A Medical Research Study to Evaluate the Effects of ACT-246475 in Adults With Coronary Artery Disease

A Multi-center, Double-blind, Randomized, Placebo-controlled Study to Assess the Pharmacodynamics, Pharmacokinetics, Tolerability, and Safety of a Single Subcutaneous Injection of ACT-246475 in Adults With Stable Coronary Artery Disease

The goal of this study is to find out if a drug called selatogrel (ACT-246475) can prevent platelets from binding together when administered by an injection under the skin in the thigh or in the belly. Another goal is to know how fast and for how long selatogrel (ACT-246475) works and if there is a difference if the drug is injected in the thigh or in the belly. This study will also help to find out more about the safety of this new drug.

Study Overview

• Status: Completed
• Conditions: Stable Coronary Artery Disease
• Intervention / Treatment: Drug: Selatogrel; Drug: Selatogrel; Drug: Placebo

Detailed Description

To investigate the pharmacodynamic (PD) and pharmacokinetic (PK) properties of selatogrel in patients with atherosclerotic disease, the present study will be conducted in patients with chronic coronary syndromes (CCS). Assessment in a population of patients with CCS allows better control and stability of concomitant treatments, and therefore more accurate characterization of the pharmacodynamic and pharmacokinetic profiles of selatogrel in the presence of background antiplatelet therapies.

The study will have 3 periods: a screening period of up to 21 days prior to randomization, a treatment period of 2 days from randomization (Day 1) to 24 hours post dose (Day 2), and a follow-up period from Day 3 to the safety follow-up telephone call 28 to 35 days after single administration of study drug (End-of-Study).

• Study Type: Interventional
• Enrollment (Actual): 346
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montréal, Quebec, Canada, H1T 1C8
      • Institut de Cardiologie de Montreal
• Denmark
  • Aarhus, Denmark, 8200
    • Aarhus University Hospital
  • Copenhagen, Denmark, 2100
    • Rigshospitalet
• Germany
  • Bad Krozingen, Germany, 79189
    • Universitäts-Herzzentrum
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • University Medical Center Groningen
  • Maastricht, Netherlands, 6229 HX
    • Maastricht UMC
  • Nieuwegein, Netherlands, 3435 CM
    • St. Antonius Ziekenhuis
• Singapore
  • Singapore, Singapore, 169609
    • National Heart Centre Singapore
• Sweden
  • Göteborg, Sweden, 40530
    • Sahlgrenska University Hospital
  • Uppsala, Sweden, 18288
    • Uppsala University Hospital
• United Kingdom
  • Newcastle Upon Tyne, United Kingdom, NE7 7DN
    • Freeman Hospital - Cardiothoracic Department
  • Sheffield, United Kingdom, S5 7AU
    • Sheffield Teaching Hospitals
  • Stevenage, United Kingdom, SG14AB
    • East & North Hertfordshire NHS Trust - Lister Hospital
• United States
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida (UF) Jacksonville
    • Tampa, Florida, United States, 33613
      • Florida Hospital Tampa - Pepin Heart Institute
  • Illinois
    • Chicago, Illinois, United States, 73104
      • NorthShore University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University School of Medicine - Krannert Institute of Cardiology
  • Maryland
    • Lutherville, Maryland, United States, 21093
      • Inova Cardiology
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai Hospital (New York)
  • Virginia
    • Falls Church, Virginia, United States, 22042
      • Inova Center for Thrombosis Research and Translational Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Main Inclusion Criteria:

1. Signed informed consent prior to any study-mandated procedure.
2. Male and female subjects aged from 18-85 years, inclusive.
3. For women of childbearing potential: Negative urine pregnancy test at Visit 1 and at Visit 2 before randomization.

4. Stable Coronary artery disease (CAD) defined by the presence of any of the following conditions:

   1. History of CAD with coronary artery stenosis on coronary angiogram ≥50%.
   2. Previously documented myocardial infarction occurring more than 3 months prior to randomization.
5. Antiplatelet background therapy stable for at least 1 month prior to randomization.
6. Body weight ≥ 40.0 kg (88.2 lbs).

