ORION-8: Trial to Assess the Effect of Long Term Dosing of Inclisiran in Subjects With High CV Risk and Elevated LDL-C

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03814187

Collaborator

(none)

3,275

Enrollment

238

Locations

Arm

56.5

Anticipated Duration (Months)

13.8

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this extension study is to evaluate the efficacy, safety, and tolerability of long-term dosing of Inclisiran. The study will be a global multicenter study.

Condition or Disease	Intervention/Treatment	Phase
ASCVD Elevated Cholesterol Heterozygous Familial Hypercholesterolemia Homozygous Familial Hypercholesterolemia	Drug: Inclisiran Sodium	Phase 3

Detailed Description

This study will be an open label, long term extension study in subjects with atherosclerotic cardiovascular disease (ASCVD), ASCVD-risk equivalents (eg, diabetes and familial hypercholesterolemia), or heterozygous or homozygous familial hypercholesterolemia (HeFH or HoFH) and elevated low density lipoprotein cholesterol (LDL-C) despite maximum tolerated dose of LDL-C lowering therapies who have completed the inclisiran Phase II trial MDCO-PCS-16-01 (ORION-3), or any of the following Phase III lipid lowering studies: MDCO-PCS-17-03 (ORION-9), MDCO-PCS-17-4 (ORION-10), or MDCO-PCS-17-08 (ORION-11)

Study Design

Study Type:

Interventional

Actual Enrollment :

3275 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An Open-label Extension Trial of the Phase III Lipid-lowering Trials to Assess the Effect of Long Term Dosing of Inclisiran Given as Subcutaneous Injections in Subjects With High Cardiovascular Risk and Elevated LDL-C

Actual Study Start Date :

Apr 16, 2019

Anticipated Primary Completion Date :

Aug 31, 2023

Anticipated Study Completion Date :

Dec 31, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Inclisiran Inclisiran sodium 300 milligrams (mg) will be administered as a single SC injection on Day 1, 90, then every 180 days to Day 990. Subjects who received blinded placebo in the feeder study will receive blinded inclisiran and subjects who received blinded inclisiran in the feeder study will receive blinded placebo on Day 1 in ORION-8. Subjects from the open label ORION-3 study will not receive any injection of study drug on Day 1. Their first dose of study medication will be at day 90	Drug: Inclisiran Sodium Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.

Arm

Intervention/Treatment

Experimental: Inclisiran

Inclisiran sodium 300 milligrams (mg) will be administered as a single SC injection on Day 1*, 90, then every 180 days to Day 990. *Subjects who received blinded placebo in the feeder study will receive blinded inclisiran and subjects who received blinded inclisiran in the feeder study will receive blinded placebo on Day 1 in ORION-8. Subjects from the open label ORION-3 study will not receive any injection of study drug on Day 1. Their first dose of study medication will be at day 90

Drug: Inclisiran Sodium

Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.

Outcome Measures

Primary Outcome Measures

Percentage of subjects achieving prespecified LDL-C targets. [Day 1080]
A primary objective of the study is to evaluate the effect of inclisiran treatment on the proportion of subjects achieving prespecified LDL-C targets at end of study.
Incidence of Adverse Events and Serious Adverse Events [Baseline, Day 1080]
Safety assessments include adverse events and serious adverse events for long-term safety profile

Secondary Outcome Measures

Absolute and percentage change in LDL-C from baseline. [Baseline, Day 1080]
A secondary objective of this study is to evaluate the effect of inclisiran on LDL-C levels.
Absolute and percentage change in other lipids and lipoprotein from baseline. [Baseline, Day 1080]
A secondary objective of this study is to evaluate the effect of inclisiran on other lipids and lipoproteins.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Completion on a previously qualifying inclisiran Phase II trial MDCO-PCS-16-01 (ORION-3), or Phase III lipid lowering ORION feeder study [MDCO-PCS-17-03 (ORION-9), MDCO-PCS-17-4 (ORION-10), or MDCO-PCS-17-08 (ORION-11)] meaning the subject received the last dose of study drug and completed the final study visit per applicable protocol.
On current lipid-lowering therapies (such as a statin and/or ezetimibe) from previous study 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:

