneous (SC) administration of ALN-PCSSC or placebo. After the first study drug administration, the participant will be observed in the clinic for at least 4 hours post injection before being discharged. Participants will return at Day 14 and then at monthly intervals for 6 months. Participants randomized to receive a second dose of study drug will receive the second injection of ALN-PCSSC or placebo at the Day 90 visit.

Efficacy assessments will include the measurement of the effects of ALN-PCSSC on levels of LDL-C lipids and lipoproteins including total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, very low-density lipoprotein (VLDL), apolipoprotein A1 (Apo-AI), apolipoprotein B (Apo-B), lipoprotein (a) [Lp(a)], C-reactive protein (CRP), and proprotein convertase subtilisin/kexin type 9 (PCSK9).

End of study (EOS) evaluations will be conducted at the EOS visit (Day 210). The expected duration of the participants' involvement in the study will be approximately 374 days, which includes screening, study drug administration, the course of single or multiple injections, and the follow-up period to Day 360.

Participants completing the study to Day 210 will be given the opportunity to enroll in a separate long-term extension study. Any participants in whom LDL-C levels have not returned to >80% of baseline values will continue to be followed as part of this study until either this level has been reached or until a maximum of Day 360, at which point they will be given the opportunity to enroll in the long-term extension study. At each visit, LDL-C levels, adverse events, serious adverse events, concomitant medications, and safety laboratory assessments will be collected.

Objectives:

Primary:

To evaluate the effect of ALN-PCSSC treatment on LDL-C levels at Day 180.

Secondary:

To evaluate the effect of ALN-PCSSC on the following:

LDL-C at Day 90
LDL-C levels at other time points
PCSK9 levels over time
Other lipids, lipoproteins, apolipoproteins
Proportion of participants achieving pre-specified global lipid guidelines
Individual responsiveness to different doses
Duration of lipid-lowering effect of different doses
Safety and tolerability profile of ALN-PCSSC

Exploratory:

To collect/evaluate the effect of ALN-PCSSC on the following:

Cardiovascular (CV) events such as CV death, non-fatal myocardial infarction, resuscitated cardiac arrest and non-fatal stroke (ischemic and hemorrhagic)
Evaluation of ADA for the investigational product

Conditions studied

Atherosclerotic Cardiovascular Disease
Familial Hypercholesterolemia
Diabetes

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In context

Cardiovascular Diseases

4,902 studies on the registry are indexed under Cardiovascular Diseases; 920 are open to participants now.

This study's enrollment of 501 is above the median of 100 across 2,738 interventional studies indexed under Cardiovascular Diseases.

Browse Cardiovascular Diseases studies →

Lead sponsor

The Medicines Company is the lead sponsor of 48 studies on the registry; none are open to participants now.

Of its 8 completed or terminated interventional studies of FDA-regulated products, 7 (88%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 99 Years
Sexes eligible: All
Accepts healthy volunteers: No

Inclusion criteria

Male or female participants ≥18 years of age.
History of ASCVD or ASCVD-risk equivalents (symptomatic atherosclerosis, Type 2 diabetes, familial hypercholesterolemia, including participants whose 10-year risk of a CV event assessed by Framingham Risk Score (Framingham Risk Score >20%) or equivalent has a target LDL-C of \<100 mg/deciliter [dL]).
Serum LDL-C ≥1.8 millimole (mmol)/liter (L) (≥70 mg/dL) for ASCVD participants or ≥2.6 mmol/L (≥100 mg/dL) for ASCVD-risk equivalent participants at screening.
Fasting triglyceride \<4.52 mmol/L (\<400 mg/dL) at screening.
Calculated glomerular filtration rate 30 mL/min or higher by estimated glomerular filtration rate (eGFR) using standardized local clinical methodology.
Participants on statins should be receiving a maximally tolerated dose (investigator's discretion).
Participants on lipid-lower therapies (such as 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.
Willing and able to give informed consent before initiation of any study-related procedures and willing to comply with all required study procedures.

Exclusion criteria

Exclusion Criteria:

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 participant at significant risk (according to investigator's [or delegate] judgment) if he/she participates in the clinical study.
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.
New York Heart Association (NYHA) class II, III, or IV heart failure or last known left ventricular ejection fraction \<30%.
Cardiac arrhythmia within 3 months prior to randomization that is not controlled by medication or via ablation.
Any history of hemorrhagic stroke.
Major adverse cardiac event within 6 months prior to randomization.
Uncontrolled severe hypertension: systolic blood pressure >180 millimeters of mercury (mmHg) or diastolic blood pressure >110 mmHg prior to randomization despite anti-hypertensive therapy.
Poorly controlled Type 2 diabetes, such as, glycated hemoglobin A1c (HbA1c)>10.0% prior to randomization.
Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the liver or unexplained alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation >2x the upper limit of normal (ULN), or total bilirubin elevation >1.5x ULN at screening confirmed by a repeat measurement at least 1 week apart.
Serious comorbid disease in which the life expectancy of the participant is shorter than the duration of the trial (for example, acute systemic infection, cancer, or other serious illnesses). This includes all cancers with the exception of treated basal-cell carcinoma occurring >5 years before screening.
Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least two methods of contraception (oral contraceptives, barrier methods, approved contraceptive implant, long-term injectable contraception, intrauterine device or tubal litigation) for the entire duration of the study. 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 randomization or surgically sterile are exempt from this exclusion.
Males who are unwilling to use an acceptable method of birth control during the entire study period (such as, condom with spermicide).
Known history of alcohol and/or drug abuse within the last 5 years.
Treatment with other investigational medicinal products or devices within 30 days or five half˗lives, whichever is longer.
Use of other investigational medicinal products or devices during the course of the study.
Any condition that according to the investigator could interfere with the conduct of the study, such as but not limited to the following:
- Inappropriate for this study, including participants who are unable to communicate or to cooperate with the investigator.
- Unable to understand the protocol requirements, instructions and study-related restrictions, the nature, scope, and possible consequences of the study (including participants whose cooperation is doubtful due to drug abuse or alcohol dependency).
- Unlikely to comply with the protocol requirements, instructions, and study-related restrictions (for example, uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study).
- Have any medical or surgical condition, which in the opinion of the investigator would put the participants at increased risk from participating in the study.
- Involved with, or a relative of, someone directly involved in the conduct of the study.
- Any known cognitive impairment (for example, Alzheimer's disease)
Previous or current treatment (within 90 days of screening) with monoclonal antibodies directed at PCSK9.

