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Clinical Trial Results:
A multi-center, open-label, randomized, study to assess the onset of platelet aggregation inhibition after a single subcutaneous injection of ACT-246475 in adults with acute myocardial infarction

Summary
EudraCT number	2018-000765-36
Trial protocol	BE
Global end of trial date	10 Nov 2018

Results information
Results version number	v1(current)
This version publication date	03 Nov 2019
First version publication date	03 Nov 2019
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

ID-076A202

ISRCTN number

US NCT number

NCT03487445

WHO universal trial number (UTN)

Sponsor organisation name

Idorsia Pharmaceuticals Ltd

Sponsor organisation address

Hegenheimermattweg 91, Allschwil, Switzerland, 4123

Public contact

Clinical Trial Disclosure Desk, Idorsia Pharmaceuticals Ltd, clinical-trials-disclosure@idorsia.com

Scientific contact

Clinical Trial Disclosure Desk, Idorsia Pharmaceuticals Ltd, clinical-trials-disclosure@idorsia.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

04 Mar 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

10 Nov 2018

Global end of trial reached?

Yes

Global end of trial date

10 Nov 2018

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the study was to assess the inhibition of adenosine diposphate (ADP)-mediated platelet aggregation 30 min after a single subcutaneous (s.c.) injection of selatogrel (ACT-246475) in subjects with acute myocardial infarction (AMI) receiving conventional antithrombotic treatment (e.g., aspirin, chronic oral P2Y12 receptor antagonists, anticoagulants).

Protection of trial subjects

Prior to the start of the study, each study site consulted an independent ethics committee, i.e., a review panel that was responsible for ensuring the protection of the rights, safety, and well-being of human subjects involved in a clinical investigation. The protocol and any material provided to the subject (such as a subject information sheet or description of the study used to obtain informed consent) were reviewed and approved by the appropriate Independent ethics committee before study was started. Eligible subjects presented with acute myocardial infarction (AMI; ST-segment elevation myocardial infarction [STEMI] or non-STEMI [NSTEMI]), a life-threatening condition, and therefore fulfilled the ICH-GCP definition of vulnerable subjects (“persons in emergency situations”). Accordingly, a specific process for obtaining consent was implemented in compliance with local regulations and approved by the independent ethics committee. An Independent Safety Event Committee had overall responsibility for safeguarding the interests of subjects.

Background therapy

Standard treatment of AMI was allowed including anticoagulants. Ticagrelor was the only oral P2Y12 receptor antagonist allowed to be initiated during the study and its administration was possible only after selatogrel administration. Use of fibrinolytics or GPIIb/IIIa inhibitors was prohibited unless required for bail-out. All other standard-of-care treatments for AMI were allowed without restriction.

Evidence for comparator

Not applicable.

Actual start date of recruitment

10 Jul 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 14

Country: Number of subjects enrolled

Israel: 1

Country: Number of subjects enrolled

Switzerland: 33

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted between 10 July 2018 and 10 November 2018.

Screening details

Of the 48 subjects screened and randomized, 47 subjects were treated. One subject randomized to the 8 mg selatogrel arm did not receive the study treatment for administrative reasons (study treatment in quarantine).

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Selatogrel - 8mg

Arm description

A single 8 mg dose of selatogrel (ACT-246475) was administered via a single subcutaneous (s.c.) injection in the thigh.

Arm type

Experimental

Investigational medicinal product name

Selatogrel

Investigational medicinal product code

ACT-246475

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

ACT-246475 for s.c. administration was supplied in sealed glass vials at a strength of 20 mg. The vials contained 22 mg of lyophilized ACT-246475A (hydrochloride salt of ACT-246475) for reconstitution with 1 mL of water for injection. The stock solution was diluted with 1 mL of NaCl 0.9% to obtain the required final concentration for injection ensuring the same volume of injection for both doses. The injected volume was 0.8 mL for all subjects. Administration was performed at the investigational site by qualified personnel.

