Clinical Trials Register

Summary
EudraCT Number:	2021-002210-13
Sponsor's Protocol Code Number:	STARC210421
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2021-10-26
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Denmark - DHMA

A.2

EudraCT number

2021-002210-13

A.3

Full title of the trial

Post-Operative Atrial Fibrillation after Surgical Aortic Valve Replacement and the influence of HMG-CoA reductase inhibitors

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Post-Operative Atrial Fibrillation after Surgical Aortic Valve Replacement and the influence of statin

A.4.1

Sponsor's protocol code number

STARC210421

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT05076019

A.5.4

Other Identifiers

Name:

US NCT - substudy 3

Number:

NCT05062239

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	The department of cardiac, thoracic and vascular surgery - Odense University Hospital
B.1.3.4	Country	Denmark
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	The department of cardiac, thoracic and vascular surgery - Odense University Hospital Denmark
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Odense University Hospital Denmark
B.5.2	Functional name of contact point	The department of cardiac surgery
B.5.3	Address:
B.5.3.1	Street Address	J. B. Winsløwsvej 4, Indgang 20 Penthouse 2. sal
B.5.3.2	Town/ city	Odense C
B.5.3.3	Post code	5000
B.5.3.4	Country	Denmark
B.5.6	E-mail	Lytfi.Krasniqi@rsyd.dk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Trial 2: Lipistad, filmovertrukne tabletter Trial 3: All statins
D.2.1.1.2	Name of the Marketing Authorisation holder	STADA (for Lipistad - Trial 2)
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ATORVASTATIN
D.3.9.1	CAS number	134523-00-5
D.3.9.2	Current sponsor code	Atorvastatin
D.3.9.3	Other descriptive name	Statin
D.3.9.4	EV Substance Code	SUB05600MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	80
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ROSUVASTATIN
D.3.9.1	CAS number	287714-41-4
D.3.9.2	Current sponsor code	ROSUVASTATIN
D.3.9.3	Other descriptive name	ROSUVASTATIN
D.3.9.4	EV Substance Code	SUB20634
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	80
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	FLUVASTATIN
D.3.9.1	CAS number	FLUVASTATIN
D.3.9.2	Current sponsor code	FLUVASTATIN
D.3.9.3	Other descriptive name	FLUVASTATIN
D.3.9.4	EV Substance Code	SUB07768MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	80
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PRAVASTATIN
D.3.9.1	CAS number	81093-37-0
D.3.9.2	Current sponsor code	PRAVASTATIN
D.3.9.3	Other descriptive name	PRAVASTATIN
D.3.9.4	EV Substance Code	SUB10004MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	80
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Simvastatin
D.3.9.1	CAS number	Simvastatin
D.3.9.2	Current sponsor code	Simvastatin
D.3.9.3	Other descriptive name	Simvastatin
D.3.9.4	EV Substance Code	SUB10529MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	80
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LOVASTATIN
D.3.9.1	CAS number	LOVASTATIN
D.3.9.2	Current sponsor code	LOVASTATIN
D.3.9.3	Other descriptive name	LOVASTATIN
D.3.9.4	EV Substance Code	SUB08604MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	80
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CERIVASTATIN
D.3.9.1	CAS number	145599-86-6
D.3.9.2	Current sponsor code	CERIVASTATIN
D.3.9.3	Other descriptive name	CERIVASTATIN
D.3.9.4	EV Substance Code	SUB07440MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	80
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CERIVASTATIN
D.3.9.1	CAS number	147511-69-1
D.3.9.2	Current sponsor code	CERIVASTATIN
D.3.9.3	Other descriptive name	PITAVASTATIN
D.3.9.4	EV Substance Code	SUB21363
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	80
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Trial 2:
Condition under investigation: Postoperative atrial fibrillation after surgical aortic valve replacement.
In patients no prior usage of statins:
14 days prior surgery to 30days after - Atorvastatin (Lipistad) 80mg vs placebo

Trial 3:
Condition under investigation: Postoperative atrial fibrillation after surgical aortic valve replacement.
In patients with prior usage of statins
Discontinuation of statin vs continuation up to 14 days prior surgery to 30days after

E.1.1.1

Medical condition in easily understood language

The effects of statins on the development of postoperative atrial fibrillation in patients undergoing aortic valve replacement with surgical procedure.