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Double (Participant, Investigator)
Enrollment: 501 participants (actual)

Study arms

Experimental
ALN-PCSSC 200 mg (bi-annual dosing)
ALN-PCSSC 200 milligram (mg) SC administration once at Day 1
Drug: ALN-PCSSC
Experimental
ALN-PCSSC 300 mg (bi-annual dosing)
ALN-PCSSC 300 mg SC administration once at Day 1
Drug: ALN-PCSSC
Experimental
ALN-PCSSC 500 mg (bi-annual dosing)
ALN-PCSSC 500 mg SC administration once at Day 1
Drug: ALN-PCSSC
Placebo comparator
Normal Saline (bi-annual dosing)
Saline SC administration once at Day 1
Drug: Normal Saline
Experimental
ALN-PCSSC 100 mg (quarterly dosing)
ALN-PCSSC 100 mg SC administration twice at Day 1 and Day 90
Drug: ALN-PCSSC
Experimental
ALN-PCSSC 200 mg (quarterly dosing)
ALN-PCSSC 200 mg SC administration twice at Day 1 and Day 90
Drug: ALN-PCSSC
Experimental
ALN-PCSSC 300 mg (quarterly dosing)
ALN-PCSSC 300 mg SC administration twice at Day 1 and Day 90
Drug: ALN-PCSSC
Placebo comparator
Normal Saline (quarterly dosing)
Saline SC administration twice at Day 1 and Day 90
Drug: Normal Saline

Interventions

DrugALN-PCSSC
ALN-PCSSC is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis and is given as SC injections
Also known as: PCSK9 synthesis inhibitor, Inclisiran
DrugNormal Saline
Saline (sterile, normal, 0.9%) solution given as SC injections

What researchers measure

Primary outcomes

Percentage Change in LDL-C From Baseline to Day 180
Percent Change in LDL-C (beta-quantification) from Baseline to Day 180 in MITT Population
Time frame: Baseline to 180 days

Secondary outcomes

Percentage Change in LDL-C From Baseline to Day 90
Percent Change in LDL-C (beta-quantification) from Baseline to Day 90 in MITT Population
Time frame: Baseline to 90 days
Percent Change From Baseline In LDL-C Levels At Day 60, Day 120, and Day 210
This outcome measure evaluated the effects of both single- and double-dose inclisiran on LDL-C levels in the mITT population from baseline to Day 60, Day 120, and Day 210.
Time frame: Baseline, Day 60, Day 120, and Day 210
Number of Participants With an LDL-C Greater Than 80% of the Baseline Value at Day 180 and Day 210
This outcome measure evaluated the number of participants (single and double dose) in the mITT population with an LDL-C greater than 80% of the baseline value at Day 180 and Day 210.
Time frame: Baseline, Day 180, Day 210
Number of Participants With Individual Responsiveness as Measured By LDL-C Levels at Day 90 and Day 180
This outcome measure evaluated the individual responsiveness of participants to inclisiran (single and double dose) in the mITT population as defined by an LDL-C level of \<25 mg/deciliter \[dL\] at Day 90 and Day 180.
Time frame: Day 90, Day 180
Number of Participants With Greater Or Equal To 50% LDL-C Reduction From Baseline At Day 180
This outcome measure evaluated the number of participants (single and double dose) in the mITT population with an LDL-C reduction greater than 50% of the baseline value at Day 180.
Time frame: Baseline, Day 180
Percentage Change in PCSK9 Levels From Baseline at Day 180
This outcome measure evaluated the percent change in proprotein convertase subtilisin/kexin type 9 (PCSK9) from baseline to Day 180 in participants (single and double dose) in the mITT population.
Time frame: Baseline, Day 180
Percentage Change in Other Lipids and Apolipoproteins From Baseline to Day 180
This outcome measure evaluated the percent change from baseline to Day 180 in cholesterol (total, high-density lipoprotein \[HDL\], non-HDL) and apolipoproteins (B, A1) in participants (single and double dose) in the mITT population.
Time frame: Baseline, Day 180
Number of Participants Who Attained Global Lipid Modification Targets for Level of Atherosclerotic Cardiovascular Disease Risk
This outcome measure evaluated the proportion of participants (single and double dose) in the mITT population who attained a global lipid modification target by baseline cardiovascular risk group, looking specifically at LDL-C levels (mg/dL) in the category of cardiovascular disease (CVD). CVD was defined as a participant who had at least 1 of the following: prior myocardial infarction, prior percutaneous coronary intervention, prior coronary artery bypass graft, prior stroke, prior transient ischemic attack, peripheral artery disease.
Time frame: Baseline, Day 180
Percentage Change in Other Lipids and Inflammatory Markers From Baseline to Day 180
This outcome measure evaluated the percent change from baseline to Day 180 in triglycerides, very-low-density lipoprotein (VLDL) cholesterol, lipoprotein(a), and high sensitivity C-reactive protein (hsCRP) in participants (single and double dose) in the mITT population.
Time frame: Baseline, Day 180