Selatogrel - 16 mg

Arm description

A single 16 mg dose of selatogrel (ACT-246475) was administered via a single subcutaneous (s.c.) injection in the thigh.

Arm type

Experimental

Investigational medicinal product name

Selatogrel

Investigational medicinal product code

ACT-246475

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

ACT-246475 for s.c. administration was supplied in sealed glass vials at a strength of 20 mg. The vials contained 22 mg of lyophilized ACT-246475A (hydrochloride salt of ACT-246475) for reconstitution with 1 mL of water for injection. The injected volume was 0.8 mL for all subjects. Administration was performed at the investigational site by qualified personnel.

Number of subjects in period 1	Selatogrel - 8mg	Selatogrel - 16 mg
Started	25	23
Completed	24	23
Not completed	1	0
Administrative reasons	1	-

Baseline characteristics

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Reporting group title

Selatogrel - 8mg

Reporting group description

A single 8 mg dose of selatogrel (ACT-246475) was administered via a single subcutaneous (s.c.) injection in the thigh.

Reporting group title

Selatogrel - 16 mg

Reporting group description

A single 16 mg dose of selatogrel (ACT-246475) was administered via a single subcutaneous (s.c.) injection in the thigh.

Reporting group values	Selatogrel - 8mg	Selatogrel - 16 mg	Total
Number of subjects	25	23	48
Age categorical
Units: Subjects
Adults (18-64 years)	10	8	18
From 65-84 years	14	15	29
85 years and over	1	0	1
Age continuous
Units: years
arithmetic mean (standard deviation)	64.3 ± 12.5	68.0 ± 10.3	-
Gender categorical
Units: Subjects
Female	8	5	13
Male	17	18	35
Race
Units: Subjects
Asian	1	2	3
White	23	21	44
Other	1	0	1
Ethnicity
Units: Subjects
Hispanic or Latino	0	0	0
Not Hispanic or Latino	25	23	48
Body mass index
Units: kg/m^2
arithmetic mean (standard deviation)	27.92 ± 4.75	26.78 ± 3.74	-

End points

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Reporting group title

Selatogrel - 8mg

Reporting group description

A single 8 mg dose of selatogrel (ACT-246475) was administered via a single subcutaneous (s.c.) injection in the thigh.

Reporting group title

Selatogrel - 16 mg

Reporting group description

A single 16 mg dose of selatogrel (ACT-246475) was administered via a single subcutaneous (s.c.) injection in the thigh.

Primary: Number of subjects achieving a PD response

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End point title

Number of subjects achieving a PD response ^[1]

End point description

The primary PD endpoint was the response to treatment, defined for each subject as a P2Y12 reaction units (PRU) value < 100 at 30 min post-dose, as measured via the VerifyNow® assay. The PRU indicates the extent of (residual) ADP-mediated platelet aggregation, specific to the P2Y12 receptor.

End point type

Primary

End point timeframe

30 minutes post treatment administration

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: A statistical analysis comparing the two doses was not planned. The main analysis (mFAS, treatment dose as received) of treatment effect on the primary endpoint was conducted independently for each dose, i.e., 8 and 16 mg, at 0.025 type I error level, with null hypothesis defined as a proportion of responding patients less or equal to 50%. If this null hypothesis was rejected, a subsequent null hypothesis of treatment effect less or equal to 85% was tested at a 0.025 level.

