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Trial to Evaluate the Effect of Inclisiran Treatment on Low Density Lipoprotein Cholesterol (LDL-C) in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH) (ORION-9)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03397121
Recruitment Status : Completed
First Posted : January 11, 2018
Results First Posted : October 28, 2020
Last Update Posted : October 28, 2020
Sponsor:
Information provided by (Responsible Party):
The Medicines Company

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Care Provider);   Primary Purpose: Treatment
Conditions Heterozygous Familial Hypercholesterolemia
Elevated Cholesterol
Interventions Drug: Inclisiran
Drug: Placebo
Enrollment 482
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Inclisiran Placebo
Hide 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: Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.

Placebo will be administered as SC injections 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 242 240
Completed 235 231
Not Completed 7 9
Arm/Group Title Inclisiran Placebo Total
Hide 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: Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.

Placebo will be administered as SC injections 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).

Total of all reporting groups
Overall Number of Baseline Participants 242 240 482
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 242 participants 240 participants 482 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
189
  78.1%
185
  77.1%
374
  77.6%
>=65 years
53
  21.9%
55
  22.9%
108
  22.4%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 242 participants 240 participants 482 participants
54.4  (12.48) 55.0  (11.81) 54.7  (12.14)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 242 participants 240 participants 482 participants
Female
130
  53.7%
125
  52.1%
255
  52.9%
Male
112
  46.3%
115
  47.9%
227
  47.1%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 242 participants 240 participants 482 participants
Hispanic or Latino
7
   2.9%
8
   3.3%
15
   3.1%
Not Hispanic or Latino
235
  97.1%
232
  96.7%
467
  96.9%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 242 participants 240 participants 482 participants
American Indian or Alaska Native
1
   0.4%
0
   0.0%
1
   0.2%
Asian
7
   2.9%
5
   2.1%
12
   2.5%
Native Hawaiian or Other Pacific Islander
0
   0.0%
1
   0.4%
1
   0.2%
Black or African American
8
   3.3%
7
   2.9%
15
   3.1%
White
226
  93.4%
227
  94.6%
453
  94.0%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 242 participants 240 participants 482 participants
Canada 12 11 23
Netherlands 19 19 38
Sweden 18 16 34
United States 33 32 65
Czechia 7 5 12
Denmark 23 26 49
South Africa 88 89 177
Spain 42 42 84
1.Primary Outcome
Title Percent Change in LDL-C From Baseline To Day 510
Hide Description [Not Specified]
Time Frame Baseline, Day 510
Hide Outcome Measure Data
Hide Analysis Population Description
ITT (intent-to-treat) Population
Arm/Group Title Inclisiran Placebo
Hide 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.
Overall Number of Participants Analyzed 242 240
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent change
-41.15
(-44.52 to -37.77)
8.37
(3.96 to 12.77)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inclisiran, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.0001
Comments The a priori threshold for statistical significance was <0.05
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -49.52
Confidence Interval (2-Sided) 95%
-55.04 to -43.99
Estimation Comments Represents the least squares mean difference from Placebo
2.Primary Outcome
Title Time-adjusted Percent Change in LDL-C From Baseline After Day 90 and up to Day 540
Hide Description Assessments performed at Baseline, Day 90, Day 540, time-adjusted percent change at Day 90 reported
Time Frame Baseline, Day 90
Hide Outcome Measure Data
Hide Analysis Population Description
ITT (intent-to-treat) Population
Arm/Group Title Inclisiran Placebo
Hide 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.
Overall Number of Participants Analyzed 242 240
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent change
-38.08
(-41.03 to -35.14)
6.22
(3.26 to 9.17)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inclisiran, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments The a priori threshold for statistical significance was <0.05
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -44.30
Confidence Interval (2-Sided) 95%
-48.48 to -40.12
Estimation Comments Represents the least squares mean difference from Placebo
3.Secondary Outcome
Title Absolute Change in LDL-C From Baseline to Day 510
Hide Description [Not Specified]
Time Frame Baseline, Day 510
Hide Outcome Measure Data
Hide Analysis Population Description
ITT (intent-to-treat) Population
Arm/Group Title Inclisiran Placebo
Hide 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.
Overall Number of Participants Analyzed 242 240
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mg/dL