Results

Posted May 17, 2019

Participant flow

Participant flow — Overall Study
Milestone	Inclisiran 200 mg (Single-dose)	Inclisiran 300 mg (Single-dose)	Inclisiran 500 mg (Single-dose)	Placebo (Single-dose)	Inclisiran 100 mg (Double-dose)	Inclisiran 200 mg (Double-dose)	Inclisiran 300 mg (Double-dose)	Placebo (Double-dose)
Started	60	62	66	65	62	63	61	62
Treated	60	61	65	65	61	62	61	62
Completed	59	59	58	60	57	59	57	60
Not completed	1	3	8	5	5	4	4	2

Outcome measures

PrimaryPercentage Change in LDL-C From Baseline to Day 180

Percent Change in LDL-C (beta-quantification) from Baseline to Day 180 in MITT Population

Time frame:: Baseline to 180 days
Reported as:: Least squares mean · Percent change

Percentage Change in LDL-C From Baseline to Day 180
Percent change	Placebo (Single Dose)	200 mg (Single Dose)	300 mg (Single Dose)	500 mg (Single Dose)	Placebo (Double Dose)	100 mg (Double Dose)	200 mg (Double Dose)	300 mg (Double Dose)
Percentage Change in LDL-C From Baseline to Day 180	2.1 (-2.9 to 7.2)	-27.9 (-33.1 to -22.7)	-38.4 (-43.6 to -33.2)	-41.9 (-47.2 to -36.7)	1.8 (-2.6 to 6.3)	-35.5 (-40.0 to -31.0)	-44.9 (-49.3 to -40.4)	-52.6 (-57.1 to -48.1)

Statistical analysis

Placebo (Single Dose) vs 200 mg (Single Dose) · t-test, 1 sided · p = <0.0001 (This P-Value applies to the comparison of the mean percent change at Day 180 for the 200 mg (Single-Dose) Inclisiran group versus Placebo (Single-Dose).)
Placebo (Single Dose) vs 300 mg (Single Dose) · t-test, 1 sided · p = <0.0001 (This P-Value applies to the comparison of the mean percent change at Day 180 for the 300 mg (Single-Dose) Inclisiran group versus Placebo (Single-Dose).)
Placebo (Single Dose) vs 500 mg (Single Dose) · t-test, 1 sided · p = <0.0001 (This P-Value applies to the comparison of the mean percent change at Day 180 for the 500 mg (Single-Dose) Inclisiran group versus Placebo (Single-Dose).)
Placebo (Double Dose) vs 100 mg (Double Dose) · t-test, 1 sided · p = <0.0001 (This P-Value applies to the comparison of the mean percent change at Day 180 for the 100 mg Double-Dose) Inclisiran group versus Placebo (Double-Dose).)
Placebo (Double Dose) vs 200 mg (Double Dose) · t-test, 1 sided · p = <0.0001 (This P-Value applies to the comparison of the mean percent change at Day 180 for the 200 mg Double-Dose) Inclisiran group versus Placebo (Double-Dose).)
Placebo (Double Dose) vs 300 mg (Double Dose) · t-test, 1 sided · p = <0.0001 (This P-Value applies to the comparison of the mean percent change at Day 180 for the 300 mg Double-Dose) Inclisiran group versus Placebo (Double-Dose).)

SecondaryPercentage Change in LDL-C From Baseline to Day 90

Percent Change in LDL-C (beta-quantification) from Baseline to Day 90 in MITT Population

Time frame:: Baseline to 90 days
Reported as:: Least squares mean · Percent change

Percentage Change in LDL-C From Baseline to Day 90
Percent change	Single Dose 500 mg	Double Dose 100 mg	Single and Double Dose Placebo	Single and Double Dose 200 mg	Single and Double Dose 300 mg
Percentage Change in LDL-C From Baseline to Day 90	-49 (-53.8 to -44.2)	-34.2 (-39.1 to -29.3)	-0.8 (-4.2 to 2.5)	-41.8 (-45.3 to -38.4)	-45.7 (-49.2 to -42.3)

SecondaryPercent Change From Baseline In LDL-C Levels At Day 60, Day 120, and Day 210

This outcome measure evaluated the effects of both single- and double-dose inclisiran on LDL-C levels in the mITT population from baseline to Day 60, Day 120, and Day 210.