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10003660
E.1.2	Term	Atrial fibrillation and flutter
E.1.2	System Organ Class	100000004849

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Trial 2:
The primary objective of this study is to establish if prophylactic regime administration of Atorvastatin 80 mg daily dose P.O. (started at least 7 to 14 days before surgery and continued until the 30th post-operative day included) in patients undergoing elective solitary SAVR with bioprosthesis and are statin-naïve leads to a reduction in the incidence of POAF evaluated by Holter monitoring.

Trial 3:
The primary objective of study 3 is to investigate if discontinuance of statins in patients undergoing elective solitary SAVR with bioprosthesis with prior usage of statin the last 3 months and of at least 7 days is associated with risk of POAF or other complications including infections evaluated by Holter monitoring, clinical presentation and biochemical parameters.

E.2.2

Secondary objectives of the trial

Trial 2:
The secondary objectives are to evaluate if prophylactic regime administration of Atorvastatin affects:
• Early (≤30 days) and intermediate (1 year) clinical outcomes as outlined under secondary endpoints.
• Prior to discharge echocardiographic outcomes as outlined under section 6.3.
• Length of hospital care or the need of readmission.

Trial 3:
The secondary objectives are to evaluate if discontinuance of statin is associated with:
• Early (≤30 days) and intermediate (1 year) clinical outcomes as outlined under secondary endpoints.
• Prior to discharge echocardiographic outcomes as outlined under secondary endpoints.
• Length of hospital care or the need of readmission

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Trial 2
Patients undergoing elective solitary SAVR with bioprosthesis
Patients who are in sinus rhythm and not taking any anti-arrhythmic medication, other than beta-adrenergic blocking agents, at the time of surgery
No prior use of statin the last 3 months and at least 7 days prior to the time of surgery
Age >60 years
Willingness and provision of informed consent to be randomized

Trial 3
Patients undergoing elective solitary SAVR with bioprosthesis
Patients who are in sinus rhythm and not taking any anti-arrhythmic medication, other than beta-adrenergic blocking agents, at the time of surgery
In treatment with statin in the past 3 months and of at least 7 days
Age >60 years
Willingness and provision of informed consent to be randomized

E.4

Principal exclusion criteria

Trial 2:
Prior history of atrial fibrillation
Prior history of cardiac surgery
Known adverse reaction to statin
Hepatic dysfunction (Alanin-aminotransferase more than twice the upper limit)
Creatinine >200 µmol/L
Known intolerance to statins or history of muscle toxicity with statins

Trial 3
Prior history of atrial fibrillation
Prior history of cardiac surgery
Hepatic dysfunction (Alanin-aminotransferase more than twice the upper limit)
Creatinine >200 µmol/L

E.5 End points

E.5.1

Primary end point(s)

Trial 2:
Primary Outcome Measure:
1.Number of Participants with POAF - In-hospital
In-hospital POAF assessed by Holter monitoring.

2.Number of Participants with POAF - Early
Early assessed by anamnesis and electronic health record (EHR).

3.Number of Participants with POAF - Intermediate
Intermediate POAF assessed by anamnesis and EHR.

Trial 3:
Primary Outcome Measure:
1.Number of Participants with POAF - In-hospital
In-hospital POAF assessed by Holter monitoring.

2.Number of Participants with POAF - Early
Early assessed by anamnesis and electronic health record (EHR).

3.Number of Participants with POAF - Intermediate
Intermediate POAF assessed by anamnesis and EHR.