-58.95
(-64.75 to -53.15)
9.94
(4.10 to 15.78)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inclisiran, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments The a priori threshold for statistical significance was <0.05
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -68.89
Confidence Interval (2-Sided) 95%
-77.11 to -60.67
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
Hide Description Assessments performed at Baseline, Day 90, Day 540, absolute change at Day 90 reported
Time Frame Baseline, Day 90
Hide Outcome Measure Data
Hide Analysis Population Description
ITT (intent-to-treat) Population
Arm/Group Title Inclisiran Placebo
Hide 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.
Overall Number of Participants Analyzed 242 240
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mg/dL
-56.58
(-60.98 to -52.17)
6.17
(1.72 to 10.62)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inclisiran, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments The a priori threshold for statistical significance was <0.05
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -62.74
Confidence Interval (2-Sided) 95%
-69.01 to -56.48
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
Hide Description [Not Specified]
Time Frame Baseline, Day 510
Hide Outcome Measure Data
Hide Analysis Population Description
ITT (intent-to-treat) Population
Arm/Group Title Inclisiran Placebo
Hide 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.
Overall Number of Participants Analyzed 242 240
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent change
-60.68
(-64.40 to -56.96)
17.66
(13.91 to 21.42)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inclisiran, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments The a priori threshold for statistical significance was <0.05
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -78.34
Confidence Interval (2-Sided) 95%
-83.65 to -73.04
Estimation Comments Represents the least squares mean difference from Placebo
6.Secondary Outcome
Title Percentage Change in Total Cholesterol From Baseline to Day 510
Hide Description [Not Specified]
Time Frame Baseline, Day 510
Hide Outcome Measure Data
Hide Analysis Population Description
ITT (intent-to-treat) Population
Arm/Group Title Inclisiran Placebo
Hide 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.s.
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.
Overall Number of Participants Analyzed 242 240
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent change
-25.11
(-27.83 to -22.39)
6.66
(3.96 to 9.36)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inclisiran, Placebo
Comments [Not Specified]
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 [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -31.77
Confidence Interval (2-Sided) 95%
-35.59 to -27.94
Estimation Comments Represents the least squares mean difference from Placebo
7.Secondary Outcome
Title Percent Change in Apolipoprotein B (Apo-B) From Baseline To Day 510
Hide Description [Not Specified]
Time Frame Baseline, Day 510
Hide Outcome Measure Data
Hide Analysis Population Description
ITT (intent-to-treat) Population
Arm/Group Title Inclisiran Placebo
Hide 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.
Overall Number of Participants Analyzed 242 240
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent change
-33.14
(-35.91 to -30.36)
2.93
(0.14 to 5.71)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inclisiran, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments The a priori threshold for statistical significance was <0.05
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -36.06
Confidence Interval (2-Sided) 95%
-39.99 to -32.14
Estimation Comments Represents the least squares mean difference from Placebo
8.Secondary Outcome
Title Percent Change in Non-high-density Lipoprotein (HDL)-C From Baseline To Day 510
Hide Description [Not Specified]
Time Frame Baseline, Day 510
Hide Outcome Measure Data
Hide Analysis Population Description
ITT (intent-to-treat) Population
Arm/Group Title Inclisiran Placebo
Hide 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.
Overall Number of Participants Analyzed 242 240
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent change
-34.93
(-38.46 to -31.40)
7.43
(3.93 to 10.92)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inclisiran, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments The a priori threshold for statistical significance was <0.05
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -42.36
Confidence Interval (2-Sided) 95%
-47.32 to -37.40
Estimation Comments Represents the least squares mean difference from Placebo
Time Frame Day 0 - 510
Adverse Event Reporting Description The safety population for adverse event collection was 481 subjects which is different from the Intent-to-Treat (ITT) population used in efficacy analysis (482 subjects). One subject was randomized in the Inclisiran arm, but never received study drug, therefore this subject not included in the safety population.
 