Main Exclusion Criteria:

1. Acute coronary syndrome, percutaneous coronary intervention or any intervention for peripheral artery disease within 3 months prior to randomization.
2. Acute ischemic stroke or transient ischemic attack (TIA) within 3 months prior to randomization.
3. Active internal bleeding, or medical history of recent (< 1 month) bleeding disorders or conditions associated with high risk of bleeding (e.g., clotting disturbances, gastrointestinal bleed, hemoptysis).
4. Hemoglobin ≤ 10 g/dL at screening.
5. Loss of at least 250 mL of blood within 3 months of screening.
6. Use of anticoagulants (oral, parenteral) or fibrinolytic therapy within 24 h prior to screening (Visit 1).
7. Known platelet disorders (e.g., thrombasthenia, thrombocytopenia, von Willebrand disease).
8. Pregnant or breastfeeding women.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Selatogrel 8 mg; Selatogrel (ACT-246475) is given as a single subcutaneous dose of 8 mg administered in a volume of 0.8 mL. Administration will be performed at the investigational site by qualified personnel.	Drug: Selatogrel; Selatogrel is a reversible P2Y12 receptor antagonist for subcutaneous administration. It is supplied in sealed glass vials at a strength of 20 mg. The vials with ACT-246475A (hydrochloride salt of ACT-246475) or matching placebo will be reconstituted with 1 mL of water for injection. Further dilution with 1 mL sodium chloride (NaCl) 0.9% will be performed for preparation of the dose of 8 mg selatogrel.; Other Names: ACT-246475; Drug: Selatogrel; Selatogrel is a reversible P2Y12 receptor antagonist for subcutaneous administration. It is supplied in sealed glass vials at a strength of 20 mg. The vials with ACT-246475A (hydrochloride salt of ACT-246475) will be reconstituted with 1 mL of water for injection.; Other Names: ACT-246575
EXPERIMENTAL: Selatogrel 16 mg; Selatogrel (ACT-246475) is given as a single subcutaneous dose of 16 mg administered in a volume of 0.8 mL. Administration will be performed at the investigational site by qualified personnel.	Drug: Selatogrel; Selatogrel is a reversible P2Y12 receptor antagonist for subcutaneous administration. It is supplied in sealed glass vials at a strength of 20 mg. The vials with ACT-246475A (hydrochloride salt of ACT-246475) or matching placebo will be reconstituted with 1 mL of water for injection. Further dilution with 1 mL sodium chloride (NaCl) 0.9% will be performed for preparation of the dose of 8 mg selatogrel.; Other Names: ACT-246475; Drug: Selatogrel; Selatogrel is a reversible P2Y12 receptor antagonist for subcutaneous administration. It is supplied in sealed glass vials at a strength of 20 mg. The vials with ACT-246475A (hydrochloride salt of ACT-246475) will be reconstituted with 1 mL of water for injection.; Other Names: ACT-246575
PLACEBO_COMPARATOR: Placebo; Placebo matching ACT-246475 is supplied in sealed glass vials for reconstitution with water for injection. Placebo will be given as a single subcutaneous dose matching selatogrel to be administered in a volume of 0.8 mL. Administration will performed at the investigational site by qualified personnel.	Drug: Placebo; Matching placebo for subcutaneous administration.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With a Pharmacodynamic Response as Assessed by the Inhibition of Platelet Aggregation	The pharmacodynamic response was determined by measuring the inhibition of platelet aggregation, using VerifyNow®. The VerifyNow® is a point-of-care test measuring platelet reactivity. The results are expressed as P2Y12 reaction units (PRU). The target of 100 PRU corresponds to 80% inhibition of ADP-induced platelet aggregation. A participant with a PRU of less than 100 starting from 30 minutes after the administration of study treatment and lasting for at least 3 hours was considered a "responder".	From 15 minutes after administration of the subcutaneous injection up to 24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Selatogrel Plasma Concentration (Cmax)	The Cmax is the peak concentration of selatogrel in the plasma after subcutaneous injection. The pharmacokinetic parameters of selatogrel (ACT-246475) were derived by non-compartmental analyses of the plasma concentration-time profiles.	Pre-dose, and from 15 minutes after administration of the subcutaneous injection up to 24 hours
Time to Reach Maximum Selatogrel Plasma Concentration (Tmax)	Time after subcutaneous injection to reach the maximum observed selatogrel plasma concentration (Cmax).	Pre-dose, and from 15 minutes after administration of the subcutaneous injection up to 24 hours
Area Under the Plasma Concentration-time Curve of Selatogrel From Time Zero to 24 Hour Time Point (AUC0-24)	The area under the plasma concentration-time curve is the integral of the concentration-time curve after subcutaneous injection of selatogrel. The plasma pharmacokinetic parameters of selatogrel (ACT-246475) were derived by non-compartmental analyses of the plasma concentration-time profiles.	Pre-dose, and from 15 minutes after administration of the subcutaneous injection up to 24 hours post-dose