Any uncontrolled or serious disease, or any medical or surgical condition, that may either interfere with participation in the clinical study, and/or put the subject at significant risk [according to investigator's (or delegate's) judgment] if he/she participates in the clinical study.
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.
Severe concomitant noncardiovascular disease that carries the risk of reducing life expectancy to less than 3 years,
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), or total bilirubin (TBIL) elevation >2x ULN at the last recorded visit in the feeder study prior to study entry visit.
Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least one method of acceptable effective contraception (eg, oral contraceptives, barrier methods, approved contraceptive implant, long-term injectable contraception, intrauterine device) for the entire duration of the study. Exemptions from this criterion:
Women >2 years postmenopausal (defined as 1 year or longer since last menstrual period) and more than 55 years of age.
Postmenopausal women (as defined above) and less than 55 years of age with a negative pregnancy test within 24 hours of randomization.
Women who are surgically sterilized at least 3 months prior to enrollment.
Planned use of other investigational medicinal products other than inclisiran 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:
Subjects 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 subjects whose cooperation is doubtful due to drug abuse or alcohol dependency)
Unlikely to comply with the protocol requirements, instructions, and study-related restrictions (eg, uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study)
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
Persons directly involved in the conduct of the study.

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 90001-005	Mission Viejo	California	United States	92691
20	Research Site 10001-043	Northridge	California	United States	91324
21	Research Site 10001-022	Northridge	California	United States	91325
22	Research Site 10001-033	Sacramento	California	United States	95821-2134
23	Research Site 10001-105	San Ramon	California	United States	94582
24	Research Site 10001-008	Santa Rosa	California	United States	95405
25	Research Site 10001-153	Spring Valley	California	United States	91978
26	Research Site 90001-015	Stanford	California	United States	94305
27	Research Site 10001-044	Torrance	California	United States	90502
28	Research Site 90001-047	Boca Raton	Florida	United States	33434
29	Research Site 10001-084	Clearwater	Florida	United States	33756
30	Research Site 10001-155	Clearwater	Florida	United States	33756
31	Research Site 10001-099	Clearwater	Florida	United States	33761
32	Research Site 10001-127	Daytona Beach	Florida	United States	32117
33	Research Site 10001-119	Fleming Island	Florida	United States	32003
34	Research Site 10001-070	Fort Lauderdale	Florida	United States	33308
35	Research Site 10001-067	Hialeah	Florida	United States	33012
36	Research Site 10001-139	Jacksonville	Florida	United States	32204
37	Research Site 10001-039	Jacksonville	Florida	United States	32216
38	Research Site 10001-098	Jacksonville	Florida	United States	32216
39	Research Site 10001-080	Miami Springs	Florida	United States	33166
40	Research Site 10001-081	Miami	Florida	United States	33126
41	Research Site 10001-140	Miami	Florida	United States	33126
42	Research Site 10001-142	Miami	Florida	United States	33126
43	Research Site 10001-030	Miami	Florida	United States	33165
44	Research Site 10001-116	Miami	Florida	United States	33183
45	Research Site 10001-027	Pembroke Pines	Florida	United States	33024
