ORION-10: Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol

• Sponsor: The Medicines Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03399370
• Collaborator: (none)
• Enrollment: 1,561
• Locations: 145
• Arms: 2
• Actual Duration (Months): 20.9
• Patients Per Site: 10.8
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This is a Phase III, placebo-controlled, double-blind, randomized study in participants with ASCVD and elevated LDL-C despite maximum tolerated dose of LDL-C lowering therapies to evaluate the efficacy, safety, and tolerability of subcutaneous (SC) inclisiran injection(s). The study will be a multicenter study in the United States.

Condition or Disease	Intervention/Treatment	Phase
ASCVD; Elevated Cholesterol	Drug: Inclisiran Sodium; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1561 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Treatment
• Official Title: A Placebo-Controlled, Double-Blind, Randomized Trial to Evaluate the Effect of 300 mg of Inclisiran Sodium Given as Subcutaneous Injections in Subjects With Atherosclerotic Cardiovascular Disease (ASCVD) and Elevated Low-Density Lipoprotein Cholesterol (LDL-C)
• Actual Study Start Date: Dec 21, 2017
• Actual Primary Completion Date: Sep 10, 2019
• Actual Study Completion Date: Sep 17, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Inclisiran Inclisiran sodium 300 milligrams (mg) will be administered as a SC injection on Day 1, Day 90, then every 6 months.	Drug: Inclisiran Sodium; Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.
Placebo Comparator: Saline Solution Placebo will be administered as a SC injection of saline solution on Day 1, Day 90, then every 6 months.	Drug: Placebo; Placebo will be supplied as sterile normal saline (0.9% sodium chloride in water for injection).; Other Names: Saline Solution

Outcome Measures

Primary Outcome Measures

1. Percentage Change in LDL-C From Baseline to Day 510 [Baseline, Day 510]

2. Time-adjusted Percentage Change in LDL-C Levels From Baseline After Day 90 and up to Day 540 [Baseline, Day 90 to Day 540]

   Assessments performed at Baseline, Day 90, Day 540, time-adjusted percent change at Day 540 reported

Secondary Outcome Measures

1. Absolute Change in LDL-C From Baseline to Day 510 [Baseline, Day 510]

2. Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540 [Baseline, Day 90 to Day 540]

   Assessments performed at Baseline, Day 90, Day 540, time-adjusted percent change at Day 540 reported

3. Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 510 [Baseline, Day 510]

4. Percentage Change in Total Cholesterol From Baseline to Day 510 [Baseline, Day 510]

5. Percentage Change in Apolipoprotein B (ApoB) From Baseline to Day 510 [Baseline, Day 510]

6. Percentage Change in Non-HDL-C From Baseline to Day 510 [Baseline, Day 510]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female participants ≥18 years of age.

2. History of ASCVD (coronary heart disease [CHD], cardiovascular disease [CVD], or peripheral arterial disease [PAD]).

3. Serum LDL-C ≥1.8 millimole (mmol)/liter (L) (≥70 mg/dL).

4. Fasting triglyceride <4.52 mmol/L (<400 mg/dL) at screening.

5. Participants on statins should be receiving a maximally tolerated dose.

6. Participants not receiving statins must have documented evidence of intolerance to all doses of at least 2 different statins.

7. 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.

Exclusion Criteria:

1. New York Heart Association (NYHA) class IV heart failure.

2. Uncontrolled cardiac arrhythmia

3. Uncontrolled severe hypertension

4. Active liver disease

5. Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least 2 methods of highly effective contraception (failure rate less than 1% per year) (for example, 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:

6. Women >2 years postmenopausal (defined as 1 year or longer since last menstrual period) and more than 55 years of age.

7. Postmenopausal women (as defined above) and less than 55 years of age with a negative pregnancy test within 24 hours of randomization.

8. Women who are surgically sterilized at least 3 months prior to enrollment.

9. Males who are unwilling to use an acceptable method of birth control during the entire study period (such as condom with spermicide).

10. Treatment with other investigational products or devices within 30 days or 5 half-lives of the screening visit, whichever is longer.

