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

NCT02597127 | Completed Phase 2 Results DMC

• 1 other identifier: MDCO-PCS-15-01
• Study Type: interventional
• Target: 501
• Locations: 5 countries
• Sites: 54

Brief 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).

Conditions

Atherosclerotic Cardiovascular Disease; Familial Hypercholesterolemia; Diabetes

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (9)

• Percentage Change in LDL-C From Baseline to Day 90

  Baseline to 90 days

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

  Baseline, Day 60, Day 120, and Day 210

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

  Baseline, Day 180, Day 210

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

  Day 90, Day 180

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

  Baseline, Day 180

Study Arms (8)

ALN-PCSSC 200 mg (bi-annual dosing)

EXPERIMENTAL

ALN-PCSSC 200 milligram (mg) SC administration once at Day 1

Drug: ALN-PCSSC

ALN-PCSSC 300 mg (bi-annual dosing)

EXPERIMENTAL

ALN-PCSSC 300 mg SC administration once at Day 1

Drug: ALN-PCSSC

ALN-PCSSC 500 mg (bi-annual dosing)

EXPERIMENTAL

ALN-PCSSC 500 mg SC administration once at Day 1

Drug: ALN-PCSSC

Normal Saline (bi-annual dosing)

PLACEBO COMPARATOR

Saline SC administration once at Day 1

Drug: Normal Saline

ALN-PCSSC 100 mg (quarterly dosing)

EXPERIMENTAL

ALN-PCSSC 100 mg SC administration twice at Day 1 and Day 90

Drug: ALN-PCSSC

ALN-PCSSC 200 mg (quarterly dosing)

EXPERIMENTAL

ALN-PCSSC 200 mg SC administration twice at Day 1 and Day 90

Drug: ALN-PCSSC

ALN-PCSSC 300 mg (quarterly dosing)

EXPERIMENTAL

ALN-PCSSC 300 mg SC administration twice at Day 1 and Day 90

Drug: ALN-PCSSC

Normal Saline (quarterly dosing)

PLACEBO COMPARATOR

Saline SC administration twice at Day 1 and Day 90

Drug: Normal Saline

Interventions

ALN-PCSSC DRUG

ALN-PCSSC is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis and is given as SC injections

Also known as: PCSK9 synthesis inhibitor, Inclisiran

ALN-PCSSC 100 mg (quarterly dosing); ALN-PCSSC 200 mg (bi-annual dosing); ALN-PCSSC 200 mg (quarterly dosing); ALN-PCSSC 300 mg (bi-annual dosing); ALN-PCSSC 300 mg (quarterly dosing); ALN-PCSSC 500 mg (bi-annual dosing)

Normal Saline DRUG

Saline (sterile, normal, 0.9%) solution given as SC injections

Normal Saline (bi-annual dosing); Normal Saline (quarterly dosing)

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female participants ≥18 years of age.
• History of ASCVD or ASCVD-risk equivalents (symptomatic atherosclerosis, Type 2 diabetes, familial hypercholesterolemia, including participants whose 10-year risk of a CV event assessed by Framingham Risk Score (Framingham Risk Score \>20%) or equivalent has a target LDL-C of \<100 mg/deciliter \[dL\]).
• Serum LDL-C ≥1.8 millimole (mmol)/liter (L) (≥70 mg/dL) for ASCVD participants or ≥2.6 mmol/L (≥100 mg/dL) for ASCVD-risk equivalent participants at screening.
• Fasting triglyceride \<4.52 mmol/L (\<400 mg/dL) at screening.
• Calculated glomerular filtration rate 30 mL/min or higher by estimated glomerular filtration rate (eGFR) using standardized local clinical methodology.
• Participants on statins should be receiving a maximally tolerated dose (investigator's discretion).
• Participants on lipid-lower therapies (such as statin and/or ezetimibe) should be on a stable dose for ≥30 days before screening with no planned medication or dose change during study participation.
• Willing and able to give informed consent before initiation of any study-related procedures and willing to comply with all required study procedures.