46	Research Site 10001-115	Pembroke Pines	Florida	United States	33027
47	Research Site 10001-048	Pembroke Pines	Florida	United States	33029
48	Research Site 10001-147	Pembroke Pines	Florida	United States	33029
49	Research Site 10001-003	Pinellas Park	Florida	United States	33781
50	Research Site 10001-104	Ponte Vedra	Florida	United States	32081
51	Research Site 10001-090	Saint Augustine	Florida	United States	32086
52	Research Site 10001-102	Saint Petersburg	Florida	United States	33713
53	Research Site 10001-123	Sarasota	Florida	United States	34239-3513
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	60652
60	Research Site 10001-036	Evanston	Illinois	United States	60201
61	Research Site 10001-082	Indianapolis	Indiana	United States	46260
62	Research Site 10001-040	Valparaiso	Indiana	United States	46383
63	Research Site 10001-074	West Des Moines	Iowa	United States	50266
64	Research Site 10001-028	Hutchinson	Kansas	United States	67502
65	Research Site 10001-125	Lexington	Kentucky	United States	40503
66	Research Site 10001-108	Lexington	Kentucky	United States	40504
67	Research Site 10001-107	Owensboro	Kentucky	United States	42303
68	Research Site 10001-144	Crowley	Louisiana	United States	70526
69	Research Site 10001-041	Lake Charles	Louisiana	United States	70601
70	Research Site 10001-101	Monroe	Louisiana	United States	71201
71	Research Site 90001-004	Boston	Massachusetts	United States	02114
72	Research Site 10001-024	Flint	Michigan	United States	48504
73	Research Site 10001-095	Grandville	Michigan	United States	49418
74	Research Site 10001-078	Sterling Heights	Michigan	United States	48310
75	Research Site 10001-034	Troy	Michigan	United States	48098
76	Research Site 10001-018	Edina	Minnesota	United States	55435
77	Research Site 90001-056	Saint Paul	Minnesota	United States	55102
78	Research Site 10001-156	Saint Louis	Missouri	United States	63136
79	Research Site 10001-007	Saint Louis	Missouri	United States	63141
80	Research Site 90001-012	Butte	Montana	United States	59701
81	Research Site 10001-053	Omaha	Nebraska	United States	68134
82	Research Site 10001-021	Omaha	Nebraska	United States	68144
83	Research Site 90001-112	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 90001-014	Summit	New Jersey	United States	07901
87	Research Site 10001-055	Warren	New Jersey	United States	07059
88	Research Site 10001-054	Albany	New York	United States	12206
89	Research Site 10001-122	Binghamton	New York	United States	13901
90	Research Site 10001-128	Endwell	New York	United States	13760
91	Research Site 10001-042	New Windsor	New York	United States	12553
92	Research Site 10001-129	Poughkeepsie	New York	United States	12601
93	Research Site 10001-110	Williamsville	New York	United States	14221
94	Research Site 10001-063	Cary	North Carolina	United States	27518
95	Research Site 10001-064	Greensboro	North Carolina	United States	27401
96	Research Site 10001-145	Mooresville	North Carolina	United States	28117
97	Research Site 10001-046	Shelby	North Carolina	United States	28150
98	Research Site 10001-016	Akron	Ohio	United States	443311
99	Research Site 10001-120	Cincinnati	Ohio	United States	45219
100	Research Site 90001-002	Cincinnati	Ohio	United States	45227
101	Research Site 10001-010	Cincinnati	Ohio	United States	45236
102	Research Site 10001-134	Cincinnati	Ohio	United States	45246
103	Research Site 10001-014	Columbus	Ohio	United States	43212
104	Research Site 10001-141	Dayton	Ohio	United States	45419
105	Research Site 10001-148	Marion	Ohio	United States	43302
106	Research Site 10001-109	Wyomissing	Pennsylvania	United States	19610
107	Research Site 10001-001	Anderson	South Carolina	United States	29621
108	Research Site 10001-006	Greer	South Carolina	United States	29651
