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

Primary Purpose

Stable Coronary Artery Disease

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Selatogrel

Placebo

Selatogrel

About this trial

This is an interventional treatment trial for Stable Coronary Artery Disease focused on measuring Chronic coronary syndrome

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Main Inclusion Criteria:

Signed informed consent prior to any study-mandated procedure.
Male and female subjects aged from 18-85 years, inclusive.
For women of childbearing potential: Negative urine pregnancy test at Visit 1 and at Visit 2 before randomization.
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.
Antiplatelet background therapy stable for at least 1 month prior to randomization.
Body weight ≥ 40.0 kg (88.2 lbs).

Main Exclusion Criteria:

Acute coronary syndrome, percutaneous coronary intervention or any intervention for peripheral artery disease within 3 months prior to randomization.
Acute ischemic stroke or transient ischemic attack (TIA) within 3 months prior to randomization.
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).
Hemoglobin ≤ 10 g/dL at screening.
Loss of at least 250 mL of blood within 3 months of screening.
Use of anticoagulants (oral, parenteral) or fibrinolytic therapy within 24 h prior to screening (Visit 1).
Known platelet disorders (e.g., thrombasthenia, thrombocytopenia, von Willebrand disease).
Pregnant or breastfeeding women.

Sites / Locations

University of Florida (UF) Jacksonville
Florida Hospital Tampa - Pepin Heart Institute
NorthShore University
Indiana University School of Medicine - Krannert Institute of Cardiology
Inova Cardiology
Mount Sinai Hospital (New York)
Inova Center for Thrombosis Research and Translational Medicine
Institut de Cardiologie de Montréal
Aarhus University Hospital
Rigshospitalet
Universitats-Herzzentrum
University Medical Center Groningen
Maastricht UMC
St. Antonius Ziekenhuis
National Heart Centre Singapore
Sahlgrenska University Hospital
Uppsala University Hospital
Freeman Hospital - Cardiothoracic Department
Sheffield Teaching Hospitals
East & North Hertfordshire NHS Trust - Lister Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Placebo Comparator

Arm Label

Selatogrel 8 mg

Selatogrel 16 mg

Placebo

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

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".

Secondary Outcome Measures

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.

Time to Reach Maximum Selatogrel Plasma Concentration (Tmax)

Time after subcutaneous injection to reach the maximum observed selatogrel plasma concentration (Cmax).

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.

Full Information

NCT ID

NCT03384966

First Posted

December 20, 2017

Last Updated

November 15, 2022

Sponsor

Idorsia Pharmaceuticals Ltd.

1. Study Identification

Unique Protocol Identification Number

NCT03384966

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2022

Overall Recruitment Status

Completed

Study Start Date

January 24, 2018 (Actual)

Primary Completion Date

August 18, 2018 (Actual)

Study Completion Date

September 18, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Idorsia Pharmaceuticals Ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Stable Coronary Artery Disease

Keywords

Chronic coronary syndrome

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

Double-blinding will apply to treatment (ACT-246475 vs placebo). The dose (8 mg vs 16 mg) will be single blinded (subject blinded). The site for the sub-cutaneous injection (thigh vs abdomen) will not be blinded.

Allocation

Randomized

Enrollment

346 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Selatogrel 8 mg

Arm Type

Experimental

Arm Description

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.

Arm Title

Selatogrel 16 mg

Arm Type

Experimental

Arm Description

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.

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Selatogrel

Other Intervention Name(s)

ACT-246475

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Matching placebo for subcutaneous administration.

Intervention Type

Drug

Intervention Name(s)

Selatogrel

Other Intervention Name(s)

ACT-246575

Intervention Description

Primary Outcome Measure Information:

Title

Number of Participants With a Pharmacodynamic Response as Assessed by the Inhibition of Platelet Aggregation

Description

Time Frame

From 15 minutes after administration of the subcutaneous injection up to 24 hours

Secondary Outcome Measure Information:

Title

Maximum Selatogrel Plasma Concentration (Cmax)

Description

Time Frame

Pre-dose, and from 15 minutes after administration of the subcutaneous injection up to 24 hours

Title

Time to Reach Maximum Selatogrel Plasma Concentration (Tmax)

Description

Time after subcutaneous injection to reach the maximum observed selatogrel plasma concentration (Cmax).

Time Frame

Pre-dose, and from 15 minutes after administration of the subcutaneous injection up to 24 hours

Title

Area Under the Plasma Concentration-time Curve of Selatogrel From Time Zero to 24 Hour Time Point (AUC0-24)

Description

Time Frame

Pre-dose, and from 15 minutes after administration of the subcutaneous injection up to 24 hours post-dose

Other Pre-specified Outcome Measures:

Title

Number of Participants With a Pharmacodynamic Response as Assessed by the Inhibition of Platelet Aggregation by Site of Treatment Administration (Thigh or Abdomen)

Description

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".