Arm/Group Title Inclisiran Placebo
Hide 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: Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.

Placebo will be administered as SC injections 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 Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   1/241 (0.41%)   1/240 (0.42%) 
Hide Serious Adverse Events
Inclisiran Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   18/241 (7.47%)   33/240 (13.75%) 
Cardiac disorders     
Acute myocardial infarction * 1  2/241 (0.83%)  1/240 (0.42%) 
Angina Pectoris * 1  1/241 (0.41%)  0/240 (0.00%) 
Angina unstable * 1  1/241 (0.41%)  4/240 (1.67%) 
Aortic valve stenosis * 1  2/241 (0.83%)  0/240 (0.00%) 
Arteriosclerosis coronary artery * 1  0/241 (0.00%)  1/240 (0.42%) 
Atrial fibrillation * 1  0/241 (0.00%)  1/240 (0.42%) 
Cardiac arrest * 1  1/241 (0.41%)  0/240 (0.00%) 
Cardiac failure * 1  1/241 (0.41%)  0/240 (0.00%) 
Cardiac failure acute * 1  1/241 (0.41%)  0/240 (0.00%) 
Coronary artery disease * 1  1/241 (0.41%)  0/240 (0.00%) 
Myocardial infarction * 1  1/241 (0.41%)  0/240 (0.00%) 
Myocardial ischaemia * 1  1/241 (0.41%)  3/240 (1.25%) 
Supraventricular tachycardia * 1  0/241 (0.00%)  1/240 (0.42%) 
Eye disorders     
Optic ischaemic neuropathy * 1  0/241 (0.00%)  2/240 (0.83%) 
Gastrointestinal disorders     
Gastritis erosive * 1  0/241 (0.00%)  1/240 (0.42%) 
Pancreatitis acute * 1  0/241 (0.00%)  1/240 (0.42%) 
General disorders     
Hernia * 1  0/241 (0.00%)  1/240 (0.42%) 
Non-cardiac chest pain * 1  0/241 (0.00%)  1/240 (0.42%) 
Hepatobiliary disorders     
Biliary colic * 1  0/241 (0.00%)  1/240 (0.42%) 
Infections and infestations     
Cellulitis * 1  1/241 (0.41%)  0/240 (0.00%) 
Diverticulitis * 1  0/241 (0.00%)  1/240 (0.42%) 
Infective tenosynovitis * 1  1/241 (0.41%)  0/240 (0.00%) 
Influenza * 1  0/241 (0.00%)  1/240 (0.42%) 
Pneumonia * 1  1/241 (0.41%)  1/240 (0.42%) 
Post procedural infection * 1  0/241 (0.00%)  1/240 (0.42%) 
Pyelitis * 1  0/241 (0.00%)  1/240 (0.42%) 
Pyelonephritis * 1  0/241 (0.00%)  1/240 (0.42%) 
Tick-borne fever * 1  0/241 (0.00%)  1/240 (0.42%) 
Viral upper respiratory tract infection * 1  0/241 (0.00%)  1/240 (0.42%) 
Wound sepsis * 1  0/241 (0.00%)  1/240 (0.42%) 
Injury, poisoning and procedural complications     
Limb injury * 1  0/241 (0.00%)  1/240 (0.42%) 
Post procedural haematuria * 1  0/241 (0.00%)  1/240 (0.42%) 
Road traffic accident * 1  0/241 (0.00%)  1/240 (0.42%) 
Soft tissue injury * 1  0/241 (0.00%)  1/240 (0.42%) 
Spinal compression fracture * 1  1/241 (0.41%)  0/240 (0.00%) 
Musculoskeletal and connective tissue disorders     
Back pain * 1  0/241 (0.00%)  2/240 (0.83%) 
Myalgia * 1  0/241 (0.00%)  1/240 (0.42%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Invasive ductal breast carcinoma * 1  0/241 (0.00%)  1/240 (0.42%) 
Malignant melanoma in situ * 1  0/241 (0.00%)  1/240 (0.42%) 
Prostate cancer * 1  1/241 (0.41%)  0/240 (0.00%) 
Squamous cell carcinoma of skin * 1  1/241 (0.41%)  1/240 (0.42%) 
Nervous system disorders     
Sensory disturbance * 1  0/241 (0.00%)  1/240 (0.42%) 
Trigeminal neuralgia * 1  0/241 (0.00%)  1/240 (0.42%) 
Product Issues     
Device loosening * 1  1/241 (0.41%)  0/240 (0.00%) 
Psychiatric disorders     
Anxiety * 1  1/241 (0.41%)  0/240 (0.00%) 
Depression * 1  0/241 (0.00%)  1/240 (0.42%) 
Major depression * 1  0/241 (0.00%)  1/240 (0.42%) 
Renal and urinary disorders     
Hydronephrosis * 1  0/241 (0.00%)  1/240 (0.42%) 
Nephrolithiasis * 1  0/241 (0.00%)  1/240 (0.42%) 
Respiratory, thoracic and mediastinal disorders     
Asthma * 1  0/241 (0.00%)  1/240 (0.42%) 
Chronic obstructive pulmonary disease * 1  0/241 (0.00%)  1/240 (0.42%) 
1
Term from vocabulary, MedDRA (20.1)
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Inclisiran Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   96/241 (39.83%)   67/240 (27.92%) 
General disorders     
Injection site reaction * 1  22/241 (9.13%)  0/240 (0.00%) 
Infections and infestations     
Influenza * 1  13/241 (5.39%)  21/240 (8.75%) 
Nasopharyngitis * 1  28/241 (11.62%)  20/240 (8.33%) 
Upper respiratory tract infection * 1  16/241 (6.64%)  16/240 (6.67%) 
Musculoskeletal and connective tissue disorders     
Back pain * 1  17/241 (7.05%)  10/240 (4.17%) 
1
Term from vocabulary, MedDRA (20.1)
*
Indicates events were collected by non-systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Vice President - Regulatory Operations
Organization: The Medicines Company
Phone: 973-985-0597
EMail: frank.bosley@novartis.com
Layout table for additonal information
Responsible Party: The Medicines Company
ClinicalTrials.gov Identifier: NCT03397121    
Other Study ID Numbers: MDCO-PCS-17-03
2017-002472-30 ( EudraCT Number )
First Submitted: January 2, 2018
First Posted: January 11, 2018
Results First Submitted: August 27, 2020
Results First Posted: October 28, 2020
Last Update Posted: October 28, 2020