11. Treatment (within 90 days of screening) with monoclonal antibodies directed towards PCSK9

The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site 10001-015	Birmingham	Alabama	United States	35211
2	Research Site 10001-138	Foley	Alabama	United States	36535
3	Research Site 10001-113	Huntsville	Alabama	United States	35801
4	Research Site 10001-058	Mobile	Alabama	United States	36608
5	Research Site 10001-037	Montgomery	Alabama	United States	36117
6	Research Site 10001-076	Saraland	Alabama	United States	36571
7	Research Site 10001-013	Chandler	Arizona	United States	85224
8	Research Site 10001-077	Mesa	Arizona	United States	85213
9	Research Site 10001-136	Phoenix	Arizona	United States	85014
10	Research Site 10001-051	Surprise	Arizona	United States	85374
11	Research Site 10001-019	Tucson	Arizona	United States	85712
12	Research Site 10001-004	Tucson	Arizona	United States	85741
13	Research Site 10001-132	Tucson	Arizona	United States	85745
14	Research Site 10001-073	Beverly Hills	California	United States	90211
15	Research Site 10001-050	Canoga Park	California	United States	91303
16	Research Site 10001-011	Carlsbad	California	United States	92008
17	Research Site 10001-065	El Cajon	California	United States	92020
18	Research Site 10001-150	Los Angeles	California	United States	90022
19	Research Site 10001-043	Northridge	California	United States	91324
20	Research Site 10001-022	Northridge	California	United States	91325
21	Research Site 10001-033	Sacramento	California	United States	95821-2134
22	Research Site 10001-105	San Ramon	California	United States	94582
23	Research Site 10001-008	Santa Rosa	California	United States	95405
24	Research Site 10001-153	Spring Valley	California	United States	91978
25	Research Site 10001-044	Torrance	California	United States	90502
26	Research Site 10001-047	Boca Raton	Florida	United States	33434
27	Research Site 10001-084	Clearwater	Florida	United States	33756
28	Research Site 10001-155	Clearwater	Florida	United States	33756
29	Research Site 10001-099	Clearwater	Florida	United States	33761
30	Research Site 10001-127	Daytona Beach	Florida	United States	32117
31	Research Site 10001-119	Fleming Island	Florida	United States	32003
32	Research Site 10001-070	Fort Lauderdale	Florida	United States	33308
33	Research Site 10001-067	Hialeah	Florida	United States	33012
34	Research Site 10001-139	Jacksonville	Florida	United States	32204
35	Research Site 10001-039	Jacksonville	Florida	United States	32216
36	Research Site 10001-098	Jacksonville	Florida	United States	32216
37	Research Site 10001-080	Miami Springs	Florida	United States	33166
38	Research Site 10001-081	Miami	Florida	United States	33126
39	Research Site 10001-140	Miami	Florida	United States	33126
40	Research Site 10001-142	Miami	Florida	United States	33126
41	Research Site 10001-030	Miami	Florida	United States	33165
42	Research Site 10001-089	Miami	Florida	United States	33173
43	Research Site 10001-116	Miami	Florida	United States	33183
44	Research Site 10001-027	Pembroke Pines	Florida	United States	33024
45	Research Site 10001-115	Pembroke Pines	Florida	United States	33027
46	Research Site 10001-048	Pembroke Pines	Florida	United States	33029
47	Research Site 10001-147	Pembroke Pines	Florida	United States	33029
48	Research Site 10001-003	Pinellas Park	Florida	United States	33781
49	Research Site 10001-104	Ponte Vedra	Florida	United States	32081
50	Research Site 10001-090	Saint Augustine	Florida	United States	32086
51	Research Site 10001-102	Saint Petersburg	Florida	United States	33713
52	Research Site 10001-123	Sarasota	Florida	United States	34239-3513
53	Research Site 10001-038	Tampa	Florida	United States	33607
54	Research Site 10001-143	Tampa	Florida	United States	33614
55	Research Site 10001-069	Atlanta	Georgia	United States	30342
56	Research Site 10001-137	Dunwoody	Georgia	United States	30338
57	Research Site 10001-092	Macon	Georgia	United States	31210
58	Research Site 10001-059	Arlington Heights	Illinois	United States	60005
59	Research Site 10001-158	Chicago	Illinois	United States	60602
60	Research Site 10001-035	Chicago	Illinois	United States	60616
61	Research Site 10001-036	Evanston	Illinois	United States	60201
62	Research Site 10001-082	Indianapolis	Indiana	United States	46260
63	Research Site 1001-020	Sellersburg	Indiana	United States	47172
64	Research Site 10001-040	Valparaiso	Indiana	United States	46383
65	Research Site 10001-074	West Des Moines	Iowa	United States	50266
66	Research Site 10001-028	Hutchinson	Kansas	United States	67502
67	Research Site 10001-125	Lexington	Kentucky	United States	40503
68	Research Site 10001-108	Lexington	Kentucky	United States	40504
69	Research Site 10001-107	Owensboro	Kentucky	United States	42303
70	Research Site 10001-144	Crowley	Louisiana	United States	70526
71	Research Site 10001-041	Lake Charles	Louisiana	United States	70601
72	Research Site 10001-101	Monroe	Louisiana	United States	71201
73	Research Site 10001-024	Flint	Michigan	United States	48504
74	Research Site 10001-095	Grandville	Michigan	United States	49418
75	Research Site 10001-078	Sterling Heights	Michigan	United States	48310
76	Research Site 10001-034	Troy	Michigan	United States	48098
77	Research Site 10001-018	Edina	Minnesota	United States	55435
78	Research Site 10001-056	Saint Paul	Minnesota	United States	55102
79	Research Site 10001-156	Saint Louis	Missouri	United States	63136
80	Research Site 10001-007	Saint Louis	Missouri	United States	63141
81	Research Site 10001-053	Omaha	Nebraska	United States	68134
82	Research Site 10001-021	Omaha	Nebraska	United States	68144
83	Research Site 10001-112	Las Vegas	Nevada	United States	89119
84	Research Site 10001-124	Las Vegas	Nevada	United States	89121
85	Research Site 10001-060	Bridgewater	New Jersey	United States	08807
86	Research Site 10001-055	Raritan	New Jersey	United States	08869
87	Research Site 10001-054	Albany	New York	United States	12206
88	Research Site 10001-122	Binghamton	New York	United States	13901
89	Research Site 10001-128	Endwell	New York	United States	13760
90	Research Site 10001-042	New Windsor	New York	United States	12553
91	Research Site 10001-129	Poughkeepsie	New York	United States	12601
92	Research Site 10001-110	Williamsville	New York	United States	14221
93	Research Site 10001-063	Cary	North Carolina	United States	27518
94	Research Site 10001-064	Greensboro	North Carolina	United States	27401
95	Research Site 10001-145	Mooresville	North Carolina	United States	28117
96	Research Site 10001-046	Shelby	North Carolina	United States	28150
97	Research Site 10001-016	Akron	Ohio	United States	443311
98	Research Site 10001-120	Cincinnati	Ohio	United States	45219
99	Research Site 10001-154	Cincinnati	Ohio	United States	45227
100	Research Site 10001-010	Cincinnati	Ohio	United States	45236
101	Research Site 10001-134	Cincinnati	Ohio	United States	45246
102	Research Site 10001-014	Columbus	Ohio	United States	43212
103	Research Site 10001-012	Columbus	Ohio	United States	43213
104	Research Site 10001-141	Dayton	Ohio	United States	45419
105	Research Site 10001-148	Marion	Ohio	United States	43302
106	Research Site 10001-017	Edmond	Oklahoma	United States	73003
107	Research Site 10001-109	Wyomissing	Pennsylvania	United States	19610
108	Research Site 10001-001	Anderson	South Carolina	United States	29621
109	Research Site 10001-006	Greer	South Carolina	United States	29651
110	Research Site 10001-075.	Greer	South Carolina	United States	29651
111	Research Site 10001-111	Myrtle Beach	South Carolina	United States	29588
112	Research Site 10001-133	Pelzer	South Carolina	United States	29669
113	Research Site 10001-026	Spartanburg	South Carolina	United States	29303
114	Research Site 10001-103	Rapid City	South Dakota	United States	57701
115	Research Site 10001-146	Athens	Tennessee	United States	37303
116	Research Site 10001-130	Kingsport	Tennessee	United States	37660
117	Research Site 10001-118	Knoxville	Tennessee	United States	37909
118	Research Site 10001-100	Amarillo	Texas	United States	79106
119	Research Site 10001-087	Austin	Texas	United States	78726
120	Research Site 10001-117	Austin	Texas	United States	78756
121	Research Site 10001-009	Dallas	Texas	United States	75234
122	Research Site 10001-068	Edinburg	Texas	United States	78503
123	Research Site 10001-126	Fort Worth	Texas	United States	76106
124	Research Site 10001-031	Houston	Texas	United States	77002
125	Research Site 10001-088	Houston	Texas	United States	77024
126	Research Site 10001-091	Houston	Texas	United States	77027
127	Research Site 10001-061	Houston	Texas	United States	77058
128	Research Site 10001-032	Houston	Texas	United States	77070
129	Research Site 10001-025	Lubbock	Texas	United States	79410
130	Research Site 10001-057	New Braunfels	Texas	United States	78130
131	Research Site 10001-106	Powell	Texas	United States	37849
132	Research Site 10001-079	Round Rock	Texas	United States	78681
133	Research Site 10001-071	San Antonio	Texas	United States	78229
134	Research Site 10001-083	Schertz	Texas	United States	78154
135	Research Site 10001-149	Shavano Park	Texas	United States	78231
136	Research Site 10001-045	Tomball	Texas	United States	77375
137	Research Site 10001-005	Layton	Utah	United States	84041
138	Research Site 10001-002	Salt Lake City	Utah	United States	84123
139	Research Site 10001-052	Salt Lake City	Utah	United States	94107
140	Research Site 10001-093	Falls Church	Virginia	United States	22042
141	Research Site 10001-085	Manassas	Virginia	United States	20110
142	Research Site 10001-094	Midlothian	Virginia	United States	23114
143	Research Site 10001-023	Richmond	Virginia	United States	23294
144	Research Site 10001-029	Suffolk	Virginia	United States	23435
145	Research Site 10001-114	Tacoma	Washington	United States	98405