End point values	Selatogrel - 8mg	Selatogrel - 16 mg
Number of subjects analysed	23 ^[2]	22 ^[3]
Units: number of subjects
Number of responders at 30 minutes	21	21

Notes
[2] - Modified full analysis set (all subjects with a 30-min post dose VerifyNow(R) blood sample analysis)
[3] - Modified full analysis set (all subjects with a 30-min post dose VerifyNow(R) blood sample analysis)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Treatment emergent adverse events (TEAEs) were those adverse events with onset date/time after the date/time of study drug administration and up to 48 hours after the date/time of study treatment administration.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

Selatogrel - 8 mg

Reporting group description

Reporting group title

Selatogrel - 16 mg

Reporting group description

Serious adverse events	Selatogrel - 8 mg	Selatogrel - 16 mg
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 24 (4.17%)	1 / 23 (4.35%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Cardiac disorders
Ventricular tachycardia
subjects affected / exposed	1 / 24 (4.17%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Selatogrel - 8 mg	Selatogrel - 16 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	12 / 24 (50.00%)	7 / 23 (30.43%)
Injury, poisoning and procedural complications
Post procedural haemorrhage
subjects affected / exposed	1 / 24 (4.17%)	0 / 23 (0.00%)
occurrences all number	1	0
Vascular pseudoaneurysm
subjects affected / exposed	1 / 24 (4.17%)	0 / 23 (0.00%)
occurrences all number	1	0
Vascular disorders
Aortic stenosis
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)
occurrences all number	0	1
Arteriovenous fistula
subjects affected / exposed	1 / 24 (4.17%)	0 / 23 (0.00%)
occurrences all number	1	0
Hypertension
subjects affected / exposed	1 / 24 (4.17%)	0 / 23 (0.00%)
occurrences all number	1	0
Hypotension
subjects affected / exposed	1 / 24 (4.17%)	0 / 23 (0.00%)
occurrences all number	1	0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	1 / 24 (4.17%)	0 / 23 (0.00%)
occurrences all number	1	0
Cardiac failure
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)
occurrences all number	0	1
Extrasystoles
subjects affected / exposed	1 / 24 (4.17%)	0 / 23 (0.00%)
occurrences all number	1	0
Mitral valve stenosis
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)
occurrences all number	0	1
Nodal rhythm
subjects affected / exposed	1 / 24 (4.17%)	0 / 23 (0.00%)
occurrences all number	1	0
Ventricular tachycardia
subjects affected / exposed	3 / 24 (12.50%)	2 / 23 (8.70%)
occurrences all number	3	2
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)
occurrences all number	0	1
Headache
subjects affected / exposed	1 / 24 (4.17%)	0 / 23 (0.00%)
occurrences all number	1	0
Immune system disorders
Hypersensitivity
subjects affected / exposed	1 / 24 (4.17%)	0 / 23 (0.00%)
occurrences all number	1	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)
occurrences all number	0	1
Pleural effusion
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)
occurrences all number	0	1
Psychiatric disorders
Agitation
subjects affected / exposed	1 / 24 (4.17%)	0 / 23 (0.00%)
occurrences all number	1	0
Confusional state
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)
occurrences all number	0	1
Delirium
subjects affected / exposed	1 / 24 (4.17%)	0 / 23 (0.00%)
occurrences all number	1	0
Infections and infestations
Herpes zoster
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)
occurrences all number	0	1
Metabolism and nutrition disorders
Dyslipidaemia
subjects affected / exposed	3 / 24 (12.50%)	2 / 23 (8.70%)
occurrences all number	3	2
Hypokalaemia
subjects affected / exposed	1 / 24 (4.17%)	0 / 23 (0.00%)
occurrences all number	1	0

More information

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
A multi-center, open-label, randomized, study to assess the onset of platelet aggregation inhibition after a single subcutaneous injection of ACT-246475 in adults with acute myocardial infarction

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of subjects achieving a PD response

Primary: Number of subjects achieving a PD response

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: A multi-center, open-label, randomized, study to assess the onset of platelet aggregation inhibition after a single subcutaneous injection of ACT-246475 in adults with acute myocardial infarction

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of subjects achieving a PD response

Primary: Number of subjects achieving a PD response

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A multi-center, open-label, randomized, study to assess the onset of platelet aggregation inhibition after a single subcutaneous injection of ACT-246475 in adults with acute myocardial infarction