You may not qualify if:

• Any uncontrolled or serious disease, or any medical or surgical condition, that may either interfere with participation in the clinical study, and/or put the participant at significant risk (according to investigator's \[or delegate\] judgment) if he/she participates in the clinical study.
• An underlying known disease, or surgical, physical, or medical condition that, in the opinion of the investigator (or delegate), might interfere with interpretation of the clinical study results.
• New York Heart Association (NYHA) class II, III, or IV heart failure or last known left ventricular ejection fraction \<30%.
• Cardiac arrhythmia within 3 months prior to randomization that is not controlled by medication or via ablation.
• Any history of hemorrhagic stroke.
• Major adverse cardiac event within 6 months prior to randomization.
• Uncontrolled severe hypertension: systolic blood pressure \>180 millimeters of mercury (mmHg) or diastolic blood pressure \>110 mmHg prior to randomization despite anti-hypertensive therapy.
• Poorly controlled Type 2 diabetes, such as, glycated hemoglobin A1c (HbA1c)\>10.0% prior to randomization.
• Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the liver or unexplained alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation \>2x the upper limit of normal (ULN), or total bilirubin elevation \>1.5x ULN at screening confirmed by a repeat measurement at least 1 week apart.
• Serious comorbid disease in which the life expectancy of the participant is shorter than the duration of the trial (for example, acute systemic infection, cancer, or other serious illnesses). This includes all cancers with the exception of treated basal-cell carcinoma occurring \>5 years before screening.
• Males who are unwilling to use an acceptable method of birth control during the entire study period (such as, condom with spermicide).
• Known history of alcohol and/or drug abuse within the last 5 years.
• Treatment with other investigational medicinal products or devices within 30 days or five half˗lives, whichever is longer.
• Use of other investigational medicinal products or devices during the course of the study.
• Any condition that according to the investigator could interfere with the conduct of the study, such as but not limited to the following:

Sponsors & Collaborators

• The Medicines Company: lead

Study Sites (54)

Jacksonville Center for Clinical Research

Jacksonville, Florida, 32216, United States

Location

Midwest Institute For Clinical Research

Indianapolis, Indiana, 46260, United States

Location

Mount Sinai Icahn School of Medicine

New York, New York, 10029, United States

Location

Metabolic And Atherosclerosis Research Center

Cincinnati, Ohio, 45227, United States

Location

Sterling Research Group

Cincinnati, Ohio, 45246, United States

Location

Wellmont CVA Heart Institute

Greeneville, Tennessee, 37745, United States

Location

Amarillo Heart Clinical Research Institute, Inc.

Amarillo, Texas, 79106, United States

Location

National Clinical Research, Inc.

Richmond, Virginia, 23294, United States

Location

St. Paul's Hospital

Vancouver, British Columbia, V6Z 1Y6, Canada

Location

St. Boniface Hospital

Winnipeg, Manitoba, R2H 2A6, Canada

Location

Eastern Regional Health Authority, Patient Research Centre

St. John's, Newfoundland and Labrador, A1B 3V6, Canada

Location

Brampton Research Associates

Brampton, Ontario, L6Z 4N5, Canada

Location

Lawson Health Research Institute

London, Ontario, N6C 2R5, Canada

Location

St. Michael's Hospital

Toronto, Ontario, M5C 2T2, Canada

Location

ECOGENE-21 Clinical Trials Center

Chicoutimi, Quebec, G7H 7K9, Canada

Location

Clinic Sante Cardio MC

Montreal, Quebec, H1T 3Y7, Canada

Location

Institut de Recherches Cliniques de Montreal

Montreal, Quebec, H2W 1R7, Canada

Location

Université Laval Quebec

Québec, Quebec, G1V 4G5, Canada

Location

Clinique des maladies lipidique Quebec

Québec, Quebec, G1V 4W2, Canada

Location

Centre intégré universitaire de santé et de services sociaux de l'Estrie - Centre hospitalier universitaire de Sherbrooke (CIUSSS de l'Estrie - CHUS)

Sherbrooke, Quebec, J1H 5N4, Canada

Location

Medical University Berlin

Berlin, 12203, Germany

Location

Medical Center Essen

Essen, 45355, Germany

Location

University Hospital Frankfurt

Frankfurt, 60590, Germany

Location

University Heart Center Hamburg

Hamburg, 20251, Germany

Location

Medical University Hospital Heidelberg, Internal medicine III

Heidelberg, 69120, Germany

Location

Technical University Munich, German Heart Center

Munich, 80636, Germany

Location

Amsterdam Medical Center

Amsterdam, 1105 AZ, Netherlands

Location

Deventer Ziekenhuis

Deventer, 7416 SE, Netherlands

Location

Andromed Eindhoven

Eindhoven, 5611 NV, Netherlands

Location

Admiraal de Ruyter Hospital, Cardiology

Goes, 4462 RA, Netherlands

Location

Bethesda Diabetes Research Center

Hoogeveen, 7909 AA, Netherlands

Location

Medisch Centrum Gorecht

Hoogezand, 9603 AE, Netherlands

Location

VOC Hoorn

Hoorn, 0031229284320, Netherlands

Location

Leids Universitair Medisch Centrum (LUMC)