Time frame:: Baseline, Day 60, Day 120, and Day 210
Reported as:: Mean · Percent change

Percent Change From Baseline In LDL-C Levels At Day 60, Day 120, and Day 210
Percent change	Placebo (Single Dose)	Inclisiran 200 mg (Single Dose)	Inclisiran 300 mg (Single Dose)	Inclisiran 500 mg (Single Dose)	Placebo (Double Dose)	Inclisiran 100 mg (Double Dose)	Inclisiran 200 mg (Double Dose)	Inclisiran 300 mg (Double Dose)
Day 60	-4.27 (-7.84 to -0.7)	-44.32 (-50.55 to -38.09)	-50.87 (-55.62 to -46.12)	-49.58 (-54.12 to -45.04)	-1.92 (-6.7 to 2.85)	-35.73 (-40.23 to -31.23)	-44.28 (-49.1 to -39.47)	-50.99 (-55.51 to -45.67)
Day 120	-0.91 (-5.17 to 3.34)	-36.94 (-42.8 to -31.08)	-43.32 (-48.95 to -37.68)	-46.42 (-50.63 to -42.22)	0.17 (-3.61 to 3.95)	-41.37 (-45.94 to -36.8)	-49.54 (-54.6 to -44.49)	-54.73 (-59.88 to -49.58)
Day 210	1.45 (-3.61 to 6.06)	-28.98 (-36.83 to -21.12)	-35.39 (-41.47 to -29.31)	-39.2 (-43.71 to -34.68)	0.58 (-4.58 to 5.74)	-31.67 (-36.08 to -27.27)	-42.59 (-47.11 to -38.08)	-50.54 (-54.83 to -46.25)

SecondaryNumber of Participants With an LDL-C Greater Than 80% of the Baseline Value at Day 180 and Day 210

This outcome measure evaluated the number of participants (single and double dose) in the mITT population with an LDL-C greater than 80% of the baseline value at Day 180 and Day 210.

Time frame:: Baseline, Day 180, Day 210
Reported as:: Count of participants · Participants

Number of Participants With an LDL-C Greater Than 80% of the Baseline Value at Day 180 and Day 210
Participants	Placebo (Single-dose)	Inclisiran 200 mg (Single-dose)	Inclisiran 300 mg (Single-dose)	Inclisiran 500 mg (Single-dose)	Placebo (Double-dose)	Inclisiran 100 mg (Double-dose)	Inclisiran 200 mg (Double-dose)	Inclisiran 300 mg (Double-dose)
Day 180	35	6	5	0	29	2	1	0
Day 210	34	8	5	2	34	1	1	1

SecondaryNumber of Participants With Individual Responsiveness as Measured By LDL-C Levels at Day 90 and Day 180

This outcome measure evaluated the individual responsiveness of participants to inclisiran (single and double dose) in the mITT population as defined by an LDL-C level of \<25 mg/deciliter \[dL\] at Day 90 and Day 180.

Time frame:: Day 90, Day 180
Reported as:: Count of participants · Participants

Number of Participants With Individual Responsiveness as Measured By LDL-C Levels at Day 90 and Day 180
Participants	Placebo (Single-dose)	Inclisiran 200 mg (Single-dose)	Inclisiran 300 mg (Single-dose)	Inclisiran 500 mg (Single-dose)	Placebo (Double-dose)	Inclisiran 100 mg (Double-dose)	Inclisiran 200 mg (Double-dose)	Inclisiran 300 mg (Double-dose)
Day 90	0	0	5	3	0	0	1	0
Day 180	0	0	1	2	0	1	2	3

SecondaryNumber of Participants With Greater Or Equal To 50% LDL-C Reduction From Baseline At Day 180

This outcome measure evaluated the number of participants (single and double dose) in the mITT population with an LDL-C reduction greater than 50% of the baseline value at Day 180.

Time frame:: Baseline, Day 180
Reported as:: Count of participants · Participants

Number of Participants With Greater Or Equal To 50% LDL-C Reduction From Baseline At Day 180
Participants	Placebo (Single-dose)	Inclisiran 200 mg (Single-dose)	Inclisiran 300 mg (Single-dose)	Inclisiran 500 mg (Single-dose)	Placebo (Double-dose)	Inclisiran 100 mg (Double-dose)	Inclisiran 200 mg (Double-dose)	Inclisiran 300 mg (Double-dose)
Number of Participants With Greater Or Equal To 50% LDL-C Reduction From Baseline At Day 180	0	9	19	16	0	14	27	32

SecondaryPercentage Change in PCSK9 Levels From Baseline at Day 180

This outcome measure evaluated the percent change in proprotein convertase subtilisin/kexin type 9 (PCSK9) from baseline to Day 180 in participants (single and double dose) in the mITT population.

Time frame:: Baseline, Day 180
Reported as:: Mean · percent change

Percentage Change in PCSK9 Levels From Baseline at Day 180
percent change	Placebo (Single Dose)	Inclisiran 200 mg (Single Dose)	Inclisiran 300 mg (Single Dose)	Inclisiran 500 mg (Single Dose)	Placebo (Double Dose)	Inclisiran 100 mg (Double Dose)	Inclisiran 200 mg (Double Dose)	Inclisiran 300 mg (Double Dose)
Percentage Change in PCSK9 Levels From Baseline at Day 180	2.2 ± 23.4	-47.9 ± 21	-56 ± 19.2	-59.3 ± 18	-1.2 ± 20.7	-53.2 ± 20.9	-66.2 ± 15.6	-69.1 ± 12.1

SecondaryPercentage Change in Other Lipids and Apolipoproteins From Baseline to Day 180

This outcome measure evaluated the percent change from baseline to Day 180 in cholesterol (total, high-density lipoprotein \[HDL\], non-HDL) and apolipoproteins (B, A1) in participants (single and double dose) in the mITT population.