E.5.1.1

Timepoint(s) of evaluation of this end point

Trial2:
1 [Time Frame: In-hospital up to 10 days]
2 [Time Frame: Early (≤30 days) incidence of POAF]
3 [Time Frame: Intermediate (1 year) incidence of POAF]

Trial 3:
1 [Time Frame: In-hospital up to 10 days.]
2 [Time Frame: Early (≤30 days) incidence of POAF]
3 [Time Frame: Intermediate (1 year) incidence of POAF]

E.5.2

Secondary end point(s)

4) Rate of All-cause mortality - In-hospital
To evaluate the effect of prophylactic regime administration of Atorvastatin on clinical outcomes.
Number of deaths in each group.
5) Rate of All-cause mortality - Early
To evaluate the effect of prophylactic regime administration of Atorvastatin on clinical outcomes.
Number of deaths in each group.
6) Rate of All-cause mortality - intermediate
To evaluate the effect of prophylactic regime administration of Atorvastatin on clinical outcomes.
Number of deaths in each group.
7) Myocardial injury - Tn
Injury assessed by serial Troponin measurements. Unit:ng/l
8) Myocardial injury - CKMB
Injury assessed by serial CKMB measurements. Unit: μg/l.
9) Stroke - Early
Number of patients with stroke in each group.
10) Stroke - Intermediate
Number of patients with stroke in each group.
11) Trans ischemic attack - Early
Number of patients with trans ischemic attack in each group.
12) Trans ischemic attack - Intermediate
Number of patients with trans ischemic attack in each group.
13) Myocardial infarction - Early
Number of patients with Myocardial infarction in each group.
14) Myocardial infarction - Intermediate
Number of patients with Myocardial infarction in each group.
15) Permanent pacemaker - Early
Number of patients with Permanent pacemaker in each group.
16) Permanent pacemaker – Intermediate
Number of patients with Permanent pacemaker in each group.
17) ICD implantation - Early
Number of patients with ICD implantation in each group.
18) ICD implantation - Intermediate
Number of patients with ICD implantation in each group.
19) Acute kidney injury - Early
Number of patients with Acute kidney injury in each group.
20) Acute kidney injury - Intermediate
Number of patients with Acute kidney injury in each group.
21) LVEF
Describe echocardiography assessed differences in pre and postoperative measurements of LVEF(left ventricular ejection fraction) between groups. Unit: %
22) Strain
Describe echocardiography assessed differences in pre and postoperative measurements of Strain between groups.Unit: %

23) Peak gradient
Describe echocardiography assessed differences in pre and postoperative measurements of peak gradient between groups. Unit: mmHg
24) Mean gradient
Describe echocardiography assessed differences in pre and postoperative measurements of mean gradient between groups. Unit: mmHg
25) TAPSE
Describe echocardiography assessed differences in pre and postoperative measurements of TAPSE (tricuspid annular plane systolic excursion) between groups. Unit: mm
26) Length of stay on ICU
Length of stay on ICU after surgery. Unit: Days
27) Length of stay in hospital
Length of stay in hospital after surgery. Unit: Days

E.5.2.1

Timepoint(s) of evaluation of this end point

Trial 2 and 3
4. In hospital up to 10 days
5. ≤30 days
6. 1 year
7. After surgery until discharge up to 10 days
8. After surgery until discharge up to 10 days
9. ≤30 days
10. 1 year
11. ≤30 days
12. 1 year
13. ≤30 days
14. 1 year
15. ≤30 days
16. 1 year
17. ≤30 days
18. 1 year
19. ≤30 days
20. 1 year
21. Before surgery compared to prior to discharge (3rd to 5th postoperative day)
22. Before surgery comp. to prior to discharge (3rd to 5th postop. day)
23. Before surgery comp. to prior to discharge (3rd to 5th postop. day)
24. Before surgery comp. to prior to discharge (3rd to 5th postop. day)
25. Before surgery comp. to prior to discharge (3rd to 5th postop. day)
26. Day of surgery to the day of discharge from ICU
27. Day of surgery to the day of discharge

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Trial 2: Double blind, Trial 3: Open

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Trial 2: Placebo, Trial 3: discontinuation of medicin

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Trial 2: After 1 year of follow up from last enrolled subject. Total subjects: 266
Trial 3: After 1 year of follow up from last enrolled subject. Total subjects: 100

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

366

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

366

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

366

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

After trial end the patients will be followed up to 15-years through electronic health record.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-12-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-01-17

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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