Sponsors and Collaborators

• The Medicines Company

Investigators

• Principal Investigator: Scott Wright, MD, Mayo Clinic

Study Documents (Full-Text)

• Study Protocol - Jan 31, 2019
• Statistical Analysis Plan - Sep 13, 2019

More Information

Publications

None provided.

• Responsible Party: The Medicines Company
• ClinicalTrials.gov Identifier: NCT03399370
• Other Study ID Numbers: MDCO-PCS-17-04
• First Posted: Jan 16, 2018
• Last Update Posted: Oct 5, 2020
• Last Verified: Sep 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by The Medicines Company: Inclisiran sodium; ASCVD; LDL-C
• Additional relevant MeSH terms: Cardiovascular Diseases; Atherosclerosis; Hypercholesterolemia

Study Results

Participant Flow

Arm/Group Title	Inclisiran	Saline Solution
Arm/Group Description	Inclisiran sodium 300 milligrams (mg) will be administered as a SC injection on Day 1, Day 90, then every 6 months. Inclisiran Sodium: Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.	Placebo will be administered as a SC injection of saline solution on Day 1, Day 90, then every 6 months. Placebo: Placebo will be supplied as sterile normal saline (0.9% sodium chloride in water for injection).
Period Title: Overall Study
STARTED	781	780
COMPLETED	721	694
NOT COMPLETED	60	86

Baseline Characteristics

Arm/Group Title	Inclisiran	Placebo	Total
Arm/Group Description	Inclisiran sodium 300 milligrams (mg) will be administered as a SC injection on Day 1, Day 90, then every 6 months. Inclisiran Sodium: Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.	Placebo will be administered as a SC injection of saline solution on Day 1, Day 90, then every 6 months. Placebo will be supplied as sterile normal saline (0.9% sodium chloride in water for injection).	Total of all reporting groups
Overall Participants	781	780	1561
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	297 38%	333 42.7%	630 40.4%
>=65 years	484 62%	447 57.3%	931 59.6%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66.4 (8.90)	65.7 (8.89)	66.0 (8.90)
Sex: Female, Male (Count of Participants)
Female	246 31.5%	232 29.7%	478 30.6%
Male	535 68.5%	548 70.3%	1083 69.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 0.3%	4 0.5%	6 0.4%
Asian	9 1.2%	1 0.1%	10 0.6%
Native Hawaiian or Other Pacific Islander	7 0.9%	3 0.4%	10 0.6%
Black or African American	110 14.1%	87 11.2%	197 12.6%
White	653 83.6%	685 87.8%	1338 85.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	781 100%	780 100%	1561 100%