Time frame:: Baseline, Day 180
Reported as:: Mean · percent change

Percentage Change in Other Lipids and Apolipoproteins From Baseline to Day 180
percent change	Placebo (Single Dose)	Inclisiran 200 mg (Single Dose)	Inclisiran 300 mg (Single Dose)	Inclisiran 500 mg (Single Dose)	Placebo (Double Dose)	Inclisiran 100 mg (Double Dose)	Inclisiran 200 mg (Double Dose)	Inclisiran 300 mg (Double Dose)
Total Cholesterol	1.8 ± 12.1	-17.6 ± 19	-23.7 ± 15.7	-26.6 ± 10.7	0.7 ± 12.3	-22.4 ± 12.4	-26.8 ± 13	33.2 ± 11.3
Non-HDL Cholesterol	1.5 ± 16.7	-25.1 ± 26.3	-35.2 ± 20.2	-36.9 ± 14	1.3 ± 16.9	-31.7 ± 15.1	-38.9 ± 16.8	-46 ± 14.6
HDL Cholesterol	3.8 ± 15.6	4.4 ± 14.8	8.8 ± 11.1	6.9 ± 14	0.5 ± 12.5	7.6 ± 12.2	10.3 ± 15.3	8.6 ± 14.9
Apolipoprotein B	1.7 ± 14.7	-22.9 ± 21	-30.8 ± 18	-33.1 ± 12.7	0.9 ± 13	-27.8 ± 13.4	-35 ± 15.8	-40.9 ± 14.8
Apolipoprotein A1	3.6 ± 10.6	2.9 ± 9.3	3.8 ± 8.9	4.1 ± 10.9	0.8 ± 8.3	5.5 ± 10.6	8.6 ± 11.5	6.2 ± 11.9

SecondaryNumber of Participants Who Attained Global Lipid Modification Targets for Level of Atherosclerotic Cardiovascular Disease Risk

This outcome measure evaluated the proportion of participants (single and double dose) in the mITT population who attained a global lipid modification target by baseline cardiovascular risk group, looking specifically at LDL-C levels (mg/dL) in the category of cardiovascular disease (CVD). CVD was defined as a participant who had at least 1 of the following: prior myocardial infarction, prior percutaneous coronary intervention, prior coronary artery bypass graft, prior stroke, prior transient ischemic attack, peripheral artery disease.

Time frame:: Baseline, Day 180
Reported as:: Count of participants · Participants

Number of Participants Who Attained Global Lipid Modification Targets for Level of Atherosclerotic Cardiovascular Disease Risk
Participants	Placebo (Single-dose)	Inclisiran 200 mg (Single-dose)	Inclisiran 300 mg (Single-dose)	Inclisiran 500 mg (Single-dose)	Placebo (Double-dose)	Inclisiran 100 mg (Double-dose)	Inclisiran 200 mg (Double-dose)	Inclisiran 300 mg (Double-dose)
CVD	45	43	46	33	45	41	39	42
<70 mg/dL	0	16	27	18	1	24	27	33

SecondaryPercentage Change in Other Lipids and Inflammatory Markers From Baseline to Day 180

This outcome measure evaluated the percent change from baseline to Day 180 in triglycerides, very-low-density lipoprotein (VLDL) cholesterol, lipoprotein(a), and high sensitivity C-reactive protein (hsCRP) in participants (single and double dose) in the mITT population.

Time frame:: Baseline, Day 180
Reported as:: Median · percent change

Percentage Change in Other Lipids and Inflammatory Markers From Baseline to Day 180
percent change	Placebo (Single Dose)	Inclisiran 200 mg (Single Dose)	Inclisiran 300 mg (Single Dose)	Inclisiran 500 mg (Single Dose)	Placebo (Double Dose)	Inclisiran 100 mg (Double Dose)	Inclisiran 200 mg (Double Dose)	Inclisiran 300 mg (Double Dose)
Triglycerides	6.4 (-15.9 to 21.9)	1.1 (-18.5 to 17.8)	-12.8 (-27.8 to 7.8)	-12.2 (-25.6 to 7.7)	-3 (-17.2 to 22.6)	-6.3 (-17.6 to 10.9)	0.7 (-22.4 to 11.3)	-14.2 (-26.4 to 5.4)
VLDL Cholesterol	2.4 (-30.7 to 30.5)	-11.6 (-35.8 to 23.3)	-23.8 (-43 to -6.4)	-14.6 (-34.8 to 3.5)	2.7 (-20 to 26.7)	-16.4 (-31.3 to 0)	-21.2 (-38.5 to 13.2)	-16 (-38.2 to 9.1)
Lipoprotein(a)	0.5 (-13.9 to 14.8)	-14.3 (-29.5 to -3.5)	-14.3 (-25.4 to -5.6)	-18.2 (-35 to 1.6)	0 (-10 to 12.4)	-14.9 (-26.2 to -1.9)	-17.3 (-31.9 to -7.7)	-25.6 (-38.5 to -15.2)
hsCRP	-5.3 (-40.8 to 28.4)	7.1 (-30.7 to 70.9)	-16.2 (-45.8 to 50)	-19.8 (-50 to 32.7)	-20 (-50 to 30)	-12.5 (-42.9 to 29.4)	-16.3 (-34.6 to 24.3)	-16.7 (-50.9 to 33.3)

