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

Stable Coronary Artery Disease Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03384966
• Other study ID #: ID-076A201
• Secondary ID: 2017-003332-36
• Status: Completed
• Phase: Phase 2
• Start date: January 24, 2018
• Est. completion date: September 18, 2018

Study information

• Verified date: November 2022
• Source: Idorsia Pharmaceuticals Ltd.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 346
• Est. completion date: September 18, 2018
• Est. primary completion date: August 18, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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.

Related Conditions & MeSH terms

• Coronary Artery Disease
• Coronary Disease
• Myocardial Ischemia
• Stable Coronary Artery Disease

Intervention

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.
• Placebo
Matching placebo for subcutaneous administration.
• 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.

Locations

Country	Name	City	State
Canada	Institut de Cardiologie de Montréal	Montréal	Quebec
Denmark	Aarhus University Hospital	Aarhus
Denmark	Rigshospitalet	Copenhagen
Germany	Universitats-Herzzentrum	Bad Krozingen
Netherlands	University Medical Center Groningen	Groningen
Netherlands	Maastricht UMC	Maastricht
Netherlands	St. Antonius Ziekenhuis	Nieuwegein
Singapore	National Heart Centre Singapore	Singapore
Sweden	Sahlgrenska University Hospital	Göteborg
Sweden	Uppsala University Hospital	Uppsala
United Kingdom	Freeman Hospital - Cardiothoracic Department	Newcastle Upon Tyne
United Kingdom	Sheffield Teaching Hospitals	Sheffield
United Kingdom	East & North Hertfordshire NHS Trust - Lister Hospital	Stevenage
United States	NorthShore University	Chicago	Illinois
United States	Inova Center for Thrombosis Research and Translational Medicine	Falls Church	Virginia
United States	Indiana University School of Medicine - Krannert Institute of Cardiology	Indianapolis	Indiana
United States	University of Florida (UF) Jacksonville	Jacksonville	Florida
United States	Inova Cardiology	Lutherville	Maryland
United States	Mount Sinai Hospital (New York)	New York	New York
United States	Florida Hospital Tampa - Pepin Heart Institute	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Idorsia Pharmaceuticals Ltd.

Countries where clinical trial is conducted

United States,  Canada,  Denmark,  Germany,  Netherlands,  Singapore,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Primary	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	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
Secondary	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
Secondary	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