Outcome Measures

1. Primary Outcome

Title	Percentage Change in LDL-C From Baseline to Day 510
Time Frame	Baseline, Day 510

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population

Arm/Group Title	Inclisiran	Placebo
Arm/Group Description	Inclisiran sodium 300 milligrams (mg) will be administered as a SC injection on Day 1, Day 90, then every 6 months. Inclisiran Sodium: Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.	Placebo administered as a subcutaneous injection of sterile saline solution (0.9% sodium chloride in water for injection) on Day 1, Day 90, and then every 6 months.
Measure Participants	781	780
Least Squares Mean (95% Confidence Interval) [percent change]	-56.34	1.30

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inclisiran, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	LS Mean Difference (95% CI) from Placebo
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	The a priori threshold for statistical significance was <0.05
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-57.64
	Confidence Interval	(2-Sided) 95%; -60.86 to -54.43
	Parameter Dispersion	Type: Value:
	Estimation Comments	Represents the least squares mean difference from Placebo

2. Primary Outcome

Title	Time-adjusted Percentage Change in LDL-C Levels From Baseline After Day 90 and up to Day 540
Description	Assessments performed at Baseline, Day 90, Day 540, time-adjusted percent change at Day 540 reported
Time Frame	Baseline, Day 90 to Day 540

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population

Arm/Group Title	Inclisiran	Placebo
Arm/Group Description	Inclisiran sodium 300 milligrams (mg) (equivalent to 284 mg inclisiran) administered as a subcutaneous injection on Day 1, Day 90, and then every 6 months.	Placebo administered as a subcutaneous injection of sterile saline solution (0.9% sodium chloride in water for injection) on Day 1, Day 90, and then every 6 months.
Measure Participants	781	790
Least Squares Mean (95% Confidence Interval) [percent change]	-51.27	2.51

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inclisiran, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	LS Mean Difference (95% CI) from Placebo
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The a priori threshold for statistical significance was <0.05
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-53.78
	Confidence Interval	(2-Sided) 95%; -56.23 to -51.33
	Parameter Dispersion	Type: Value:
	Estimation Comments	Represents the least squares mean difference from Placebo

3. Secondary Outcome

Title	Absolute Change in LDL-C From Baseline to Day 510
Time Frame	Baseline, Day 510

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population

Arm/Group Title	Inclisiran	Placebo
Arm/Group Description	Inclisiran sodium 300 milligrams (mg) (equivalent to 284 mg inclisiran) administered as a subcutaneous injection on Day 1, Day 90, and then every 6 months.	Placebo administered as a subcutaneous injection of sterile saline solution (0.9% sodium chloride in water for injection) on Day 1, Day 90, and then every 6 months.
Measure Participants	781	780
Least Squares Mean (95% Confidence Interval) [mg/dL]	-56.18	-2.06

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inclisiran, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	LS Mean Difference (95% CI) from Placebo
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The a priori threshold for statistical significance was <0.05
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-54.12
	Confidence Interval	(2-Sided) 95%; -57.37 to -50.88
	Parameter Dispersion	Type: Value:
	Estimation Comments	Represents the least squares mean difference from Placebo

4. Secondary Outcome

Title	Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540
Description	Assessments performed at Baseline, Day 90, Day 540, time-adjusted percent change at Day 540 reported
Time Frame	Baseline, Day 90 to Day 540

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population

Arm/Group Title	Inclisiran	Placebo
Arm/Group Description	Inclisiran sodium 300 milligrams (mg) (equivalent to 284 mg inclisiran) administered as a subcutaneous injection on Day 1, Day 90, and then every 6 months.	Placebo administered as a subcutaneous injection of sterile saline solution (0.9% sodium chloride in water for injection) on Day 1, Day 90, and then every 6 months.
Measure Participants	781	780
Least Squares Mean (95% Confidence Interval) [mg/dL]	-53.66	-0.39

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inclisiran, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The a priori threshold for statistical significance was <0.05
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-53.28
	Confidence Interval	(2-Sided) 95%; -55.75 to -50.80
	Parameter Dispersion	Type: Value:
	Estimation Comments	Represents the least squares mean difference from Placebo

5. Secondary Outcome

Title	Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 510
Time Frame	Baseline, Day 510

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population

Arm/Group Title	Inclisiran	Placebo
Arm/Group Description	Inclisiran sodium 300 milligrams (mg) (equivalent to 284 mg inclisiran) administered as a subcutaneous injection on Day 1, Day 90, and then every 6 months.	Placebo administered as a subcutaneous injection of sterile saline solution (0.9% sodium chloride in water for injection) on Day 1, Day 90, and then every 6 months.
Measure Participants	781	780
Least Squares Mean (95% Confidence Interval) [percent change]	-69.78	13.52

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inclisiran, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The a priori threshold for statistical significance was <0.05
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-83.80
	Confidence Interval	(2-Sided) 95%; -89.25 to -77.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	Represents the least squares mean difference from Placebo