Adverse events

Collected over Treatment Emergent Adverse Events up to Day 360. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Placebo (Single Dose)	0/65 (0%)	3/65 (4.6%)	50/65 (76.9%)
Inclisiran 200 mg (Single Dose)	0/60 (0%)	11/60 (18.3%)	49/60 (81.7%)
Inclisiran 300 mg (Single Dose)	0/61 (0%)	11/61 (18%)	49/61 (80.3%)
Inclisiran 500 mg (Single Dose)	1/65 (1.5%)	8/65 (12.3%)	54/65 (83.1%)
Placebo (Double Dose)	0/62 (0%)	7/62 (11.3%)	51/62 (82.3%)
Inclisiran 100 mg (Double Dose)	0/61 (0%)	13/61 (21.3%)	47/61 (77%)
Inclisiran 200 mg (Double Dose)	1/62 (1.6%)	8/62 (12.9%)	49/62 (79%)
Inclisiran 300 mg (Double Dose)	0/61 (0%)	9/61 (14.8%)	51/61 (83.6%)

Most frequent serious events

Showing 10 of 88

Most frequent serious events
Event	Placebo (Single Dose)	Inclisiran 200 mg (Single Dose)	Inclisiran 300 mg (Single Dose)	Inclisiran 500 mg (Single Dose)	Placebo (Double Dose)	Inclisiran 100 mg (Double Dose)	Inclisiran 200 mg (Double Dose)	Inclisiran 300 mg (Double Dose)
Prostate cancerNeoplasms benign, malignant and unspecified (incl cysts and polyps)	0/65	2/60	0/61	0/65	0/62	0/61	0/62	0/61
Coronary artery diseaseCardiac disorders	0/65	0/60	0/61	0/65	0/62	0/61	0/62	2/61
Post procedural complicationInjury, poisoning and procedural complications	0/65	0/60	0/61	1/65	0/62	0/61	2/62	0/61
Myocardial infarctionCardiac disorders	0/65	1/60	0/61	2/65	0/62	0/61	0/62	1/61
Angina pectorisCardiac disorders	0/65	1/60	1/61	1/65	0/62	0/61	0/62	0/61
Inguinal herniaGastrointestinal disorders	0/65	1/60	0/61	0/65	0/62	0/61	0/62	0/61
VolvulusGastrointestinal disorders	0/65	1/60	0/61	0/65	0/62	0/61	0/62	0/61
Limb crushing injuryInjury, poisoning and procedural complications	0/65	1/60	0/61	0/65	0/62	0/61	0/62	0/61
OsteitisMusculoskeletal and connective tissue disorders	0/65	1/60	0/61	0/65	0/62	0/61	0/62	0/61
Oesophageal adenocarcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)	0/65	1/60	0/61	0/65	0/62	0/61	0/62	0/61

Most frequent other events

Showing 10 of 25

Most frequent other events
Event	Placebo (Single Dose)	Inclisiran 200 mg (Single Dose)	Inclisiran 300 mg (Single Dose)	Inclisiran 500 mg (Single Dose)	Placebo (Double Dose)	Inclisiran 100 mg (Double Dose)	Inclisiran 200 mg (Double Dose)	Inclisiran 300 mg (Double Dose)
NasopharyngitisInfections and infestations	4/65	8/60	9/61	9/65	8/62	8/61	5/62	11/61
MyalgiaMusculoskeletal and connective tissue disorders	3/65	2/60	6/61	3/65	3/62	7/61	5/62	5/61
CoughRespiratory, thoracic and mediastinal disorders	2/65	4/60	7/61	3/65	3/62	1/61	6/62	3/61
DiarrhoeaGastrointestinal disorders	1/65	1/60	4/61	4/65	2/62	3/61	7/62	5/61
Back painMusculoskeletal and connective tissue disorders	5/65	4/60	4/61	4/65	2/62	6/61	1/62	4/61
Musculoskeletal painMusculoskeletal and connective tissue disorders	1/65	2/60	0/61	1/65	4/62	0/61	0/62	6/61
FatigueGeneral disorders	5/65	2/60	4/61	2/65	6/62	2/61	0/62	1/61
DizzinessNervous system disorders	3/65	1/60	2/61	2/65	6/62	3/61	3/62	3/61
HeadacheNervous system disorders	6/65	2/60	2/61	2/65	5/62	5/61	1/62	5/61
InfluenzaInfections and infestations	3/65	3/60	4/61	5/65	2/62	3/61	4/62	5/61

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)	Placebo (Single-dose)	Inclisiran 200 mg (Single-dose)	Inclisiran 300 mg (Single-dose)	Inclisiran 500 mg (Single-dose)	Placebo (Double-dose)	Inclisiran 100 mg (Double-dose)	Inclisiran 200 mg (Double-dose)	Inclisiran 300 mg (Double-dose)	Total
<=18 years	0	0	0	0	0	0	0	0	0
Between 18 and 65 years	40	30	27	32	32	24	37	31	253
>=65 years	25	30	35	34	30	38	26	30	248