Time Frame

From 15 minutes after administration of the subcutaneous injection up to 24 hours

Title

Number of Participants With a Pharmacodynamic Response as Assessed by the Inhibition of Platelet Aggregation - Sensitivity Analysis

Description

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".

Time Frame

From 15 minutes after administration of the subcutaneous injection up to 24 hours

Title

Change From Baseline in Maximum Platelet Aggregation (MPA) as Measured by Light Transmission Aggregometry (LTA)

Description

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.

Time Frame

Pre-dose, and from 30 minutes after administration of the subcutaneous injection up to 8 hours

Title

Number of Participants With Bleeding Events

Description

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).

Time Frame

From study treatment administration on Day 1 up to 48 hours

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

85 Years

Accepts Healthy Volunteers

Eligibility Criteria

Main Inclusion Criteria: Signed informed consent prior to any study-mandated procedure. Male and female subjects aged from 18-85 years, inclusive. For women of childbearing potential: Negative urine pregnancy test at Visit 1 and at Visit 2 before randomization. Stable Coronary artery disease (CAD) defined by the presence of any of the following conditions: History of CAD with coronary artery stenosis on coronary angiogram ≥50%. Previously documented myocardial infarction occurring more than 3 months prior to randomization. Antiplatelet background therapy stable for at least 1 month prior to randomization. Body weight ≥ 40.0 kg (88.2 lbs). Main Exclusion Criteria: Acute coronary syndrome, percutaneous coronary intervention or any intervention for peripheral artery disease within 3 months prior to randomization. Acute ischemic stroke or transient ischemic attack (TIA) within 3 months prior to randomization. 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). Hemoglobin ≤ 10 g/dL at screening. Loss of at least 250 mL of blood within 3 months of screening. Use of anticoagulants (oral, parenteral) or fibrinolytic therapy within 24 h prior to screening (Visit 1). Known platelet disorders (e.g., thrombasthenia, thrombocytopenia, von Willebrand disease). Pregnant or breastfeeding women.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Clinical Trials

Organizational Affiliation

Idorsia Pharmaceuticals Ltd.

Official's Role

Study Director

Facility Information:

Facility Name

University of Florida (UF) Jacksonville

City

Jacksonville

State/Province

Florida

ZIP/Postal Code

32209

Country

United States

Facility Name

Florida Hospital Tampa - Pepin Heart Institute

City

Tampa

State/Province

Florida

ZIP/Postal Code

33613

Country

United States

Facility Name

NorthShore University

City

Chicago

State/Province

Illinois

ZIP/Postal Code

73104

Country

United States

Facility Name

Indiana University School of Medicine - Krannert Institute of Cardiology

City

Indianapolis

State/Province

Indiana

ZIP/Postal Code

46202

Country

United States

Facility Name

Inova Cardiology

City

Lutherville

State/Province

Maryland

ZIP/Postal Code

21093

Country

United States

Facility Name

Mount Sinai Hospital (New York)

City

New York

State/Province

New York

ZIP/Postal Code

10029

Country

United States

Facility Name

Inova Center for Thrombosis Research and Translational Medicine

City

Falls Church

State/Province

Virginia

ZIP/Postal Code

22042

Country

United States

Facility Name

Institut de Cardiologie de Montréal

City

Montréal

State/Province

Quebec

ZIP/Postal Code

H1T 1C8

Country

Canada

Facility Name

Aarhus University Hospital

City

Aarhus

ZIP/Postal Code

8200

Country

Denmark

Facility Name

Rigshospitalet

City

Copenhagen

ZIP/Postal Code

2100

Country

Denmark

Facility Name

Universitats-Herzzentrum

City

Bad Krozingen

ZIP/Postal Code

79189

Country

Germany

Facility Name

University Medical Center Groningen

City

Groningen

ZIP/Postal Code

9713 GZ

Country

Netherlands

Facility Name

Maastricht UMC

City

Maastricht

ZIP/Postal Code

6229 HX

Country

Netherlands

Facility Name

St. Antonius Ziekenhuis

City

Nieuwegein

ZIP/Postal Code

3435 CM

Country

Netherlands

Facility Name

National Heart Centre Singapore

City

Singapore

ZIP/Postal Code

169609

Country

Singapore

Facility Name

Sahlgrenska University Hospital

City

Göteborg

ZIP/Postal Code

40530

Country

Sweden

Facility Name

Uppsala University Hospital

City

Uppsala

ZIP/Postal Code

18288

Country

Sweden

Facility Name

Freeman Hospital - Cardiothoracic Department

City

Newcastle Upon Tyne

ZIP/Postal Code

NE7 7DN

Country

United Kingdom

Facility Name

Sheffield Teaching Hospitals

City

Sheffield

ZIP/Postal Code

S5 7AU

Country

United Kingdom

Facility Name

East & North Hertfordshire NHS Trust - Lister Hospital

City

Stevenage

ZIP/Postal Code

SG14AB

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

31994703

Citation

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.

Results Reference

derived

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

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