109	Research Site 10001-075.	Greer	South Carolina	United States	29651
110	Research Site 10001-111	Myrtle Beach	South Carolina	United States	29588
111	Research Site 10001-133	Pelzer	South Carolina	United States	29669
112	Research Site 10001-103	Rapid City	South Dakota	United States	57701
113	Research Site 10001-146	Athens	Tennessee	United States	37303
114	Research Site 10001-130	Kingsport	Tennessee	United States	37660
115	Research Site 10001-118	Knoxville	Tennessee	United States	37909
116	Research Site 10001-106	Knoxville	Tennessee	United States	37917
117	Research Site 10001-100	Amarillo	Texas	United States	79106
118	Research Site 10001-087	Austin	Texas	United States	78726
119	Research Site 10001-117	Austin	Texas	United States	78756
120	Research Site 10001-009	Dallas	Texas	United States	75234
121	Research Site 10001-068	Edinburg	Texas	United States	78503
122	Research Site 10001-031	Houston	Texas	United States	77002
123	Research Site 10001-088	Houston	Texas	United States	77024
124	Research Site 10001-091	Houston	Texas	United States	77027
125	Research Site 10001-061	Houston	Texas	United States	77058
126	Research Site 10001-032	Houston	Texas	United States	77070
127	Research Site 10001-057	New Braunfels	Texas	United States	78130
128	Research Site 10001-079	Round Rock	Texas	United States	78681
129	Research Site 10001-071	San Antonio	Texas	United States	78229
130	Research Site 10001-083	Schertz	Texas	United States	78154
131	Research Site 10001-149	Shavano Park	Texas	United States	78231
132	Research Site 10001-045	Tomball	Texas	United States	77375
133	Research Site 10001-005	Layton	Utah	United States	84041
134	Research Site 10001-002	Salt Lake City	Utah	United States	84123
135	Research Site 10001-052	Salt Lake City	Utah	United States	94107
136	Research Site 10001-093	Falls Church	Virginia	United States	22042
137	Research Site 10001-085	Manassas	Virginia	United States	20110
138	Research Site 10001-094	Midlothian	Virginia	United States	23114
139	Research Site 10001-023	Richmond	Virginia	United States	23294
140	Research Site 10001-029	Suffolk	Virginia	United States	23435
141	Research Site 10001-114	Tacoma	Washington	United States	98405
142	Research Site 90011-005	Chicoutimi	Quebec	Canada	G7H 7K9
143	Research Site 90011-001	Montréal	Quebec	Canada	H2W 1R7
144	Research Site 90011-002	Québec	Quebec	Canada	GIV 4W2
145	Research Site 11420-002	Chomutov		Czechia	430 02
146	Research Site 90420-001	Praha		Czechia	140 21
147	Research Site 90420-006	Praha		Czechia	180 81
148	Research Site 11420-003	Uherské Hradiště		Czechia	686 01
149	Research Site 90045-001	Aalborg	Nordjylland	Denmark	9000
150	Research Site 90045-004	Esbjerg		Denmark	6700
151	Research Site 90045-003	Herning		Denmark	7400
152	Research Site 90045-006	Hvidovre		Denmark	2650
153	Research Site 90045-002	Roskilde		Denmark	4000
154	Research Site 90045-005	Viborg		Denmark	8800
155	Research Site 11049-006	Berlin		Germany	12627
156	Research Site 11049-002	Bochum		Germany	47787
157	Research Site 11049-003	Frankfurt		Germany	60313
158	Research Site 11049-001	Heidelberg		Germany	69120
159	Research Site 11049-007	Heidelberg		Germany	69120
160	Research Site 11036-001	Budapest		Hungary
161	Research Site 11036-004	Debrecen		Hungary
162	Research Site 11036-002	Hatvan		Hungary
163	Research Site 11036-003	Zalaegerszeg		Hungary
164	Research Site 90031-001	Amersfoort		Netherlands	3813 TZ
165	Research Site 90031-003	Amsterdam		Netherlands	1105 AZ
166	Research Site 90031-006	Goes		Netherlands	4462 RA
167	Research Site 90031-009	Hoorn		Netherlands	1624 NP
168	Research Site 90031-005	Utrecht		Netherlands
169	Research SIte 11048-016	Brzozowie		Poland
