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

Diabetes Clinical Trial

— ORION-1  

Official title:

A Placebo-controlled, Double-blind, Randomized Trial to Compare the Effect of Different Doses of ALN-PCSSC Given as Single or Multiple Subcutaneous Injections in Subjects With High Cardiovascular Risk and Elevated LDL-C

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02597127
• Other study ID #: MDCO-PCS-15-01
• Status: Completed
• Phase: Phase 2
• Start date: January 2016
• Est. completion date: June 7, 2017

Study information

• Verified date: April 2019
• Source: The Medicines Company
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 501
• Est. completion date: June 7, 2017
• Est. primary completion date: June 7, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

Inclusion Criteria:

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

2. 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]).

3. 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.

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

5. Calculated glomerular filtration rate 30 mL/min or higher by estimated glomerular filtration rate (eGFR) using standardized local clinical methodology.

6. Participants on statins should be receiving a maximally tolerated dose (investigator's discretion).

7. 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.

8. 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:

1. 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.

2. 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.

3. New York Heart Association (NYHA) class II, III, or IV heart failure or last known left ventricular ejection fraction <30%.

4. Cardiac arrhythmia within 3 months prior to randomization that is not controlled by medication or via ablation.

5. Any history of hemorrhagic stroke.

6. Major adverse cardiac event within 6 months prior to randomization.

7. Uncontrolled severe hypertension: systolic blood pressure >180 millimeters of mercury (mmHg) or diastolic blood pressure >110 mmHg prior to randomization despite anti-hypertensive therapy.

8. Poorly controlled Type 2 diabetes, such as, glycated hemoglobin A1c (HbA1c)>10.0% prior to randomization.

9. 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.

10. 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.

11. 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.

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

13. Known history of alcohol and/or drug abuse within the last 5 years.

14. Treatment with other investigational medicinal products or devices within 30 days or five half?lives, whichever is longer.

15. Use of other investigational medicinal products or devices during the course of the study.

16. 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)

17. Previous or current treatment (within 90 days of screening) with monoclonal antibodies directed at PCSK9.

Related Conditions & MeSH terms

• Atherosclerosis
• Atherosclerotic Cardiovascular Disease
• Cardiovascular Diseases
• Diabetes
• Familial Hypercholesterolemia
• Hypercholesterolemia
• Hyperlipoproteinemia Type II

Intervention

Drug:
• ALN-PCSSC
ALN-PCSSC is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis and is given as SC injections
• Normal Saline
Saline (sterile, normal, 0.9%) solution given as SC injections

Locations

Country	Name	City	State
Canada	Brampton Research Associates	Brampton	Ontario
Canada	ECOGENE-21 Clinical Trials Center	Chicoutimi	Quebec
Canada	Lawson Health Research Institute	London	Ontario
Canada	Clinic Sante Cardio MC	Montreal	Quebec
Canada	Institut de Recherches Cliniques de Montreal	Montreal	Quebec
Canada	Clinique des maladies lipidique Quebec	Quebec City	Quebec
Canada	Université Laval Quebec	Quebec City	Quebec
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
Canada	Eastern Regional Health Authority, Patient Research Centre	St. Johns	Newfoundland and Labrador
Canada	St. Michael's Hospital	Toronto	Ontario
Canada	St. Paul's Hospital	Vancouver	British Columbia
Canada	St. Boniface Hospital	Winnipeg	Manitoba
Germany	Medical University Berlin	Berlin
Germany	Medical Center Essen	Essen
Germany	University Hospital Frankfurt	Frankfurt
Germany	University Heart Center Hamburg	Hamburg
Germany	Medical University Hospital Heidelberg, Internal medicine III	Heidelberg
Germany	Technical University Munich, German Heart Center	Munich
Netherlands	Amsterdam Medical Center	Amsterdam
Netherlands	Haga Hospital	Den Haag
Netherlands	Deventer Ziekenhuis	Deventer
Netherlands	Andromed Eindhoven	Eindhoven
Netherlands	Admiraal de Ruyter Hospital, Cardiology	Goes
Netherlands	Bethesda Diabetes Research Center	Hoogeveen
Netherlands	Medisch Centrum Gorecht	Hoogezand
Netherlands	VOC Hoorn	Hoorn
Netherlands	Leids Universitair Medisch Centrum (LUMC)	Leiden
Netherlands	Andromed Rotterdam	Rotterdam
Netherlands	Diakonessenhuis, Vascular Policlinic	Utrecht
Netherlands	UMC Utrecht	Utrecht
Netherlands	VieCurie Venlo, Cardiology	Venlo
Netherlands	Albert Schweitzer Hospital, Cardiology	Zwijndrecht
United Kingdom	Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust	Birmingham
United Kingdom	Edinburgh Royal Infirmary	Edinburgh
United Kingdom	The Royal Devon and Exeter NHS Trust	Exeter
United Kingdom	Fowey River Practice	Fowey
United Kingdom	Buckinghamshire NHS Trust	High Wycombe
United Kingdom	Oak Tree Surgery	Liskeard
United Kingdom	Royal Free Hospital	London
United Kingdom	Central Manchester University Hospital NHS Foundation Trust	Manchester
United Kingdom	The Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital	Newcastle upon Tyne
United Kingdom	The Alverton Practice	Penzance
United Kingdom	Knowle House Surgery	Plymouth
United Kingdom	Brannel Surgery	St. Austell
United Kingdom	Rame Medical Ltd (Rame Research)	Torpoint
United Kingdom	Worcestershire Acute NHS Trust	Worcester
United States	Amarillo Heart Clinical Research Institute, Inc.	Amarillo	Texas
United States	Metabolic And Atherosclerosis Research Center	Cincinnati	Ohio
United States	Sterling Research Group	Cincinnati	Ohio
United States	Wellmont CVA Heart Institute	Greeneville	Tennessee
United States	Midwest Institute For Clinical Research	Indianapolis	Indiana
United States	Jacksonville Center for Clinical Research	Jacksonville	Florida
United States	Mount Sinai Icahn School of Medicine	New York	New York
United States	National Clinical Research, Inc.	Richmond	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
The Medicines Company

Countries where clinical trial is conducted

United States,  Canada,  Germany,  Netherlands,  United Kingdom, 

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* Note: There are 36 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Baseline to 180 days
Secondary	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	Baseline to 90 days
Secondary	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.	Baseline, Day 60, Day 120, and Day 210
Secondary	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.	Baseline, Day 180, Day 210
Secondary	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.	Day 90, Day 180
Secondary	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.	Baseline, Day 180
Secondary	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.	Baseline, Day 180
Secondary	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.	Baseline, Day 180
Secondary	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.	Baseline, Day 180
Secondary	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.	Baseline, Day 180