6. Secondary Outcome

Title	Percentage Change in Total Cholesterol From Baseline to Day 510
Time Frame	Baseline, Day 510

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population

Arm/Group Title	Inclisiran	Placebo
Arm/Group Description	Inclisiran sodium 300 milligrams (mg) (equivalent to 284 mg inclisiran) administered as a subcutaneous injection on Day 1, Day 90, and then every 6 months.	Placebo administered as a subcutaneous injection of sterile saline solution (0.9% sodium chloride in water for injection) on Day 1, Day 90, and then every 6 months.
Measure Participants	781	781
Least Squares Mean (95% Confidence Interval) [percent change]	-33.56	-0.42

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inclisiran, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The a priori threshold for statistical significance was <0.05
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-33.13
	Confidence Interval	(2-Sided) 95%; -35.30 to -30.97
	Parameter Dispersion	Type: Value:
	Estimation Comments	Represents the least squares mean difference from Placebo

7. Secondary Outcome

Title	Percentage Change in Apolipoprotein B (ApoB) From Baseline to Day 510
Time Frame	Baseline, Day 510

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population

Arm/Group Title	Inclisiran	Placebo
Arm/Group Description	Inclisiran sodium 300 milligrams (mg) (equivalent to 284 mg inclisiran) administered as a subcutaneous injection on Day 1, Day 90, and then every 6 months.	Placebo administered as a subcutaneous injection of sterile saline solution (0.9% sodium chloride in water for injection) on Day 1, Day 90, and then every 6 months.
Measure Participants	781	780
Least Squares Mean (95% Confidence Interval) [percent change]	-44.81	-1.72

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inclisiran, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	The a priori threshold for statistical significance was <0.05
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-43.09
	Confidence Interval	(2-Sided) 95%; -45.50 to -40.67
	Parameter Dispersion	Type: Value:
	Estimation Comments	Represents the least squares mean difference from Placebo

8. Secondary Outcome

Title	Percentage Change in Non-HDL-C From Baseline to Day 510
Time Frame	Baseline, Day 510

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population

Arm/Group Title	Inclisiran	Placebo
Arm/Group Description	Inclisiran sodium 300 milligrams (mg) (equivalent to 284 mg inclisiran) administered as a subcutaneous injection on Day 1, Day 90, and then every 6 months.	Placebo administered as a subcutaneous injection of sterile saline solution (0.9% sodium chloride in water for injection) on Day 1, Day 90, and then every 6 months.
Measure Participants	781	780
Least Squares Mean (95% Confidence Interval) [percent change]	-47.41	-0.05

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inclisiran, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The a priori threshold for statistical significance was <0.05
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-47.36
	Confidence Interval	(2-Sided) 95%; -50.25 to -44.47
	Parameter Dispersion	Type: Value:
	Estimation Comments	Represents the least squares mean difference from Placebo