170	Research Site 11048-018	Bydgoszcz		Poland	85-079
171	Research Site 11048-011	Bydgoszcz		Poland
172	Research Site 11048-004	Gdańsk		Poland
173	Research Site 11048-005	Gdynia		Poland
174	Research Site 11048-007	Katowice		Poland
175	Research SIte 11048-012	Katowice		Poland
176	Research Site 11048-003	Kraków		Poland
177	Research SIte 11048-014	Kraków		Poland
178	Research Site 11048-008	Lublin		Poland
179	Research Site 11048-001	Poznań		Poland
180	Research Site 11048-019	Ruda Śląska		Poland	41-709
181	Research SIte 11048-013	Rzeszów		Poland
182	Research SIte 11048-015	Tarnów		Poland
183	Research Site 11048-006	Warsaw		Poland
184	Research Site 11048-009	Warsaw		Poland
185	Research Site 11048-002	Wrocław		Poland
186	Research Site 11048-010	Wrocław		Poland
187	Research Site 90027-008	Bellville	Cape Town	South Africa	7530
188	Research Site 90027-007	Lyttelton	Cape Town	South Africa	0157
189	Research Site 90027-003	Bloemfontein	Free State	South Africa	9301
190	Research Site 90027-010	Johannesburg	Gauteng	South Africa	2193
191	Research Site 11027-005	Kempton Park	Gauteng	South Africa	1619
192	Research Site 90027-006	Pretoria	Gauteng	South Africa	0184
193	Research Site 90027-009	Witbank	Gauteng	South Africa	1035
194	Research Site 90027-001	Cape Town	Western Cape	South Africa	7500
195	Research Site 11027-007	Kuilsrivier	Western Cape	South Africa	7580
196	Research Site 11027-013	Paarl	Western Cape	South Africa	7646
197	Research Site 90027-004	Somerset West	Western Cape	South Africa	7130
198	Research Site 90027-005	Somerset West	Western Cape	South Africa	7130
199	Research Site 90034-004	Córdoba	Andalucia	Spain	14004
200	Research Site 90034-002	Zaragoza	Aragon	Spain	5009
201	Research Site 90034-005	Barcelona	Cataluna	Spain	08036
202	Research Site 90034-006	Barcelona	Cataluna	Spain	08907
203	Research Site 90034-001	Reus	Cataluna	Spain	43204
204	Research Site 90034-003	La Coruña	Galicia	Spain	15002
205	Research Site 90046-002	Göteborg		Sweden	SE-41346
206	Research Site 90046-001	Stockholm		Sweden	SE-11446
207	Research Site 90046-003	Stockholm		Sweden	SE-14186
208	Research Site 11380-005	Cherkasy		Ukraine
209	Research Site 11380-008	Kharkiv		Ukraine	61176
210	Research Site 11380-001	Kyiv		Ukraine	02002
211	Research Site 11380-002	Kyiv		Ukraine	03037
212	Research Site 11380-003	Kyiv		Ukraine	03049
213	Research Site 11380-004	Kyiv		Ukraine
214	Research Site 11380-009	Zaporizhzhya		Ukraine
215	Research Site 11380-006	Úzhgorod		Ukraine	88000
216	Research Site 11044-028	Bollington	Cheshire	United Kingdom	SK10 5JH
217	Research Site 11044-026	Bury		United Kingdom
218	Research Site 11044-024	Cheadle Hulme		United Kingdom
219	Research Site 11044-014	Chorley		United Kingdom
220	Research Site 11044-012	Cornwell		United Kingdom
221	Research Site 11044-010	Derby		United Kingdom
222	Research Site 11044-006	Edgbaston		United Kingdom
223	Research Site 11044-009	Exeter		United Kingdom
224	Research Site 11044-001	Glasgow		United Kingdom
225	Research Site 11044-008	Hexham		United Kingdom
226	Research SIte 11044-020	Macclesfield		United Kingdom
227	Research Site 11044-005	Manchester		United Kingdom
228	Research Site 11044-025	Manchester		United Kingdom
229	Research Site 11044-027	Manchester		United Kingdom
230	Research Site 11044-029	Manchester		United Kingdom
231	Research Site 11044-019	Plymouth		United Kingdom
232	Research Site 11044-003	Reading		United Kingdom
233	Research Site 11044-022	Sale		United Kingdom
234	Research Site 11044-023	Sale		United Kingdom
235	Research Site 11044-002	Stockton-on-Tees		United Kingdom
236	Research Site 11044-021	Timperley		United Kingdom
237	Research Site 11044-007	Wales		United Kingdom
238	Research Site 11044-004	Waterloo		United Kingdom