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With a Pharmacodynamic Response as Assessed by the Inhibition of Platelet Aggregation by Site of Treatment Administration (Thigh or Abdomen)	The inhibition of platelet aggregation based on the route of administration, i.e. whether the pharmacodynamic response was different if selatogrel was administered subcutaneously in the thigh or in the abdomen, was analyzed. The pharmacodynamic response was determined by measuring the inhibition of platelet aggregation, using VerifyNow®. The VerifyNow® is a point-of-care test measuring platelet reactivity. The results are expressed as P2Y12 reaction units (PRU). The target of 100 PRU corresponds to 80% inhibition of ADP-induced platelet aggregation. A participant with a PRU of less than 100 starting from 30 minutes after the administration of study treatment and lasting for at least 3 hours was considered a "responder".	From 15 minutes after administration of the subcutaneous injection up to 24 hours
Number of Participants With a Pharmacodynamic Response as Assessed by the Inhibition of Platelet Aggregation - Sensitivity Analysis	To assess the robustness of results for the pharmacodynamic response, the main analysis was repeated for the per protocol participants. The pharmacodynamic response was determined by measuring the inhibition of platelet aggregation, using VerifyNow®. The VerifyNow® is a point-of-care test measuring platelet reactivity. The results are expressed as P2Y12 reaction units (PRU). The target of 100 PRU corresponds to 80% inhibition of ADP-induced platelet aggregation. A participant with a PRU of less than 100 starting from 30 minutes after the administration of study treatment and lasting for at least 3 hours was considered a "responder".	From 15 minutes after administration of the subcutaneous injection up to 24 hours
Change From Baseline in Maximum Platelet Aggregation (MPA) as Measured by Light Transmission Aggregometry (LTA)	Light transmission aggregometry was used as complementary method to the VerifyNow® to evaluate the effect of selatogrel on platelet aggregation. Platelet aggregation was triggered by addition of Adenosine diphosphate (ADP) 20 µM (micromole per liter) and monitored over 6 minutes. Maximum Platelet Aggregation (MPA) to 20 μM ADP was assessed by light transmission aggregometry (LTA), an assay that measures platelet aggregation by determining the amount of light transmitted through a cuvette containing platelet-rich plasma stimulated with 20 µM ADP, relative to platelet-poor plasma (100% light transmittance). A lower MPA % reflects stronger platelet inhibition, whereas a higher MPA % reflects weaker inhibition.	Pre-dose, and from 30 minutes after administration of the subcutaneous injection up to 8 hours
Number of Participants With Bleeding Events	Treatment-emergent adverse events in the category "Haemorrhage (excluding laboratory terms)" were of special interest and their incidence listed below. The role of the Independent Safety Event Committee was to monitor unblinded safety data obtained in the study, with a specific focus on study-drug-related clinically relevant major bleeding events, occurring within 48 hours after dosing (i.e. the treatment period).	From study treatment administration on Day 1 up to 48 hours

Collaborators and Investigators

• Sponsor: Idorsia Pharmaceuticals Ltd.

Publications and helpful links

General Publications

• Storey RF, Gurbel PA, Ten Berg J, Bernaud C, Dangas GD, Frenoux JM, Gorog DA, Hmissi A, Kunadian V, James SK, Tanguay JF, Tran H, Trenk D, Ufer M, Van der Harst P, Van't Hof AWJ, Angiolillo DJ. Pharmacodynamics, pharmacokinetics, and safety of single-dose subcutaneous administration of selatogrel, a novel P2Y12 receptor antagonist, in patients with chronic coronary syndromes. Eur Heart J. 2020 Sep 1;41(33):3132-3140. doi: 10.1093/eurheartj/ehz807.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 24, 2018
• Primary Completion (ACTUAL): August 18, 2018
• Study Completion (ACTUAL): September 18, 2018

Study Registration Dates

• First Submitted: December 20, 2017
• First Submitted That Met QC Criteria: December 20, 2017
• First Posted (ACTUAL): December 28, 2017

Study Record Updates

• Last Update Posted (ACTUAL): November 17, 2022
• Last Update Submitted That Met QC Criteria: November 15, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Chronic coronary syndrome
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease
• Other Study ID Numbers: ID-076A201; 2017-003332-36 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No