Age, Continuous
Age, Continuous(years)	Placebo (Single-dose)	Inclisiran 200 mg (Single-dose)	Inclisiran 300 mg (Single-dose)	Inclisiran 500 mg (Single-dose)	Placebo (Double-dose)	Inclisiran 100 mg (Double-dose)	Inclisiran 200 mg (Double-dose)	Inclisiran 300 mg (Double-dose)	Total
Mean	62.0 ± 11.4	63.9 ± 10.8	64.1 ± 12.8	62.1 ± 12.4	62.8 ± 10.3	65.2 ± 9.4	62.3 ± 10.8	64.1 ± 9.4	63.6 ± 10.0

Sex: Female, Male
Sex: Female, Male(Participants)	Placebo (Single-dose)	Inclisiran 200 mg (Single-dose)	Inclisiran 300 mg (Single-dose)	Inclisiran 500 mg (Single-dose)	Placebo (Double-dose)	Inclisiran 100 mg (Double-dose)	Inclisiran 200 mg (Double-dose)	Inclisiran 300 mg (Double-dose)	Total
Female	23	21	20	19	29	23	24	16	175
Male	42	39	42	47	33	39	39	45	326

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	Placebo (Single-dose)	Inclisiran 200 mg (Single-dose)	Inclisiran 300 mg (Single-dose)	Inclisiran 500 mg (Single-dose)	Placebo (Double-dose)	Inclisiran 100 mg (Double-dose)	Inclisiran 200 mg (Double-dose)	Inclisiran 300 mg (Double-dose)	Total
Hispanic or Latino	7	4	3	1	2	2	6	4	29
Not Hispanic or Latino	58	56	59	65	60	60	57	57	472
Unknown or Not Reported	0	0	0	0	0	0	0	0	0

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Placebo (Single-dose)	Inclisiran 200 mg (Single-dose)	Inclisiran 300 mg (Single-dose)	Inclisiran 500 mg (Single-dose)	Placebo (Double-dose)	Inclisiran 100 mg (Double-dose)	Inclisiran 200 mg (Double-dose)	Inclisiran 300 mg (Double-dose)	Total
American Indian or Alaska Native	1	0	1	1	0	2	0	1	6
Asian	0	2	2	2	1	1	0	1	9
Native Hawaiian or Other Pacific Islander	0	0	1	0	0	0	0	0	1
Black or African American	4	4	2	0	3	2	2	1	18
White	59	53	56	63	58	57	61	58	465
More than one race	0	0	0	0	0	0	0	0	0
Unknown or Not Reported	1	1	0	0	0	0	0	0	2

Region of Enrollment
Region of Enrollment(Participants)	Placebo (Single-dose)	Inclisiran 200 mg (Single-dose)	Inclisiran 300 mg (Single-dose)	Inclisiran 500 mg (Single-dose)	Placebo (Double-dose)	Inclisiran 100 mg (Double-dose)	Inclisiran 200 mg (Double-dose)	Inclisiran 300 mg (Double-dose)	Total
Canada	8	8	7	12	10	10	7	9	71
Netherlands	22	21	21	21	20	20	23	21	169
United States	12	10	10	12	8	10	12	10	84
United Kingdom	11	11	11	11	10	9	11	12	86
Germany	12	10	13	10	14	13	10	9	91