Leiden, 2333 ZA, Netherlands

Location

Andromed Rotterdam

Rotterdam, 3021 HC, Netherlands

Location

Haga Hospital

The Hague, 2545 CH, Netherlands

Location

Diakonessenhuis, Vascular Policlinic

Utrecht, 3582 KE, Netherlands

Location

UMC Utrecht

Utrecht, 3584 CX, Netherlands

Location

VieCurie Venlo, Cardiology

Venlo, 5912 BL, Netherlands

Location

Albert Schweitzer Hospital, Cardiology

Zwijndrecht, 3331 LZ, Netherlands

Location

Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust

Birmingham, B15 2TH, United Kingdom

Location

Edinburgh Royal Infirmary

Edinburgh, EH16 4SA, United Kingdom

Location

The Royal Devon and Exeter NHS Trust

Exeter, EX2 5DW, United Kingdom

Location

Fowey River Practice

Fowey, PL23 1DT, United Kingdom

Location

Buckinghamshire NHS Trust

High Wycombe, HP11 2TT, United Kingdom

Location

Oak Tree Surgery

Liskeard, Oak Tree Surgery, United Kingdom

Location

Royal Free Hospital

London, NW3 2QG, United Kingdom

Location

Central Manchester University Hospital NHS Foundation Trust

Manchester, M13 9WL, United Kingdom

Location

The Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital

Newcastle upon Tyne, NE1 4LP, United Kingdom

Location

The Alverton Practice

Penzance, TR18 4JH, United Kingdom

Location

Knowle House Surgery

Plymouth, PL5 3JB, United Kingdom

Location

Brannel Surgery

St Austell, St. Austell, United Kingdom

Location

Rame Medical Ltd (Rame Research)

Torpoint, PL11 2TB, United Kingdom

Location

Worcestershire Acute NHS Trust

Worcester, WR5 1DD, United Kingdom

Location

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• Leiter LA, Teoh H, Kallend D, Wright RS, Landmesser U, Wijngaard PLJ, Kastelein JJP, Ray KK. Inclisiran Lowers LDL-C and PCSK9 Irrespective of Diabetes Status: The ORION-1 Randomized Clinical Trial. Diabetes Care. 2019 Jan;42(1):173-176. doi: 10.2337/dc18-1491. Epub 2018 Nov 28.

  PMID: 30487231 DERIVED

• Ray KK, Stoekenbroek RM, Kallend D, Leiter LA, Landmesser U, Wright RS, Wijngaard P, Kastelein JJP. Effect of an siRNA Therapeutic Targeting PCSK9 on Atherogenic Lipoproteins: Prespecified Secondary End Points in ORION 1. Circulation. 2018 Sep 25;138(13):1304-1316. doi: 10.1161/CIRCULATIONAHA.118.034710.

  PMID: 29735484 DERIVED

• Ray KK, Landmesser U, Leiter LA, Kallend D, Dufour R, Karakas M, Hall T, Troquay RP, Turner T, Visseren FL, Wijngaard P, Wright RS, Kastelein JJ. Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. N Engl J Med. 2017 Apr 13;376(15):1430-1440. doi: 10.1056/NEJMoa1615758. Epub 2017 Mar 17.

  PMID: 28306389 DERIVED

MeSH Terms

Conditions

Atherosclerosis; Hyperlipoproteinemia Type II; Diabetes Mellitus

Interventions

ALN-PCS; Saline Solution

Condition Hierarchy (Ancestors)

Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases; Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hyperlipoproteinemias; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Glucose Metabolism Disorders; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Results Point of Contact

• Title: Global Health Science Center
• Organization: The Medicine's Company

Medical.Information@themedco.com

1-888-997-6326

Study Officials

• Kausik K Ray, MD

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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 3, 2015
• First Posted: November 5, 2015
• Study Start: January 1, 2016
• Primary Completion: June 7, 2017
• Study Completion: June 7, 2017
• Last Updated: May 17, 2019
• Results First Posted: May 17, 2019

Record last verified: 2019-04

Locations

CA (12); US (8); GB (14); DE (6); NL (14)