Adverse Events

Time Frame	18 months
Arm/Group Title	Inclisiran		Saline Solution
Arm/Group Description	Inclisiran sodium 300 milligrams (mg) will be administered as a SC injection on Day 1, Day 90, then every 6 months. Inclisiran Sodium: Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.		Placebo will be administered as a SC injection of saline solution on Day 1, Day 90, then every 6 months. Placebo: Placebo will be supplied as sterile normal saline (0.9% sodium chloride in water for injection).
All Cause Mortality
	Inclisiran		Saline Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/781 (1.5%)		11/778 (1.4%)
Serious Adverse Events
	Inclisiran		Saline Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	175/781 (22.4%)		205/778 (26.3%)
Blood and lymphatic system disorders
Anaemia	3/781 (0.4%)		1/778 (0.1%)
Haemorrhagic anaemia	2/781 (0.3%)		0/778 (0%)
Iron deficiency anaemia	0/781 (0%)		1/778 (0.1%)
Leukocytosis	0/781 (0%)		1/778 (0.1%)
Leukopenia	1/781 (0.1%)		0/778 (0%)
Thrombocytopenia	1/781 (0.1%)		0/778 (0%)
Cardiac disorders
Acute coronary syndrome	0/781 (0%)		2/778 (0.3%)
Acute myocardial infarction	14/781 (1.8%)		12/778 (1.5%)
Angina pectoris	6/781 (0.8%)		7/778 (0.9%)
Angina unstable	4/781 (0.5%)		10/778 (1.3%)
Arteriosclerosis coronary artery	0/781 (0%)		1/778 (0.1%)
Atrial fibrillation	10/781 (1.3%)		8/778 (1%)
Atrial flutter	0/781 (0%)		1/778 (0.1%)
Atrioventricular block	2/781 (0.3%)		0/778 (0%)
Atrioventricular block complete	1/781 (0.1%)		0/778 (0%)
Atrioventricular block second degree	0/781 (0%)		1/778 (0.1%)
Bradycardia	1/781 (0.1%)		2/778 (0.3%)
Cardiac arrest	1/781 (0.1%)		1/778 (0.1%)
Cardiac failure	0/781 (0%)		1/778 (0.1%)
Cardiac failure acute	1/781 (0.1%)		1/778 (0.1%)
Cardiac failure congestive	7/781 (0.9%)		20/778 (2.6%)
Cardio-respiratory arrest	1/781 (0.1%)		0/778 (0%)
Cardiomyopathy	2/781 (0.3%)		0/778 (0%)
Coronary artery disease	15/781 (1.9%)		22/778 (2.8%)
Coronary artery occlusion	1/781 (0.1%)		2/778 (0.3%)
Ischaemic cardiomyopathy	1/781 (0.1%)		0/778 (0%)
Left ventricular failure	3/781 (0.4%)		1/778 (0.1%)
Mitral valve incompetence	0/781 (0%)		3/778 (0.4%)
Myocardial infarction	6/781 (0.8%)		6/778 (0.8%)
Nodal arrythmia	0/781 (0%)		1/778 (0.1%)
Palpitations	0/781 (0%)		1/778 (0.1%)
Pericardial effusion	0/781 (0%)		1/778 (0.1%)
Pericarditis	0/781 (0%)		2/778 (0.3%)
Sinus node dysfunction	0/781 (0%)		2/778 (0.3%)
Supraventricular tachycardia	0/781 (0%)		2/778 (0.3%)
Tachycardia	0/781 (0%)		1/778 (0.1%)
Ventricular extrasystoles	1/781 (0.1%)		0/778 (0%)
Ventricular fibrillation	0/781 (0%)		2/778 (0.3%)
Ventricular tachyarrhythmia	1/781 (0.1%)		0/778 (0%)
Ventricular tachycardia	2/781 (0.3%)		4/778 (0.5%)
Congenital, familial and genetic disorders
Atrial septal defect	0/781 (0%)		1/778 (0.1%)
Endocrine disorders
Ectopic hyperthyroidism	1/781 (0.1%)		0/778 (0%)
Eye disorders
Ophthalmic vein thrombosis	0/781 (0%)		1/778 (0.1%)
Retinal artery occlusion	1/781 (0.1%)		0/778 (0%)
Visual impairment	0/781 (0%)		1/778 (0.1%)
Gastrointestinal disorders
Abdominal pain	0/781 (0%)		1/778 (0.1%)
Abdominal pain upper	1/781 (0.1%)		0/778 (0%)
Anal fistula	0/781 (0%)		1/778 (0.1%)
Colitis ischaemic	1/781 (0.1%)		2/778 (0.3%)
Constipation	1/781 (0.1%)		0/778 (0%)
Diarrhoea	0/781 (0%)		2/778 (0.3%)
Diverticulum	0/781 (0%)		1/778 (0.1%)
Diverticulum intestinal haemorrhagic	0/781 (0%)		1/778 (0.1%)
Duodenal polyp	1/781 (0.1%)		0/778 (0%)
Enteritis	0/781 (0%)		1/778 (0.1%)
Gastritis erosive	1/781 (0.1%)		0/778 (0%)
Gastrointestinal haemorrhage	0/781 (0%)		2/778 (0.3%)
Intestinal infarction	0/781 (0%)		1/778 (0.1%)
Intestinal ischaemia	0/781 (0%)		1/778 (0.1%)
Intestinal obstruction	0/781 (0%)		1/778 (0.1%)
Larger intestine perforation	0/781 (0%)		1/778 (0.1%)
Oesophageal varices haemorrhage	1/781 (0.1%)		0/778 (0%)
Pancreatic mass	0/781 (0%)		1/778 (0.1%)
Pancreatitis	1/781 (0.1%)		0/778 (0%)
Rectal haemorrhage	0/781 (0%)		1/778 (0.1%)
Retroperitoneal haemorrhage	0/781 (0%)		1/778 (0.1%)
Small intestinal obstruction	4/781 (0.5%)		0/778 (0%)
Upper gastrointestinal haemorrhage	1/781 (0.1%)		1/778 (0.1%)