Study locations

54 sites

Jacksonville Center for Clinical Research
Jacksonville, Florida 32216, United States
Midwest Institute For Clinical Research
Indianapolis, Indiana 46260, United States
Mount Sinai Icahn School of Medicine
New York, New York 10029, United States
Metabolic And Atherosclerosis Research Center
Cincinnati, Ohio 45227, United States
Sterling Research Group
Cincinnati, Ohio 45246, United States
Wellmont CVA Heart Institute
Greeneville, Tennessee 37745, United States
Amarillo Heart Clinical Research Institute, Inc.
Amarillo, Texas 79106, United States
National Clinical Research, Inc.
Richmond, Virginia 23294, United States
St. Paul's Hospital
Vancouver, British Columbia V6Z 1Y6, Canada
St. Boniface Hospital
Winnipeg, Manitoba R2H 2A6, Canada
Eastern Regional Health Authority, Patient Research Centre
St. Johns, Newfoundland and Labrador A1B 3V6, Canada
Brampton Research Associates
Brampton, Ontario L6Z 4N5, Canada
Lawson Health Research Institute
London, Ontario N6C 2R5, Canada
St. Michael's Hospital
Toronto, Ontario M5C 2T2, Canada
ECOGENE-21 Clinical Trials Center
Chicoutimi, Quebec G7H 7K9, Canada
Clinic Sante Cardio MC
Montreal, Quebec H1T 3Y7, Canada
Institut de Recherches Cliniques de Montreal
Montreal, Quebec H2W 1R7, Canada
Université Laval Quebec
Quebec City, Quebec G1V 4G5, Canada
Clinique des maladies lipidique Quebec
Quebec City, Quebec G1V 4W2, Canada
Centre intégré universitaire de santé et de services sociaux de l'Estrie - Centre hospitalier universitaire de Sherbrooke (CIUSSS de l'Estrie - CHUS)
Sherbrooke, Quebec J1H 5N4, Canada
Medical University Berlin
Berlin, 12203, Germany
Medical Center Essen
Essen, 45355, Germany
University Hospital Frankfurt
Frankfurt, 60590, Germany
University Heart Center Hamburg
Hamburg, 20251, Germany
Medical University Hospital Heidelberg, Internal medicine III
Heidelberg, 69120, Germany
Technical University Munich, German Heart Center
Munich, 80636, Germany
Amsterdam Medical Center
Amsterdam, 1105 AZ, Netherlands
Haga Hospital
Den Haag, 2545 CH, Netherlands
Deventer Ziekenhuis
Deventer, 7416 SE, Netherlands
Andromed Eindhoven
Eindhoven, 5611 NV, Netherlands
Admiraal de Ruyter Hospital, Cardiology
Goes, 4462 RA, Netherlands
Bethesda Diabetes Research Center
Hoogeveen, 7909 AA, Netherlands
Medisch Centrum Gorecht
Hoogezand, 9603 AE, Netherlands
VOC Hoorn
Hoorn, 0031229284320, Netherlands
Leids Universitair Medisch Centrum (LUMC)
Leiden, 2333 ZA, Netherlands
Andromed Rotterdam
Rotterdam, 3021 HC, Netherlands
Diakonessenhuis, Vascular Policlinic
Utrecht, 3582 KE, Netherlands
UMC Utrecht
Utrecht, 3584 CX, Netherlands
VieCurie Venlo, Cardiology
Venlo, 5912 BL, Netherlands
Albert Schweitzer Hospital, Cardiology
Zwijndrecht, 3331 LZ, Netherlands
Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust
Birmingham, B15 2TH, United Kingdom
Edinburgh Royal Infirmary
Edinburgh, EH16 4SA, United Kingdom
The Royal Devon and Exeter NHS Trust
Exeter, EX2 5DW, United Kingdom
Fowey River Practice
Fowey, PL23 1DT, United Kingdom
Buckinghamshire NHS Trust
High Wycombe, HP11 2TT, United Kingdom
Oak Tree Surgery
Liskeard, Oak Tree Surgery, United Kingdom
Royal Free Hospital
London, NW3 2QG, United Kingdom
Central Manchester University Hospital NHS Foundation Trust
Manchester, M13 9WL, United Kingdom
The Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital
Newcastle upon Tyne, NE1 4LP, United Kingdom
The Alverton Practice
Penzance, TR18 4JH, United Kingdom
Knowle House Surgery
Plymouth, PL5 3JB, United Kingdom
Brannel Surgery
St. Austell, St. Austell, United Kingdom
Rame Medical Ltd (Rame Research)
Torpoint, PL11 2TB, United Kingdom
Worcestershire Acute NHS Trust
Worcester, WR5 1DD, United Kingdom

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Ray KK, Stoekenbroek RM, Kallend D, Nishikido T, Leiter LA, Landmesser U, Wright RS, Wijngaard PLJ, Kastelein JJP. Effect of 1 or 2 Doses of Inclisiran on Low-Density Lipoprotein Cholesterol Levels: One-Year Follow-up of the ORION-1 Randomized Clinical Trial. JAMA Cardiol. 2019 Nov 1;4(11):1067-1075. doi: 10.1001/jamacardio.2019.3502. PubMed 31553410 ↗
Leiter LA, Teoh H, Kallend D, Wright RS, Landmesser U, Wijngaard PLJ, Kastelein JJP, Ray KK. Inclisiran Lowers LDL-C and PCSK9 Irrespective of Diabetes Status: The ORION-1 Randomized Clinical Trial. Diabetes Care. 2019 Jan;42(1):173-176. doi: 10.2337/dc18-1491. Epub 2018 Nov 28. PubMed 30487231 ↗
Ray KK, Stoekenbroek RM, Kallend D, Leiter LA, Landmesser U, Wright RS, Wijngaard P, Kastelein JJP. Effect of an siRNA Therapeutic Targeting PCSK9 on Atherogenic Lipoproteins: Prespecified Secondary End Points in ORION 1. Circulation. 2018 Sep 25;138(13):1304-1316. doi: 10.1161/CIRCULATIONAHA.118.034710. PubMed 29735484 ↗
Ray KK, Landmesser U, Leiter LA, Kallend D, Dufour R, Karakas M, Hall T, Troquay RP, Turner T, Visseren FL, Wijngaard P, Wright RS, Kastelein JJ. Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. N Engl J Med. 2017 Apr 13;376(15):1430-1440. doi: 10.1056/NEJMoa1615758. Epub 2017 Mar 17. PubMed 28306389 ↗

Study documents

Study protocol · Apr 12, 2016
Statistical analysis plan · Jan 11, 2016

Documents are hosted by the registry — open the source record to download them.

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on May 17, 2019, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT02597127
Lead sponsor: The Medicines Company
Responsible party: Sponsor
First posted: Nov 5, 2015
Start date: Jan 2016
Primary completion: Jun 7, 2017
Completion: Jun 7, 2017
Results posted: May 17, 2019
Last update: May 17, 2019

Study contacts

Kausik K Ray, MD

principal investigator · Department of Public Health and Primary Care, Imperial College London, Reynolds Building

Oversight

Data monitoring committee: Yes

View the source record on ClinicalTrials.gov ↗

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