Vomiting	0/781 (0%)		1/778 (0.1%)
General disorders
Asthenia	0/781 (0%)		3/778 (0.4%)
Chest pain	2/781 (0.3%)		3/778 (0.4%)
Death	2/781 (0.3%)		1/778 (0.1%)
Gait disturbance	0/781 (0%)		1/778 (0.1%)
Hypothermia	0/781 (0%)		1/778 (0.1%)
Multiple organ dysfunction syndrome	0/781 (0%)		1/778 (0.1%)
Non-cardiac chest pain	10/781 (1.3%)		9/778 (1.2%)
Pyrexia	1/781 (0.1%)		0/778 (0%)
Sensation of foreign body	1/781 (0.1%)		0/778 (0%)
Ulcer haemorrhage	0/781 (0%)		1/778 (0.1%)
Vascular stent restenosis	0/781 (0%)		1/778 (0.1%)
Hepatobiliary disorders
Bile duct stone	1/781 (0.1%)		1/778 (0.1%)
Cholecystitis	0/781 (0%)		1/778 (0.1%)
Cholecystitis acute	1/781 (0.1%)		2/778 (0.3%)
Cholelithiasis	0/781 (0%)		2/778 (0.3%)
Hepatic cirrhosis	1/781 (0.1%)		0/778 (0%)
Immune system disorders
Anaphylactic reaction	0/781 (0%)		1/778 (0.1%)
Infections and infestations
Anal abscess	1/781 (0.1%)		0/778 (0%)
Appendicitis	2/781 (0.3%)		1/778 (0.1%)
Appendicitis perforated	1/781 (0.1%)		0/778 (0%)
Arthritis infective	1/781 (0.1%)		0/778 (0%)
Bacterial pyelonephritis	0/781 (0%)		1/778 (0.1%)
Bronchitis	2/781 (0.3%)		2/778 (0.3%)
Cavernous sinus thrombosis	0/781 (0%)		1/778 (0.1%)
Cellulitis	4/781 (0.5%)		2/778 (0.3%)
Clostridium difficile colitis	1/781 (0.1%)		1/778 (0.1%)
Cystitis	1/781 (0.1%)		0/778 (0%)
Device related infection	1/781 (0.1%)		0/778 (0%)
Diabetic foot infection	1/781 (0.1%)		0/778 (0%)
Diverticultis	2/781 (0.3%)		2/778 (0.3%)
Escherichia bacteraemia	1/781 (0.1%)		1/778 (0.1%)
Gangrene	0/781 (0%)		1/778 (0.1%)
Gastroenteritis	2/781 (0.3%)		0/778 (0%)
Gastroenteritis norovirus	0/781 (0%)		1/778 (0.1%)
Infectious colitis	0/781 (0%)		1/778 (0.1%)
Influenza	2/781 (0.3%)		1/778 (0.1%)
Localised infection	2/781 (0.3%)		0/778 (0%)
Osteomyelitis	1/781 (0.1%)		2/778 (0.3%)
Osteomyelitis acute	1/781 (0.1%)		0/778 (0%)
Periorbital cellulitis	1/781 (0.1%)		0/778 (0%)
Periotinitis	1/781 (0.1%)		0/778 (0%)
Pneumonia	11/781 (1.4%)		9/778 (1.2%)
Pneumonia bacterial	1/781 (0.1%)		0/778 (0%)
Pneumonia viral	1/781 (0.1%)		0/778 (0%)
Post procedural infection	1/781 (0.1%)		0/778 (0%)
Postoperative wound infection	0/781 (0%)		1/778 (0.1%)
Pyelonephritis	0/781 (0%)		1/778 (0.1%)
Sepsis	6/781 (0.8%)		4/778 (0.5%)
Sepsis syndrome	0/781 (0%)		1/778 (0.1%)
Septic shock	1/781 (0.1%)		1/778 (0.1%)
Staphylococcal abscess	1/781 (0.1%)		0/778 (0%)
Urinary tract infection	0/781 (0%)		3/778 (0.4%)
Injury, poisoning and procedural complications
Accidental overdose	0/781 (0%)		1/778 (0.1%)
Cardiac contusion	0/781 (0%)		1/778 (0.1%)
Cardiac valve replacement complication	0/781 (0%)		1/778 (0.1%)
Chemical burn	1/781 (0.1%)		0/778 (0%)
Contusion	1/781 (0.1%)		0/778 (0%)
Craniocerebral injury	0/781 (0%)		1/778 (0.1%)
Facial bones fracture	0/781 (0%)		1/778 (0.1%)
Fall	2/781 (0.3%)		0/778 (0%)
Femoral neck fracture	0/781 (0%)		2/778 (0.3%)
Foot fracture	1/781 (0.1%)		0/778 (0%)
Gun shot wound	0/781 (0%)		1/778 (0.1%)
Head injury	1/781 (0.1%)		0/778 (0%)
Hip fracture	0/781 (0%)		1/778 (0.1%)
Humerus fracture	0/781 (0%)		1/778 (0.1%)
Incisional hernia, obstructive	1/781 (0.1%)		0/778 (0%)
Joint dislocation	1/781 (0.1%)		0/778 (0%)
Lumbar vertebral fracture	1/781 (0.1%)		0/778 (0%)
Multiple injuries	1/781 (0.1%)		0/778 (0%)
Occupational exposure to product	1/781 (0.1%)		0/778 (0%)
Post procedural haematuria	0/781 (0%)		1/778 (0.1%)
Post procedural hawmorrhage	1/781 (0.1%)		0/778 (0%)
Procedural pain	0/781 (0%)		1/778 (0.1%)
Rib fracture	1/781 (0.1%)		1/778 (0.1%)
Road traffic accident	1/781 (0.1%)		1/778 (0.1%)
Spinal compression fracture	0/781 (0%)		1/778 (0.1%)
Subarachnoid haemorrhage	0/781 (0%)		1/778 (0.1%)
Subdural haemorrhage	0/781 (0%)		1/778 (0.1%)
Thoracic vertebral fracture	0/781 (0%)		1/778 (0.1%)
Tibia fracture	0/781 (0%)		1/778 (0.1%)
Vascular pseudoaneurysm	1/781 (0.1%)		0/778 (0%)
Wrist fracture	0/781 (0%)		1/778 (0.1%)
Investigations
Blood pressure increased	0/781 (0%)		1/778 (0.1%)
Metabolism and nutrition disorders
Dehydration	0/781 (0%)		2/778 (0.3%)
Diabetes Mellitus	0/781 (0%)		2/778 (0.3%)
Diabetes mellitus inadequate control	0/781 (0%)		2/778 (0.3%)
Diabetic ketoacidosis	1/781 (0.1%)		1/778 (0.1%)
Fluid overload	1/781 (0.1%)		0/778 (0%)
Gout	0/781 (0%)		2/778 (0.3%)
Hypercalcaemia	1/781 (0.1%)		0/778 (0%)
Hyperglycaemia	3/781 (0.4%)		0/778 (0%)
Hyperkalaemia	0/781 (0%)		1/778 (0.1%)
Hypoglycaemia	1/781 (0.1%)		0/778 (0%)
Hypokalaemia	1/781 (0.1%)		1/778 (0.1%)
Hyponatraemia	0/781 (0%)		1/778 (0.1%)
Hypovolaemia	1/781 (0.1%)		1/778 (0.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/781 (0.3%)		0/778 (0%)
Arthritis	0/781 (0%)		1/778 (0.1%)
Back pain	1/781 (0.1%)		2/778 (0.3%)
Cervical spinal stenosis	0/781 (0%)		3/778 (0.4%)
Fracture malunion	0/781 (0%)		1/778 (0.1%)
Intervertebral disc degeneration	0/781 (0%)		1/778 (0.1%)
Lumbar spinal stenosis	1/781 (0.1%)		4/778 (0.5%)
Muscular weakness	0/781 (0%)		1/778 (0.1%)
Musculoskeletal pain	0/781 (0%)		1/778 (0.1%)
Osteoarthritis	2/781 (0.3%)		2/778 (0.3%)
Rhabdomyolysis	0/781 (0%)		1/778 (0.1%)
Spinal column stenosis	1/781 (0.1%)		1/778 (0.1%)
Spinal osteoarthritis	0/781 (0%)		2/778 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	1/781 (0.1%)		0/778 (0%)
Adenocarcinoma	0/781 (0%)		1/778 (0.1%)
Adenocarcinoma of colon	0/781 (0%)		1/778 (0.1%)
Bladder cancer	1/781 (0.1%)		0/778 (0%)
Bladder transitional cell carcinoma	0/781 (0%)		1/778 (0.1%)
Bowen's disease	3/781 (0.4%)		0/778 (0%)
Breast cancer	1/781 (0.1%)		0/778 (0%)
Breast cancer stage 1	0/781 (0%)		1/778 (0.1%)
Carcinoid tumour of the stomach	0/781 (0%)		2/778 (0.3%)
Clear cell renal cell carcinoma	0/781 (0%)		1/778 (0.1%)
Colon cancer metastatic	0/781 (0%)		1/778 (0.1%)
Endometrial cancer	0/781 (0%)		2/778 (0.3%)
Gastrointestinal lymphoma	1/781 (0.1%)		0/778 (0%)
Gastrooesophageal cancer	0/781 (0%)		1/778 (0.1%)
Hepatic cancer	1/781 (0.1%)		0/778 (0%)
Invasive ductal breast carcinoma	0/781 (0%)		1/778 (0.1%)
Liposarcoma recurrent	0/781 (0%)		1/778 (0.1%)
Lung adenocarcinoma	0/781 (0%)		3/778 (0.4%)
Malignant melanoma	0/781 (0%)		1/778 (0.1%)
Meningioma	0/781 (0%)		1/778 (0.1%)
Metastases to central nervous system	1/781 (0.1%)		0/778 (0%)
Metastases to liver	0/781 (0%)		2/778 (0.3%)
Myelodyplastic syndrome	0/781 (0%)		1/778 (0.1%)
Non-small cell lung cancer	1/781 (0.1%)		1/778 (0.1%)
Pancreatic carcinoma metastatic	0/781 (0%)		1/778 (0.1%)
Prostate cancer	4/781 (0.5%)		2/778 (0.3%)
Prostate cancer recurrent	1/781 (0.1%)		1/778 (0.1%)
Renal cancer	1/781 (0.1%)		0/778 (0%)
Renal cell carcinoma	1/781 (0.1%)		0/778 (0%)
Squamous cell carcinoma	3/781 (0.4%)		2/778 (0.3%)
Squamous cell carcinoma of lung	2/781 (0.3%)		1/778 (0.1%)
Squamous cell carcinoma of skin	5/781 (0.6%)		1/778 (0.1%)
Nervous system disorders
Carotid artery disease	1/781 (0.1%)		1/778 (0.1%)
Carotid artery stenosis	3/781 (0.4%)		2/778 (0.3%)
Cerebral haemorrhage	1/781 (0.1%)		0/778 (0%)
Cerebral infarction	1/781 (0.1%)		1/778 (0.1%)
Cerebrovascular accident	4/781 (0.5%)		3/778 (0.4%)
Cerebrovascular disorder	1/781 (0.1%)		0/778 (0%)
Cervical radiculopathy	0/781 (0%)		2/778 (0.3%)
Demetia	0/781 (0%)		1/778 (0.1%)
Dizziness	3/781 (0.4%)		0/778 (0%)
Headache	1/781 (0.1%)		1/778 (0.1%)
Hemiparesis	0/781 (0%)		1/778 (0.1%)
Ischaemic stroke	7/781 (0.9%)		4/778 (0.5%)
Metabolic encephalopathy	0/781 (0%)		1/778 (0.1%)
Migraine	1/781 (0.1%)		0/778 (0%)
Myelopathy	0/781 (0%)		1/778 (0.1%)
Nerve compression	0/781 (0%)		1/778 (0.1%)
Normal pressure hydrocephalus	0/781 (0%)		2/778 (0.3%)
Presyncope	2/781 (0.3%)		0/778 (0%)
Radiculopathy	0/781 (0%)		1/778 (0.1%)
Seizure	0/781 (0%)		1/778 (0.1%)
Spinal subdural haematoma	0/781 (0%)		1/778 (0.1%)
Status migrainosus	1/781 (0.1%)		0/778 (0%)
Syncope	4/781 (0.5%)		7/778 (0.9%)
Other (Not Including Serious) Adverse Events
	Inclisiran		Saline Solution
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	247/781 (31.6%)		219/778 (28.1%)
Infections and infestations
Bronchitis	46/781 (5.9%)		30/778 (3.9%)
Metabolism and nutrition disorders
Diabetes mellitus	120/781 (15.4%)		108/778 (13.9%)
Musculoskeletal and connective tissue disorders
Back pain	39/781 (5%)		39/778 (5%)
Vascular disorders
Hypertension	42/781 (5.4%)		42/778 (5.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.